INTRODUCTION

Heart failure is a clinical entity diagnosed by doctors. The key features of the syndrome are an abnormality of the heart and the presence of symptoms, typically, tiredness and shortness of breath, which is worse on exercise. Heart failure is common, becoming more common, can be easily diagnosed, is detectable, and effective treatments are available. Death in heart failure occurs most commonly as a result of a cardiac event such as an arrhythmia (sudden death), ischemia of the heart muscle (e.g., myocardial infarction, heart attack), or decompensated heart failure. Thus the natural history of heart failure begins and ends with the heart (Fig. 3-1). But almost all of the clinical characteristics of patients with heart failure result from persistent stimulation of interacting compensatory mechanisms not just in the heart but in the peripheral circulation and body organs. The clinical manifestations and pathophysiology of heart failure should be considered as a multisystem disease.


DEFINITION

The most widely quoted definition of heart failure is that heart failure is “A pathophysiological state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commensurate with the requirements of the metabolising tissues.”1 Other early definitions have emphasized one or other physiological or biochemical abnormalities. More recently, definitions have emphasized the clinical nature of heart failure, for example, “A clinical syndrome caused by an abnormality of the heart and recognized by a characteristic pattern of haemodynamic, renal, neural, and hormonal responses.”2,3 The European Society of Cardiology emphasized the need for three criteria: typical symptoms and signs, an abnormality of the heart, and preferably a response to treatment.4 More recently the American College of Cardiology and the American Heart Association stated “Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.” A similar definition has been used in major guidelines.5


These recent definitions encompass the obvious central premise that a primary disease or dysfunction of the heart is present. Cardiac failure is a syndrome, not a specific disease. Management should be targeted to treat the cause as well as the spectrum of pathophysiology that comprises the syndrome. Thus, it is logical to classify the causes of cardiac failure based upon disease pathology.


DIFFERENT SYNDROMES REFERRED TO AS HEART FAILURE TO AND FUNDAMENTAL CAUSES

A simple but clinically useful way to consider heart failure is to first make the distinction between acute heart failure, shock, and chronic heart failure (Table 3-1). Acute heart failure is synonymous with pulmonary edema and is a medical emergency. The extreme symptom of breathlessness is closely related to the elevated left ventricular pressure. Shock is a condition characterized by a low systolic blood pressure (systolic pressure <90 mm Hg), oliguria or anuria, and evidence of a constricted circulation such as cold periphery, sweating, and mental confusion. Chronic heart failure is a condition where persistent damage to the heart leads to a progressive state with persistent symptoms. Many adjectives are added to the term to emphasize one or other feature (Table 3-1).


The fundamental causes of heart failure are easily stated and reflect the anatomical and physiological features of the heart (Table 3-2). The most common is myocardial disease. Myocardial damage has traditionally been classified as due to one or other manifestation of coronary heart disease or as a cardiomyopathy (Table 3-3). Hypertension is commonly associated with heart failure and particularly with the progression of heart failure. But hypertension is rarely the immediate or only cause of heart failure. Patients with hypertension often have coronary heart disease because hypertension is an important risk factor causing damage to the endothelium and promoting the development of atherosclerosis. Such classifications focus on clinical characteristics. A different approach is to consider the basic mechanisms of heart failure but that has no clinical application at present (Table 3-4).


Many words are added to the term heart failure (Table 3-5). These are often jargon. Forward and backward failure reflects old ideas on the pathophysiology of heart failure and should no longer be used. Right and left heart failure usually refer to pulmonary edema and breathlessness (left heart failure) or evidence of fluid overload such as raised venous pressure, enlarged liver, and peripheral edema (right heart failure). This jargon is largely nonsense, since the commonest cause of right heart failure is left heart failure; fluid retention in chronic heart failure is a consequence of retention of salt and water as a result of underperfusion of the kidney.


In recent years, a distinction has been made between systolic and diastolic heart failure. Diastolic heart failure is often referred to as heart failure with preserved ventricular function. This distinction is the source of much discussion and controversy. In simple terms, diastolic function exists when the heart remains of a normal size and systolic heart failure exists when the heart is enlarged. The old adage was that “a big heart is a bad heart.” Diastolic heart failure is common in the elderly and in the presence of myocardial ischemia and hypertension.


