ESSENTIAL

CARDIOVASCULAR
MEDICIN
6th Edition

MOHAMED S. ELGUINDY
AHMED M. ELGUINDY Volume I
 V

Contents

Preface
Chapter 1: The History...............................................................................................................1
Chapter 2: Physical examination......................... 7
Chapter 3: Electrocardiography.............................................................................................. 45
Chapter 4: Exercise electrocardiographic testing ................................................................... 63
Chapter 5: Echocardiography................................................................................................... 85
Chapter 6: Plain radiology of the heart.................................................................................... 99
Chapter 7: Nuclear Cardiology............................................................................................... 107
Chapter 8: Cardiovascular magnetic resonance imaging........................................................ 125
Chapter 9: Cardiovascular computed tomography................................................................ 137
Chapter 10: Cardiac catheterization.........................................................................................149
Chapter 11: Coronary arteriography, ventriculography and intracoronary imaging................ 164
Chapter 12: Heart failure...........................................................................................................183
• Acute heart failure ...................................................................................... 235
• Heart failure with preserved ejection fraction ............................................ 246
Chapter 13: Cardiac arrhythmias............................................................................................ 252
• Electrophysiological considerations............................................................. 252
• Mechanisms of arrhythmias.......................................................................... 257
• Evaluation of cardiac arrhythmias.................................................................265
• Sinus nodal disturbances...............................................................................:^77
• Atrial arrhythmias.......................................................................................... 286
• Atrioventricular junctional arrhythmias........................................................ 317
• Arrhythmias involving the atrioventricular junction................................... 310
• Summary of ECG diagnosis of supraventricular tachycardia......................... 319
• Ventricular arrhythmias................................................................................ 325
• Heart block....................................................................................................348
• AV dissociation............................................................................................. 355
• Other abnormalities leading to cardiac arrhythmias .................................... 357
• Antiarrhythmic drugs ...................................................................................358
• Cardiac pacemakers ...................................................................................... 373
• Implantable cardioverter defibrillator (ICD) and other non- ..............................
pharmacological treatment of cardiac arrhythmias....................................... 384
Chapter 14: Cardiac arrest and sudden cardiac death ............................................................... 393
Chapter 15: Cardiopulmonary and Cardiocerebral resuscitation.............................................. 402
Chapter 16: Syncope .........................................................................................................411
Chapter 17: The biology of atherosclerosis and the prevention of coronary....................................
heart disease .........................................................................................................422
Chapter 18: Lipoprotein disorders.............................................................................................. 445
Chapter 19: Stable angina .........................................................................................................471
Chapter 20: Unstable angina and non-ST-elevation myocardial infarction............................... 503
Chapter 21: ST-elevation myocardial infarction........................................................................ 530
Chapter 22: Percutaneous coronary Intervention (PCI)..............................................................574
Chapter 23: Arterial hypertension.............................................................................................. 597
Chapter 24: Pulmonary hypertension......................................................................................... 643
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Chapter 25: Deep venous thrombosis and pulmonary thromboembolism................................. 661

Chapter 26: Valvular heart disease ........................................................................................... 677
• Mitral stenosis .................................................................................................. 680
• Mitral regurgitation........................................................................................... 688
• Mitral valve prolapse ........................................................................................ 695
• Aortic stenosis.................................................................................................. 701
• Aortic regurgitation........................................................................................... 711
• Tricuspid stenosis ............................................................................................. 721
• Tricuspid regurgitation .....................................................................................723
• Pulmonary stenosis .......................................................................................... 727
• Pulmonary regurgitation ...................................................................................727
• Multivalvular disease........................................................................................ 730
• Drug-induced valve disease ............................................................................. 731
• Prosthetic heart valves ...................................................................................... 732
• Percutaneous valve replacement and repair...................................................... 739
Chapter 27: Infective endocarditits........................................................................................... 740
Chapter 28: Congenital heart disease........................................................................................ 754
• Effects of congenital cardiac lesions................................................................. 763
« Atrial septal defect........................................................................................... 769
• Patent foramen ovale ........................................................................................ 772
• Ventricular septal defect....................................................................................773
• Patent ductus arteriosus..................................................................................... 777
• Atrioventricular septal defect (endocardial cushion defect) ......................... 779
• Partial anomalous pulmonary venous connection ............................................ 783
• Pulmonary stenosis............................................................................................ 786
• Peripheral pulmonary artery stenosis................................................................ 788
• Congenital aortic stenosis..................................................................................789
• Coarctation of the aorta ....................................................................................794
• Tetralogy of Fallot ...................................................... 799
• Tetralogy of Fallot with absent pulmonary valve.............................................. 804
• Complete transposition of the great arteries .................................................... 805
• Congenitally corrected transposition of great arteries.......................................811
® Tricuspid atresia ..............................................................................................814
• Fontan procedure.............................................................................................. 816
• Pulmonary atresia with intact ventricular septum............................................. 820
• Ebstein's anomaly............................................................................................... 822
• Persistent truncus arteriosus............................................................................. 825
• Double inlet ventricle (single ventricle)............................................................. 828
• Double outlet right ventricle 830
• Total anomalous pulmonary .venous connection................................................ 833
• Hypoplasic left heart syndrome......................................................................... 836
• Eisenmenger syndrome..................................................................................... 839
• Heterotaxia........................................................................................................ 841
• Chamber localization and cardiac malposition................................................. 843
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• Vascular ring..................................................................................................... 845

• Congenital anomalies of the coronary circulation ........................................... 847
• Syndromes of congenital heart disease............................................................. 851
• Summary of operations for congenital heart diseases....................................... 853
Chapter 29: Molecular biology and genetic aspects of cardiovascular disease.......................... 856
Chapter 30: Cardiomyopathies .................................................................................................. 884
• Dilated cardiomyopathy...................................................................................885
• Hypertrophic cardiomyopathy......................................................................... 889
• Restrictive and infiltrative cardiomyopathies.................................................. 900
• Arrhythmogenic right ventricular cardiomyopathy (dysplasia).......................910
• Left ventricular noncompaction........................................................................ 912
• Hypertensive cardiomyopathy.......................................................................... 913
• Metabolic cardiomyopathy ............................................................................. 913
• Takotsubo cardiomyopathy.............................................................................. 913
• Tachycardia-induced cardiomyopathy..............................................................914
• Ischaemic cardiomyopathy ............................................................................. 914
• Muscular dystrophy cardiomyopathy ..............................................................916
Chapter 31: Myocarditis ........................................................................................................ 918
Chapter 32: Cardiac tumours ............................................................................................ 924
Chapter 33: Diseases of the pericardium......................................................................................931
Chapter 34: Diseases of the aorta and its main branches........................................................... 954
Chapter 35: Peripheral arterial diseases ..................................................................................... 983
Chapter 36: Pregnancy and cardiovascular disease ................................................................. 1004
Chapter 37: Non cardiac surgery in patients with heart disease............................................... 1018
Chapter 38: Medical management of patients undergoing cardiac surgery............................. 1028
Chapter 39: Cardiovascular disease in the elderly................................................................... 1041
Chapter 40: Cardiovascular disease in women ........................................................................ 1050
Chapter 41: Cardiovascular disease in athletes........................................................................ 1056
Chapter 42: Metabolic and endocrine disorders....................................................................... 1061
Chapter 43: Erectile dysfunction............................................................................................... 1082
Chapter 44: Rheumatic fever.................................................................................................... 1085
Chapter 45: cardiac involvement in other rheumatic disorders................................................. 1091
Chapter 46: Cardiovascular affection in HIV infection............................................................ 1103
Chapter 47: Cardiovascular manifestations of cancer.............................................................. 1106
Chapter 48: Psychiatric aspects of cardiovascular disease...................................................... 1112
Chapter 49: Neurological disorders and cardiovascular disease.............................................. 1117
Chapter 50: Renal disorders and cardiovascular disease.......................................................... 1124
Chapter 51: Cardiac rehabilitation........................................................................................... 1136

Index
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CHAPTER 12

HEART FAILURE
Definition
Heart failure is physiologically defined as a state in which the heart is unable to pump blood at a rate
adequate for satisfying the requirements of the tissues or can do so only from an elevated filling
pressure.
Although this definition may be conceptually useful, it relies on laboratory studies and is of little
clinical relevance. A more practical definition is that it represents a clinical syndrome characterized
by abnormalities of ventricular function and neurohormonal regulation which are accompanied by
effort intolerance, fluid retention and reduced longevity.

Aetiology
Heart failure is the final common result of almost any insult to cardiac function. The leading causes
include the following:
• Coronary heart disease.
• Valvular diseases.
• Cardiomyopathies
• Hypertension
• Cardiac arrhythmias
• Obstructive, interstitial or vascular pulmonary diseases
• Congenital heart diseases
• Pericardial constriction or tamponade
• Hyperkinetic circulatory states (e.g. anaemia, thyrotoxicosis, arteriovenous fistula, beriberi, liver
cirrhosis)
Precipitating factors
These conditions are encountered in the majority of cases of heart failure. Their recognition and
management is important in the management of heart failure. They include:
• Inappropriate reduction of therapy, be it dietary salt, fluid restriction or pharmacological agents.
This is the commonest cause of decompensation In a previously compensated patient.
• Arrhythmias including tachyarrhythmia (especially atrial fibrillation), marked bradycardia,
atrioventricular dissociation and abnormal intraventricular conduction. Persistent tachyarrhythmia
may cause a reversible dilated cardiomyopathy (tachycardia-induced cardiomyopathy).
• Myocardial ischemia and infarction.
• Systemic infection. Pro-inflammatory cytokines depress myocardial function.
• Pulmonary embolism. This increases the haemodynamic burden on the right ventricle and may
result in tachycardia and hypoxoemia which depress myocardial function.
• Physical, emotional and environmental stresses including intense exertion, emotional crises and
hot, humid environment.
• Cardiac infections and inflammation including myocarditis and infective endocarditis.
• Development of unrelated illness such as renal failure which may exacerbate salt and fluid
retention.
• Administration of cardiac depressants (e.g. alcohol, anti-arrhythmic drugs), toxins (e.g. cocaine) or
salt retaining drugs (e.g. steroids, non-steroidal anti-inflammatory drugs).
• Hyperkinetic circulatory states such as pregnancy, anaemia, thyrotoxicosis and liver cirrhosis.

Types of heart failure

• Acute and chronic heart failure:
The manifestations of heart failure depend on the rate at which the syndrome develops. If the
underlying condition develops rapidly (e.g. acute extensive myocardial infarction); the result may
be inadequate organ perfusion or acute venous (systemic or pulmonary) congestion causing
sudden cardiac decompensation and acute onset of symptoms. On the other hand If the underlying
cardiac abnormality develops slowly, compensatory mechanisms will have time to develop and
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the patient will be able to adjust to the reduction in cardiac output with less difficulty. A patient
with chronic heart failure may achieve compensation, but then may experience acute
decompensation as a result of a precipitating factor.
• Left and right sided heart failure:
Heart failure is often limited to one side of the heart when the onset is abrupt. The pulmonary
venous reservoir is smaller than is the systemic venous system and increased venous pressures
associated with symptoms occur after a relatively smaller accumulation of fluid in left sided than
in right sided heart failure. However biventricular failure usually follows especially when the left
ventricle is the site of initial damage. Both ventricles have a common interventricular septum and
biochemical changes are not confined to the stressed ventricle but also involve the opposite
ventricle. Additionally because all four cardiac chambers are enclosed in the pericardial sac, when
the size of any chamber suddenly increases, the opposite chambers are compressed and the filling
pressure of the normal ventricle rises (ventricular interdependence). Right sided failure often
follows left sided heart failure, but left heart failure rarely follows isolated right heart failure
without concomitant separate disease of the left heart (e.g. coronary artery disease). In patients
with left ventricular failure, subsequent right heart failure may relieve the respiratory symptoms
generally associated with left heart failure.
• Low-output and high-output heart failure:
Most cases of heart failure are associated with low output states that cause peripheral
vasoconstriction. High output heart failure is less common and is usually associated with a
hyperkinetic circulatory state (e.g. anaemia, thyrotoxicosis, liver cirrhosis, arteriovenous fistula,
Paget's bone disease). These states usually trigger heart failure when superimposed on underlying
heart disease. High output failure is associated with vasodilatation, the patient exhibits warm and
flushed skin and a bounding pulse. Although the cardiac index is usually higher than normal, it is
generally lower than before the onset of heart failure and is insufficient to meet the increased
oxygen demands of tissues.
• Backward and forward heart failure:
In the majority of patients with chronic heart failure, the clinical manifestations arise as a result of
damming up the blood behind one or both ventricles (backward failure) and inadequate cardiac
output (forward failure). Based on the underlying aetiology, haemodynamic abnormalities and
abruptness of the disease process, one or the other mechanism may initially predominate. It is no
longer rewarding to make a rigid distinction between backward and forward heart failure because
both mechanisms appear to operate eventually.
• Systolic and diastolic heart failure:
The manifestations of heart failure can be caused by either an abnormality in systolic function that
leads to a defect In the ejection of blood from the heart (heart failure with reduced ejection
fraction or systolic heart failure) or an abnormality in diastolic function that result in defective
ventricular filling (heart failure with preserved ejection fraction or diastolic heart failure).
Reduced left ventricular filling caused by diastolic dysfunction leads to decreased stroke volume
and associated symptoms of low cardiac output whereas increased filling pressures lead to
symptoms of pulmonary congestion.
Heart failure with reduced ejection fraction (HFREF) Is caused by acute or chronic contractile
dysfunction but heart failure with preserved ejection fraction (HFPEF) is primarily due to impaired
ventricular relaxation and/or increased ventricular stiffness (reduced compliance) caused by any of
the following conditions:
- Ventricular hypertrophy
- Ischemic heart disease: acute, chronic
- Cardiomyopathies: hypertrophic, restrictive
- Ageing
- Obesity
- Diabetes mellitus
- Post-heart transplantation
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The principal manifestations of systolic failure result from inadequate forward cardiac output
whereas those of diastolic failure relate to elevation of venous pressure upstream to the affected
ventricle causing pulmonary and/or systemic venous congestion.
As many as 40-50 % of all patients with heart failure have preserved left ventricular systolic
function and many of these have diastolic dysfunction.

Pathophysiology
The pathophysiological changes of heart failure comprises both cardiac and systemic responses. In the
initial stages, such responses are adaptive (truly compensatory) to reduced cardiac contractility that is
probably perceived systemically as a drop in blood pressure. However, as heart failure becomes
chronic, several of these changes become maladaptive and lead to declining cardiac function and
progressive systemic disease. Most of these changes are descriptive and it is often unclear whether
they are the cause of heart failure or are just associated with the condition.

A) Cardiac changes
® Myocyte loss; necrosis, apoptosis and autophagy:
- Cardiac contraction is impaired when the proportion of viable myocytes in the ventricular
muscle is reduced. The commonest cause is myocardial necrosis (e.g. in myocardial infarction)
Apoptosis (programmed cell death) is accelerated in heart failure. It is an energy dependent
process by which a specific genetic program leads to the activation of a molecular cascade that
causes the degradation of nuclear DNA. In heart failure, it is induced by the high levels of
circulating catecholamines, angiotensin II, reactive oxygen species, nitric oxide and
inflammatory cytokines as well as by mechanical strain.
• Autophagy is a third process that is Involved in heart failure. It Involves recycling of proteins
within organelles. This process may be activated by the presence of damaged proteins. The
system Is designed to assess proteins, determine whether they are functional and remove them If
they are not (protein quality control).
• Myocardial remodeling:
This is considered the structural hallmark of heart failure. Remodeling is defined as a progressive
change in the size and shape of the heart in response to
o acute myocardial injury,
o altered loading conditions and
o excessive neurohormonal activation.
Sometimes genetic mutations are the driving force whereas in other cases, prolonged
haemodynamic stress or myocardial damage can lead to progressive deterioration.
In patients with systolic heart failure (reduced left ventricular ejection fraction), the left ventricular
chamber gradually dilates to allow for short-term maintenance of adequate stroke volume in the
face of an impaired myocardial performance. In the long-term, wall stress can remain increased
disproportionate to the increase in wall thickness, raising afterload and further reducing myocardial
performance. The heart changes from an ellipsoid to a more spherical shape as the chambers
increase in size. Geometric distortion of the chamber displaces the mitral and, tricuspid papillary
muscles as well as cause annular dilatation leading to valvular regurgitation. Progressive chamber
enlargement also distorts chamber coordination by delaying interchamber conduction pattern
leading to further pump inefficiency.
Hypertrophy of cardiac myocytes Is accompanied by the synthesis of new sarcomeres that are laid
in parallel (due to pressure overload) and in series (due to volume overload) thus elongating and
thickening the cells. Mitochondria proliferate and capillary density and coronary flow reserve are
reduced. The net result is that cardiac chambers increase in size and the structural changes are
accompanied by impaired function, arrhythmias and reduced coronary blood flow in response to
stress.
In patients with diastolic heart failure (preserved left ventricular ejection fraction), there may not
be compensatory ventricular dilatation, but Instead there may be progressive hypertrophy or
increased stiffness of chamber walls. Fibrosis, cellular disarray and hypertrophy contribute to
diastolic dysfunction. Diastolic asynergy and asynchrony also interfere with early filling. As a
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result, the ventricle becomes more restricted or confined rather than dilated and therefore does not
fill properly and is unable to generate adequate stroke volume.
• Myocyte hypertrophy elongation and connection:
- In response to increased haemodynamic load, activation of gene transcription leads to myocyte
hypertrophy (increased size). Pressure overload leads to concentric hypertrophy in which
ventricular wall Is thickened without an increase in cavity size due to parallel replication of
sarcomeres. Volume overload gives rise to eccentric hypertrophy characterized by cavity
enlargement without a corresponding increase in wall thickness due to replication of sarcomeres
in series. The majority of cardiomyocytes are terminally differentiated and possess no
regenerative capacity. However, a small number of progenitor cells do exist and these retain the
ability to divide and form mature cardiomyocytes. It is unclear whether these ceils are a specific
population of myocytes present within the myocardium from birth or whether they represent a
population of circulating stem cells capable of differentiating into numerous specialized tissue
types upon appropriate stimulus. At present the widely held consensus is that any compensatory
response to augment cardiac performance is primarily via hypertrophy (increase in contractile
protein content and sarcomere number) of preexisting cells rather than by division and expansion
of the cell population.
• The interstitial matrix:
Normally the collagen Interstitial matrix is regulated by matrix metalloproteinases (MMP) and
tissue inhibitors of metalloproteinases (TIMP) which respectively degrade and inhibit degradation
of collagen. Isoforms such as MMP-13 are expressed at very low levels in normal hearts and
substantially upregulated in heart failure, whereas MMPs expressed in the normal hearts are
downregulated in heart failure. TIMPs are upregulated in heart failure and contribute to the overall
defective turnover and accumulation of collagen seen in the failing heart. Two to three fold
collagen excess impairs diastolic relaxation and fourfold or greater excess affects systolic
contraction. Increased expression of MMP may lead to destruction of the fibrillar collagen matrix
that runs perpendicular to cardiac myocytes. This can result in myocyte slippage and consequently
ventricular thinning as part of the remodeling process.
• Alteration of myocyte function:
- Adrenergic receptors exhibit several alterations in heart failure:
o pi-adrenergic receptors are downregulated.
o Both p 1 and 32-adrenergic receptors are uncoupled from their signal transduction pathways
by phosphorylation-induced desensitization due to upregulation of p-adrenergic receptor
kinase-1 (P-APK-1).
o The inhibitory G protein (Gi) is upregulated.
o Adenyl cyclase activity and myocardial level of cyclic adenosine monophosphate (cAMP)
are decreased.
Desensitization of P-adrenergic receptors in heart failure is related to chronic sympathetic over-
stimulation. Since catecholamine stimulation of pi and 32 adrenergic receptors enhances systolic
contraction and diastolic relaxation, subsensitivity of these receptors contributes to the contractile
abnormalities seen in failing hearts and to the blunted response to catecholamine inotropic agents.
- Calcium homeostasis is disturbed:
o The normally close structural and functional relationship between the L-type voltage
dependent Ca2+ charnels and the cardiac ryanodine receptor (RyR2) in the sarcoplasmic
reticulum membrane is disrupted in heart failure. This is partly due to loss of the T-tubule
network at the base of which the L-type Ca2+ channels are located and partly due to
dissociation of the RyR2 associated regulatory protein FKBP 12.6 which facilitates the
coupling of the Ca2+ channels and the ryanodine receptor.
o The activity of sarcoendoplasmic reticulum Ca+2 ATPase (SERCA) (responsible for uptake of
calcium ion into the sarcoplasmic reticulum), phospholamban (a major inhibitor of SERCA)
and the sarcoplasmic reticulum calcium release channels are all reduced in heart failure.
• Disturbed myocardial energy metabolism:
- Creatine kinase content and activity, phosphocreatine content and the phosphocreatine / ATP
ratio are all reduced in heart failure.
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- Cardiac hypertrophy due to increased workload involves isoform switching for some of the
major cardiac proteins, from the normally expressed adult or postnatal program to the fetal
isoform. This leads to shift in substrate utilization from fatty acids to glucose with subsequent
altered regulation of glucose transporters and the enzymes of fatty acid metabolism.
- Defects in mitochondrial oxidative phosphorylation and mitochondrial Ca2+ metabolism may
also be associated with myocardial failure.
• Cardiac contractile proteins exhibit various changes:
o Downregulation of the alpha-myosin heavy chain (a-MHC) gene which encodes for the fast
isoform of MHC with high ATPase activity (VI isoform).
o Downregulation of protein kinase A (PKA) which is responsible for phosphorylation of the
regulatory protein troponin I.
o Re-expression of fetal (less effective) isoforms of atrial myosin light chain 1A (MLC1A)
and troponin T2.
B) Systemic changes
1. Increased sympathetic activity (Fig. 12.1).
Sympathetic overstimulation is an early feature of heart failure. Plasma and urinary norepinephrine
values are elevated (secondary to spill-over from the sympathetic nerve terminals rather than to
adrenal overactivity). The trigger for sympathetic overactivity includes abnormal function of
baroreceptors, ergoreceptors and cardiopulmonary reflexes. The consequences of long term
sympathetic overstimulation include:
i. Cardiac effects: abnormal p-adrenergic receptor numbers and function, myocyte
hypertrophy, necrosis and apoptosis, myocardial fibrosis, arrhythmias, impaired and
incoordinate myocardial contraction and generation of reactive oxygen species.
ii. Renal effects: tubular absorption of sodium, activation of renin-angiotensin-aldosterone
system and decreased response to natriuretic peptides.
iii. Peripheral vascular effects. Vasoconstriction and hypertrophy of smooth muscle cells.

2. Activation of the renin-angiotensin-aldosterone system (Fig.12.2).

In heart failure, renin release is stimulated by reduced renal blood flow, enhanced sympathetic
activity and hyponatraemia. Increased renin activity leads to increased production of angiotensin II
which produces the following effects:
- Cardiac effects: positive inotropic effect on atrial muscle, diastolic dysfunction, arrhythmias,
subendocardial Ischaemia as well as myocardial necrosis, hypertrophy and remodeling.
- Peripheral vascular effects: vasoconstriction, redistribution of regional blood flow, increased
norepinephrine release and glomerular efferent arteriolar constriction.
- Aldosterone and vasopressin release. Aldosterone is a potent inducer of myocardial and
vascular inflammation. It also induces NADPH oxidase within the vasculature which in turn is
a major source of superoxide anions and a cause of oxidative stress-induced inflammation. In
addition aldosterone has a direct effect on the turnover and composition of extracellular matrix
proteins such as collagen. This effect together with its pro-inflammatory action makes
aldosterone a potent cause of myocardial and vascular fibrosis In patients with heart failure.
In addition to the hormonal effects of circulating angiotensin II, components of the renin-
angiotensin-aldosterone system are present in the heart, blood vessels, kidney and brain. Such
tissue renin-angiotensin system may be activated in compensated heart failure at a time when the
activity of the circulating system can be relatively normal. The tissue production of angiotensin II
may also occur by another pathway independent of angiotensin converting enzyme (ACE), the
chymase pathway.
3. Cytokine activation.
The circulating levels of many inflammatory cytokines (including tumour necrosis factor a,
interleukins, interferon y, adhesion molecules) are increased in patients with heart failure. The
failing myocardium itself may be the source of such inflammatory mediators. Many of the features
of chronic heart failure may be produced by the effects of these molecules including impaired
myocardial contraction, apoptosis, oxygen free radical production, peripheral and pulmonary
oedema, reduced peripheral blood flow and P-adrenergic receptor uncoupling. A syndrome of
cachexia with metabolic and immune dysfunction and with poor prognosis may also occur.
188

Efferents

Peripheral
vascular
resistance

;enal vascular
resistance

TPeripheral
vascular
resistance

Fig. 12.1. Mechanisms for generalized sympathetic activation and parasympathetic withdrawal in heart
failure. A, Under normal conditions, inhibitory [-} inputs from arterial and cardiopulmonary baroreceptor
afferent nerves are the principal influence on sympathetic outflow. Parasympathetic control of heart rate
is also under potent arterial baroreflex control. Efferent sympathetic traffic and arterial catecholamines
are low, and heart rate variability is high. B, As heart failure progresses, inhibitory input from arterial and
cardiopulmonary receptors decreases and excitatory (+] input increases. The net response to this altered
balance includes a generalized increase in sympathetic nerve traffic, blunted parasympathetic control of
heart rate, and impairment of the reflex sympathetic regulation of vascular resistance. Anterior wall
ischaemia has additional excitatory effects on efferent sympathetic nerve traffic. Ach, acetylcholine; CNS,
central nervous system; E, epinephrine; Na+, sodium; NE, norepinephrine.
 189

Systemic (circulatory) Tissue (local)

Liver
r
Angiotensinegen
Tissue (heart, brain,

_
vasculature)

\ t issue renin +
Renal renin I cathepsin G +
; -I : kailikrein

Angiotensin!Qther
ATfssoe j proteases
Lung ACE j ( ACE j «,g„
7 ^7 chymase
-Angiotensin II-

Inactive ‘Active” fragments

fragments Ang 111, Ang IV,
Ang 1-7

extracellular
Intracellular

Internalization Gene Regulation

Inactivation Angiotensinegen
Reran
CellularResponse
ACE
Contraction
Secretion Angiotensin
receptor

Fig. 12.2 The systemic and tissue components of the renin-angiotensin system. Several tissues including
myocardium, vasculature, kidney, and brain have the capacity to generate angiotensin II independent of
the circulating renin-angiotensin system. Angiotensin II produced at the tissue level may play an
important role in the pathophysiology of heart failure. ACE, angiotensin-converting enzyme.

4. Other hormonal changes may develop:

- Elevation of circulating level of argenine vasopressin due to decreased sensitivity of atrial
stretch receptors.
- Elevation of circulating level of atrial and brain (ventricular) natriuretic peptides. The atrial
natriuretic peptide (ANP) is secreted from both the atria and ventricles, in normal hearts, it is
secreted at low levels but levels rise dramatically in heart failure. A more sensitive marker of
myocardial dysfunction is the brain (ventricular) natriuretic peptide (BNP) which Is secreted
only in heart failure and not under normal circumstances due to foetal-like genetic
programming of the ventricular myocytes. Natriuretic peptides promote natriuresis, produce
vasodilatation, inhibit endothelin secretion and may protect against fibrosis and ventricular
remodeling. However, in heart failure, such beneficial actions fail to compensate for renin-
angiotensin-aldosterone system activation.
- Elevation of circulating levels of endothelin-1 which promotes myocardial fibrosis, renal
retention of sodium and contributes to the development of pulmonary hypertension.
5. Increased systemic vascular resistance.
This is a cardinal feature of heart failure. It results from multiple factors including:
- Vasoconstriction due to:
o Neuroendocrine activation (norepinephrine, angiotensin II, vasopressin, endothelin).
o Reduced response to nitric oxide mediated by oxygen free radicals,
o Na+1 Ca2+ exchange.
- Anatomical alteration:
190

o Thickened capillary basement membrane.

o Vascular remodeling (smooth muscle cell hyperplasia and proliferation)
o Microvascular infarction.
The role of nitric oxide in the failing heart is complex. While smaller physiological amounts
of constitutive nitric oxide synthase are necessary for normal function and may exert cellular
protective effect, high levels of nitric oxide in the heart may exert pro-apoptotic and cytotoxic
effects. The inducible isoform of nitric oxide synthase is overexpressed in human heart failure and
therefore may contribute to worsening heart failure.
6. Reduced skeletal muscle mass secondary to abnormal skeletal muscle metabolism. Defects in
skeletal muscle ryanodine receptor (RyRl) occur in heart failure. Vasoconstriction serves the
short-term purpose of redistributing systemic blood flow to the brain and the heart because those
organs exhibit autoregulatory control of flow (vasodilatation as a result of local autoregulation).
However, the function of other important organs such as the kidney, skeletal muscles and
splanchnic beds is ultimately compromised. So, this mechanism is not the optimal way to deal with
the limited cardiac output associated with heart failure. Vasodilatator therapy aims at correcting
this basic abnormality in patients with heart failure.

Renal responses in chronic heart failure

In chronic heart failure, whole body sodium and water increase by 5-40% and whole body potassium
decreases by 5-20%. In moderate to severe conditions, hypomagnesoemia and azotoemia also
develop. These changes are related to the following mechanisms:
• A fall in cardiac output and renal blood flow is accompanied by activation of sympathetic nervous
system, the renin-angiotensin system (circulating and local) and renal prostaglandins that augment
the vascular tone of the glomerular efferent arteriole relative to that of afferent arteriole. This
maintains the glomerular filtration and elevates the filtration fraction (glomerular filtration rate /
renal blood flow). The increase in filtration fraction leads to substantial rise in the oncotic pressure
(because most proteins are not filtered by normal glomerular membrane) and a fall in the
hydrostatic pressure of the blood leaving the glomerulus to enter the peritubular capillaries. These
factors augment NaCl-H2O uptake into the postglomerular peritubular capillary network from the
proximal renal tubules and adjacent interstitial space.
• As the filtrate and sodium delivery to the distal tubule falls, the macula densa cells of the distal
tubule activate the adjacent juxtaglomerular cells to secrete more renin with consequent increase of
angiotensin II and aldosterone. Angiotensin II and norepinephrine augment sodium reabsorption
by the proximal tubule, while aldosterone augment sodium reabsorption by the distal tubule and
collecting duct.
• In severe heart failure, renal cortical flow is shifted to medullary nephrons which have greater
capacity to reabsorb NaCl and H2O.
• Elevated levels of circulating and local arginine vasopressin enhances water retention by the
collecting ducts and the thirst provoked by elevated angiotensin II levels exacerbates the water
imbalance and leads to the development dilutional hyponatraemia in advanced heart failure.
• Aldosterone-induced sodium reabsorption by the distal tubule is accompanied by 1:1 exchange for
potassium or hydrogen ions and consequently their urinary loss. Respiratory and metabolic
alkalosis which commonly occur in heart failure further augment potassium loss by causing distal
tubular retention of hydrogen ions. Additionally diuretics which increase the delivery of sodium to
the distal tubule enhance exchange for potassium and thereby promote kaluresis.
• Excessive renal loss of magnesium and hypomagnesoemia develop in advanced heart failure
particularly with prolonged diuretic therapy.
• Tubular urea movement generally follows that of water. Therefore as renal uptake of NaCl-H2O
increases in heart failure, more urea is retained. Serum creatinine will not increase until the
glomerular filtration rate falls below 30 ml/min. The azotoemia of heart failure is prerenal with
greater retention of blood urea nitrogen (BUN) than of creatinine and with a serum BUN to
creatinine ratio of > 10:1.
• Atrial and brain (ventricular) natriuretic peptides normally inhibit serum aldosterone, arginine
vasopressin and norepinephrine release and their renal effects and preferentially relax the afferent
renal arterioles. However in advanced heart failure, these favourable effects wane.
 191
Venous congestion may directly impact on filtration gradient across the glomeruli or indirectly
cause tubular injury.

Pressure-volume relationships:
• The cycle of ventricular contraction and relaxation can be depicted by plotting instantaneous
recordings of ventricular pressure against ventricular volume.
• The loop starts at the point that marks end-diastole and is plotted counter-clockwise as the
cardiac cycle goes through isovolumic contraction, ejection, isovolumic relaxation and filling
(fig. 12.3)
• The pressure-volume loops are defined by two bounders.
a) The end-systolic pressure-volume relationship (ESPVR).
b) The end-diastolic pressure-volume relationship (EDPVR).
• The ESPVR is a linear relationship that represents the contractile properties of the ventricular
chamber when the myocardium is maximally contracted. The EDPVR is a non linear
relationship that represents the stiffness properties of the ventricular chamber when the
myocardium is maximally relaxed and undergoing filling. Both the ESPVR and EDPVR
remain constant despite changing loading conditions on the heart.
• The slope of the ESPVR is called “end systolic elastance” and serves as a surrogate for
cardiac contractility. Positive inotropic agents will increase the steepness of the slope causing
a leftward shift in ESPVR, while negative inotropic agents will cause a right shift.
• The EDPVR is not a linear relationship. At low chamber volumes, increases in volume are
associated with minimal changes in pressure because of high LV compliance. However at
higher volumes when chamber compliance has decreased due to stretch of elastic elements,
further increase in volume result in steep changes in pressure. The ratio of change in pressure
to change in volume, known as “chamber stiffness” increases as end-diastolic volume and
pressure increase. The EDPVR typically changes when the intrinsic properties of the
myocardium change as in ischaemia, fibrosis, hypertrophy or infiltrative disease. Chamber
stiffness is a function of LV wall and chamber volume. When the LV wall volume increase
disproportionately to chamber volume as in hypertrophic cardiomyopathy, chamber stiffness
increases. Physiological changes in which the LV wall volume increases in proportion to
chamber volume such as normal growth or athletic hypertrophy do not affect chamber
stiffness.
• Stroke work represents the area of the pressure-volume loop. Stroke work is estimated by
multiplying the stroke volume by the mean LV or mean aortic pressure during ejection.
• The width of the pressure-volume loop is the stroke volume (difference between end-diastolic
and end systolic volumes). The ejection fraction is the ratio between the width of the loop and
the end-diastolic volume (EF= end-diastolic volume-end systolic volume/end-diastolic
volume). Clinically the EF is used to define the contractile state of the LV but clearly it is
only a surrogate for the line of contractility as it is significantly affected by afterload and to a
less extent by preload changes.
• The slope of a line drawn across the loop from the end-diastolic volume point to the end-
systolic point is referred to as the arterial elastance (Ea). It represents the ratio of the end-
systolic pressure to the width of the loop (stroke volume). It is a surrogate of the afterload.
Increased afterload without change in end-diastolic volume is associated with increased slope
of Ea and therefore narrows the pressure volume loop and decreases the ejection fraction. On
the other hand decrease in the afterload without change in end-diastolic volume decreases the
slope of Ea and consequently widens the pressure volume loop and increases the ejection
fraction (fig. 12.4). Such changes in ejection fraction occur despite on changes in contractility.

Clinical picture
Patients with ventricular dysfunction often remain asymptomatic for a prolonged period. At this stage,
cardiac and systemic compensatory mechanisms are sufficient to maintain the patient's functional
status. Initially, the progression of heart failure is characterized by the neurohormonal response but in
severe heart failure, the inflammatory response is activated. Generally, there is little relation between
192

left ventricular function (as measured by ejection fraction) and exercise capacity in heart failure.
Symptoms correlate better with changes in circulatory, pulmonary and skeletal muscle function.
Symptoms
• Dyspnoea:
Dyspnoea and fatigue are the earliest and most frequent symptoms of heart failure. Initially,
dyspnoea occurs on exertion and will be noted by a change in the extent of physical activity that
causes shortness of breath.
As heart failure worsens, the intensity of exertion required will decrease. The patient will
progressively develop paroxysmal nocturnal dyspnoea, orthopnoea and eventually dyspnoea at
rest.
Mechanism:
In left sided heart failure, engorgement of the pulmonary vessels will result in the following
changes:
a. Lung stiffness
b. Reduction in the calibre of peripheral airways
c. Alteration in distribution of ventilation and perfusion resulting in hypoxoemia
d. Stimulation of the stretch "J" receptors in the pulmonary vessels and interstitium
Such changes increase the work of breathing which combined with a low cardiac output result in
fatigue and ultimately the sensation of dyspnoea.
Dyspnoea is usually less prominent In right ventricular failure because pulmonary congestion is
not present. The severity of dyspnoea in left ventricular failure decreases after the patient
develops right ventricular failure. However, patients with right ventricular failure can develop
severe dyspnoea presumably as a consequence of reduced cardiac output and poor perfusion of
respiratory muscles and associated hypoxia leading to metabolic acidosis.

Ventricular Pressure-Volume Loop

Figure 3
Ventricular Pressure-Volume Loop

Fig.12.3 Ventricular pressure-volume loop

The ESPVR and the EDPVR are the boundaries of the PV loop. The loop begins at end-diastole when the
ventricle is full, and is drawn counterclockwise. Ees is a surrogate for cardiac contractility and is
represented by the slope of the ESPVR.
EDPVR= end-diastolic pressure-volume relationship; Ees= end-systolic elastance; ESPVR= end-systolic
pressure-volume relationship.
 133

• Orthopnoea:
This is defined as dyspnoea which occurs when the patient assumes a supine position but is
relieved by sitting up or elevation of the head with pillows. In severely affected patients, the
patient usually sleeps sitting upright in a chair.
Mechanism:
The failing left ventricle cannot readily accept and pump the extra blood volume delivered to it by
the right ventricle in the supine position. Pulmonary venous engorgement occurs and leads to
dyspnoea through the above mentioned mechanisms.
Orthopnoea Is not specific to heart failure; it may occur in any condition that decreases the vital
capacity e.g. pleural effusion, chronic obstructive lung disease, ascites or abdominal obesity.
Trepopnoea is a rare form of orthopnoea which occurs In one lateral decubitus position due to
distortion of great vessels in this position.

The Measurement of the Ejection Fraction and the

Effect of Changing Afterload and Contractility
Baseline

Changing Afterload (Ea) Changing Contractility (ESPVR)

Fig.12.4. The measurement of the ejection fraction and effect of changing afterload and contractility.
In panel (A], the ejection fraction (EF] is defined as the width of the pressure-volume (P-V) loop (stroke
volume) divided by the left ventricular end-diastolic volume (LVEDV). Panel (B) examines the effect of
changes in afterload, as defined by the slope of the arterial elastance (Ea). A reduced sfterload widens the
P-V loop and increases EF, an increased afterload has the opposite effect. Panel (C) examines the effects of
contractility change on the EF. An increase in contractility (steeper slope) increases the width of the P-V
loop and reduces the left ventricular end-systolic volume (LVESV) increasing the EF. A reduction in
contractility does just the opposite.
Ea=arterial elastance; EF=ejection fraction; ESPVR=end-systolic P-V relationship; LVEDV=left
ventricularend-diastolic volume; P-V=pressure-volume; SV=stroke volume.
194

Bendopnea is a newly recognized symptoms in patients with advanced heart failure. It refers to
dyspnoea when bending forward such as when tying one’s shoes. These patients have significant
elevation of the right atrial and pulmonary capillary wedge pressures and low cardiac index.
• Paroxysmal nocturnal dyspnoea:
After sleep at night by about 1-2 hours, the patient awakens suddenly with severe anxiety and
suffocation. He sits upright and gasps for breath. Bronchospasm caused by congestion of the
bronchial mucosa and interstial pulmonary oedema compress the small airways and increases the
work of breathing. The attack may require 30 minutes or longer for relief.
Mechanism:
After sleeping, a combination of several factors is responsible for these attacks:
a. Absorption of interstitial fluid from dependent portions of the body with consequent
expansion of thoracic blood volume.
b. Reduction of adrenergic support of the left ventricle.
c. Normal nocturnal depression of the respiratory centre.
d. Elevation of the diaphragm during recumbency.
Chyene-Stokes respiration is a common association with paroxysmal nocturnal dyspnoea. It
consists of periodic waxing and waning of respiration alternating with periods of apnoea that last
15-60 seconds. This pattern of breathing may be seen during sleep in normal individuals, but its
occurrence in the conscious patient suggests heart failure. It also develops in cerebrovascular
disease. In heart failure, it is attributed to the following factors.
a. Depression In the sensitivity of the respiratory centre to carbon dioxide which is exaggerated
by associated cerebral atherosclerosis, sleep and use of narcotics.
b. During the apnoeic phase, arterial PO2 falls and PCO2 rises. This combination excites the
depressed respiratory centre, resulting in hyperventilation and subsequently hypocapnoea
followed by another period of apnoea.
c. Prolongation of the lung to brain circulation time results in a sluggish response of the
respiratory centre that prevents return to a steady state of ventilation.
Central and obstructive sleep apnoea may occur in patients with advanced heart failure.
During apnoeas, patients with heart failure show a large reduction in cardiac output and stroke
volume due to combination of increased LV afterload and decreased preload. However, heart
failure patients with sleep-disordered breathing are less likely to report day time somnolence than
those without heart failure, possibly due to the alerting influence of sympathetic stimulation.
Sleep disordered breathing is associated with recurrent hypoxoemia, reoxygenation stress,
hypercapnoea, endothelial dysfunction, Inflammation, hypercoagulable state, metabolic
dysregulation and increased sympathetic activity.
Heart failure patients with sleep-disordered breathing have a worse prognosis than those with
similar severity of heart failure but no sleep-disordered breathing.
• Acute cardiogenic pulmonary oedema:
Severe pulmonary congestion results in transfer of fluid from the pulmonary capillaries to the
alveoli. Alveolar flooding can proceed to such a degree that many large airways become filled
with blood tinged fluid. Extreme breathlessness develops suddenly and the patient becomes
extremely anxious and coughs and expectorates pink frothy liquid. The patient sits upright or may
stand and thrash about. The respiratory rate is elevated, the alae nasi are dilated and there is
inspiratory retraction of intercostals spaces and supraclavicular fossae. The patient often grasps the
sides of the bed to allow the use of the accessory muscles of respiration. Respiration is noisy with
loud inspiratory and expiratory gurgling sounds that are often easily audible. Sweating Is profuse
and the skin is usually cold and cyanotic reflecting low cardiac output and increased sympathetic
activity.
Mechanism:
Pulmonary oedema develops when the pulmonary capillary pressure (normally 8-12 mmHg) rises
above the plasma colloidal osmotic pressure (normally about 28 mmHg) and the resulting fluid
transudation across the alveolocapillary membrane exceeds the capacity of the pulmonary
lymphatics to drain it. The development of hypoalbuminoemia in heart failure (due to hepatic
congestion, diminished appetite and occasionally protein-losing enteropathy) enhances such
transudation by decreasing the plasma colloidal osmotic pressure.
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• Cough:
This may be caused by pulmonary congestion and occurs during the same circumstances as
dyspnoea i.e. on exertion or recumbency and is relieved by treatment of heart failure.
Occasionally, cough may be related to treatment with angiotensin converting enzyme (ACE)
inhibitors.
• Fatigue and weakness:
These symptoms are related to poor perfusion and altered metabolism of the skeletal muscle in
patient with low cardiac output. They may be worsened by excessive treatment with diuretics and
beta-adrenergic blockers.
The limited exercise tolerance in patients with heart failure is primarily related to the development
of dyspnoea and insufficient blood flow to exercising muscles. Other contributory factors include,
abnormal skeletal metabolism, deconditioning of skeletal and respiratory muscles and anxiety.
• Nocturia and oliguria:
Urine formation may be suppressed during the day when the patient is upright and active due to
redistribution of blood flow away from the kidney during activity. When the patient rests in the
recumbent position at night, the cardiac output increases due to enhanced venous return, renal
vasoconstriction diminishes and urine formation increases. Oliguria is a sign of late heart failure
and is related to suppression of urine formation due to severely reduced cardiac output.
• Cerebral symptoms:
Elderly patients with advanced heart failure may develop confusion, memory impairment, anxiety,
headache, insomnia and occasionally delirium and hallucinations. These symptoms are related to
reduce cardiac output and poor perfusion of the nervous system.
• Abdominal symptoms:
In patients with predominant right-sided heart failure, congestive hepatomegaly may produce dull
ache or heaviness in the right upper quadrant or epigastrium. This is caused by stretching of the
hepatic capsule. Anorexia, nausea, bloating, sense of fullness after meals and constipation may
occur due to congestion of the liver and gastrointestinal tract. In terminal conditions, inadequate
bowel perfusion may cause abdominal pain, distension and bloody stools.

Assessing cardiovascular disability (see also chapter 1)

The functional activity of patients with heart disease Is commonly assessed by the New York Heart
Association (NYHA) functional classification. However this system Is limited by its dependence on
subjective assessment, the use of some imprecise terms (e.g. ordinary activity, undue fatigue) and the
frequent changes in patient's functional class over short periods of time. More recently, the NYHA
changed its evaluation from functional activity to a broader one called cardiac status which classified
cardiac status as:
• Uncompromised
• Slightly compromised
• Moderately compromised
• Severely compromised
Somewhat more detailed classification were provided by the Canadian Cardiovascular Society (CCS)
(see Table 1.1), but this classification is limited to patients with angina pectoris.
A specific activity scale classification is also available which is based on the metabolic cost of various
activities and appears more reproducible and predictive of exercise tolerance than either the NYHA or
CCS classifications (Table 1.1).

Assessment of health status and quality of life:

A number of heart failure-specific questionnaires have been developed in an attempt to understand
how heart failure affects the patients’ quality of life.
• The Minnesota living with heart failure questionnaire poses 21 specific questions about how
heart failure affects various aspects of daily life ranging from its effect on mood to travel, to
sexual function. Increasing scores correlate with worsening symptoms.
• The Kansas City cardiomyopathy questionnaire is a similar survey. It is more reliable in
stable patients and more sensitive to clinical changes and response to therapy.
Signs
196

• General appearance:
Patients with long standing heart failure frequently appear malnourished and occasionally
cachectic. This arises from anorexia secondary to hepatic and intestinal congestion or drug (e.g.
digitalis) therapy. Rarely patients may experience impaired fat absorption and in some cases
protein-losing enteropathy. Patients may have increased body metabolism from increased
myocardial oxygen consumption, excessive work of breathing or elevated levels of circulating
catecholamines and other neurohormones. The combination of reduced caloric intake and
increased energy expenditure can lead to a reduction of tissue mass and thus in severe cases to
cachexia.
• Increased adrenergic activity:
Pallor, coldness of the limbs, cyanosis of the digits and diaphoresis may occur due to
vasoconstriction and sympathetic stimulation. Sinus tachycardia develops in an attempt to
maintain the cardiac output.
With severe (particularly acute) heart failure, the systolic blood pressure may be reduced and the
proportional pulse pressure (pulse pressure/systolic pressure) declines in correlation with the
reduction in cardiac output.
• Systemic venous hypertension:
This is detected by abnormal distension of the jugular veins. Although the jugular venous pressure
normally declines on inspiration, it may rise in patients with right sided heart failure (Kussmaul's
sign). In patients with mild right sided heart failure, the jugular venous pressure may be normal at
rest but rises to abnormal levels with compression of the right upper abdomen for > 15 seconds
(hepatojugular reflux).
The liver often enlarges before oedema develops and may remain so even after other symptoms of
right sided heart failure have disappeared. If hepatomegaly has developed rapidly and relatively
recently, the liver is usually tender due to rapid stretching of its capsule. In long standing heart
failure this tenderness frequently disappears.
In patients with tricuspid regurgitation, systolic expansion of jugular veins and systolic pulsations
of the liver occur.
Splenomegaly may develop In the presence of severe congestive hepatomegaly.
• Pulsus altemans:
This Is characterized by a regular rhythm with alternating strong and weak arterial pulsations. It is
detected by palpation of the peripheral pulses (particularly the femoral) or by sphygmomanometry.
As the cuff is slowly deflated, only alternate beats are audible for a variable interval below the
systolic level and then all beats are heard. Rarely the weak beat is so small that the aortic valve is
not opened and this results in an apparent halving of the pulse rate (total altemans). Pulsus
altemans may be accompanied by alteration in the intensity of the heart sounds and of existing
heart murmurs.
Mechanism:
Pulsus altemans is attributed to alternation In the stroke volume of the left ventricle possibly
because of Incomplete recovery and hence failure of contraction of some myocardial cells every
other cycle. It signifies advanced systolic heart failure and often disappears with treatment. It can
be often elicited by assumption of the erect posture and is often initiated by a premature beat.
• Abnormal response to the Valsalva maneuver:
The patient is asked to blow against an anaeroid manometer and to maintain a pressure of 40
mmHg for 30 seconds. Normal arterial pressure tracings exhibit 4 phases:
In heart failure, the heart operates on the flat position of the Starling curve, so the decrease in
venous return during the straining phase does not affect the stroke volume. Consequently the
baroreceptors reflex is not activated and no overshoot on release of the strain occurs (square-wave
appearance of the tracing).
• Pulmonary crackles (crepitations):
These are heard over the lung bases in patients with moderately severe heart failure. It results from
transudation of fluids into the alveoli and then into the airways. The presence of crackles generally
reflects the rapidity of onset of heart failure rather than the degree of volume overload; hence
finding of clear lung fields on physical examination in a patient with chronic heart failure should
not suggest that fluid retention has been adequately treated. In acute pulmonary oedema, coarse
 197

bubbling crackles and wheezes are heard' over both lung fields and are accompanied by
expectoration of blood-tinged sputum.
• Hydrothorax:
This is usually bilateral but when unilateral, it is usually confined to the right side. It is related to
elevation of venous pressure in the both systemic and pulmonary vascular beds. It is usually
reabsorbed slowly as heart failure improves but may persist for many days particularly when
loculated.
• Oedema:
Oedema in heart failure is usually symmetrical, pitting and generally occurs in the dependent
position of the body. In ambulatory patients, it is usually first noted in the feet or ankles at the end
of the day and generally improves overnight. In bedridden patients, it is most commonly found
over the sacrum. Late in the course of heart failure, oedema may become massive and generalized
(anasarca). Approximately 4 litres of extracellular fluid might accumulate before peripheral
oedema occurs. Chronic oedema results in increased pigmentation, redness and induration of the
skin of the lower extremities.
Mechanism:
The development of oedema depends on one or more alterations in the Starling equilibrium which
is indicated by the following equation:
Extravascular transudation rate =
Hydraulic conductance x (intravascular - interstitial hydrostatic pressures)
- reflector coefficient x (intravascular - interstitial colloidal osmotic pressures)
In heart failure, alterations in the Starling equilibrium result from:
a. Salt and water retention (see renal responses in chronic heart failure).
b. In right-heart failure, the rise of pressures in the systemic veins and capillaries enhances the
transudation of fluid into interstial spaces.
c. Hypoalbuminaemia as a result of hepatic impairment (congestion and ischemia), diminished
protein intake (anorexia and intestinal congestion and occasionally protein losing enteropathy
leads to diminished colloidal osmotic pressure and further enhances fluid transudation to the
interstitial spaces.
• Ascites:
This occurs in patients with increased pressures in the hepatic veins and in the veins draining the
peritoneum. In patients with organic tricuspid valve disease or chronic constrictive pericarditis,
ascites may be more prominent than subcutaneous oedema. Hypoalbuminoemia lowers the
threshold for the development of ascites.
• Cardiac signs:
a. Cardiomegaly, with laterally displaced, enlarged and sustained ventricular impulse occurs in
the majority of patients with chronic systolic heart failure. Exceptions include heart failure
with preserved EF due to chronic hypertension, chronic constrictive pericarditis, restrictive
cardiomyopathy as well as acute forms of heart failure.
b. Auscultation may reveal:
o Gallop sounds: The decrease in ventricular compliance may Initially become apparent by
the development of presystolic atrial sound (S4 gallop). In more advanced heart failure, a
protodiastolic sound (S3 gallop) appears.
0 Accentuation of P2 due to development of pulmonary hypertension in patients with left
ventricular failure.
0 Systolic murmurs due to development of mitral or tricuspid regurgitation secondary to
ventricular dilatation. The murmurs frequently diminish or disappear with adequate
treatment of heart failure.