One further distinction is of clinical importance. There exists a group of conditions where the cardiac output is greatly elevated in the presence of symptoms and signs identical to those found in heart failure (Table 3-6). This is often referred to as high-output heart failure but such a phrase is misleading as the fundamental cause is not the heart but other features of the circulation or body systems. A better terminology is to refer to these conditions as circulatory failure.


Diseases of any of the constitutive component tissues of the heart and associated great vessels can result in cardiac failure. The etiology can be approached from a reductionist perspective, starting at the whole organ and tissue level, and progressing to the cellular, subcellular, and molecular causes (proteomic and genomic), or vice versa from the expansionist perspective, starting at the molecular level, and “expanding up to the tissue and organ level.”


The prevalence of the different causes varies depending upon gender, age, and geographical region. In the Caucasian population of Western Europe, the United States, and Australasia, ischemic heart disease predominates, whereas in the Afro-Caribbean population, hypertension is the commonest cause. Chagas’ disease caused by the parasite Trypanosoma cruzi is responsible for 20% of cardiac failure in South America/Brazil,6 but is only seen in returning travelers and immigrants from this region in European hospitals.


Coronary Heart Disease—Acute Occlusion


Coronary heart disease, consequent to atherosclerosis, is the commonest cause of heart failure in Western populations, accounting for up to 70% of cases.7,8 The heart is critically dependent on a supply of oxygen from the coronary circulation; the adenosine triphosphate (ATP) in heart muscle will support about five beats. An acute coronary occlusion causes diastolic contractile dysfunction within 6 seconds and systolic dysfunction within 20 seconds. Intracellular acidosis develops with the switch from aerobic to anaerobic metabolism, and the intracellular accumulation of phosphate from the breakdown of creatine phosphate and ATP. Hydrogen and phosphate ions interfere directly with the contractile proteins to promote the formation of weak myofilament cross bridges. The ATP depletion reduces sarcoplasmic reticulum calcium ATPase and sodium-potassium ATPase activity. The ATP-inhibited K+ channel opens, and triggers an efflux of potassium out of the cell (within seconds), which is subsequently amplified by reduced sodium-potassium ATPase activity. This disrupts the ionic fluxes across the sarcolemma and reduces the calcium removal from the cytoplasm during diastole, depleting the sarocoplasmic reticulum calcium stores and resulting in smaller systolic calcium transients. Lactate accumulation causes mitochondrial damage and disrupts action potential generation. The result is cardiac tissue with abnormal electrical activity, excitation-contraction coupling, and reduced contractile tension. Total occlusion of the artery leads to hemorrhagic necrosis of the myocardium supplied by the artery, leading to irreversible myocardial infarction. If the occluded coronary is reopened after an initial delay of 30 minutes or more, but before complete necrosis has developed, then the return of oxygen results in the rapid production of free radicals within 2–4 minutes of reperfusion (reperfusion injury).9 These free radicals damage nucleic acids, cell membranes, and intracellular proteins, initiating the intracellular cascade via the p38 kinase and c-Jun N-terminal kinase pathways, activation of the caspase cascades, resulting in apoptosis and further myocardial damage (Fig. 3-2).


The wave front of infarction starts at the endocardial border and progresses to the epicardium in areas of severe ischemia. The infarcted wall becomes acutely dyskinetic (paradoxical outward movement during systole), and ventricular dilatation begins. This occurs within the constraints of the pericardium, which reaches its limits of compliance in the acute phase and exerts a constrictive effect on the acutely infarcted ventricle. The increase in left ventricular diastolic pressure after acute coronary occlusion in the dog angioplasty model can be inhibited by prior removal of the pericardium.10


Should the patient survive the acute episode of myocardial infarction, a process of left ventricular remodeling is initiated, with further architectural and structural changes to the ventricle (Tables 3-7 and 3-8). The word was first used in 1982 so as to distinguish between extension of an infarct, expansion of an infarct, and changes in distant myocardium.11,12 Remodeling occurs in both the infarcted and remaining noninfarcted regions, further contributing to ventricular dysfunction. The extent of ventricular dysfunction depends on the size and location of the infarct, the presence of previous infarcts elsewhere in the heart, the remaining coronary supply with or without collaterals, and the involvement of other cardiac structures, which influence ventricular function such as the conducting tissue, heart valves, and pericardium.