Clinical findings are not reliable in differentiating between heart failure with reduced vs preserved
ejection fraction

Investigations
• Electrocardiography:
198

Changes In the ECG are generally non specific. Sinus tachycardia usually occurs in
uncompensated heart failure. Isolated premature ventricular beats are common and complex
ventricular arrhythmias can be detected in most patients during prolonged (24-48 h) Holter
monitoring. Evidence of atrial and ventricular enlargement and interventricular conduction delays
such as left bundle branch block are commonly encountered. A normal ECG virtually excludes LV
systolic dysfunction.
• Stress testing:
Exercise stress testing can be conducted safely. It can be performed either by having the patient
perform a 6-minute walk test or more formally with either a bicycle ergometer or treadmill
simultaneously with respiratory gas analysis.
In the 6-minute walk test, the patient is asked to walk along a level corridor as far as he can in 6
minutes. A formal graded exercise test provides more detailed information regarding the cause of
exercise limitation. Monitoring gas exchange allows a more precise assessment of the exercise
burden by measuring the maximum oxygen consumption and anaerobic threshold (the point at
which the respiratory quotient rises as a result of production of excess lactate). Patients with
maximum oxygen consumption < 10-12 ml/kg/min have been shown to have a better survival if
transplanted than If treated medically.
• Chest radiography:
Cardiomegaly (cardiothoracic ratio >50%) is encountered in the majority of patients. However, the
heart size is more often normal in patients with left ventricular diastolic dysfunction and in acute
compared to chronic heart failure. Normally, the lower lung lobes are better perfused than are the
upper lobes. With heart failure, there is progressive compression of the lower lobe vessels by
interstitial and perivascular oedema and redistribution of the pulmonary flow to the upper lobes.
When the pulmonary capillary pressure rises to 13-17 mmHg, cephalization of the pulmonary
vasculature develops in the erect position with constriction of lower lobe vessels and dilatation of
upper lobe vessels. When the pulmonary capillary pressure exceeds 20-25 mmHg, interstitial
pulmonary oedema occurs. This manifest by the appearance of Kerley's lines (sharp linear
densities of interlobular interstitial oedema), perivascular oedema and subpleural oedema (spindle-
shaped accumulation of fluid between the lung and adjacent pleural surface). When the pulmonary
capillary pressure exceeds 25 mmHg, alveolar oedema appears as cloud like areas of fluid around
the hili In a "butterfly" pattern with large pleural effusion.
• Echocardiography: (see also chapter 5)
The value of echocardiography in the diagnosis of chronic heart failure is given in table 12.1. In
analysis of the echocardiogram, the following should be observed:
- Patients with a left ventricular ejection fraction less than 40% are considered to have systolic
dysfunction and those with left ventricular ejection fraction > 50% are considered to have
preserved systolic function. This clearly leaves a grey area in the range of 40-50% (heart failure
with mid range EF). Because the volume measurements required to calculate the ejection
fraction are time consuming and subject to error, it can be visually estimated. In this regards,
the E point-septal separation (EPSS) is helpful. This denotes the distance between the left
ventricular septal endocardium and tip of the anterior mitral leaflet at peak (E) filling.
Normally, It is <0.7 cm, in the range from 0.7-1.0 cm, the ejection fraction is mildly reduced
and when >1.0 cm and aortic insufficiency and mitral stenosis are ruled out; the ejection
fraction is markedly reduced.
- Segmental left ventricular wall hypokinesis or akinesis especially when accompanied by
thinning and scar formation is usually suggestive of coronary heart disease. Unfortunately,
coronary artery disease can cause non-focal left ventricular dysfunction and non-ischaemic
cardiomyopathy may cause segmental hypokinesis. Consequently, most patients with left
ventricular systolic dysfunction should undergo angiography.
- Dobutamine (or exercise) stress echocardiography may be used to detect Ischaemia as a cause
of cardiac dysfunction and to assess myocardial viability in the presence of marked hypokinesia
or akinesia. It may be used to identify stunned and hibernating myocardium.
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Table 12.1. The main echocardiographic features of chronic heart failure

Feature Echocardiographic Method Comment

LV size (end- M-mode short-axis dimension - The most useful screening method for
diastolic) identifying LV dilatation.
- Upper limit of normal=5.5 cm
- Subject to error due to variation in
cardiac position and shape.
2D Simpson rule: calculation of
volumes from planimetry in the four- - The most accurate method when
and two-chamber views. ventricular geometry is abnormal
(myocardial infarction).
- Upper limit ofnormal=65 ml/m2.

LV systolic M-mode fractional shortening: - Useful for screening.

function Diastolic dimension - systolic - Lower limit of normal=25%.
dimension / diastolic dimension
- May overestimate ejection fraction with
apical infarction or underestimate it with
posterior infarction.
2-D Ejection fraction
2-D Simpson rule: diastolic volume - - Lower limit of normal=55%.
systolic volume / diastolic volume. - Errors due to underestimation of
2-D visual estimation. volumes, especially in end-systole.
- Sufficient for most clinical purposes.
- Especially accurate in short-axis view.

LV wall M-mode septal and posterior wall - Identifies concentric hypertrophy.

thickness (end- thickness. - Upper limit of normal for septum=l.l
diastolic) cm, for posterior wall=l .0 cm.
- Does not correlate well with LV mass,
because does not consider LV size.

LV mass Calculated from myocardial volume: - Upper limit of normal=130 g/m2.

total LV volume - LV cavity volume - May be greatly Increased in patients with
by an area-length geometric formula. systolic dysfunction despite normal or
decreased wall thickness.

LA size (end- M-mode LA anteroposterior - Upper limit of normal=4.2 cm. in the

systolic) dimension. absence of mitral valve disease and atrial
fibrillation, dilatation usually reflects
elevated LV filling pressure.
2D Simpson rule: planimetry in the - Upper limit of normal=28 ml/m2.
four- and two-chamber views.

RV size (end- M-mode anteroposterior dimension - With sustained elevation of LA pressure,

diastolic) RV dilatations and failure are common,
leading to "pancardiomegaly".
- Upper limit of normal=3.5cm.

Cardiac catheterization:
Right heart catheterization may be particularly useful in patients with cardiogenic shock, poor
response to standard therapy, uncertain hypotension and hypoperfusion or volume status and
obscure pulmonary oedema. It is also commonly employed in the evaluation of pulmonary
hypertension and in preparation for heart transplantation.
Left heart catheterization and angiography are necessary when the presence and extent of coronary
artery disease need to be determined particularly if revascularization is being considered.
200

The invasive measurement of right atrial pressure (or noninvasively, the jugular venous pressure)
and pulmonary capillary wedge pressure are significantly correlated in patients with ischaemic and
nonischaemic cardiomyopathy. An elevation of right atrial pressure to > 10 mmHg correlates with
elevation of pulmonary wedge pressure to > 22 mmHg. This also holds for patients with heart
failure with preserved ejection fraction. Exceptions to this correlation include patients with chronic
obstructive pulmonary disease, pulmonary embolism, pulmonary arterial hypertension, restrictive
lung disease, obstructive sleep apnea and acute myocardial infarction.
• Endomyocardial biopsy:
This is indicated when the results will have a meaningful impact on subsequent therapeutic
decisions. It may guide the selection of specific therapy (e.g. for haemochromatosis or
sarcoidosis), or heart transplantation (e.g. for giant cell myocarditis).
•' Magnetic resonance imaging (MRI) or computed tomography (CT): may be helpful in evaluating
ventricular mass, detecting right ventricular dysplasia or recognizing the presence of pericardial
disease. MEI allows comprehensive and reproducible analysis of cardiac anatomy and function.
When combined with contrast agents such as gadolinium, it provides information on myocardial
perfusion at rest or following pharmacological intervention. MRI is now the gold standard for the
assessment of volumes and wall motion.
• Implantable monitors:
These are Implantable devices to assess haemodynamics especially volume status on an ongoing
basis. These devices may be stand alone or incorporated into implantable cardioverter
defibrillators or pacemakers. The value of such devices in guiding therapy and improving
outcomes is still debated but promising.
• Laboratory blood tests:
a. Anaemia:
o Anaemia may be the cause or consequence of heart failure. It is common especially in
advanced heart failure and is associated with a worse prognosis. Causes may include
hamodilution, renal dysfunction, poor nutrition, inflammation, blood loss related to
medication, reduced production (or response to) erythropoietin and defective iron
utilization. Iron deficiency exists in about 40% of patients including those without
anoemia . It impairs myocardial and musculoskeletal metabolism. In heart failure higher
cut offs of ferritin are used to define iron deficiency (<100-300).

b. Serum electrolytes:
o Dilutional hyponatraemia may develop in severe heart failure due to the combination of
sodium restriction, intensive diuretic therapy and elevated levels of arginin vasopressin.
o Serum potassium. Hypokaloemia is very common with use of diuretics especially long
acting thiazides. Hyperkaloemia may occur in patients with very low cardiac output or
renal insufficiency especially with administration of additional potassium, potassium
sparing diuretics or angiotensin-converting enzyme (ACE) inhibitors.
o BUN and to a less extent creatinine may be elevated as a result of reduced renal blood
flow.

c. Liver function tests:

o Serum aspartate aminotransferase (AST) and, alanine aminotransferase (ALT) are often
elevated as a result of hepatic congestion and cardiac cirrhosis.
o Hyperbilirubinoemia may develop with acute hepatic congestion. This is often associated
with elevation of serum alkaline phosphatase and prolongation of prothrombin time.

d. All the three natriuretic peptides, ANP, BNP and C-natriuretic peptide (CNP) are markedly
elevated in patients with heart failure. Because plasma BNP release is less affected by atrial
filling pressure, it provides a better reflection of myocardial disease and helps distinguish
between cardiac and noncardiac causes of dyspnoea. The N-terminal of pro BNP (NT-pro
BNP is another diagnostic marker for heart failure. Unlike BNP, NT-pro BNP is
predominantly cleared by the kidney which limits its diagnostic value in patients with renal
failure.
 201

Low natruretic peptides levels (BNP <100pg/ml or NT-pro-BNP <400pg/ml) have a very
high negative predictive value, making it a useful rule-out test. High values (BNP
>400pg/ml or NT pro BNP >2000pg/ml) suggest that heart failure is likely. The diagnosis is
uncertain with intermediate values. The values of these peptides are raised with advanced
age, female sex and renal insufficiency and lowered with obesity. The sensitivity and
specificity of BNP and NT-pro-BNP for the diagnosis of heart failure are lower in non-acute
patients and their value to guide therapy is not well established.
In patients with HFPEF, BNP levels are considerably lower than in patients with HFREF.

e. Cardiac troponins (T and I) are elevated in 23% of patients with stable chronic heart failure
and 55% of acute decompensated heart failure. It is an independent predictor of mortality.

Population screening for heart failure

At present, there Is little information to support screening of broad populations to detect heart failure.
However, those at high risk of developing cardiomyopathy (e.g. those with strong family history of
cardiomyopathy or those receiving cardiotoxic interventions) are appropriate targets for aggressive
screening including echocardiography to assess LV function.
Several clinical scoring systems have been developed to screen for heart failure in population-based
studies including the Framingham Criteria and the National Health and Nutrition Survey (NHANES)
Criteria (Table 12.2). Additional laboratory testing is usually necessary to confirm diagnosis of heart
failure when these methodologies are used.
When familial cardiomyopathy is suspected, an extended family history dating back at least three
generations should be obtained. Genetic testing is recommended in the family member who present
with the most obvious phenotypic features of the disease (i.e. the proband). If the primary affected
family member tests positive for a known mutation, the first degree relatives can then be tested for the
same mutation and avoid being tested for all possible genes or mutations. Any asymptomatic family
member who tests positive for the gene should undergo a full clinical screening evaluation and close
surveillance. The frequency of screening varies by the disease type.

Stages of heart failure

Heart failure is a continuum that comprises four Interrelated stages
Stage A: includes patients who are at high risk for developing heart failure but without structural heart
disease or symptoms of heart failure (e.g. patients with diabetes or hypertension).
Stage B: includes patients who have structural heart disease but without symptoms of heart failure
(e.g. patients with a previous myocardial infarction or asymptomatic LV dysfunction).
Stage C: includes patients who have structural heart disease who have developed symptoms of heart
failure (e.g. patients with a previous myocardial infarction with shortness of breath and
fatigue).
Stage D: includes patients with refractory heart failure requiring special intervention (e.g. patients
awaiting cardiac transplantation).

Table 12.3 and Fig. 12.5. illustrate these stages of heart failure and the recommended therapy for each
stage.

Treatment of heart failure with reduced ejection fraction (HFREF)

General therapeutic measures
• Preventive measures:
Prevention of heart failure may be achieved by improving ventricular function before symptoms
develop. This entails detecting and controlling hypertension, managing metabolic abnormalities
Including hyperlipidaemia and diabetes mellitus and treating myocardial ischaemia before damage
to the myocardium occurs.
• Correction of precipitating factors:
a. Reversible causes of heart failure should be searched for and treated. These include endocrine
abnormalities, valvular dysfunction, intracardiac shunts, high cardiac output states,
arrhythmias, systemic hypertension, cardiotoxic drugs (e.g. ethanol, anthracyclines),
202

myocarditis and Takotsubo (stress-induced cardiomyopathy). Coronary revascularization

should be considered in patients with coronary artery disease in whom symptomatic or
demonstrable myocardial ischaemia is believed to be exerting a deleterious effect on cardiac
fimction.
b. Precipitating factors of heart failure should be identified and corrected to avoid recurrence or
refractoriness to therapy. Immunization with influenza and pneumococcus vaccines may
reduce the risk of respiratory infection.
• Diet and changes in activity:
a. Restriction of sodium intake to 1.5-2 g/day (4-5 g/d of sodium chloride) is necessary to reduce
water retention with a concomitant reduction in cardiac work.
b. Fluid restriction is rarely necessary. Although fluid overload and hypervoloemia associated
with heart failure make fluid restriction appealing such an approach is rarely successful.
Chronic hyponatraemia rarely causes problems and excessive hyponatraemia can be
successfully treated by modifying the diuretic regimen and the use of angiotensin converting
enzyme inhibitors.
c. Caloric restriction is necessary in overweight patients because weight reduction lowers
demands on the heart and can provide significant symptomatic relief.
d. In moderate to severe heart failure restriction of physical activity and adequate bed rest often
help improve the clinical condition temporarily particularly during periods of acute
decompensation or suspected myocarditis. Patients should maintain some level of
conditioning with mild to moderate regimens of aerobic exercise.

Pharmacological treatment
Most patients with heart failure should be routinely managed with a combination of 3 types of drugs:
a diuretic, an angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker and a
beta blocker. Patients with evidence of fluid retention should take a diuretic until a euvoloemic state is
achieved, and diuretic therapy should be continued to prevent the recurrence of fluid retention.
Therapy with digoxin as a fourth agent may be initiated at anytime to reduce symptoms, prevent
hospitalization, control rhythm and enhance exercise tolerance. An algorithm for treatment of chronic
heart failure is shown in fig. 12.6.

Table 12.2. Diagnostic criteria for heart failure (HF) in population-based studies

Framingham criteria [*]

Major criteria Minor criteria Major or minor criteria
Paroxysmal nocturnal dyspnea Ankle oedema, night cough Weight loss > 4.5 kg in 5 days in
or orthopnea. response to treatment.
Neck-vein distention. Dyspnoea on exertion
Rales. Hepatomegaly
Cardiomegaly. Pleural effusion
Acute pulmonary oedema, S3 Vital capacity decreased one
gallop third from maximal capacity
Increased venous pressure (> 16 Tachycardia (rate > 120/min)
cm H2O)
Hepatojugular reflux

’The diagnosis of HF using the Framingham criteria requires the simultaneous presence of
at least two major criteria or one major criterion in conjunction with two minor criteria.
Minor criteria are acceptable only if they cannot be attributed to another medical condition
(e.g., pulmonary hypertension, chronic lung disease, cirrhosis, ascites, nephrotic syndrome).
 203

Table 12.3. ACC/AHA stags of heart failure and recommended therapy by stage

Stage Features Examples Recommended therapy

A Patients at risk Hypertension 1. Treat hypertension

of heart failure Coronary artery 2. Encourage smoking cessation
but without disease 3. Treat lipid disorders
structural heart Diabetes 4. Encourage regular exercise
disease or Family history of 5. Stop alcohol intake
symptoms of cardiomyopathy 6. ACE Inhibitors or ARBs in patients with
heart failure. history of atherosclerotic vascular
disease, diabetes, hypertension or CV risk
factors
B Patients with Previous • All measures under stage A
structural heart myocardial • ACE inhibitors or ARBs in patients with
disease but infarction myocardial infarction or reduced EF
without Left ventricular • Beta-blockers in patients with reduced EF
symptoms of systolic • Valve surgery for patients with
heart failure. dysfunction significant valve disease
Asymptomatic • Implantable defibrillator in selected
valvular disease patients

C Patients with Patients with known 1. All measures under stages A and B
structural heart structural heart 2. Dietary salt restriction
disease but with disease and shortness 3. Drugs for routine use:
prior or current of breath, fatigue Diuretics
symptoms of and/or reduced ACE Inhibitors
heart failure. exercise tolerance Beta-blockers
4. Drugs and devices for selected patients:
Aldosterone antagonists
- ARBs
Digitalis
Hydralazine / nitrates
Biventricular pacing
- ICD

D Patients with Patients who have 1. All measures under stage A, B, C

refractory heart marked symptoms at 2. Continuous IV inotropic Infusion
failure requiring rest despite maximal 3. Mechanical assist devices
specialized medical treatment 4. Heart transplantation
interventions.

1. Diuretics (fig 12.7, tables 12-4 and 12-5)

These drugs promote excretion of sodium and water, help lower plasma volume, reduce pulmonary
and systemic congestion and thereby improve symptoms and functional capacity. The goal is
ventricular filling pressure that will maintain cardiac output and relieve pulmonary congestion without
causing orthostatic hypotension. Overdiuresis should be avoided since it may significantly reduce
intravascular volume and cardiac output.
Loop diuretics increase sodium excretion up to 20% to 25% of the filtered load of sodium, enhance
free water clearance and maintain their efficacy unless renal function is severely impaired. In contrast
thiazide diuretics increase the fractional excretion of sodium to only 5% to 10% of the filtered load,
tend to decrease free water clearance and lose their effectiveness in patients with impaired renal
204

function (creatinine clearance less than 40 ml/min). Consequently loop diuretics have emerged as the
preferred diuretic agents for use in most patients with heart failure, however, thiazide diuretics may be
preferred in hypertensive heart failure patients with mild fluid retention because they confer more
persistent antihypertensive effects.
Therapy is commonly initiated with low doses of diuretic and the dose is increased until urine output
increases and weight decreases generally by 0.5 to 1.0 kg/day. The ultimate goal of diuretic treatment
is to eliminate clinical evidence of fluid retention such as jugular venous pressure elevation and
peripheral oedema. Once fluid retention has resolved, treatment with the diuretic should be
maintained to prevent recurrence of volume overload. In many cases, dose adjustment can be
accomplished by having patients record their weight each day and make changes in their diuretic
dosage if the weight increases or decreases beyond a specified range.

Thiazides
These drugs are secreted into the lumen of the proximal convoluted tubule. They act by inhibiting the
Na+/CF cotransporter of the distal convoluted tubule. Increased delivery of NaCl and fluid into the
collecting duct directly enhances K+ and tT secretion by this segment and may lead to hypokaloemic
alkalosis. Thiazides increase Ca2+ resorption in the distal nephron but diminish Mg2+ resorption.
Prolonged use therefore may result in hypomagnesoemia and rarely hypercalcoemia.

Fig. 12.5 Stages in the evolution of heart failure (HFj and recommended therapy by stage. ACEI,
angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; EF, ejection fraction; FHx,
family history of cardiomyopathy; IV, intravenous; LV, left ventricular; MI, myocardial infarction.
 205

Table 12-4. Common oral diuretics used in treatment of heart failure

Diuretic Dose (mg/day) Site and mechanism of action

Thiazides:
Chlorothiazide 500-1000 Distal tubules:
Hydrochlorothiazide 25-200 Inhibit Na+/CF cotransporter
25-100
Chlorothalidone
5-20
Metolazone 2.5-5
Indapamide

Loop diuretics:
Frusemide 20-600 Thick ascending limb of the loop of Henle:
Bumetanide 0.5-10 Inhibit NaT/K+/2CF cotransporter
50-200
Ethacrinic acid
10-200
Torsemide

Potassium-sparing diuretics:
Triamtrene 50-200 Collecting duct:
Ameloride 5-20 Inhibit membrane Na+ conductance
12.5-50 Aldosterone antagonism
Spironolactone

Table 12-5. Intravenous diuretics used in treatment of heart failure

Drug Initial dose Maximum single dose

Loop diuretics:
Bumetanide 1.0 mg 4 to 8 mg
Frusemide 40 mg 160-200 mg
Torsemide 10 mg 100 to 200 mg

Thiazide diuretics:
Chlorothiazide 500 mg 1000 mg

Intravenous infusions:
Bumetanide 1 mg IV load then 0.5 to 2 mg per hour infusion
Frusemide 40 mg IV load then 10 to 40 mg per hour infusion
Torsemide 20 mg TV load then 5 to 20 mg per hour infusion

In renal failure endogenous organic acid end products may accumulate and compete with thiazdes for
access into the tubular lumen. Thiazides are therefore generally not effective when the glomerular
filtration rate falls below 40 ml/minute. However, metolazone appears to keep its efficacy with a
glomerular filtration rate as low as 10 ml/minute.