The region of necrosis involves damaged myocytes and disruption of the extracellular matrix. Loss of type I collagen fibers and intermyocyte collagen struts occurs due to activation of matrix metalloproteinases (1, 2, and 9 predominate in the heart), and is replaced by a deposition of collagen III and IV from fibroblasts, stimulated by aldosterone and angiotensin II.13,14 There is an overall increase in the myocardial collagen content from 5% up to 25%, but it is laid down in an irregular fashion, which disrupts the fine myocardial architecture. This allows myocyte slippage in the longitudinal direction, leading with the loss of cells and vasculature to infarct thinning and expansion.15,16


PCI—percutaneous coronary intervention

This is more extensive in areas with complete absence of blood supply. The presence of collaterals, or late revascularization of the culprit vessel, reduces infarct expansion. It is more evident in anterior infarcts, and leads to an increase in left ventricular circumference up to 25% during the first week. This expansion alters the geometry of the left ventricle, with the normal ellipsoid shape progressively replaced by a more spherical shape. Sphericity indices have been used to quantify this change, based upon the ratio of the observed biplane ventricular volume divided by the volume of a theoretical ventricle with the same biplane circumference but perfectly spherical geometry. The normal human left ventricle has a sphericity index of 0.66 at end diastole and 0.55 at end systole. After anterior myocardial infarction, the sphericity index increases, with the subsequent reduction in efficiency of blood ejection from the chamber, higher filling pressures, and reduced exercise capacity.17


The infarction of one region of the left ventricular wall requires the remaining myocardium to compensate mechanically in order to maintain adequate cardiac output. Eccentric hypertrophy with sarcomeric replication in series occurs,18 resulting in further increases in ventricular dimensions and compliance. The increased wall stress may stimulate the remaining noninfarcted myocardium to hypertrophy in a concentric manner, most commonly seen at the border zone of the infarct. This process starts 1–2 months after the initial infarction, and may progress for years unless a terminal cardiac event intervenes.


Transient ischemia can produce temporary reduction in contractile function, which is termed myocardial stunning (Tables 3-7 and 3-8). A definition of stunned myocardium (stunning) is mechanical dysfunction that persists after reperfusion despite the absence of irreversible damage and despite the restoration of normal or near-normal coronary flow.19 The delayed recovery, from a few hours up to several days, occurs despite restoration of normal coronary flow in the absence of irreversible damage. At a cellular level, there is a transient increase in oxygen consumption, despite continuous impairment of mechanical function. This inefficient utilization of oxygen may represent reduced myofilament calcium sensitivity despite increases in cytosolic calcium levels, possibly due to changes in myosin ATPase activity. This is compounded by smaller degrees of free radical production, including nitric oxide-derived free radicals, which also contribute to the dysfunction of myocardial stunning. Stunning can occur in a variety of clinical settings. Early reperfusion after myocardial infarction, whether spontaneous or secondary to therapeutic thrombolysis or primary angioplasty, may salvage ischemic but noninfarcted myocardium within the territory of the culprit vessel. This is of significant importance clinically, as imaging may reveal large areas of akinetic or dyskinetic myocardium in the early post-infarct recovery period, but after allowing the stunned myocardium to recover, the long-term dysfunction may not be so severe, with the associated prognostic implications.20 During unstable angina, and after exercise in patients with stable but critical epicardial stenoses, regional wall motion abnormalities have been demonstrated, which recover with relief of angina and/or rest.21 The recovery time is related to the duration of angina on the treadmill or at rest, and may take over 24 hours in severe cases. Myocardial stunning is common after cardiac surgery requiring cardioplegia and cardiopulmonary bypass, due to the global myocardial ischemia generated with cessation of coronary flow.22 This setting demonstrated that whilst inotropic agents can increase contractile function of stunned myocardium, the increase in oxygen consumption induced by the inotropic stimulation is out of proportion to the mechanical improvement. Sudden increases in myocardial oxygen consumption, such as the catecholamine surges seen in acute subarachnoid hemorrhage and pheochromocytoma patients,23,24 create a supply-demand mismatch and can cause myocardial stunning.