Loop diuretics
Like thiazides, these agents are also secreted into the proximal tubule, but they Inhibit the Na+/K+/2C1'
cotransporter in the thick ascending limb of loop of Henle. This results in marked increase in Na+ and
CV excretion. By inhibiting the concentration of solute within the medullary interstitium, these drugs
also reduce water reabsorption in the collecting duct. The delivery of large amounts of Na+ and fluid
to the distal nephron increases both K+ and Ef secretion. These drugs also increase the excretion of
Ca2+ and Mg2+. Following intravenous bolus infusion of frusemide, an increase in venous capacitance
and lowering of pulmonary capillary wedge pressure occur within minutes. However, this is often
associated with an acute increase in systemic vascular resistance due to transient activation of the
systemic and vascular renin angiotensin system.
206

Fig. 12.6. Treatment algorithm for patients with chronic heart failure
MR= Mineralocorticoid
CRT= Cardiac resynchronization therapy
CRT-D= Cardiac resynchronization therapy with implantable cardioverter defibrillator
H-1SDN= Hydralazine-isosorbid dinitrite
LVAT= LV assist device
ICD= Implantable cardioverter defibrillator.
ARNI: angiotensin receptor/neprilysin inhibitor.
 207

Fig. 12.7 Tubular sites of action of the major diuretics used in clinical medicine.

The diuretic effect of these agents is seen within 30 minutes and peaks in 1-2 hours. They are
generally preferred in severe heart failure when the patient is unresponsive to other diuretics as well
as in patients with diminished glomerular filtration rate (<50% of normal).
Loop diuretics may be given with a thiazide (e.g. metolazone) to patients with severe fluid retention.
Torsemide, which has better absorption that frusemide, may be prescribed for refractory fluid
retention.

Potassium sparing diuretics

Active sodium reabsorption in the distal tubule and collecting duct is accomplished in exchange for
potassium and hydrogen ions. Sodium reabsorption is activated through Na+ selective channels. This
is partly mediated through the action of aldosterone. Amiloride and triamtrene directly inhibit sodium
conductance by these channels and spironolactone competitively inhibits the binding of aldosterone to
mineralocorticoid (or type I) receptors thereby these drugs inhibit Na+ reabsorption and K+ and Bfl
secretion.
Onset of diuretic action is fairly rapid with amiloride and triamtrene (2-4 h) and their effect may
persist for 24 hours. A more gradual onset of diuresis is exhibited with spironolactone for which the
maximum effect occurs in 3 days which may be due in part to a progressive accumulation of the drug
or its active metabolites. Increased diuretic activity may persist for 2-3 days after treatment with
spironolactone has ended because of the longer half-life of the active metabolite.

Complications of diuretic therapy

• Altered potassium homeostasis:
In patients with chronic heart failure, both hypokaloemia (caused by K+ wasting diuretic) and
hyperkaloemia (caused by K+ supplements, K+ sparing diuretics or renin-angiotensin antagonists)
may occur. For patients with heart failure, it is recommended to maintain serum potassium
208

between 4.0 and 5.0 mEq/L. If potassium supplementation is necessary, oral KC1 extended release
tablets or liquid concentrates should be used whenever possible. Concomitant administration of
ACE inhibitors alone or in combination with potassium retaining agents (e.g. spironolactone) can
prevent electrolyte depletion in most patients taking a loop diuretic.
• Other electrolyte disturbances:
Hyponatraemia, hypomagnesoemia and metabolic alkalosis may occur. Hyponatraemia can be
treated by modification of diuretic regimen and increased renin-angiotensin inhibitors. Water
restriction is rarely needed. Magnesium replacement should be given for signs and symptoms that
could be due to hypomagnesoemia (e.g. arrhythmias, muscle cramps) and it can be given routinely
to all subjects receiving large doses of diuretics or requiring large amounts ofK+ replacement.
Metabolic alkalosis can be treated by increasing KC1 supplementation, lowering diuretic doses.
• Glucose intolerance and hyperlipidoemia. These are not usually clinically significant and blood
glucose and lipids should be controlled according to standard guidelines regardless of diuretic
therapy.
• Hyperuricoemia may occasionally precipitate gout particularly in predisposed subjects or in the
presence of renal dysfunction. Allopurinol can be administered to reduce uric acid synthesis.

Diuretic resistance
The effectiveness of diuretics (Including the potent loop diuretics) may decrease with worsening of
heart failure. This is attributed to a variety of factors:
• Delay in drug absorption.
• Increased sympathetic nerve activity which leads to avid renal sodium retention by all nephron
segments.
• Inadequate salt restriction.
• Compensatory' hypertrophy of the tubular epithelium distal to the site of diuretic action (breaking
phenomenon).
• Development of renal Impairment with consequent reduction of functioning nephrons.
• Concurrent administration of other drugs including nonsteroidal anti-inflammatory drugs
(decrease renal synthesis of vasodilator prostaglandins) and some antibiotics (compete with
secretion of most diuretics into the proximal tubular lumen).
• Use of increasing dose of vasodilators which despite increasing the cardiac output may lower the
renal perfusion pressure.

Treatment of diuretic resistance

• Concomitant administration of renin-angiotensin inhibitors to increase the cardiac output and
inhibit aldosterone secretion.
• Increasing frequency of loop diuretic dosing and switching to IV admnistration.
• Concomitant administration of more distally acting diuretic e.g. metolazone or spironolactone.
• Dopamine administration at doses that cause selective dopaminergic receptor stimulation (<2
pg/kg/minute) and consequently may increase renal blood flow and decrease tubular solute
reabsorption.
• Short term infusion of the recombinant human brain natriuretic peptide (rBNP, nesiritide) and/or
selective VI and V2 vasopressin receptor antagonists.
• Mechanical circulatory support may be necessary In patients with marginal cardiac output.
• Percutaneous angioplasty for patients with renal artery stenosis.
• Ultrafiltration particularly in the setting of rising serum creatinine and hyponatraemia. It relieves
pulmonary oedema, reduces ascites/oedema, corrects electrolyte abnormalities, improves
haemodynamics and restores diuretic responsiveness.

2. Angiotensin-converting enzyme (ACE) inhibitors (Table 12.6)

Mechanism of action
ACE inhibitors were originally developed as vasodilators, but when their clinical effects proved to be
out of proportion to their relatively weak vasodilator effect, It become apparent that another
mechanism was operative. That mechanism is the prevention of angiotensin II-mediated remodeling.
 209

The generation of angiotensin II is accomplished by two pathways, one uses converting enzyme found
in abundance in endothelium and the other uses the chymase enzyme found in the interstitial cells.
In heart failure, the ACE gene expression and enzyme activity are increased but the chymase gene
expression is not. Increased levels of angiotensin II have several adverse effects on the cardiovascular
system including cardiac myocyte hypertrophy, myocyte apoptosis, norepinephrine release and
mitogenic effects on fibroblasts.
ACE inhibitors exert their primary effect by inhibiting the converting enzyme responsible for the
formation of angiotensin II. They may indirectly decrease the elevated levels of circulating
catecholamines and decrease plasma vasopressin and endothelin levels. Because their chemical
structure is similar to kininase, ACE inhibitors prevent degradation of bradykinin, thereby increasing
production of nitric oxide by endothelial cells. They may also stimulate the synthesis of
prostaglandins.

Clinical effects:
In patients with heart failure, ACE inhibition produces a moderate increase in cardiac output, decrease
In right and left ventricular filling pressures decrease in pulmonary and systemic vascular resistance
and In mean arterial pressure without increasing the heart rate. Other beneficial effects include a
reduction in the incidence of ventricular arrhythmias, decreased end-systolic and end-diastolic
dimensions and sustained improvements in symptoms, exercise duration and quality of life.
ACE inhibitors improve the natural history of all subjects with heart failure and reduce mortality in
direct relation to the degree of severity of chronic heart failure. Therefore an ACE inhibitor Is
considered a mandatory treatment in heart failure as well as in asymptomatic left ventricular systolic
dysfunction. In post infarction population with ejection fraction <40%, ACE Inhibitors reduce the
incidence of recurrent infarction.
Current guidelines recommend the routine use of ACE inhibitors in symptomatic and asymptomatic
patients with heart failure and LVEF <40%.

Pharmacokinetics
Differences among various ACE Inhibitors are primarily related to pharmacokinetic and
haemodynamic properties. The peak haemodynamic response to captopril usually occurs within 30-90
minutes, the peak haemodynamic response to enalapril occurs 4-5 hours after administration and that
of lisinopril even later. Compared with captopril, both enalapril and lisinopril have delayed onset of
action and prolonged duration of haemodynamic effects. Progressive renal failure and hyperkaloemia
are less prominent during treatment with captopril than with enalapril and lisinopril. Generally longer-
acting agents appear to have little clinical advantage over shorter-acting ones and may in fact increase
the risk of adverse effects particularly when used in large fixed doses. Long-acting agents however
may increase patient compliance because of their convenient once-a-day dosing.
Treatment with ACE Inhibitors should be initiated at low doses followed by gradual increments In
dose if lower doses have been well tolerated. Renal fimction and serum potassium should be assessed
within 1 to 2 weeks of Initiation of therapy and periodically thereafter. Attempts should be made to
reach target doses that have been shown to reduce the risk of cardiovascular events in clinical trials.

Table 12.6. Angiotensin-converting enzyme (ACE) inhibitors

Drug Dose (mg/d) Pro-drug Peak action (h) Method of excretion

Captopril 25-150 No 1-1.5 Liver

Enalapril 5-40 Yes 4-6 Renal
Lisinopril 5-40 No 6 Renal
Quinapril 10-40 Yes 2-4 Renal
Ramipril 5-20 Yes 3-6 Renal and GI
Fusinopril 10-40 Yes 2-6 Liver and renal
Benzapril 10-14 Yes 2-4 Renal
210

If these doses cannot be used or are poorly tolerated, intermediate doses should be used with the
expectation that there are likely to be only small differences in efficacy between low and high doses.
Although symptoms may improve in some patients within 48 hours of therapy with an ACE inhibitor,
the clinical response to these drugs are generally delayed and may require several weeks, months or
more to become apparent. Even if symptoms do not improve, long term treatment with an ACE
inhibitor should be maintained to reduce the risk of death or hospitalization. Abrupt withdrawal of
treatment with ACE inhibitors should be avoided in absence of life-threatening complications (e.g.
angioedema) because clinical deterioration may occur.

Safety and side effects

Most of the available ACE inhibitors are safe and well tolerated and have a similar range and
incidence of adverse effects when used in the recommended doses.
• The most common adverse effects of ACE inhibitors are dizziness (6%), headache (5%) and
fatigue (30%). Some patients are sensitive to the hypotensive effect of the drugs, particularly those
who are dependent on the renin-angiotensin-aldosterone system for blood pressure maintenance.
These include patients with hyponatraemia and hypovoloemia, those receiving high doses of
diuretic therapy and those with bilateral renal artery stenosis.
• Minor deterioration of renal function as evidenced by rise of serum creatinine up to 2.5 mg/dl
frequently occurs particularly with long-acting agents. However, renal function usually returns to
baseline or stabilizes at a new steady state despite continued treatment with ACE inhibitors. A
significant increase in serum creatinine (e.g. by > 0.3 mg/dl) with the use of ACE Inhibitors Is
observed in 15% to 30% of patients with severe heart failure, but in only 5% to 15% of patients
with mild to moderate heart failure symptoms. The risk is substantially greater in patients with
bilateral renal artery stenosis or those taking NSAIDs.
• Rare cases of neutropenia have been reported during treatment with both captopril and enalapril.
• Taste alteration and recurrent cough have been reported in some patients. Cough occurs in
approximately 5-10% of patients and rises to nearly 50% in Chinese patients. It is
characteristically non productive, is accompanied by a persistent annoying tickle in the throat and
usually appears within the first month of therapy. It disappears within 1-2 weeks of discontinuing
treatment and recurs within days of rechallenge. Patients who cannot tolerate ACE inhibition due
to cough or angioedema are likely to benefit from angiotensin II type 1 receptor blockade (ARB).
However, angioedema may still develop in some patients taking ARBs.
The absolute contraindications of ACE inhibitors are few. These include bilateral renal artery
stenosis, pregnancy, lactation and previously documented angioedema. Occasionally, however
symptomatic hypotension, progressive azotoemia or an intolerable cough forces the
discontinuation of the ACE Inhibitor. Aspirin and non-steroidal anti-inflammatory drugs can block
the favourable effects of ACE inhibitors and increase the likelihood for renal insufficiency. This
effect is not seen with non-aspirin antiplatelet agents (e.g. clopidogrel).

3. Beta-blockers
Mechanism of action
Beta-blockers act principally to inhibit the adverse effects of sympathetic nervous system activation in
patients with heart failure and these effects far outweigh their known negative Inotropic effects.
Whereas cardiac adrenergic drive initially supports the performance of the failing heart, long term
activation of the sympathetic nervous system exerts deleterious effects that can be antagonized by the
use of beta-blockers. Sympathetic activation can increase ventricular volumes and pressure by causing
peripheral vasoconstriction and by impairing sodium excretion by the kidneys. Norepinephrine can
also induce cardiac hypertrophy but restrict the ability of the coronary arteries to supply blood to the
thickened ventricular wall, leading to myocardial Ischaemia. Activation of the sympathetic nervous
system can also provoke arrhythmias by increasing the automaticity of cardiac cells, increasing
triggered activity in the heart and promoting the development of hypokaloemia. Norepinephrine can
also increase the heart rate and potentiate the activity and actions of other neurohormonal systems.
Finally by stimulating growth and oxidative stress in terminally differentiated cells, norepinephrine
can trigger programmed cell death or apotosis. These deleterious effects are mediated through actions
of alpha-1, beta-1 and beta-2 adrenergic receptors.
 211

The failing heart is adrenergically activated. It is the increased cardiac adrenergic drive rather than an
increase in circulating norepinephrine that is both Initially supportive and then ultimately damaging to
the failing heart. In these circumstances, beta-adrenergic signal transduction is reduced secondary to
desensitization changes at the level of pi and 32 receptors, the inhibitory G protein (Gi) and an
enzyme responsible for modulating receptor activity by phosphorylation (3 adrenergic receptor
kinase) as well as by changes in expression of the adenyl cyclase enzyme. Such desensitization
changes are adaptive changes that may be further promoted by using beta adrenergic blocking agents.
Three beta-blockers have been shown to be effective in reducing the risk of death in patients with
chronic heart failure; bisoprolol and sustained-release metoprolol succinate (not tartarate) which
selectively blocks beta-1 receptors and carvedilol which blocks alpha-1, beta-1 and beta-2 receptors.
Regardless of the beta-adrenergic blocking agent used, treatment should start with extremely low dose
(1/8-1/16 of target dose) and gradually increase the dose every 1-2 weeks to full beta blocking dose.
Every effort should be made to achieve the target doses shown to be effective in major clinical trials.

Clinical effects
Beta-adrenergic blockers produce the greatest increase In ejection fraction in comparison with other
forms of therapy of heart failure. They improve functional status and significantly decrease mortality
(30-35%) from all causes. These findings have led to the recommendation for use of beta-adrenergic
blockers in the management of all patients with stable heart failure due to reduced left ventricular
ejection fraction unless they have a contraindication to their use or have been shown to be unable to
tolerate treatment with these drugs. Treatment with beta-blockers should be initiated as soon as left
ventricular dysfunction is diagnosed. Even when symptoms are mild or have responded to other
therapies, beta-blocker therapy is important and should not be delayed until symptoms return. Patients
should have no or minimal evidence of fluid overload or volume depletion and should not have
required recent treatment with an intravenous positive inotropic agent. Patients should be monitored
closely for changes in vital signs and symptoms during this uptitration period. Patients should weigh
themselves daily to mange any increase in weight by Immediately increasing the dose of diuretics
until weight is resorted to pretreatment levels. The clinical responses to the drug are generally delayed
and may require 2 to 3 months to become apparent. If hypotension develops and is associated with
evidence of hypoperfusion or the need for use of Intravenous inotropic drugs, beta-blockers may be
temporarily stopped until the patient's status is stabilized. In such patients, positive inotropic agents
whose effect is mediated independently of the beta-receptor (e.g. a phosphdiesterase inhibitor such as
milrinone) may be preferred. Once stabilized, the beta-blocker should be reintroduced to reduce the
risk of deterioration.
It Is likely that the effect size (degree of mortality reduction) of beta-adrenergic blockade decreases
with increasing severity of heart failure in contrast with the effect size of ACE inhibitors or
aldosterone Inhibition which increases with increasing severity of heart failure. This Is probably
because of the greater dependence of patients with advanced heart failure on beta-adrenergic support
of myocardial function.

Carvedilol
This is a 31, 32 and al receptor blocker with antioxidant effect. Treatment should be initiated at
3.125-6.25 mg twice daily. The dose may be titrated upwards by doubling the dose every 2-4 weeks
with a goal of achieving 25 mg twice daily or for patients weighing more than 85 kg, 50 mg twice
daily.

Metoprolol succinate
This is a pi receptor (selective) blocker. Therapy should be initiated with 12.5-25 mg and the dose
titrated upward by doubling it every 2-4 weeks up to 150 mg/day.

Bisoprolol
This is a pi receptor (selective) blocking agent. Treatment is Initiated with 1.25 mg/day and increased
by doubling the dose every 2-4 weeks up to 10 mg/day.
212

Carvedilol has greater efficacy in treating concomitant hypertension and has been associated with less
insulin resistance and less new-onset diabetes. Metoprolol succinate offers once daily dosing and is
likely associated with less bronchospasm and less hypotensive symptoms.

4. Angiotensin II type -1 (ATI) receptor blockers (ARBs) (Tablel2.7)

These agents provide direct blockade of angiotensin II type-1 (ATI) receptor activation. This action
results in effective blockade of the potentially harmful effects of angiotensin II on tissues. It takes
place regardless of angiotensin II generation by ACE dependent pathway or alternative (e.g. chymase)
pathways. In addition, this effect is achieved without accumulation of bradykinin which is considered
responsible for some adverse reactions associated with the use of ACE inhibitors such as persistent
cough, angioedema and significant hypotension.
Current guidelines recommend ARBs for symptomatic and asymptomatic patients with heart failure
and LVEF <40% who are intolerant to ACE inhibitors for reasons other than hyperkaloemia or renal
insufficiency. The addition of an ARB may be considered in persistently symptomatic patients with
reduced LVEF who are already being treated with conventional therapy (Including ACE inhibitors
and beta blockers). Routine administration of an ARB is not recommended in addition to ACE
inhibitor and beta blocker therapy in patients with acute myocardial Infarction and reduced LVEF.
Routine combined use of ACE inhibitor, ARB and aldosterone receptor blocker is also not
recommended.

5. Aldosterone receptor blockers

ACE inhibitors do not completely inhibit tissue renin-angiotensin system, and after several months of
treatment escape can occur with increase in systemic angiotensin II or aldosterone levels. Additional
inhibition of the renin-angiotensin system was tried with spironolactone. In patients with symptomatic
heart failure and NYHA class III-IV who was receiving ACE inhibitors and loop diuretics treatment
with spironolactone (up to 25-50 mg/d) resulted In a significantly reduced mortality rates from all
causes, sudden death and hospitalization. This may be related to antagonizing the deleterious
cardiovascular effects of aldosterone which include activation of the sympathetic nervous system,
inhibition of parasympathetic flow, injury and fibrosis of myocardial, vascular, renal and cerebral
tissue as well as cardiac and vascular remodeling.
Eplerenone, a selective aldosterone antagonists has much less adverse effects than spironolactone
especially gynaecomastia. In patients with myocardial infarction and LVEF < 40%, eplerenone
reduces all-cause mortality by 15%.
Spironolactone should be initiated at a dose of 12.5 to 25 mg daily and occasionally on alternate days.
Eplerenone is given at doses of 25 mg/day increasing to 50 mg/day. Potassium supplementation is
generally stopped after initiation of aldosterone antagonists and high potassium-containing foods
should be avoided. Non-steroidal anti-inflammatory agents can lead to worsening of renal function
and hyperkaloemia and therefore should not be given.
Current guidelines recommend aldosterone-receptor blockers for patients with heart failure (NYHA
class II-IV) and LVEF <35% and consideration of this therapy in patients post myocardial infarction
with clinical heart failure (or diabetes mellitus) and LVEF <40%. This therapy is not recommended
for patients with serum creatinine >2.5 mg/dl (eGFR <30 ml/min) or serum potassium >5.0 mmol/L
or in those receiving other potassium sparing diuretic.

Table 12.7. Angiotensin II type-1 (ATI) receptor blockers

Drug Dose (mg/d) Method of excretion

Losartan 25-100 Liver
Candesartan 8-32 Liver
Irbesartan 150-300 Liver and renal
Valsartan 80-320 Liver and renal
Telmisartan 40-80 Liver
 213

6. Hydralazine-isosorbide dinitrate
• Nitrates have a greater effect on venous capacitance than on the arterial system because of the
greater production of cyclic guanosine monophosphate in veins than in arteries. Intravenous
administration however may produce significant arteriolar vasodilatation and improve
pulmonary congestion by lowering pulmonary capillary wedge pressure and pulmonary artery
pressure. It also relieves myocardial ischaemia by coronary artery dilatation and improved
collateral flow.
Isosorbide dinitrate produces sustained decrease in left ventricular filling pressure and is the
least likely to produce activation of endogenous neurohormones. However, when used alone,
it produces only modest clinical improvement in severe heart failure and abrupt withdrawal
after long-term oral therapy may be associated a rebound phenomenon. Combined
administration of isosorbide dinitrate (target dose 40 mg tid) and hydralazine (target dose 75
mg tid) to patients with moderately severe heart failure resulted in improvement of left
ventricular ejection fraction and modest but significant reduction of mortality from all causes.
Intravenous nitroglycerin is infused at 5-10 mcg/min and titrated upward to achieve favorable
haemodynamic parameters.

The main problem with sustained use of nitrates (>24 hours) is the development of tolerance
which may be minimized by providing a daily nitrate-free interval of 8-12 hours with the oral
preparations or increasing the dose of IV preparations. Methaemoglobinaemia is a rare
complication of nitroglycerin infusion which manifests with profound cyanosis associated with
normal PO2. If methamoglobin concentration exceeds 15%, it Is treated with methylene blue.
• Hydralazine
This is an effective direct-acting smooth muscle relaxant that dilates arterioles predominantly.
During treatment, the systemic vascular resistance decreases and the cardiac output increases
both at rest and during exercise. However, this beneficial haemodynamic effects do not
always translate into sustained clinical benefits. A better response is obtained in patients with
left ventricular dilatation (end-diastolic dimension > 60 mm by echocardiography). Such
patients rarely develop reflex tachycardia or hypotension, in contrast to patients with smaller
ventricles who can develop clinical deterioration with hydralazine therapy. When used in
combination with isosorbide dintrate, short term increase in cardiac output and decrease in
left ventricular filling pressure occur. Because of the superiority of angiotensin converting
enzyme inhibitors to this combination, hydralazine-isosorbide dinitrate is reserved for
subjects who cannot tolerate angiotensin converting enzyme inhibitors, angiotensin receptor
blockers or who have need for additional afterload reduction. In the African American
population with heart failure, the addition of hydralazine and isosorbide dinitrate to standard
therapy with an ACE inhibitor or a beta blocker has a significant benefit presumably related
to enhanced nitric oxide bioavailability.

7. Digitalis glycosides (Fig. 12.8)

Mechanism of action
Cardiac glycosides act on various tissues by binding to extracytplasmic face of the alpha subunit of
sodium-potassium adenosine triphosphatase (Na+, K+ - ATPase) (the enzymatic equivalent of the
cellular sodium pump) after phosphorylation of aspartate on its cytoplasmic face (such
phosphorylation is inhibited by extracellular K+). Inhibition of Na+, K+- ATPase causes intracellular
Na+ to increase which is then exchanged for extracellular Ca2+ via Na+ - Ca2+ exchanger. The positive
inotropic effect of digitalis glycosides is due to such increase In the availability of cytosolic Ca2+
during systole, thus increasing the velocity and extent of sarcomere shortening. Inhibition of Na+, K+ -
ATPase in vagal afferent fibers acts to sensitize cardiac baroreceptors which in turn reduces
sympathetic outflow from the central nervous system. In addition, by inhibiting Na+, K+ - ATPase in
the kidney, digitalis reduces the renal tubular reabsorption of sodium and the resulting increase in the
delivery of sodium to the distal tubules leads to the suppression of renin secretion from the kidneys.
These observations have led to the hypothesis that digitalis acts In heart failure primarily by
attenuating the activation of neurohormonal system and not as a positive inotropic drug.
214

Digitalis glycosides as well prolong the effective refractory period and decrease the conduction
velocity of the AV node cells by augmentation of vagal tone and decreasing sympathetic activity and
by direct effect in large doses.