Hibernating myocardium is another description of myocardial dysfunction, which has become widespread.25 The word was first used by Diamond in 1978 when he commented, “Reports of sometimes dramatic improvement in segmental left ventricular function following coronary bypass surgery, although not universal, leaves the clear implication that ischemic noninfarcted myocardium can exist in a state of function hibernation.”26 But the term was popularized by Rahimtoola in 1985 who described it thus “A state of persistently impaired myocardial and left ventricular dysfunction at rest due to reduced coronary blood flow that can be partially or completely restored to normal if the myocardial oxygen supply/demand relationship is favorably altered, either by improving blood flow and/or reducing demand.”27 Hibernation refers to viable myocardium, which is exposed to chronic ischemia, with hypocontractility, which is reversible on restoration of normal blood flow. As implicated by this definition, hibernation can only be diagnosed with absolute accuracy in retrospect after revascularization has been performed. In contrast to the pathology of acute occlusion described earlier, mild-moderate ischemia results in transient reduction of creatine phosphate and increase in lactate production, but by 60–85 minutes these return to near normal, and infarction does not occur, despite persistent hypoperfusion. The subsequent changes may represent an evolutionary “protective” mechanism, as fetal cardiac gene expression patterns are activated, and the chronically ischemic myocytes undergo structural cellular changes with sarcomere loss, increased abundance of glycogen granules, rough endoplasmic reticulum and mitochondria, and an increase in collagen strands.28 These changes occur over a timescale of days to weeks, and with initially isolated functional hibernation, progressing later to structural and functional hibernation, which may be associated with wall thinning.29


The classical changes in left ventricular function caused by coronary artery disease and described above occur within the region supplied by the stenotic or occluded artery. Therefore, regional wall motion abnormalities can be explained by coronary disease. However, global left ventricular dysfunction without regional variation can also be caused by coronary disease. This is usually advanced three vessel disease, and may be the result of infarction, hibernation, and/or stunning. This often occurs in patients without symptoms of angina, who present with symptoms of cardiac failure. In a study of patients with global left ventricular impairment (without a history of ischemic heart disease [symptoms or documented previous history]), 52% of patients <72 years of age had coronary artery disease as defined by at least one epicardial stenosis of ≥50%.30 Furthermore milder stenoses, which are not flow-limiting, may cause downstream myocardial dysfunction through a variety of mechanisms including cholesterol and thrombus embolism, previous occlusion and recanalization, and as regions initiating focal spasm.


Other Conditions Causing Reduced Coronary Blood Flow

Whilst atherosclerosis is the commonest form of coronary disease, many other conditions can cause heart failure by reducing coronary blood supply. These include congenital coronary anomalies, especially the interarterial anomalous left coronary artery, coronary artery fistulae, the left main stem arising from the pulmonary trunk, and the stenosed “slit-like” left main orifice. Coronary vasculitides, for example, periarteritis nodosa, Kawasaki disease, systemic lupus erythematosus (SLE), aortic dissection involving the coronary ostia or aortic valve may all cause myocardial dysfunction.


Hypertension

Hypertension is also a common cause of heart failure, accounting for 14% cases in one U.K. population-based study.8 In the Framingham study, a 20 mm Hg increase in systolic blood pressure was associated with a 56% increased risk for developing heart failure.31 Advances in primary care have led to a decrease in the incidence with improved detection and treatment. The majority of hypertensive patients have no specific identifiable cause, so called “essential hypertension,” which places an insidious after-load strain on the heart through a variety of mechanisms including sodium and water retention, arteriolar vasoconstriction, reduced vascular compliance, faster reflection of the pulse wave from stiffer small peripheral arteries, and activation of a range of neurohormonal systems. The left ventricle demonstrates subtle abnormalities in hypertensive patients even before hypertrophy develops. These start with supranormal contraction with increased fractional shortening and wall stress. The left ventricle hypertrophies in a concentric manner to compensate, although animal studies using gene knockout techniques have revealed that left ventricular hypertrophy (LVH) is not necessary for maintenance of adequate cardiac output in the setting of increased afterload.32 The transcriptional changes bringing about cardiac hypertrophy occur over different timescales (Table 3-9). Therefore, pathological hypertrophy should be viewed as the first stage of hypertensive cardiac failure, although cardiac output is maintained.