Clinical effects
Digitalis glycosides improve myocardial contractility, and increase cardiac output and renal perfusion.
Neurohormonal modulation occurs with decrease in plasma renin and norepinephrine levels and
attenuation of sympathetic derive.
The beneficial effect of digitalis glycosides in patients with heart failure and atrial fibrillation is well
documented. In patients with mild to moderate heart failure (NYHA II-IH) associated with sinus
rhythm, digitalis exerts sustained beneficial haemodynamic effects accompanied by Improvement in
both clinical status and exercise tolerance. In such patients, the trend towards a decrease in deaths due
to progressive failure is balanced by an increase in sudden and other non-pump failure cardiac deaths
with a net neutral effect on mortality. Adding digoxin should be considered in patients with persistent
symptoms of heart failure during therapy with diuretics, an ACE inhibitors (or ARBs) and a beta
blocker. Digoxin may also be added to the initial regimen in patients with severe symptoms who have
not yet responded symptomatically during treatment with diuretics, an ACE inhibitor and beta
blockers. Another strategy is to initiate aldosterone antagonists in this type of symptomatic patient
and delay the addition of digoxin except in patients who do not respond or who cannot tolerate
aldosterone antagonists.

Pharmacokinetics and dosing:

Digoxin is 60-80% absorped (depending on the preparation), 25% protein bound and Is eliminated
primarily by renal mechanisms. The half life for digoxin elimination Is 36-48 hours in patients with
normal or near normal renal function which permits once-daily dosing.

ISOPROTERENOL nnmiK
-40 mV DIGITALIS^ mV
DPI 201-1OS
ins
Ca2*

ALMOKALANT
Vssnarinone
(OPC8212)
IV

-90 mV

Fig. 12.8. Site and mechanism of action of various inotropic drugs.

 215

Digoxin is preferably given intravenously for patients with supraventricular tachycardias and fast
ventricular response. The initial dose is 0.5 mg given slowly over 10-20 minutes. If necessary,
additional dose of 0.125-0.25 IV can be given every 4 hours. Younger patients generally require a
total dose of 1 mg for a foil effect, smaller doses are recommended for the elderly and for patients
with smaller total lean body mass. The initial effect is not seen until after 30 minutes and peak effect
may occur at 2-3 hours.
Orally, digoxin can be given as a loading dose over 24 hour period followed by daily maintenance
doses If a rapid effect is required or preferably as a daily maintenance dose from the start for a slower
effect. The oral loading dose is 0.75-1.25 mg divided into 3-4 equal doses over 24 hours. The oral
daily maintenance dose is 0.0625-0.25 mg/day depending on renal function, lean body mass and other
factors that affect the drug pharmacokinetics (given later). In the absence of loading doses, nearly
steady state blood levels are achieved in 4-5 half lives, or about 1 week after initiation of maintenance
therapy if renal fimction is normal.
The optimal trough serum digoxin level is 0.5-0.8 ng/ml with blood samples taken at least 6-8 hours
following the last digoxin dose. Levels of digoxin >1.0 ng/ml are not associated with a superior
outcome.
Downward adjustment of the loading and maintenance doses is Indicated in patients with renal
insufficiency, hypothyroidism and hypochlorhydria. Hypokaloemia, hypercalcoemia and
hypomagnesoemia lower the threshold for digoxin-induced cardiac arrhythmias. Hyperkaloemia may
exacerbate digoxin-induced conduction disorders.

Digitalis toxicity
Digitalis toxicity tends to emerge at serum concentration >2.0 ng/ml, but substantial overlap exists in
serum levels among patients with and without evidence of Intoxication. The common manifestations
are anorexia, nausea, vomiting, cardiac arrhythmias, malaise, drowziness, headache, altered colour
vision and gynaecomastia. Almost all known cardiac arrhythmias can be caused by digitalis, the most
common are premature ventricular beats, sinus bradycardia, junctional tachycardia, second or third-
degree heart block and paroxysmal atrial tachycardia with block. The concomitant use of
clarithromycin, erythromycin, amiodarone, itraconazole, cyclosporine, verapamil or quinidine can
increase serum digoxin concentrations and may increase the likelihood of digitalis toxicity. A low
lean body mass and impaired renal fimction can elevate serum digoxin levels which may explain the
Increased risk of digitalis toxicity in elderly patients. One study suggests that women may not benefit
from digoxin therapy and may be at increased risk for death. Digoxin should be used with caution or
not used at all in post-MI patients particularly if they have ongoing ischaemia.

Treatment of digitalis toxicity

Drug intake should be stopped and the following measures undertaken:
• Oral potassium administration. This Is often effective for ectopic rhythms even when serum
potassium is normal unless high-grade AV block Is also present.
• Atropine is usually effective for bradycardia and AV conduction disturbances but temporary
ventricular pacing is sometimes necessary.
• Magnesium may be useful in patients with atrial fibrillation and an accessory pathway in whom
digoxin facilitated rapid accessory pathway-mediated ventricular response.
• Lidocaine and phenytoin are useful for worsening ventricular arrhythmias that threaten
haemodynamic compromise.
• Purified Fab fragments from digoxin specific sera are given for life threatening toxicity. Dose of
Fab is calculated using the formula:
Dose of Fab fragments (mg) =
50,000 x 64 x total body digoxin content (mg)
Molecular mass of digoxin (=781)
Where total body digoxin content (mg) equals the amount of digoxin ingested x 0.8 (oral
bioavailability of tablet).
• Electrical cardioversion should be used cautiously because It can precipitate serious arrhythmias in
patients with overt digitalis toxicity.
216

8. Neprilysin inhibitor combined with angiotensin receptor blocker: (sacubitril-valsartan

inhibitor) Neprilysin is a peptide that degrades natriuretic peptides, bradykinin and
adrenomedullin. Neprilysin inhibition increases the level of those substances counteracting
vasoconstriction, sodium retention and LV remodeling. Neprilysin inhibitor combined with
valsartan (in one molecule, not just one pill) reduces two-year mortality by 3% in comparison
with ACEI (relative risk reduction 16%). Hospitalization for heart failure is also reduced by 3%.
The incidence of renal dysfunction and hyperkaloemia is less than with ACEI but symptomatic
hypotension Is more. Even patients with early stage heart failure who are stable on ACEI are
better switched to this therapy. A washout period of 36 hours is recommended between stopping
ACEI and starting sacubitril-valsartan. A prior history of angioedema with ACE inhibitor
contraindicates the use of cabubitril-valsartan but a prior history of cough does not. Neprilysin
inhibitor is the only therapy of heart failure that increases BNP.

9. Ivabradine
This is a selective inhibitor of hyperpolarization-activated cyclic nucleotide-gated funny current
(L) Involved in pacemaking generation. Unlike beta-blockers, ivabradine has no effect on
ventricular contractility. It has been found to reduce the composite endpoint of cardiovascular
death and heart failure hospitalization. It is recommended to reduce heart failure hospitalizations
in patients with symptomatic heart failure and LVEF < 35% who have resting rate > 70 bpm and
are either on maximally tolerated doses of beta-blockers or have a contraindication to beta-
blocker use.

Anti-ischaemic therapy
Most cases of heart failure associated with coronary artery disease are secondary to mechanical
complications from myocardial infarction (e.g. pump failure, mitral regurgitation, septal rupture).
Beta blockers and nitrates are the first line of therapy for patients with heart failure and stable angina.
Other antianginal agents may be added for refractory cases but coronary revascularization (PCI or
CABG) is recommended when angina persists despite treatment with two antianginal agents.

Anticoagulation
Chronic oral anticoagulation is indicated in patients with heart failure associated with atrial
fibrillation, visualized left ventricular thrombus (especially mobile) or with a history of a
thromboembolic event. Anticoagulation should also be considered in patients with underlying
disorders that may be associated with an increased thromboembolic risk (e.g. hypercoagulable states,
LV aneurysms and patent foramen ovale).

Treatment of sleep apnoea

Both central and obstructive sleep apnoea may occur in patients with heart failure. Sleep apnoea
causes nocturnal catecholamine surges, hypertension, arrhythmias and may represent and independent
risk factor for increased mortality in heart failure. Patients suspected of having sleep apnoea should
undergo polysomnography. Central sleep apnoea improves with intensification of heart failure therapy
and nocturnal oxygen administration. Persistent central sleep apnoea should be treated with
continuous positive airway pressure (CPAP). Obstructive sleep apnoea may improve with weight loss
and avoidance of alcohol and sedatives. CPAP is indicated for moderately severe obstructive sleep
apnoea associated with daily somnolence. The role of surgical procedures and mandibular
advancement devices has not been studied In heart failure population.

Iron therapy
Iron deficiency Is treated with intravenous iron. Erythropoietin does not provide any benefit.

Statins
Statins should not be used solely for the purpose of improving outcomes in patients with heart failure.

Device therapy
Implantable cardiac defibrillator (ICD)
 217

Indications
• Survivors of cardiac arrest due to ventricular tachycardia/ventricular fibrillation.
• Sustained ventricular tachycardia.
• Non-sustained but inducible sustained ventricular tachycardia or ventricular fibrillation during
electrophysiological study.
• Primary prevention In post-myocardial infarction patients by at least 40 days who have LVEF <
35%, NYHA class II-III or LVEF <30% and NYHA class I and reasonable expectation of survival
for > 1 year.
• Primary prevention in nonischaemic heart failure patients who have LVEF < 35%, NYHA class II-
III and reasonable expectation for survival > 1 year.
Generally, patients with class IV heart failure without dyssynchrony (see below) are not considered
for ICD therapy because of high nonarrhythmic mortality unless they are ambulatory or awaiting
cardiac transplantation.

Cardiac resynchronization therapy

• About one third of patients with low EF and class HI to IV symptoms of heart failure manifest
QRS duration greater than 120 ms. This electrocardiographic representation of abnormal cardiac
conduction has been used to identify patients with dyssynchronous ventricular contraction. Cardiac
dyssynchrony can take many forms which commonly coexist. These Include atrioventricular (AV),
intraventricular and interventricular dyssynchrony. Delayed activation of papillary muscles leading
to mitral regurgitation is an Important aspect of dyssynchrony. The mechanical consequences of
dyssynchrony include suboptimal ventricular filling, a reduction in left ventricular rate of rise of
ventricular contractile force or pressure (dp/dt), prolonged duration (and hence severity) of mitral
regurgitation and paradoxical septal motion. Ventricular dyssynchrony has also been associated
with increased mortality in heart failure patients. Dyssynchronous contraction can be addressed by
electrically activating the right and left ventricles in a synchronized manner with a biventricular
pacemaker device. This cardiac resynchronization therapy (CRT) may enhance ventricular,
contraction and reduce degree of secondary mitral regurgitation. In addition, the short term use of
CRT is associated with improvement of cardiac function and haemodynamics without an
accompanying Increase in oxygen utilization as well as adaptive changes in the biochemistry of the
failing heart.
• CRT utilizes a three-lead system consisting of a right atrial lead, right ventricular lead and a left
ventricular lead placed via the coronary sinus into a left lateral cardiac vein percutaneously or
directly onto the lateral left ventricular wall via a surgical approach.
• Current indications for CRT include the following groups of patients on guideline directed medical
treatment:
- NYHA class I patients with EF <30%, QRS duration >150 ms, left bundle branch block pattern
and evidence of myocardial Ischaemia.
- NYHA class II, III and ambulatory IV patients with EF <35% and any of the following,
• QRS duration >120 ms, left bundle branch block pattern and in sinus rhythm.
• QRS duration >150 ms, non-left bundle branch block pattern.
• Atrial fibrillation with AV nodal ablation or pharmacological rate control and need for
near 100% ventricular pacing.
• Anticipated ventricular pacing > 40% of time.
- CRT Is not indicated in patients with NYHA class I-II, non-LBBB and QRS duration <150 ms.
• CRT improves symptoms, exercise tolerance, quality of life, left ventricular ejection fraction,
mitral regurgitation and survival. Improvement in systolic function is usually noticed within a
week but LV remodeling takes at least 3 or more months to occur. The use of an ICD in
combination with CRT (CRT/-D) should be based on the indications for ICD therapy.
• In patients with heart failure without a conventional indication for pacing, a single chamber ICD
programmed to pace as rarely as possible is indicated. But in patients with heart failure who have a
conventional indication for ventricular pacing, strong consideration should be given for inserting a
biventricular system even In the absence of intraventricular conduction system delay (remains
speculative pending more clinical trial data).
218

• Using wide QRS as the sole inclusion criterion for dyssynchrony is likely an oversimplification
because mechanical dyssynchrony may be absent in approximately 30% of patients with wide
QRS complex. Mechanical dyssynchrony can be measured by echocardiography, radionuclide
ventriculography or tagged MRI. Interventricular dyssynchrony can be measured by difference in
the aortic and pulmonary pre-ejection times (measured from the beginning of the QRS to aortic or
pulmonary valve opening). A significant difference is 40 msec or more. Intraventricular
dyssynchrony (differences in regional wall motion) can be assessed by tissue Doppler imaging
(TDI) looking at the time to peak systolic contraction and strain rate in different segments of the
left ventricle. However, these criteria are not used for selecting patients for CRT at present.
• Up to 30% of patients receiving CRT are nonresponders. This may be related to ineffective lead
placement, suboptimal AV timing, arrhythmias interfering with biventricular pacing, suboptimal
medical therapy, < 90% biventricular pacing and LV lead noncapture.

Assisted circulation
Mechanical circulatory assist devices Include intra-aortic balloon counterpulsation and ventricular
assist devices.
Intra-aortic balloon counterpulsation (IABP)
This is an intravascular catheter-based device with a balloon volume of 30 to 50 ml. It is generally
positioned within the thoracic aorta distal to the left subclavian artery and proximal to the renal
arteries. The balloon Itself may be inserted percutaneously through direct arterial cannulation from the
femoral artery, the axillary artery or in cases of post-cardiotomy shock, directly through a purse-string
suture in the thoracic aorta.
With appropriate synchronization by arterial blood pressure tracing or electrocardiogram, a set
volume of gas (usually helium) is injected Into the balloon from a bedside console during diastole and
withdrawn during systole. Balloon Inflation thus increases diastolic pressure, thereby augmenting
coronary blood flow and myocardial oxygen supply, deflation reduce the afterload component of
cardiac work during ventricular contraction and thereby decreases myocardial oxygen consumption.
The frequency with which the balloon inflates can be timed to each, every other, or every third
cardiac cycle and balloon support may be adjusted by this method. IABP assistance has only modest
effect on cardiac output, limited naturally by overall myocardial contractility. With severe non-
revascularized coronary disease, IABP relieves ischaemia more through decreased left ventricular
wall stress and decreased myocardial oxygen consumption than through Increased coronary perfusion.

Indications of intra-aortic balloon counterpulsation

• Cardiogenic shock.
• Severe left ventricular dysfunction.
• High risk coronary angioplasty.
• Refractory unstable angina.
• Ischaemic ventricular arrhythmias.
• Bridge to ventricular assist devices and/or cardiac transplantation.
• Weaning from cardiopulmonary bypass.

Contraindications io intra-aortic balloon counterpulsation

• Aortic dissection.
• Aortic aneurysm.
• Severe peripheral vascular disease.
• Moderate to severe aortic insufficiency.
• Aortic or peripheral vascular grafts.

Complications of intra-aortic balloon counterpulsation

• Limb ischaemia.
• Aortic dissection or laceration.
• Insertion site bleeding, Infection or pseudoaneurysm.
• Retroperitoneal haemorrhage.
• Renal Ischaemia from malposition.
 219

• Myocardial ischaemia from inappropriate timing of balloon augmentation.

• Infection (local and systemic).
• Balloon entrapment.
• Balloon rupture and gas embolism.

Ventricular assist devices (VADs) (Fig. 12.9)

Unlike the IABP, VADs function to reduce myocardial work by completely unloading the ventricle
while maintaining its output. They may be employed for right ventricular, left ventricular or
biventricular support; for short term (< 1 week) or longer term support and for permanent use. The
device may be completely extracorporeal, paracorporeal, implantable but with percutaneous power
support or totally implantable and it may provide continuous or pulsatile flow.

Indicationsfor ventricular assist devices:

These include five categories:
• Bridge-to-recovery: for patients with potentially reversible conditions e.g. myocarditis or
postcardiotomy shock. Chronic mechanical unloading may permit reverse remodeling with
downregulation of hypertrophy and collagen production as well as decrease in circulating
inflammatory cytokines. Sufficient recovery from chronic heart failure to allow device removal
has been reported in 15-20% of patients after 1-2 years.
• Bridge-to-bridge: for patients with cardiogenic shock who start with short-term assistance and then
need to be transferred to long-term more durable assist devices.

Fig. 12.9 Components of the left ventricular assist device. The inflow cannula is inserted into the apex of
the left ventricle and the outflow cannula is anastomosed to the ascending aorta. Blood returns from the
lungs to the left side of the heart and exits through the left ventricular apex and across an inflow valve
into the prosthetic pumping chamber. Blood is then actively pumped through an outflow valve into the
ascending aorta. The pumping chamber is placed within the abdominal wall or peritoneal cavity. A
percutaneous drive line carries the electrical cable and air vent to the battery packs (only the pack on the
right side is shown) and electronic controls, which are worn on a shoulder holster or belt, respectively.
220

• Bridge to decision: for patients with insufficient information about their acute illness to make a
decision about transplantation or other advanced therapies e.g. to allow end-organ function to
stabilize and then determine further actions.
- Bridge-to-transplantation for patients who meet criteria for transplantation to improve their overall
candidacy for the procedure.
• Destination (permanent) therapy for patients who are not transplant candidate and need permanent
circulatory support. Occasionally, some of these patients have improvement in conditions that
have precluded them from eligibility for transplantation earlier in their course (e.g. renal failure or
pulmonary hypertension) and are able to be reevaluated for transplantation.
The spectrum of diseases for which VADs is implanted include:
• Cardiac transplantation candidates
• Postcardiotomy shock
• Cardiogenic shock after acute myocardial infarction
• Fulminant myocarditis
• Refractory ventricular arrhythmias
These patients should not be able to maintain haemodynamic stability despite maximal
pharmacological therapy:
The INTERMACS registry (Interagency Registry for Mechanically Assisted Circulatory Support) has
identified seven profiles characterizing patients receiving implantable devices. Profiles 1 (cardiogenic
shock) and 2 (progressive decline of LV function) have poorer 6-month outcomes compared to
patients with other profiles to their higher risk features at the time of implant.
Device selection
• Left ventricular assist device (LVADs) are divided into three categories:
. a) Left atrial to aorta assist device (the Tandem heart). This device pumps blood
extracorporeally from the inflow cannula in the left atrium (via femoral vein and trans-septal
puncture) to the outflow cannula in the femoral artery. It increase cardiac output by 3.5-4
L/min.
b) Left ventricular to aorta assist device (Impella). This device pumps blood from the LV to the
ascending aorta. It unloads the LV, increases cardiac output (maximum flow 2.5 L/min with
impella 2.5, 3-4 L/min with impella CP and 5 l/min with impella 5) and reduces myocardial
oxygen consumption. The approach is via the right femoral artery but the axillary artery may
be used to increase mobility and long-term support.
c) Right sided support is accomplished with two venous cannula and extracorporeal membrane
oxygenation (ECMO), Tandom Heart (from the right atrium to the main pulmonary artery)
and the RP impella device (from the inferior vena cava to the pulmonary artery).
• The first-generation of LVADs were pulsatile flow-pumps (Heart Mate XVE) (fig 12-10), the
second-generation devices are continuous flow pumps with axial flow (Heart Mate II, Jarvik
2000) (Fig 12-11) and the third generation are continuous-flow pumps with centrifugal flow.
Continuous-flow LVADs are smaller than pulsatile LVADs and can accommodate most patients
including small women and children. A head-to-head comparison between continuous flow
devices and pulsatile devices revealed that the former provide better actuarial survival, better
quality of life and functional capacity and less incidence of stroke and reoperation to repair or
replace the device.

Management
• Anticoagulation and antiplatelet therapy are necessary for patients undergoing LVAD placement,
with close monitoring of haemoglobin, platelet, prothrombin time, INR, lactate dehydrogenase
and serum haptoglobin. Device thrombosis, thromboembolism and haemolysis may occur.
Arteriovenous malformation may develop in the gastrointestinal tract and lead to bleeding. Stroke
and bleeding account for more than one fifth of deaths that occur after LVAD surgery.
• Infection accounts for 15% of deaths in patients with LVAD therapy. The transcutaneous drive
line increases the likelihood that bacteria will enter the body and position of mechanical pump
hardware makes it difficult to successfully treat a device infection.
 221

• Suction events may occur where the orifice of the inlet canula abuts the ventricular septum in the
case of a small or underfilled chamber. This blockage of the canula can lead to cessation of pump
flow and/or ventricular arrhythmia. LV myotomy may be needed at the time of implantation.
• Aortic valve replacement or approximation of the aortic valve cusps is necessary at the time of
implantation in patients with moderate or severe aortic insufficiency.
A mechanical aortic prosthesis should be replaced with a bioprosthesis to avoid the risk of
thrombosis in the immobile mechanical valve.
While functional mitral regurgitation is common in patients undergoing LVAD placement, the
unloading that occurs with LVAD therapy acts as an effective treatment by reducing the
ventricular size and by improving the valve geometry.
• The development of right heart failure after LVAD placement may lead to low pump flow and
end-organ hypoperfusion. While it is possible to support the RV mechanically, biventricular
support raises the risk of life-threatening complications and reduces the likelihood for hospital
discharge.
• Hepatic dysfunction represents a marker for preoperative bleeding and poor outcomes.
• Anaemia, thrombocytopenia and coagulopathies are associated with poor outcome following
LVAD therapy. High molecular weight von Willibrand factor multimers have been shown to be
depleted in most patients following LVAD implantation.

Contraindications to ventricular assist devices

• Uncontrolled sepsis
• Aortic valve incompetence
• Severe mitral stenosis
• Pre-existing mechanical prosthetic valves
• Hypercoagulable states
• Aortic aneurysm or dissection
• Bleeding diathesis
• Patent foramen ovale or atrial septal defect
• Recent or evolving cerebrovascular disease
• Multiorgan failure
• Metastatic tumours

Complications of ventricular assist devices

• Perioperative bleeding due to excess fibrinolysis and platelet consumption.
• Malignant arrhythmias due to ischaemia, chamber dilatation and the use of inotropic agents.
• Infection, the most serious being VAD endocarditis.
• Thromboembolic complications.

Surgical therapy
Heart transplantation
Indications
Heart transplantation is generally indicated for end-stage heart disease with estimated short- and
intermediate-term survival significantly lower than that estimated for heart transplantation. Table 12.8
shows the commonest indications for heart transplantation.
Contraindications
Table 12.9 shows the absolute/relative contraindications to heart transplantation. Reversible or
surgically amenable cardiac disease should not be considered for heart transplantation and optimal
medical management should be implemented before transplantation is considered

Criteria for donor selection

• Age <55 years.
• No history of chest trauma or cardiac disease.
• No prolonged hypotension or hypoxoemia.
• Meats haemodynamic criteria.
222

Vent Adapter &

XVE System Vent Filter
Controller

Fig. 12.10 Heart Mate XVE left ventricular assist system.

Fig. 12.11 The second-generation HeartMate II device has an inlet cannula of sintered titanium and a
Dacron outflow cannula shown here with bend relief to reduce kinking and injury at resternotomy (A).
The system provides mobility for the patient [B],
 223

Table. 12.8 Indications of cardiac transplantation

• Cardiogenic shock requiring either continous inotropic support or mechanical support
(IABP or ventricular assist device).
• Persistent symptoms (NYHA III-IV) refractory to maximum medical therapy (including
^synchronization); LVEF <20% and a maximal (RER >1.05) functional metabolic stress
test showing a peak VO2EIO-I2 ml/kg/min or <55 % of age predicted peak VO2.
• Intractable or severe anginal symptoms with no revascularization options.
• Intractable life-threatening arrhythmias unresponsive to medical therapy, catheter-based
intervention, or implantable cardioverter/defibrillator.