Many of the molecular cascades, which induce hypertrophy, also cause myocyte apoptosis and lead to myocyte dysfunction. Angiotensin II, endothelin, the gp130 signaling family, calcineurin-mediated gene expression, stretch-induced free radical production, and the three subfamilies of the mitogen-activated protein kinase family (ERK, JNK, and p38 kinase) are all activated during development of ventricular hypertrophy, and play roles in the transformation from the hypertrophied but stable myocardium to the irreversibly damaged and dysfunctional myocardium of the failing heart.33,34 Gap junction remodeling also occurs between hypertrophied cardiac myocytes, leading to increased dispersion of electrical activity.35,36


LVH causes reduced diastolic compliance, longer isovolumic relaxation time, leading to increased dependence on the atrial systole for ventricular filling. Acute pulmonary edema is often due to the inability to increase their end-diastolic volume (preload reserve) in response to increased preload or afterload, due to reduced compliance and relaxation. Coronary vasodilatory capacity is reduced in LVH, and hypertensives also develop atherosclerotic coronary disease. As the hypertrophy progresses, myocardial fiber shortening reduces, particularly in the midwall, and hypertrophy allows total wall shortening to be maintained despite this reduction in fiber shortening. Perivascular fibrosis spreads through the myocardium inducing myocyte necrosis as the capillary network is destroyed, and apoptosis.37 If the hypertension remains poorly controlled, the hypertrophied ventricle progressively dilates, the wall thins, and the ventricle takes on the appearance and mechanical characteristics of the dilated failing ventricle with systolic dysfunction. The prognosis at this stage is very poor,38 unless a significant proportion of the ventricular dysfunction can be accounted for by coexisting coronary disease amenable to revascularization. This is a dynamic process, and hypertensive cardiac failure is a good example of a disease, which progresses through various subtypes of cardiac failure (hypertrophic, dilated, diastolic, systolic), exposing the limitations of such classifications.


Valve Disease

Primary valvular disease accounts for 7% of cardiac failure cases, and the majority involves disease of the left-sided cardiac valves. Incompetence of the aortic and/or mitral valve results in a dilated ventricular phenotype, to compensate for the regurgitant volume by increasing stroke volume. This requires the development of eccentric ventricular hypertrophy to maintain the increased ventricular output. Total ventricular muscle mass is increased, although wall thickness may remain within normal limits. Initially, the dilated ventricle of the regurgitant valve can sustain the increased ventricular ejection fraction required, provided there are no coexisting threats to the myocardium, for example, ischemic heart disease. However, the chronic strain of this increased effort eventually leads to the development of myocardial failure, with changes in excitation-contraction coupling, b-adrenoceptor expression and coupling, and interstitial fibrosis.39 The aim of medical management is to predict this transformation in the natural history of the individual’s valvular disease, in order to time valve surgery optimally.40,41 Acute, severe regurgitation, such as that seen after papillary muscle rupture or aggressive Staphylococcal aureus endocarditis, cannot be tolerated and requires emergency surgery. Lesser degrees of regurgitation can be tolerated for long periods, particularly with appropriate heart failure medication, and providing arrhythmic complication do not intervene. A combination of symptom development and monitoring end-systolic diameter/volume is the most effective strategy at present; although the role of brain natriuretic peptide (BNP) monitoring in this setting has yet to be defined. Type III mitral regurgitation occurs secondary to left ventricular dilation and dysfunction, due to annular enlargement, lateral displacement of the posterior papillary muscles with resulting apical displacement of the coaptation point of the mitral valve leaflets in a tethered position.42 These changes result in a central regurgitant jet, and this should not be confused with primary disease of the mitral valve leaflets causing mitral regurgitation. Type III mitral regurgitation responds best to treatment of the left ventricular failure, whereas the latter requires mitral valve surgery.


Aortic stenosis results in a phenotype similar to hypertensive cardiac failure, as both result in increased afterload. LVH develops initially, via the same mechanisms and with the predominant problem of diastolic filling described above. If left untreated, then the left ventricle also fails with transformation to a dilated phenotype with a reduced ejection fraction.43 Aortic stenosis usually occurs at the level of the valve cusps, and is most commonly due to a congenital bicuspid valve in the young and middle-aged adult (6% associated with aortic coarctation), whereas atherosclerotic plaque disease on the aortic surface of the cusps is the commonest cause in the over 65 population.


With the increasing elderly population, this degenerative aortic stenosis has become the commonest valvular disease in the Western world, with between 2–9% of the population over 65 years affected.44 Rheumatic stenosis of the aortic valve is common in the developing world, and always occurs in association with rheumatic mitral disease. Rarely, aortic stenosis occurs at a supravalvular level (Williams syndrome),45 which can be associated with coronary anomalies, or at the subvalvular level in the left ventricular outflow tract, usually in the form of a shelf of tissue obstructing the outflow tract.