Table. 12.9. Contraindications to cardiac transplantation

Absolute contraindications:
• Any systemic illness with a life expectancy <2 y.
• Active or recent solid organ or blood malignancy within 5 y.
• AIDS with frequent opportunistic infections.
• Active systemic lupus erythematosis, sarcoid and amyloid with multisystem involvement.
• Irreversible renal or hepatic failure being considered for only heart transplant.
• Significant obstructive pulmonary disease (FEVi <1).
• Fixed pulmonary hypertension:
- PASP >60 mmHg.
- Mean TPG >15 mmHg.
- Pulmonary vascular resistance >6 Wood units.

Relative contraindications:
• Age >65-70 y.
• Active infection except device related infection In VAD patients.
• Active peptic ulcer disease.
• Severe diabetes with end organ damage (neuropathy, retinopathy).
• Severe peripheral arterial disease not amenable to intervention.
• Morbid obesity (BMI >35 kg/m2) or cachexia (BMI <18 kg/m2).
• Creatinine >2.5 mg/dl, or creatinine clearance <25 mL/min.
• Bilirubin >2.5 mg/dl, serum transaminases >3 * normal, INR >1.5 off warfarin.
• Severe pulmonary dysfunction with FEVj <40% of normal.
• Recent pulmonary Infarction within 6-8 weeks.
• Difficult to control hypertension.
• Irreversible neurologic or neuromuscular disorder.
• Active mental illness or psychological instability.
• Drug, tobacco or alcohol abuse within 6 months.
• Heparin-induced thrombocytopenia within 100 days.

- mean arterial pressure > 60 mmHg

- central venous pressure 8-12 mmHg
- inotropic support (dopamine or dobutamine) <10 mcg/kg/min.
• Normal ECG, echocardiogram and cardiac angiography.
• Negative HBsAg, HCV and HIV serologies.

Several basic tests are required for recipient evaluation (table 12.10). Once inclusion and exclusion
criteria are met, the patient will be listed for transplantation.
224

Donor and recipient matching

Donor / recipient matching parameters for heart transplantation include the following:
• ABO compatibility (incompatibility may lead to hyperacute rejection).
8 Height and weight differences within 30%.
• For recipients with a high level of presensitization to HLA (often due to prior transfusion or
pregnancies), detected by elevated panel reactive antibody (PRA) titre, a negative cross match with
donor lymphocytes is necessary (positive cross match indicates a likelihood of hyperacute
rejection).

Determination of priority:
Patients who qualify for cardiac transplantation get a priority based on the severity of illness:
• Status 1A (highest priority): defined as patients limited to ICU who are dependent on
mechanical circulatory support devices or high-dose IV inotropes plus Swan-Ganz catheter.
• Status IB: includes patients on continuous IV inotropes or had ventricular assist device after
30 days status 1A time has expired.
• Status 2: includes patients who do not meet criteria of status 1A or IB.
• Status 7: includes patients who are temporarily unsuitable to receive a transplant.

Heart transplant surgery (Fig. 12.12)

There are three basic implantation techniques:
• The bi-atrial orthotopic technique
• The bi-caval orthotopic technique
• Heterotopic technique (rarely)

Key to success of transplant Is the donor ischaemic time, defined as the time from aortic cross-
clamping in the donor to release of aortic cross-clamp in the recipient. An acceptable ischaemic time
is considered to be less than 4 hours.
Concern about loss of normal atrial anatomy using the bi-atrial technique has led to more frequent use
of the bi-caval technique. The latter technique may result in longer donor heart ischaemic time, but is
associated with lower right atrial pressure, lower incidence of atrial tachyarrhythmias and less
tricuspid regurgitation.
Heterotopic heart transplantation is performed with the donor heart placed in the right chest In parallel
to the recipient heart which is left in place. The indications for heteretopic heart transplantation
include significant pulmonary hypertension, a smaller donor heart and a donor heart with poor initial
function. This technique accounts only for 0.3% of all heart transplants.

Cardiac allograft rejection

There are three types of rejection:
• Acute cellular rejection which Is the most common form of rejection and occurs at least once in
approximately 35% of heart transplant recipients. Even though the propensity toward allograft
rejection decreases over time and nearly half of the rejection episodes occur in the first 2-3
months, late rejection can and does occur. Acute cellular rejection is primarily a T-lymphocyte-
mediated process. It may occur from the first week after transplantation up to many years out. A
histological grading system was developed based on the amount of inflammatory infiltrate and the
presence or absence of myocyte necrosis (table 12.11). Rejection is considered significant when
the biopsy is graded at least 2R or If there is any evidence of haemodynamic compromise
regardless of grade.
• Antibody mediated rejection (AMR) which manifests by otherwise unexplained cardiac allograft
dysfunction without significant cellular infiltrate. AMR Is classified into either absent (0) or
present (1). The criteria for AMR are:
- Histological evidence of myocardial capillary injury with endothelial swelling and
intravascular macrophage accumulation.
- Positive immunofluorescence or positive immunoperoxidase staining for AMR (+ CD68,
C4d).
 225

Table 12.10. Recommended evaluation prior to transplantation

Complete history and physical examination

Laboratory investigations:
• Complete blood count (CBC) with differential, complete metabolic panel
• Thyroid function studies (thyroid stimulating hormone, TSH)
• Liver function panel, creatinine clearance
• Lipid profile, haemoglobin Al C, urinalysis

Immunologic data:
• Blood type and antibody screen
• Human leukocyte antigen (HLA) typing
• Panel of reactive antibodies (PRAs) screen

Serology for infectious diseases:

• Hepatitis HBsAg, HBsAb, HepCAb
• Herpes group virus
• Human immunodeficiency virus
• Cytomegalovirus (CMV) IgG antibody
• Toxoplasmosis
• Varicella and rubella titres
• Ebstein-Barr virus IgG and IgM antibodies
• Venereal Disease Research Laboratory (VDRL) or Rapid Plasma Reagin (RPR)

Cardiovascular investigations:
• Electrocardiogram (ECG), chest X-ray, echocardiogram
• Exercise test with oxygen consumption
• Right- and left-heart catheterization
• Myocardial biopsy (if indicated, for example to rule out infiltrative process such as
amyloidosis)

Vascular assessment:
• Carotid Doppler
• Peripheral vascular assessment (ankle-brachial index and/or duplex ultrasound)
• Abdominal ultrasound
• Ophthalmology examination (if indicated, for example to rule out diabetic
retinopathy)

Cancer screening:
• Prostate-specific antigen (PSA) (in men, if indicated)
• Papanicolau smear (PAP smear), mammography (in women, if indicated)
• Colonoscopy (if indicated)
Psychosocial evaluation:
• Support system
• Substance abuse history (alcohol, tobacco and drug use)
• Psychiatric history
Baseline investigations:
• Dental examination
• Bone density scan
• Pulmonary function tests
226

Rejection surveillance
• Endomyocardial biopsy remains the “gold standard” for the diagnosis of acute rejection after
cardiac transplantation. Recently, molecular gene expression testing in peripheral blood has been
utilized to detect acute rejection. The test has a high negative predictive value (95%) but low
sensitivity.
• Rejection is the leading cause of death in the first year after heart transplantation and accounts for
about 20% of all deaths. Generally, routine endomyocardial biopsy is performed weekly for the
first month, then every 2 weeks during the second month and then the interval is increased
through months 8-12. After one year, biopsies are obtained every 4-6 months. Following a treated
rejection episode, endomyocardial biopsy is repeated within 2 weeks to assure adequate
treatment.

Immunosuppression
• Immunosuppression is required to prevent rejection and is generally required for life (tablel2.12).
• Early rejection prophylaxis generally involves the use of triple therapy which consists of
- A calcineurin inhibitor: cyclosporine or tacrolimus. Calcineurin is a phosphatase enzyme that
triggers transcription of new messenger RNA after activation of T-call receptor by an
appropriate antigen leading to increased gene expression of interleukin-2 and other important
cytokines. Calcineurin Inhibitors anatagonize this phosphatase actively, thereby preventing
synthesis of these cytokines which prevents B- and T-cell proliferation.
- Mycophenolate mofetil, azathioprine (both inhibit DNA synthesis) or sirolimus (Inhibits the
target of rapamycin enzyme thus blocking the cellular response to cytokines).
- Corticosteroids. These drugs bind to the nuclear receptors thereby preventing gene expression
of various cytokines important for B- and T-cell activation and proliferation. Additionally,
steroids have anti-inflammatory properties and suppress macrophage activity.
• Drug level monitoring is important to ensure adequacy of immunosuppression and avoid untoward
adverse events. Because the propensity for rejection decreases over time, dosages of all these
drugs generally decrease accordingly. Steroids can be withdrawn in many patients who
demonstrate a low propensity to reject or if they experience steroid-related adverse effects.
• Induction therapy at time of transplant with antithymocyte globulin (induce complement-mediated
lymphocytolysis) or interleukin-2 receptor antagonist (basiliximab, dactizumab) is chosen by
some centres. However, the advantage of this approach remains controversial.

Other postoperative complications

In addition to various forms of rejection, potential long term complications may emerge, mostly
related to chronic immunosuppression.
• Infections
The types of infection in recipients vary depending on the time from transplant because of the
variable intensity of immunosuppression over time. Bacteria account for more than 80% of
Infections and are mostly nosocomial due to infected catheters and lines and gram negative
pneumonias. Most viral infections are caused by the herpes viruses: cytomegalovirus, herpes
zoster and herpes simplex. Table 12.13 shows the prophylactic regimens to be used during the
first post-transplant year.

Table. 12.11. Pathological grading of acute cellular rejection (ACR)

____________________________ Grade OR-No ACR____________________________

Grade 1R- Mild, low grade, ACR: Interstitial and/or perivascular infiltrate with up to one
focus of myocyte damage.
Grade 2R- Moderate, intermediate grade,ACR: two or more foci of infiltrate with
associated myocyte damage.
Grade 3R- Severe, high grade, ACR: diffuse infiltrate with multifocal myocyte damage
±oedema ± haemorrhage i vasculitis.
 227

Fig. 12.12. Surgical techniques for cardiac transplantation. A, Standard lower-Shumway (biatrial)
orthotopic heart transplantation. B, Bicaval technique of orthotopic heart transplntation. C, Heterotopic
heart transplnatation.
228

Table 12.12. Immunosuppressive agents

Agent Mechanism of Administration Toxicity Drug

action interactions

Cyclosporine Binds to PO or IV Renal effects, Metabolism

cyclophilin, Oral to IV dose is hypertension, decreased by
inhibits 3:1 gingival hyperplasia, ketoconazoles,
calcineurin- Oral dosage 3-5 hirsutism, tremor, diltiazem,
dependent mg/kg/d adjusted to headache, verapamil,
transcription and level paraesthesias, erythromycin,
translation of flushing cimetedine,
cytokine genes, grapefruit;
particularly IL-2 metabolism
increased by
phenytoin,
Phenobarbital,
isoniazid,
rifampicin,
carbamazepine

Tacrolimus Binds to FK- PO or IV Renal effects, Similar to

binding protein, Oral to IV dose is hypertension, tremor, cyclosporine
inhibits 5:1 headache, flushing,
calcineurin- Oral dosage 0.05- paraesthesias, glucose
dependent 0.15 mg/kg/d intolerance
transcription and targeted to level
translation of
cytokine genes,
particularly IL-2

Azathioprine Inhibits purine PO or IV Macrocytic anaemia, Allopurinol

biosynthesis, No significant oral leucopenia, slows
decreasing to IV adjustment pancreatitis, metabolism by
synthesis of DNA 1-2 mg/kg/d, white cholestatic jaundice, inhibiting
and RNA cell count to remain hepatitis xanthine
> 4000/mm3 oxidases

Mycophenolate Inhibits inosine PO or IV Gastrointestinal No significant

mofetil monophosphate No significant oral distress, leucopenia interactions
dehydrogenase, to IV adjustment
inhibiting the de 2000-6000 mg/d
novo pathway for
guanine nucleotide
biosynthesis

Sirolimus Binds to FK- PO 1-2 mg/d Hypertriglyceridemia, Metabolism

binding protein, thrombocytopenia, decreased by
inhibits IL-2- and leucopenia, serositis, diltiazem and
IL-6-driven events peripheral oedema, ketoconazole;
delayed wound metabolism
healing increased by
rifampicin

Corticosteroids Lymphocytolysis, PO or IV with Cushingoid habitus, Multiple drug

inhibits release and methylprednisolone glucose intolerance, interactions,
action of various Maintenance dose hyperlipidemia, none clinically
interleukins, with prednisone is cataracts, myopathy, significant
interferes with 0.0-0.1 mg/kg/d osteoporosis
antigen-receptor
interactions
 229

Table 12,13. Infection prophylaxis after cardiac transplantation

Organism Criteria

Cytomegalovirus (recipient or Valgancyclovir 450-900 mg PO dally for 4 weeks then

donor seropositive) acyclovir 800 mg PO daily until 2-3 months post-transplant;
monitor for cytomegalovirus antigenemia

Cytomegalovirus (recipient or No specific prophylaxis

donor seronegative)

Herpes simplex Acyclovir 200 mg PO QID until prednisolone dosage < 20

mg/d

Epstein-Barr virus (recipient Acyclovir 800 mg PO QID for 12 months, then 200 mg PO
seronegative and donor QID
seropositive)

Toxoplasma Gondii (donor or Pyrimethamine 25 mg PO QD for 6 weeks and leucovorin

recipient seropositive) calcium 5-10 mg PO QD for 6 weeks

Pneumocystis Jerovicii Trimethoprim maleate/sulfamethoxazole 160 mg/800 mg PO

3-7 times per week or dapsone 75-100 mg PO QD if sulfa
allergic

Candida albicans Nystatin 10 ml swish and swallow QID or clotrimazole

troche PO QID until prednisolone dosage < 20 mg/d

• Hypertension
This reflects the interplay of several pathogenic mechanisms including pre-existing hypertension,
altered vascular reactivity and sympathetic neuroactivation and drug effects. It occurs In 70-90%
of cyclosporine-treated and 30-50% of tacrolimus treated patients.
Combination therapy with both an ACE inhibitor and a calcium channel blocker is commonly
employed for treatment. Diltiazem has the advantage of increasing cyclosporine level by
competing with cytochrome P450, thereby decreasing the required cyclosporine dose.

• Diabetes mellitus
Nearly 20% of transplant patients have diabetes mellitus at the time of transplant and another 10-
15% develops diabetes within the subsequent 5 years. The incidence appears higher in recipients
receiving tacrolimus and higher doses of steroids.

• Chronic renal dysfunction

Calcineurin inhibitors (cyclosporine and tacrolimus) produce a nephropathy characterized by
decreased glomerular filtration rate, afferent arteriopathy and tubulointerstitial fibrosis. This is
partly attributed to increased systemic vascular resistance induced by effects on smooth muscle
and increased sympathetic activity. Initiation of cyclosporine or tacrolimus should be delayed
postoperatively in patients at high risk of nephrotoxicity and induction therapy Is used instead.

• Osteoporosis
Glucocorticoids and calcineurin inhibitors are associated with rapid bone loss and high fracture
rates. Patients at high risk should be treated (even prior to transplantation) by calcium carbonate,
vitamin D and bisphosphonates.
230

• Hyperlipidaemia
This occurs in 60-80% of recipients due to pre-existing lipid abnormalities, cyclosporine and
corticosteroids. Approximately 1 month after heart transplantation, recipients frequently
demonstrate an increase in total cholesterol, low density lipoprotein (LDL) cholesterol,
apolipoprotein B and triglyceride levels. All heart transplant patients should receive a statin
independent of lipid levels to improve survival. Gemfibrozil is used to treat
hypertriglyceridoemia. The combination of cyclosporine and a statin increases the risk of
rhabdomyolysis and should in general be avoided.

« Gout
Gouty arthritis occurs in 8-17% of patients following heart transplantation, particularly among
cyclosporine-treated patients. It is usually polyarticular and progressive.
Colchicine is effective in treating gouty episodes and providing prophylaxis against recurrent
episodes. However, recipients treated with cyclosporine may be at increased risk of acute
colchicine-induced mononeuropathy especially in the setting of concurrent renal insufficiency.
Corticosteroids may be the safest approach in the management of gout in patients with renal
dysfunction. Allopurinal blocks the xanthine oxidase pathway by which azathioprine is
metabolized resulting in potentially toxic levels of the latter drug which should be substituted
with mycophenolate mofetil.

• Coronary vasculopathy
This Is a major cause of morbidity and mortality following heart transplantation. Angiographic
evidence of transplant vasculopathy is seen in 50-60% of recipients by 10 years. IVUS detects an
abnormal coronary Intimal thickness In 50% of patients as early as 1 year after transplantation.
. The condition is most likely related to immune and ischaemic endothelial injury In the setting of
hyperlipidoemia. Risk factors include increasing donor age, coronary artery disease prior to
transplant, diabetes mellitus, hypertension, hyperlipidoemia, frequency and type of rejection,
cytomegalovirus infection and the degree of HLA matching.
Coronary vasculopathy Involves the entire length of the arterial vasculature and occasionally the
veins. Histologically, it is characterized by concentric intimal thickening comprising proliferative
smooth muscle cells and extracellular matrix. The media and adventitia are relatively unaffected.
Clinical presentation includes acute myocardial infarction, arrhythmias, new wall motion
abnormalities and sudden death. Since the allograft Is functionally denervated for years after
transplant, angina is rare. Later, typical angina may occur due to regional reinnervation.
Most coronary allograft vasculopathy is diagnosed by routinely scheduled yearly angiography.
Dobutamine stress echocardiography has a better predictive accuracy than nuclear perfusion in
evaluating these patients.
The mainstay of therapy of coronary vasculopathy is prevention and modification of coronary risk
factors including weight loss, lipid reduction and controlling hypertension and diabetes. PCI may
provide only short-term palliation for discrete lesions (high restenosis rate) and CABG is limited
by involvement of distal vessels. Retransplantation is an option but the risk is higher than at the
first transplant.

• Malignancy
Malignancy Is Identified in 3-18% of recipients with a yearly risk of 1-2%. It ranks second to
coronary vasculopathy as a major cause of mortality accounting for 10-23% of all deaths
following heart transplantation. Cutaneous malignancy Is the most common type with
predominance of squamous cell carcinoma. Post-transplant lymphoproliferative disorder is a
frequent fatal complication occurring in 1.7-6% of cardiac transplant recipients with peaking
occurrence at 12-18 months after transplantation. A strong association with Epstein-Barr virus
has been observed. The initial management of such lymphoproliferative disorder is usually
involves reduction in immunosuppression. Nonresponders may require aggressive combination
chemotherapy but mortality is approximately 80%.

Tricuspid regurgitation
 231

Mild tricuspid regurgitation is present in virtually all transplanted hearts. Moderate-severe

tricuspid regurgitation is present in up to 50% of transplant patients at 5 years post transplant.
Responsible factors include mechanical traction on tricuspid annulus (particularly with biatrial
anastmosis), preexisting pulmonary hypertension and repeated endomyocardial biopsy which may
damage the tricuspid apparatus. Generally the condition (even if severe) is well tolerated but
tricuspid replacement may be needed in <3% of all heart transplants.
Long-term outcome
The current survival rate after heart transplantation is approximately 90% at 1 year and 50% at 12
years.
Re-transplantation
Graft failure is the primary cause of death during the first 30 days posttransplantation. After the first
month and up to one year, non CMV infections account for almost 35% of deaths. After 5 years
coronary vasculopathy and graft failure combined account for 30% of deaths, while malignancies
account for 24% and non-CMV infections for 10%. Cardiac retransplantation remains a viable
therapeutic strategy for select patients with severe coronary artery disease as the cause of allograft
dysfunction.

Heart-lung transplantation
• The most common indications for heart-lung transplantation are pulmonary hypertension
secondary to congenital heart disease, primary pulmonary hypertension and cystic fibrosis.
• The bicaval technique is most often used with the pulmonary hila positioned anterior to phrenic
nerve pedicle.
• Survival rates at 1, 5 and 10 years are 61,40 and 25% respectively.

Myocardial revascularization
Heart failure associated with myocardial ischaemia may be improved by myocardial
revascularization. Patients with multivessel coronary artery disease and evidence of abnormal left
ventricular function have improved clinical outcome after myocardial revascularization. The potential
for improvement is great enough to recommend revascularization when the total hibernating
(ischaemic but viable) myocardium is higher than four segments of the left ventricle. However,
evidence of myocardial viability with single photon emission computed tomography or dobutamine
echocardiography in patients with EF < 35% did not identify patients more likely to benefit from
CABG.

Ventricular aneurysmectomy
Left ventricular aneurysmectomy and myocardial revascularization should be considered for patients
with ventricular aneurysm presenting with refractory heart failure. It usually improves the symptoms
of heart failure and can possibly improve survival.

Mitral valve surgery

Medical therapy including cardiac resynchronization therapy has a primary role in the treatment of
secondary mitral regurgitation, surgical mitral valve repair has not been consistently shown to
improve survival over medical therapy or revascularization of coronary artery disease alone. As a
result current guidelines suggest that mitral valve repair may be considered for patients with chronic
severe LV dysfunction (EF < 30%) who have persistent NYHA class III-IV symptoms despite optimal
therapy for heart failure including biventricular pacing. The Mitraclip is considered for patients with
severe symptoms despite optimal medical therapy and who are considered inoperable because of
comorbidities. The role of mitral valve replacement is still under evaluation but generally repair is
associated with lower preoperative mortality and morbidity but a higher rate of recurrent mitral
regurgitation then replacement.

Left ventricular reconstructive procedures

The original procedure known as the Batista operation involved the resection of a piece of
myocardium at the posterolateral wall between the anterolateral and posteromedial papillary muscles
232

in non-ischaemic cardiomyopathy with or without mitral annuloplasty or mitral valve replacement.

The initial enthusiasm for such procedure quickly waned because of the poor intermediate results.
A more recent remodeling procedure is called endoventricular circular patch plasty (EVCPP) or Dor
procedure. It is suitable for patients with a left anterior descending artery territory scar or aneurysm
with relatively preserved lateral and posterior left ventricular wall fimction. It involves opening of the
akinetic or dyskinetic scar and placing a purse-string suture at the boundaries of the scar or aneurysm
and tightening it down. The residual opening may be closed with a Dacron patch, after which the
ventriculotomy is closed by running sutures. This procedure is accompanied by coronary bypass
grafting in more than 90% of cases. Additional valve and ablative surgical procedures are commonly
performed. While surgical ventricular reconstruction leads to reduced LV volume, It does not improve
symptoms, exercise tolerance, hospitalization or mortality.

Treatment of acute cardiogenic pulmonary oedema

• Oxygen is given to maintain PO2 above 60 mmHg. Oxygen may be given through nasal prongs,
Venturi mask or reservoir bag. Noninvasive ventilation by either continuous positive airway
pressure (CPAP) ventilation or bilevel positive airway pressure may become necessary. Failing
these interventions, intubation and mechanical ventilation may be needed to improve oxygenation
and hypercapnoea.
• Patients are placed In the sitting position to Improve lung function. It is often helpful to seat the
patient at the side of the bed or in chair to lower the feet and thereby diminish further the venous
return.
• Sublingual nitroglycerin 0.3-0.6 mg is given and may be repeated twice every 5 minutes to
decrease preload. In severe conditions TV nitroglycerin infusion can be started at a rate of 5
pg/minute and increased by 5-10 pg/minute every 3-5 minutes to a maximum dose of 300
pg/minute If tolerated. The dose of nitroglycerin should not be increased when the systolic arterial
pressure is < 90 mmHg. Caution should be taken when administering nitrates in patients with
aortic stenosis or hypertrophic obstructive cardiomyopathy.
• If further reduction of afterload is required e.g. In conditions for severe hypertension, sodium
nitroprusside should be substituted or added to IV nitroglycerin. Start at 0.3 pg/kg/minute and
titrate up to 10 pg/kg/minute as needed. Nitroprusside is most beneficial for hypertensive patients
or patients with an elevated filling pressure > 20 mmHg and a systemic arterial pressure of > 100
mmHg. Nesiritide (recombinant human BNP) may be considered when the patient does not
respond rapidly to conventional measures. It Is given as an IV bolus of 2 pg/kg followed by a
continuous infusion of 0.01 pg/kg/min.
• Intravenous frusemide 40-80 mg should be administered early in the clinical course of the
condition and repeated in 30 minutes if dyspnoea persists and blood pressure is stable. In acute
heart failure, intravascular volume is often normal or low and therefore overdiuresis should be
avoided as it may result in severe hypotension. Improvement of dyspnoea usually occurs within 10
minutes of frusemide administration as a result of its venodilator action. Failure to respond to the
second dose of diuretics Is an indication for preload and afterload reducing agents. High bolus
doses (> 1 mg/kg) of diuretics may lead to reflex vasoconstriction and increased LV afterload. In
patients with severe renal dysfunction and refractory fluid retention, continuous venovenous
ultrafiltration may become necessary. The typical volume of water removed per ultrafiltration
session is 3000-4000 ml.
• Morphine sulfate. It may have an immediate haemodynamic effect through its preload reducing
properties and because it alleviates anxiety and blunts the catecholamine response to the acute
illness. It is given as 3-5 mg IV over 3 minutes and may be repeated 2-3 times at 15 minutes
intervals. Caution must be used, however in patients with evidence of respiratory or metabolic
acidosis and in those with significant obstructive lung disease. Morphine should be avoided if the
pulmonary oedema Is associated with hypotension, intracranial bleeding, disturbed consciousness,
bronchial asthma, chronic pulmonary disease or reduced ventilation. The use of morphine may be
associated with an increase in adverse events including intubation. Naloxone 0.4 mg IV repeated at
4-minute intervals is given if respiratory depression occurs (maximum 1.2 mg).
• If hypotension develops, dobutamine 2-15 pg/kg/minute should be tried. For severe hypotension
dopamine 2.5-10 pg/kg/minute Is given.
 233

• If bronchospasm and diaphragmatic fatigue are prominent feature, aminophylline may be

administered. It is given as a loading dose of 2-5 mg/kg slowly over 20 minutes followed by a
maintenance continuous infusion of 0.3-0.6 mg/kg/hour. Smaller doses must be used in the elderly
and those using concomitant drugs that raise theophylline blood level.
• The cardiac rhythm should be determined immediately because supravnetricular or ventricular
tacharrhythmias may be the precipitating factor. These should be electrically cardioverted. If
electrical cardioversion cannot be utilized, IV digoxin is given for supravnetricular arrhythmias
and IV amiodarone for ventricular tachycardia.
• Intra-aortic balloon pump and ventricular assist devices may be valuable in patients with refractory
heart failure or refractory ischaemia.

Table 12.14 shows the differences between cardiogenic and noncardiogenic pulmonary oedema. The
distinction between these two conditions can usually be made by clinical data. A normal
echo/Doppler assessment of LV systolic and diastolic functions strongly points toward a
noncardiogenic cause of pulmonary oedema. If uncertainty persists, it is reasonable to obtain
haemodynamic information via a pulmonary artery balloon floatation catheter.

Prognosis
The overall 5-year mortality for all patients with heart failure is approximately 50%, and the 1-year
mortality in patients with severe heart failure may be as high as 35-40% (worse than most
malignancies). Survival in patients with diastolic heart failure is as poor as or slightly better than
those with systolic heart failure. Over 90% of deaths in patients with heart failure are due to
cardiovascular causes, most commonly progressive pump failure and sudden cardiac death (almost
half of all deaths) presumably due to arrhythmias. The factors that correlate with mortality in patients
with heart failure fall into 4 major categories:

Table 12.14. Differentiation of noncardiogenic from cardiogenic pulmonary oedema based on

clinical data
Noncardiogenic Cardiogenic

History Underlying disease (e.g. Acute cardiac event (e.g.

pancreatitis, sepsis) myocardial infarction)

Physical Warm periphery Cool, mottled periphery

examination Bounding pulses Small-volume pulse
Normal-sized heart Cardiomegaly
Normal JVP Elevated JVP
No S3 S3
No murmurs Systolic and diastolic murmurs

ECG ECG usually normal ST segment and QRS

abnormalities

Chest X-ray film Pulmonary Infiltrates Perihilar infiltrates

Laboratory test Normal enzymes Elevated biomarkers

BNP <100 mg/ml

Ventilatory needs Higher FiO2 and PEEP to Lower FiQ2 and PEEP to
oxygenate oxygenate

BNP, brain natriuretic peptide; FiO2, inspired oxygen concentration; JVP, jugular venous pressure; PEEP,
positive end-expiratory pressure
234

• Clinical: including age, underlying coronary artery disease, high NYHA class, reduced exercise
capacity and reduced peak O2 consumption during a progressive exercise testing. Frailty is an
independent predictor of mortality. Several scores have been developed to quantify the degree of
frailty, most of them incorporate both subjective (e.g. questionnaire) and objective (e.g. handgrip
strength, gait speed) measures.
• Haemodynamic: including reduced cardiac index, left ventricular dilatation and reduced left and
right ventricular ejection fractions.
• Biochemical/haematological: including anaemia, evidence of renal insufficiency, elevated levels of
plasma norepinephrine, renin, brain natriuretic peptide, endothelin-1 and interleukin-6 as well as
hyponatraemia.
• Electrophysiological: including frequent ventricular premature beats, ventricular tachycardia, left
bundle branch block and atrial fibrillation. However, such arrhythmias may be just indicators of
the severity of left ventricular dysfunction.
 235

ACUTE HEART FAILURE

Definition
Acute heart failure (AHF) is defined as the rapid onset of symptoms and signs secondary to abnormal
cardiac function that requires urgent therapy. It may occur with or without previous cardiac disease.
Cardiac dysfunction can be related to systolic or diastolic dysfunction, to abnormalities of cardiac
rhythm or to preload and afterload mismatch.

Causes
• Decompensation of pre-existing chronic heart failure.
• Acute coronary syndromes.
• Hypertensive crisis.
• Acute arrhythmias.
• Valvular disorders (severe aortic stenosis or valvular regurgitation).
• Severe myocarditis or cardiomyopathy.
° Cardiac tamponade.
• Aortic dissection.
• High output syndromes (septicaemia, thyrotoxicosis, anaemia, shunt syndromes).

Classification
Patients with AHF may present with six distinct clinical conditions.
• Acute decompensated heart failure or decompensation of chronic heart failure. Patients typically
present with mild to moderate symptoms and signs of congestion and do not meet criteria for other
categories.
• Hypertensive acute heart failure. Patients present with symptoms and signs of heart failure
accompanied by high blood pressure, relatively preserved LV systolic function and X-ray features
of pulmonary congestion.
9 Pulmonary oedema. Patients present with severe respiratory distress, crackles over the lungs,
arterial oxygen saturation < 90% on room air and X-ray evidence of pulmonary oedema.
• Cardiogenic shock. Patients present with reduced blood pressure (systolic < 90 mmHg or drop of
mean blood pressure by > 30 mmHg), pulse rate > 90 bpm, evidence of tissue hypoperfusion after
correction of filling pressures and urine output < 0.5 ml/kg/hr.
• High output failure. Patients present with elevated heart rate, warm extremities, pulmonary
congestion and underlying conditions such as thyrotoxicosis, anaemia and arrhythmias.
• Right-sided heart failure. Patients present with increased jugular venous pressure, tender
hepatomegaly and hypotension.

Table 12.15 shows the common clinical and haemodynamic features of various categories of acute
heart failure.

Haemodynamic profiles
Patients with advanced or acute heart failure can be assigned to one quadrant of a 2 X 2 table defined
by the presence or absence of evidence of congestion (wet or dry) and low perfusion (cold or warm).
Manifestations of congestion and low perfusion are shown In figure 12.14. Such a classification
assists in selecting initial therapy and providing prognostic information. When patients with suspected
AHF present with profile A (warm and dry), their symptoms are often due to conditions other than
heart failure (e.g. pulmonary or hepatic disease or transient myocardial Ischaemia).
More commonly, patients with AHF present with profile B (warm and wet) which includes most
patients with acute pulmonary oedema due to elevation of left ventricular filling pressure.
Less commonly, patients with AHF present with profile C (cold and wet) due to reduction of cardiac
output and elevated filling pressure. The therapeutic goal in AHF should be to restore patients to a
normal haemodynamic profile (profile A). Patients with profile A have a 6 month mortality of 11%
compared to 40% for profile C.
236

Table 12.5. Classification and common features of various categories of acute heart failure

Symptom Signs and

Clinical Classification Onset Symptoms Hemodynamics Other Diagnostics

I Acute decompensated Usually gradual Peripheral SBP: Low normal/high CXR: Normal or
congestive heart failure edema (often CI: Low normal/high mild interstitial
significant), PCWP: Mildly increased edema, possible
dyspnoea, pleural effusion
usually well-
perfused
extremities

II Acute heart failure with Often very Dyspnea, altered SBP: High (>180/100 mm CXR: Normal or
hypertension/hypertensiv gradual mental status, Hg) interstitial edema
e crisis possible CI: Usually normal
oliguria/anuria PCWP: >18 mm Hg

HI Acute heart failure Rapid or Severe dyspnea, SBP: Low normal SaO2: <90%
with pulmonary edema gradual tachypnea, CXR: Alveolar
tachycardia edema

IVa Cardiogenic Usually gradual Evidence SBP: Low normal

shock/low output of CI: Low, <2.2 liters/min/m2
syndrome hypoperfu PCWP: >16 mmHg
sion;
oliguria

IVb Severe cardiogenic Often rapid Marked SBP: <90 mm Hg Usually in

shock hypoperfusion; CI: Very low, < 1.8 presence of severe
oliguria/anuria L/min/m2 LV systolic
PCWP: >18 mmHg dysfunction

V High output failure Rapid or Well-perfused SBP: Variable

gradual extremities; CI: Increased
often PCWP: Normal or
tachycardic increased

VI Right-sided acute Rapid or Edema, SBP: Low CXR: often clear

heart failure gradual markedly CI: Low lung fields with
elevated PCWP: Low evidence of
neck veins, pulmonary
often poor hypertension; BNP
perfusion, may be elevated in
but clear pulmonary
lungs embolus

BNP = B-type natriuretic peptide; CI = cardiac index; CXR = chest x-ray; PCWP = pulmonary capillary wedge
pressure; SBP = systolic blood pressure.
 237

Pathophysiology
AHF shares many of the basic pathophysiological aspects of chronic heart failure. However, there are
specific features relevant to AHF including those related to cardiac dysfunction, vascular dysfunction
and renal dysfunction.
Cardiac dysfunction
• Systolic dysfunction occurs in approximately one-half of patients with AHF. This may be a
permanent or transient feature. Pre-existing permanent systolic dysfunction may be aggravated by
additional transient myocardial depression (e.g. ischaemia or increased loading conditions).
• Approximately one-half of patients with AHF have preserved systolic function but impaired LV
diastolic properties which make these patients sensitive to changes in preload and afterload.
• Myocardial ischaemia, arrhythmias and other factors can exacerbate both systolic and diastolic
dysfunction and readily precipitate AHF.
• The right ventricle is readily susceptible to AHF with relatively modest increase in afterload (e.g.
in pulmonary embolism) and in the presence of ischaemia and infarction. RV dilatation inside the
intact pericardium often occurs at the expense of the LV, ultimately producing decreased LV
output.
Vascular dysfunction
• Vasoconstriction is a central abnormality in most cases of AHF. It redistributes blood centrally
increasing pulmonary congestion and oedema. Elevated central venous pressure reduces renal
function resulting in greater fluid retention that further elevates the venous pressure. Peripheral
vasoconstriction also increases LV afterload leading to increased LV wall stress and consequently
myocardial ischaemia and arrhythmias.

Evidence of congestion
(elevated filling pressure)
Orthopnea
High jugular venous
pressure
Increasing S3
Loud P2
Oedema
Ascites
Rales (uncommon)
Abdominojugular reflux
Valsalva square wave

Evidence of low perfusion

Congestion at rest?
Narrow pulse pressure
Pulsus altemans
NO YES
Cool forearms and legs
May be sleepy, obtunded Low perfusion Warm and dry Warm and wet
ACE inhibitor-related at rest?
A B
symptomatic hypotension
Declining serum sodium level Cold and dry Cold and wet
Worsening renal function C
L

Fig. 12.14 Haemodynamic profiles of patients presenting with advanced or acute heart failure as
described by a 2X2 table.
238

• Hypertension is the most common comorbidity in patients with AHF. Endothelial dysfunction and
abnormal arterial compliance predispose these patients to marked lability of blood pressure in
response to relatively minor changes in intravascular volume.

Renal dysfunction
• At least 30% of patients of AHF have renal dysfunction partly due to the commonly associated
hypertension and diabetes mellitus.
• Neurohormonal stimulation of the kidney results in activation of the renin-angiotensin-aldosterone
system as well as endothelin production, resulting in vasoconstriction.
• Increased salt and water retention is mediated by the kidney through the effect of these
neurohormones as well as cytokine production (e.g. transforming growth factor-beta).
• Progressive renal dysfunction results in a state of volume overload that is refractory or resistant to
treatment. This condition is known as the cardiorenal syndrome and includes five subtypes (table
12.16). The term is generally applied to the coexistant cardiac and renal dysfunction. Contributing
factors include: reduction of renal blood flow, altered balance of vasoconstrictor and vasodilator
hormones, diabetes, hypertension and peripheral vascular disease. Risk factors include old age,
baseline renal insufficiency, diabetes, hypotension, diuretic-induced reduction in glomerular
filtration rate and neurohormonal activation.

Precipitating factors
AHF is episodic in nature and specific precipitating factors are identified in about half of the patients.
These include the following
• Lack of compliance to medical treatment.
• Volume overload.
• Infections, particularly pneumonia or septicaemia.
• Severe brain Injury.
• Major surgery.
• Reduced renal function.
• Asthma.
• Alcohol or drug abuse.
• Pheochromocytoma.

Table 12,16. Cardiorenal syndrome

Type 1: acute cardiorenal syndrome

Abrupt worsening of cardiac function (e.g. acute cardiogenic shock, or ADHF) leading to acute kidney
injury.

Type 2: chronic cardiorenal syndrome

Chronic abnormalities in cardiac function (e.g. chronic HF) causing progressive and potentially
permanent chronic kidney disease.

Type 3: acute renocardiac syndrome

Abrupt worsening of renal function (e.g. acute kidney ischaemia or glomerulonephritis) causing acute
cardiac disorders (e.g. HF, arrhythmia, ischaemia)

Type 4:chronic renocardiac syndrome

Chronic kidney disease (e.g. chronic glomerular or Interstitial disease) contributing to decreased cardiac
function, cardiac hypertrophy, and/or Increased risk of adverse cardiovascular events.

Type 5: secondary cardiorenal syndrome

Systemic conditions (e.g. diabetes mellitus, sepsis) causing both cardiac and renal dysfunction.
 239
Clinical picture
Symptoms
• The most common symptoms are related to congestion and less often, hypoperfusion. Therefore,
dyspnea, fatigue, peripheral oedema and right upper quadrant abdominal pain (due to hepatic
congestion) are common presentations.
• Palpitation is commonly due to atrial fibrillation that precipitate AHF.
• Altered mental state, depression, sleep disturbances and drowsiness are common problems due to
impaired cerebral circulation secondary to the low cardiac output, abnormal endothelial function,
atrial fibrillation, hypercoagulable state and advanced age of most patients.
Signs
• Pallor and dusky discolouration of the skin suggests marked decrease of cardiac output and
cardiogenic shock. Cool extremities with palpable pulse (to rule out peripheral vascular disease)
suggests decreased peripheral perfusion consistent with a marginal cardiac index, marked
vasoconstriction or both.
• Manifestations of systemic venous congestion include elevated jugular venous pressure, ascites,
peripheral oedema, tender hepatomegaly and whole body anasarca.
• Low grade fever (> 38 °C) may occur due to marked cutaneous vasoconstriction. Persistence of
fever after treatment of heart failure requires further diagnostic evaluation.
• Blood pressure is typically normal or elevated. Only 2% of patients present with hypotension
(systolic blood pressure < 90 mmHg) or cardiogenic shock. Low pulse pressure is a marker of low
cardiac output and increases the risk of mortality. A proportional pulse pressure (pulse
pressure/systolic pressure) < 25% is a sensitive and specific indicator of cardiac index < 2.2
L/min/m2.
• Cardiac examination may reveal S3 or S4 heart sounds, accentuated P2 and systolic and diastolic
murmurs depending on the aetiology of AHF.
• Pulmonary examination frequently reveals inspiratory crackles, rhonchi and evidence of pleural
effusion.

Investigations
• ECG may reveal ischaemic changes, atrial fibrillation or conduction defects. A normal ECG is
encountered in 13% of patients.
• Chest X-ray reveals evidence of pulmonary congestion in more than 80% of patients.
• Echocardiography is the most useful test in evaluating the aetiology of AHF. Moderate to severe
systolic or diastolic dysfunction and mitral and/or tricuspid regurgitation are usually detected.
• Pulmonary artery catheter provides important haemodynamic data including central venous,
pulmonary artery and pulmonary capillary wedge pressure. Cardiac output can be assessed either
through thermodilution or oxygen consumption techniques. From these measures, a variety of
use&l derived values may be calculated including systemic and pulmonary vascular resistance and
stroke volume. These data help differentiate cardiogenic from noncardiogenic pulmonary oedema
and enable exquisite tailoring of therapy to specific haemodynamic goals.
• Laboratory studies include serum electrolytes, BUN, serum creatinine, liver function tests,
haematological studies, natriuretic peptides and biomarkers of myocardial injury (troponins and
CK-MB) reveal findings similar to those found in chronic heart failure. Estimated glomerular
filtration rates should be calculated because serum creatinine levels may greatly underestimate the
degree of renal dysfunction.

Treatment
Management of patients with AHF is carried out in three stages:
• Stage 1: urgent care in the emergency department.
• Stage 2: hospital care in a monitored facility.
• Stage 3: predischarge care.
Urgent care
The goals of this stage is to expeditiously establish the diagnosis, identify the aetiology and the
precipitating factors of heart failure, treat life-threatening abnormalities and rapidly provide symptom
relief.
240

• Morphine is given to relieve anxiety, distress and dyspnoea.

• Supplemental oxygen is administered for hypoxoemia (SaO2< 95%). Noninvasive ventilator
support such as continuous positive airway pressure (CPAP), bilevel positive pressure ventilation
(BiPAP) and noninvasive positive pressure ventilation (NIPPV) significantly reduce hospital
mortality (by 40%) and markedly decrease intubation rates (by > 50%). Mechanical ventilation
with endotracheal intubation is needed in about 5 % of patients particularly in the setting of
respiratory failure from muscle fatigue or in the presence of high risk acute coronary syndromes.
• Atrial fibrillation with rapid ventricular response should be treated with IV digoxin, beta blockers
or diltiazem or emergent cardioversion.
• Vasodilators are indicated for patients presenting with pulmonary oedema in absence of
hypotension. These include nitroglycerin (see treatment of heart failure), nitroprusside and
neseritide.
Nitroprusside
This is an intravenous vasodilator that lowers the arterial blood pressure, pulmonary capillary
wedge pressure, pulmonary artery pressure, right atrial pressure, arterial stiffness and arterial wave
reflectance. It is rapidly metabolized by the liver into nitric oxide and cyanides. Nitric oxide
activates guanylate cyclase in smooth muscle and epithelial cells which increases the intracellular
concentration of cGMP resulting in smooth muscle relaxation and vasodilatation.
Nitroprusside is used to treat acute pulmonary oedema, decompensated heart failure or
hypertensive urgencies in an ICU setting with invasive haemodynamic monitoring to guide
therapy. It is administered by continuous infusion at doses of 0.3-10 mcg/kg/min (average 3
mcg/kg/min).
Hypotension Is a common side effect and it may cause coronary steal syndrome, therefore it
should be avoided in active Ischaemia. Prolonged infusion, especially in patients with hepatic or
renal dysfunction leads to cyanide and thiocyanate toxicity respectively (confusion, seizures,
hyperreflexia). Discontinuation of infusion may result in rebound worsening of haemodynamics.

Nesiritide
This is the generic name of synthetic BNP. It is a balanced vasodilator with modest diuretic
properties. It acts via natriuretic peptide receptors on the cell surface of smooth muscle and
endothelial cells, increasing concentration of cGMP and leading to smooth muscle relaxation and
vasodilatation.
Nesiritide may be used to treat patients with decompensated heart failure, fluid overload and
dyspnoea at rest. It Is given as 2 mcg/kg bolus followed by 0.01 mcg/kg/min infusion. Invasive
haemodynamic monitoring is not usually required but telemetry monitoring, BP recordings and
electrolyte determinations are mandatory. The drug is infused for 1-2 days, along with IV diuretics
while oral heart failure therapy is augmented. Side effects include headache and hypotension.
Nesiritide treated patients report greater relief from dyspnoea but experience no improvement in
renal function, heart failure admission or death at 30 days. However the drug is still occasionally
used in patients who remain symptomatic even with IV diuretics or to lower the pulmonary artery
pressure in patients awaiting heart transplantation.
• Cardiogenic shock is treated with inotropic agents and vasoconstrictors. Mechanical circulatory
support with intraaortic balloon pump or left ventricular assist device is needed in critical
refractory cases.
In the failing heart, beta adrenergic pathways undergo desensitization that may approach 50-60%
in advanced conditions. However, the majority of such patients still exhibit substantial inotropic
response to beta-agonists.
All beta-agonists are given intravenously for decompensated heart failure. They are all
arrhythmogenic and are subject to the development of desensitization phenomenon.

Dobutamine
This is a synthetic catecholamine that stimulates both 01 and p2 adrenergic receptors. It increases
adenyl cyclase which converts ATP to cyclic adenosine monophosphate (cAMP). cAMP acts as a
second messenger that releases calcium from the sarcoplasmic reticulum leading to enhanced
contractility. Dobutamine increases the cardiac output by 10-15% and in lower doses (< 5
 241

gg/kg/min) produces mild degree of systemic vasodilatation and mild decline in pulmonary
vascular resistance. Because of its afterload reducing effect, it is preferable to dopamine (that has
no effect or increase afterload) for most patients with advanced decompensated heart failure who
have not responded adequately to intravenous diuretics. Additionally, dobutamine does not
produce much increase in heart rate at doses of 10 gg/kg/min or less.
Dobutamine is used to treat hypotensive patients with heart failure and cardiogenic shock and may
serve as a bridge to cardiac transplant or LV assist devices. The best use of the drug is a short-term
infusion guided by haemodynamic monitoring to stabilize a hypotensive heart failure patient.
Occasionally, continuous infusions are used as palliative therapy for end-stage heart failure to
prevent recurrent or prolonged hospitalization. However, intermittent outpatient infusion therapy is
not recommended.
Dobutamine infusions are initiated at 2-3 gg/kg/min and are titrated upward according to the
patient's haemodynamic response, usually not higher than 20 gg/kg/min.
At higher doses, dobutamine begin to stimulate a 1-adrenergic receptors thereby preventing
vasodilatation.
Eosinophilic myocarditis often accompanied by peripheral eosinophilia is a rare complication of
prolonged dobutamine use and may be related to an allergic reaction to the sodium bisulfite
stabilizer in the infusion. Hypotension while uncommon, can occur in hypovolaemic patients.

Dopamine
This is an endogenous catecholamine that is the precursor to norepinephrine in the catecholamine
synthetic pathway. When initially administered, it releases norepinephrine through a tyramine-like
effect. It also prevents its neuronal uptake and stimulates both postsynaptic (DI) and presynaptic
(D2) dopamine receptors.
At lower doses (< 2 gg/kg/min), dopamine causes vasodilatation of splanchinic and renal arterial
beds thus promoting renal blood flow. It also has direct renal tubular effect that promotes
natriuresis.
At intermediate doses (2-10 gg/kg/min), it enhances release and inhibits neuronal uptake of
norepinephrine from myocardial and vascular adrenergic neurons resulting in increased cardiac
output and increased peripheral vascular resistance. In patients with advanced heart failure who
have depleted intracardiac norepinephrine sites, dopamine is a less effective positive inotropic
drug than other directly acting inotropes.
At higher infusion rates (5-20 gg/kg/min), peripheral vasoconstriction occurs as a result of direct
alpha-adrenergic receptor stimulation.
On initial administration, tachycardia and arrhythmia tend to be more pronounced than with
dobutamine.
The safety and efficacy of renal dose dopamine have not been proven.
In order to achieve clinical or haemodynamic goals, low-dose dopamine may be combined with
other inotropic or vasodilator therapy. In patients with severe LV dysfunction, dobutamine may be
added to augment the level of positive inotropic support provided by dopamine alone. To
counteract increased afterload and peripheral vasoconstriction, high dose dopamine may be
combined with a vasodilator such as nitroglycerin.
Like dobutamine, the inotropic response to dopamine may be attenuated in patients with advanced
heart failure and higher doses may cause tachyarrhythmias.

Phosphodiesterase inhibitors
Mechanism of action
These drugs inhibit the enzyme phosphodiesterase type HI which is associated with the
sarcoplasmic reticulum in cardiac myocytes and vascular smooth muscles thus preventing the
breakdown of cAMP into AMP. Elevations in cAMP in the vicinity of the sarcoplasmic reticulum
can then activate local protein kinase A which will phosphorylate phospholamban and relieve this
molecule's inhibition of sarcoplasmic reticulum function. In the vascular smooth muscle,
elevations in cAMP activate protein kinase C which leads to prominent vasodilatation. Type III
phosphodiesterase inhibitors also inhibit platelet aggregation, dilate epicardial coronary arteries
and bypass grafts and inhibit proinflammtory cytokine formation.
242

Before administration of such agents, it is necessary to be certain of an elevated left ventricular

filling pressure otherwise a precipitous drop in blood pressure may occur.
Clinical effects
Phosphodiesterase inhibitors improve both systolic and diastolic left ventricular function. They
increase cardiac output and preferentially increase skeletal muscle blood flow. However, given in
doses that produce large haemodynamic effects, they increase mortality presumably because of
development of arrhythmias. However using lower doses (1/6-1/3 usual dose) or combining them
with beta-blocking agents may retain their haemodynamic benefits and avoid their proarrhythmic
effects.
Subjects chronically receiving beta blocking agents who decompensate to the point of needing
positive inotropic support should be treated with phosphodiesterase inhibitors (rather than
dobutamine or other beta agonists) because their site of action is beyond the beta adrenergic
receptors.

Milrinone
In addition to its effect as type III phosphodiesterase inhibitor, It stimulates Ca2+ release channel
and affects sarcoplasmic Ca2+ ATPase. It is usually administered as 25-75 gg/kg bolus over 10-20
minutes followed by 0.375-0.75 gg/kg/mln continuous infusion. Unlike amrinone, it does not
commonly cause thrombocytopenia.
Milrinone is used to treat patients with hypotensive heart failure and cardiogenic shock. It may
serve as a bridge to cardiac transplantation or LV assist devices. The use of milrinone with
concomitant beta-blocker therapy is possible In appropriate clinical situations as they have
different mechanisms of action. Continuous-infusion milrinone occasionally is used as palliative
therapy for end-stage heart failure. Intermittent infusions are not recommended.
The use of other inotropes including vesnarinone (phosphodiesterase inhibitor and K+ channel
antagonist), primobendan and levosimendan (both are phosphodiesterase inhibitor and calcium
sensitizers), Ibopamine (oral dopamine agonist) and xameterol (pi selective partial agonist) and
omecamtiv mecarbil (cardiac myosin activator) appears to be associated with adverse clinical
outcomes and seems inadvisable.
The commonly used drags in acute heart failure are given In table 12.17.

Hospital care
• Most patients are admitted to a telemetry unit. Severe cases have to be admitted to ICU/CCU.
• The goals of this stage are to complete the diagnostic and therapeutic processes that were initiated
in the emergency department, optimize the patient’s haemodynamic profile, relieve symptoms and
initiate a maintenance regimen.
• Dietary sodium restriction with low-sodium diet (2 g daily) is useful to restore and maintain
euvoloemia. Fluid restriction (2 L/day) may be recommended for patients with moderate or severe
hyponatraemia (Na < 130 mEq/L).
• Definitive treatment relies on information obtained from three main aspects: blood pressure,
volume status and renal function (table 12.18)

1. Most patients present with elevated blood pressure and consequently benefit from vasodilators
(nitrates, nitroprusside, nesiritide). The selection of agent depends on the clinical situation,
local practice and availability.
2. Hypotension (BP < 90 mmHg) Is a poor prognostic sign and needs treatment of underlying
aetiology (e.g. acute coronary syndrome, pulmonary embolism, hypovoloemia), inotropic
therapy (dobutamine, dopamine, milrinone) and occasionally the use of vasoconstrictors (high
dose dopamine, phenylephrine, epinephrine, norepinephrine, vasopressin).
3. Most patients have volume overload that needs treatment with IV diuretics.
Furosemide is the most commonly used loop diuretic. It can be administered intravenously in
doses ranging from 20-240 mg (or higher) every 4-6 hours. In patients already receiving loop
diuretics, the initial IV dose should equal or exceed the chronic oral dose. A continuous
infusion (5-40 mg/h) is not superior to intermittent bolus dosing in either efficacy or safety.
 243

Ultrafiltration is used for patients with marked fluid overload that is unresponsive to diuretics
or for those who develop worsening renal fimction requiring discontinuation of diuretics. It
removes excess plasma volume without causing significant change in electrolytes.

Table 12.17. Intravenous vasoactive agents for the treatment of acute heart failure

Intravenous Initial Dose Effective Dose Comments

Medication Range

Diuretics
Furosemide 20-80 mg 20-500 mg bolus Continuous Infusion: 5-40 mg/hr;
bolus ototoxicity risk increases with higher
(>240 mg boluses)

Bumetanide 0.5-2 mg bolus 0.5-4 mg bolus Continuous infusion: 0.1-0.5 mg/hr

Torsemide 10-40 mg 20-200 mg bolus Continuous infusion: 5-20 mg/hr

bolus

Vasodilators
Nitroglycerin, 20 gg/min 40-400 gg/min Hypotension, headache; tolerance with
glyceryl trinitrate, continuous use after 24 hr
5-mononitrate
Isosorbide 1 mg/hr 2-10 mg/hr Hypotension, headache; tolerance with
dinitrate continuous use within 24 hr
Nitroprusside 10 gg/min 30-350 gg/min; Caution In patients with active
0.3-5 gg/kg/min myocardial Ischemia
(usually <4
gg/kg/min) Hypotension; cyanide side effects
(nausea, dysphoria); thiocyanate
toxicity; light sensitive

Nesiritide 2 gg/kg bolus 0.010-0.030 Uptitratlon: 1 gg/kg bolus, then

with 0.010- gg/kg/min increase infusion rate by 0.005
0.030 gg/kg/min (no more frequently than
gg/kg/min every 3 hr, up to a maximum of 0.03
infusion gg/kg/min)
Hypotension, headache (less than
organic nitrates); ? worsens renal
function, mortality

Inotropes
Dobutamine 1-2 gg/kg/min 2-20 gg/kg/min For Inotropy and vasodilation;
hypotension, tachycardia,
arrhythmias; ?mortality

Dopamine 1-2 gg/kg/min 2-4 gg/kg/min For inotropy and vasodilation;

hypotension, tachycardia,
arrhythmias; ?mortality
4-5 gg/kg/min 5-20 gg/kg/min For inotropy and vasoconstriction;
tachycardia, arrhythmias; ?mortality
244

Intravenous Initial Dose Effective Dose Comments

Medication Range
Milrinone 25-75 gg/kg 0.10-0.75 For vasodilation and inotropy;
bolus over 10- gg/kg/min hypotension, tachycardia,
20 min arrhythmias; renal excretion;
followed by ?mortality
infusion
Enoximone 0.25-0.75 1.25-7.5 For vasodilation and inotropy;
mg/kg gg/kg/min hypotension, tachycardia,
arrhythmias; ?mortality
Levosimendan 12-24 gg/kg 0.5-2.0 For vasodilation and inotropy; active
bolus over 10 gg/kg/min metabolite present for ~84 hr;
min followed hypotension, tachycardia,
by infusion arrhythmias; ?mortality
Epinephrine 0.05-0.5 For vasoconstriction and inotropy;
gg/kg/min tachycardia, arrhythmias, end-organ
hypoperfusion; ?mortality
Norepinephrine 0.2-1.0 For vasoconstriction and Inotropy;
gg/kg/min tachycardia, arrhythmias, end-organ
hypoperfusion; ?mortality

4. Approximately two thirds of the patients present with at least moderate renal insufficiency. In
some patients, this is secondary to worsening of heart failure and treatment of the latter restores
normal renal function. In other patients, renal insufficiency necessitates more intensive diuretic
regimens and intravenous inotropic therapy. Progressive deterioration of renal function (BUN >
80 mg/dl) and creatinine > 3 mg/dl) or hyperkalaemia may necessitate discontinuation of ACE
inhibitors and spironolactone. Ultimately, renal replacement therapy (ultrafiltration or
haemodialysis) may be necessary.
5. In patients with advanced heart failure in whom pulmonary artery catheters are used to tailor
therapy, targets of therapy include pulmonary capillary wedge pressure <16 mmHg, right atrial
pressure < 8 mmHg and systemic vascular resistance between 1000 to 1200 dynes/sec.cm'5.
6. Most outpatient medications should be continued, but patients with worsening of renal function
often have ACE inhibitors withheld. Patients should continue on beta-blockers (or have them
started) unless significant hypotension or cardiogenic shock are present.
7. Comorbidities including hypertension and diabetes should be aggressively treated.

Predischarge care
• The goals of this stage are to optimize oral therapy and instruct the patient on the pathophysiology
of heart failure and the use of drugs.
• Discharge criteria include treating exacerbating factors, near-optimal volume status, transition
from Intravenous to oral medications and completing patient and family eduation.
• Follow up clinic visit is scheduled usually within 7-10 days.

Prognosis
AHF remains a therapeutic challenge. Hospital mortality ranges between 4 to 7% and postdischarge
mortality at 2-3 months varies between 8 and 10% and at 1 year Is about 30%. Main predictors of
mortality are renal dysfunction and hypotension. Patients with admission BUN > 43 mg/dl, serum
creatinine > 2.75 and systolic blood pressure <115 have in-hospital mortality of 21.9% compared to
2.1% in patients without any of these predictors. Even minor abnormalities in renal function and
blood pressure have tremendous impact on mortality.
 245

Table 12.18. Treatment strategies for acute heart failure

Systolic blood pressure
Volume Worsening
overload renal >100 mmHg 90-100 mmHg <90 mmHg
function

Yes Yes Vasodilator Vasodilator Inotrope (dopamine)

Diuretics (consider (cautiously) and/or Consider norepinephrine or
infusion or inotrope other vasopressorS
combination Diuretics (consider Diuretics (consider infusion
therapy) infusion or or combination therapy)
Consider combination therapy)
ultrafiltration

Yes No Vasodilators Vasodilator Recheck volume status

Diuretics (cautiously) and/or Inotrope (dopamine)
Consider ultrafiltration inotrope Consider norepinephrine or
other vasopressors
Diuretics (consider infusion
or combination therapy)

No Yes Vasodilator for Vasodilator Recheck volume status

hypertensive HF (cautiously) and/or ? volume repletion
inotrope Inotrope (dopamine)
Consider norepinephrine or
other vasopressors

No No Vasodilator Consider normotensive Recheck volume status

cardiogenic shock ? volume repletion
(then treat as if SBP Inotrope (dopamine)
<90 mmHg) Consider norepinephrine or
other vasopressors
246

HEART FAILURE WITH

PRESERVED EJECTION FRACTION
Definition
Heart failure with preserved ejection fraction (HFPEF) is a preferred term over diastolic heart failure
because the physiological abnormalities are not restricted to diastole. It refers to the association of
three features:
• Symptoms and/or signs of heart failure.
• Normal or mildly abnormal systolic LV function.
• Evidence of diastolic dysfunction.
The European society of cardiology (ESC) proposed an algorithm for diagnosis of HFPEF based on
cardiac catheterization, echo and BNP features (Fig 12.15)
Conditions that may produce symptoms and signs of heart failure In the presence of normal ejection
fraction need to be excluded. These include valvular disease, constrictive pericarditis, hypertrophic
cardiomyomathy, pulmonary disease, anaemia and deconditioning.

Prevalence
HFPEF accounts for 50-55% of heart failure patients. Its prevalence increases with ageing and is
much more common In women than in men at any age.

Causes
• Myocardial ischaemia
• Hypertension
• Hypertrophic and restrictive cardiomyopathies
• Diabetes mellitus
• Chronic renal disease
• Obesity

Pathophysiology
• Phases of diastole include
Isovolumic relaxation phase
Early rapid filling which is driven by the left atrial to left ventricle pressure gradient. This
depends on the interplay between active myocardial relaxation, LV diastolic stiffness, LV
elastic recoil, LV contractile state, left atrial pressure, ventricular interaction, pericardial
constraint, left atrial stiffness, pulmonary vein properties and mitral valve area. Normally,
this phase contributes to 70-80% of left ventricular filling, but this contribution decreases
with age and various disease states.
Diastasis which is the period of diastole when the left atrial and left ventricular pressures
are almost equal. It normally contributes < 5% of LV filling and Its duration shortens with
tachycardia.
Atrial systole which normally contributes 15-25% of LV filling without raising the mean
left atrial pressure. This contribution depends on the PR interval, atrial contractility, atrial
preload and afterload, autonomic tone and heart rate.
• HFPEF is mainly due to abnormal diastolic function, but other mechanisms including ventricular-
vascular coupling, volume overload, left atrial dysfunction, left ventricular systolic dysfunction,
chronotropic incompetence and endothelial dysfunction may contribute to a lesser extent.
• Although diastolic function Is complex, the most important components are
LV relaxation
LV diastolic stiffness
• Left ventricular relaxation is an active energy-dependent process that begins during the ejection
phase of systole and continues through the isovolumic relaxation and rapid filling phases. It is
under the triple control of systolic load, myofibre inactivation (detachment of actin-myosin cross
bridges) and the uniformity of load and inactivation In space (synchrony of relaxation) and time
(with late left ventricular systolic overload hastening the onset but slowing the rate of relaxation).
 247

Symptoms and signs of HF

I

Normal LV EF and normal or midly dilated LV size

Cath criteria: BNP >200 pg/ml

-LVEDP >16 mmHg
-PCWP >12 mmHg +

E/E’ 9-14
Or low E’
Or PA pressure >35
Or B-bump on M-mode of MV

Fig. 12.15. Diagnosis by HFpEF by catheterization, echo, or BNP features, according to ESC criteria. A
normal or midly dilated LV is defined as LV end-diastolic volume < 75 ml/m2 or 96 ml/m2, respectively.

Left ventricular relaxation is best assessed by the time constant of relaxation (tau, r) which
describes the rate of LV pressure decay during isovolumic relaxation using a high-fidelity
manometer-tipped LV catheter. Normally, tau is < 40 ms and relaxation is complete by 3.5 X tau
(< 140 ms). The larger the value of tau, the longer it takes for the LV to relax and the more
impaired is relaxation.
Noninvasively, Doppler and tissue Doppler echocardiography are used to assess relaxation
employing the transmitral flow velocity, pulmonary venous flow and the velocity of diastolic
mitral annular ascent (relatively preload independent. Figure 12.16 illustrates the progression of
LV diastolic function abnormalities and their correlation with invasively measured diastolic
properties.
In patients with HFPEF, the average value of tau is approximately 60 ms at rest and 86 ms during
exercise. Doppler echocardiography reveals impairment of diastolic fimction progressing from
impaired relaxation through pseudonormalization to reversible then irreversible restrictive patterns.
In patients with impaired relaxation and increased dependence on atrial contraction for LV filling,
the onset of atrial fibrillation is associated with acute elevation of left atrial pressure and
impairment of LV filling which may induce acute pulmonary oedema and low cardiac output.
• Left ventricular diastolic stiffness is defined as the relationship between the changes in LV
diastolic stress and strain. Increases in LV diastolic stiffness mandates higher left atrial pressures
to maintain LV filling and thus promotes elevated pulmonary venous pressure and pulmonary
congestion when left atrial pressures are elevated or reduced cardiac output when left atrial
pressures are not elevated.
LV diastolic stiffness is affected by several factors, which influence the cardiac extracellular
matrix, cellular processes at the myocyte level and myofibrils themselves. The extracellular matrix
consists of collagen (types I and HI), elastin, proteoglycans, basement membrane protein (collagen
type IV), laminin and fibronectin. The extracellular matrix is increased In conditions associated
248

with HFPEF. The giant molecule spring titin also contributes to myocardial diastolic stiffness.
Titin isoform switches (to the less compliant N2B isoform), titin phosphorylation and titin calcium
interaction may contribute to diastolic stiffness. The role of alteration of titin in HFPEF remains to
be clarified.
The concept that diastolic stiffness (in contrast to relaxation) is a passive phenomenon is
inaccurate because reductions in energy supply (e.g. in ischaemia) can result in decreased diastolic
distensibility.
Measurement of LV diastolic stiffness requires the simultaneous measurement of LV pressure and
volume during acute alteration in preload to define the end-diastolic pressure volume relationship
over a range of preloads. This may be done over a single or multiple beats using a conductance
catheter (for instantaneous pressure-volume measurements) or combined invasive LV pressure
measurement and echocardiography or contrast or radionuclide ventriculography for volume
measurements.

itIOBJI
Mlill

Fig. 12.16. Proposed progression of diastolic function abnormalities as assessed with comprehensive
Doppler echocardiography, with correlation of invasively measured diastolic properties. A
comprehensive Doppler assessment as outlined here can yield useful information regarding relaxation,
filling pressures, and indirectly diastolic stiffness in most patients but require careful data acquisition and
informed interpretation. A, transmitral flow velocity with atrial contraction; Adur,. duration of A above;
AR, flow from left atrium to pulmonary veins during atrial contraction; ARdur, duration of AR; D,
diastolic; DT, deceleration time; E, early diastolic transmitral flow velocity; e', velocity of early diastolic
mitral annular motion; S, systolic.
 249

Doppler echocardiography can provide indirect information regarding LV stiffness. If there Is

Doppler evidence of elevated LV filling pressure (increased E/e’ ratio, E/A reversal with Valsalva
manoeuvre or reduced pulmonary venous systolic flow velocity, and LV dimensions or volumes
are normal, increased stiffness is inferred. Additionally, if the deceleration time of the early
diastolic transmittal flow velocity is short despite evidence of impaired relaxation (reduced early
diastolic annular velocity with tissue Doppler imaging), rapid equalization of LV and left atrial
pressures during early diastolic filling and increased LV diastolic filling Is inferred.
• By definition, LV ejection fraction is normal or near-normal in patients with HFPEF. However, the
role of subtle changes in systolic performance that may coexist with diastolic dysfunction in
patients with HFPEF remains unclear. The capacity to enhance contractility in response to stress
(e.g. exercise) is markedly attenuated in HEPEF.

Clinical picture
Symptoms
These are similar to those of systolic heart failure. Fatigue, dyspnea, wheezes, abdominal bloating and
peripheral oedema may occur in isolation or in any combination. Syncope or sudden death may occur
due to tachyarrhythmias or bradyarrhythmias.

Signs
These are neither sensitive nor specific to HFPEF and are also Indistinguishable from those of systolic
heart failure. They include elevated jugular venous pressure, displaced apical Impulse, S3 and S4
sounds, pulmonary crackles, tender hepatomegaly and oedema.
None of the clinical features can be used to distinguish patients with HFPEF reliably from those of
HF with reduced EF. Thus assessment of EF with cardiac imaging is needed to distinguish between
these two types of heart failure.

Investigations
• ECG. The most common abnormality seen is LV hypertrophy caused by systemic hypertension.
Previous myocardial Infarction, evidence of atrial abnormalities, conduction defects and atrial
fibrillation may occur. A normal resting ECG does not rule out the diagnosis.
• Chest X-ray. In the compensated state, the chest X-ray may be normal. In decompensated states,
pulmonary venous hypertension or pulmonary oedema are frequently observed. Cardiomegaly and
pulmonary venous hypertension occur with almost the same frequency as is systolic heart failure.
• Echocardiography is pivotal in making the diagnosis of HFPEF by documenting normal or near­
normal systolic function (EF > 40%), evidence and stage of diastolic dysfunction and by assessing
ventricular mass. There are multiple echo-derived indices of diastolic function that have been well
validated and are useful in determining the presence and severity of diastolic abnormalities and
differentiating HFPEF from constrictive pericarditis and cardiac tamponade (see chapter 33).
• Cardiac catheterization provides accurate assessment of LV relaxation and may be very helpful in
differentiating between restrictive and constrictive physiologies when noninvasive techniques fail
to do so.
• Radionuclide techniques. Normalized peak filling rate is a noninvasive Index of LV relaxation.
However, it is load-dependent and does not provide filling pressures. It is rarely used.
• Magnetic resonance imaging (MRI). MRI can provide gold-standard measurements of left atrial
and left ventricular volumes and mass as well as LV filling parameters similar to those obtained by
echocardiography. It is an acceptable alternative to echo If image quality from transthoracic
echocardiography Is poor. It is also useful in assessment of constriction versus restriction and in
differentiating hypertrophic form infiltrative cardiomyopathy.
° Laboratory investigations include determination of plasma glucose (diabetes), ferritin
(haemochromatosis), serum calcium, angiotensin converting enzyme (sarcoidosis), autoantibodies
and protein electrophoresis (amyloidosis).
• Brain natriuretic peptide (BNP) and N-terminal (NT) pro BNP are elevated in patients with
HFPEF but their values are on the average lower than in HF with reduced EF. Normal values may
be used to exclude heart failure as a cause of dyspnoea.
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• Cardiac troponin Is elevated In conditions secondary to coronary artery disease, infiltrative

cardiomyopathy or myocarditis.
• Endomyocardial biopsy may be used if there is a strong suspicion of infiltrative myocardial
disease. However, many infiltrative diseases especially sarcoidosis are patchy in distribution and
may be missed by endomyocardial biopsy.

Treatment
Present treatment strategies are largely based on assumptions regarding the pathophysiological
changes that lead to diastolic heart failure and on extrapolations form proven strategies used in heart
failure with reduced EF. Current guidelines recommend control of blood pressure, atrial fibrillation,
tachycardia and evaluation for ischaemia in appropriate patients.
A. Nonpharmacological therapy
The general measures used in the management of patients with HFPEF are not different from
those pursued in patients with heart failure and a reduced EF. They include attention to diet and
lifestyle, patient education and close medical follow up. Aggressive control of hypertension,
myocardial ischemia, tachycardia and other potential precipitants of heart failure decompensation
should be emphasized. Exercise training is possibly effective in decreasing symptoms and
improving quality of life.
B. Pharmacological therapy
• Diuretics should be used to reduce pulmonary congestion and peripheral edema. Caution must
however be taken not to over-diurese, because many patients require elevated filling pressures
to ensure adequate stroke volume.
The use of beta-adrenergic blockers, angiotensin convertening enzyme inhibitors, angiotensin-
receptor blockers, calcium antagonists or digitalis may be effective to minimize symptoms of
heart failure. Spironolactone results in a small reduction in heart failure hospitalization but no
reduction of the composite endpoint of cardiovascular mortality, cardiac arrest or heart failure
hospitalization compared to placebo.
Ventricular rate should be controlled in the presence of atrial fibrillation. Beta blockers and
calcium channel blockers allow improved diastolic filling by slowing the heart rate. However,
neither has been shown to do more than reduce symptoms. Their use in patients with moderate
or severe diastolic dysfunction should be undertaken with caution.
• If atrial fibrillation is poorly controlled, restoration and maintenance of sinus rhythm seems of
logical benefit.
• Nitrates may provide symptomatic relief, but should be used cautiously so as not to precipitate
hypotension. Cautious administration of intravenous nitrates with invasive haemodynamic
monitoring can effectively treat acute decompensation and acute pulmonary edema related to
diastolic dysfunction.
• Dialysis is occasionally used to unload the ventricle in severe cases when diuresis cannot be
achieved because of cardiorenal salt and water retaining states that occur in many such patients.
• Therapy of specific pathological processes such as sarcoidosis, haemochromatosis, diabetes and
chronic renal disease.
• Ongoing trials on HFPEF are testing the efficacy of aldosterone antagonists, natriuretic
peptides, nitric oxide, sildenafil and statins.
C. Surgical therapy
• Coronary revascularization should be considered in patients with coronary heart disease in whom
ischaemia is thought to have an adverse effect on cardiac function.
• Cardiac transplantation has been successful in patients with idiopathic restrictive cardiomyopathy.

Prognosis
The mortality and morbidity of patients with HFPEF is similar to or slightly better than that of HF
with reduced EF. Although survival has improved with modem therapy for patients with HF with
reduced EF, it has not changed for patients with HFPEF.

Additional reading
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• Brignole M et al. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therayy: the Task Force on Cardiac
Pacing and Resynchronization Therapy of the European Society if Cardiology (ESC). Developed in collaboration with the
European Heart Rhythm Association (EHRA). Eur Heart J. 103 Aug;34(29):2291-329.
• Kaber L et al; DANISH Investigators. Defibrillator implantationin patients with nonischemic systolic heart failure. N Engl J
Med. 2016 Sep 29;375(I3): 1221-30.
• Ponikowski P et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for
the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology' (ESC). Developed with
the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J Fail. 2016 Aug;18(8):891-975.
• Yancy CW et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013
ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/ American Heart
Association Task Force on Clinical Practice Guidelines and die Heart Failure Society of America. Circulation. 2016 Sep
27;68(13):1476-88.