Mitral stenosis is predominantly due to rheumatic heart disease after infection with a Group A b-hemolytic Streptococcus pyogenes. It is common in the developing world,46 whereas it is only seen in the surviving elderly and late middle-aged populations in the developed world. Mitral stenosis in isolation causes raised left atrial pressure, pulmonary venous and arterial hypertension, with development of right ventricular failure and atrial fibrillation.47 However, the stenotic valve is often also regurgitant due to restricted leaflet movement, and the inflammatory pannus of rheumatic disease may extend down the chordae tendinea onto the endocardial surface of the left ventricle, both leading to left ventricular dysfunction.48


These principles also apply to the pulmonary and tricuspid valves, and right ventricular physiology, although the etiology of right-sided valvular disease is very different. Pulmonary hypertension, infective endocarditis, especially from intravenous drug abuse, and hospital-acquired intravenous cannulae and indwelling devices, carcinoid syndrome, rheumatic heart disease, and congenital anomalies, for example, pulmonary valve stenosis and Ebstein’s anomaly, account for the majority.


Primary Disease of Cardiac Muscle—the Cardiomyopathies

Primary disease of the cardiac muscle can present in a number of guises, and previously, classification has been based on the appearance and physiology at echocardiography (ECG) and/or cardiac catheterization, and pathological findings.5 However, advances in molecular biology, and specifically genotyping have resulted in a reevaluation of this classification.49 The majority of research on the disease has been presented under the traditional classification, and we will discuss the cardiomyopathies using the classical terms, and then introduce the potential future molecular classification.


In order to diagnose these conditions, it is clearly essential to exclude other causative factors such as those discussed above. However, multiple diseases can coexist and this requires assessment of the time course of the disease as a means to confirm the diagnosis. As alluded to earlier, the presence of milder, non-flow-limiting coronary disease, or a history of hypertension, may complicate the clinical scenario.

There are other forms of heart muscle disease, which extend this classification but are rare, such as arrhythmogenic right ventricular dysplasia, noncompacted left (or right) ventricle and catecholomine-induced myocardial stunning.


DCM is a syndrome characterized by cardiac enlargement and impaired systolic function of one or both ventricles, in the setting of normal coronary arteries, and absence of other structural or systemic causes (Table 3-10). The formal diagnosis requires the left ventricle to be dilated with the internal end-diastolic dimension (LVEDD) >2.7 m2 of body surface area and either ejection fraction <45% or M-mode fractional shortening <30%.5 However, the normal distribution of ventricular dimension across the healthy population results in 1–2.5% of healthy individuals fitting either of these parameters.50

In addition, screening of families with affected individuals frequently reveals asymptomatic relatives with borderline normal ventricular dimensions, which leads to difficulties in prognostic and therapeutic advice.


About 10% of cases of congestive cardiac failure in Western societies are due to DCM.8 There are numerous causes of DCM (Table 3-10), but in over 50% no underlying cause is found. Whether these reflect unknown genetic mutations, previous viral myocarditis, or toxin exposure, with or without autoimmune destruction, is not known, and it is possible that an environmental insult unmasking a genetic weakness may account for a large proportion.


Whatever the etiology, the final cardiac phenotype appears to follow a common pathological pathway in response to myocardial damage. Some cases result from the progressive deterioration in ventricular muscle function with ongoing damage, whereas others result from a single episode of damage to which the ventricle responds by remodeling and hypertrophy of the remaining myocytes. The myocardium of DCM, whatever the cause, is never normal. Usually there is dilatation of all four chambers. The dilated left ventricle becomes more spherical in shape, sometimes with evidence of hypertrophy, though this is not a dominant feature. Microscopically, myocyte orientation is more tangential to the circumference, and individual myocytes are elongated with an increased cross-sectional area, but reduced intermyocyte connections and gap junction formation. Together with extensive areas of interstitial and perivascular fibrosis, the result is a disorganized tissue with abnormal contractile and relaxation properties, and heterogeneous electrical conduction.50 DCM patients with interventricular conduction defects have significantly worse systolic function, due in part to ventricular incoordination, particularly if total isovolumic time is increased, and a worse prognosis.51 However, the clinical course is highly varied, and particularly in the group where a single short-lived event is the sole cause, the prognosis may be excellent.


Familial linkage of DCM may account for up to 30% of cases. Mutations at 14 different chromosomal loci have been described, affecting a variety of proteins in the cardiomyocyte52 (Tables 3-11 and 3-12). These proteins can broadly be divided into sarcomeric/myofilament proteins, titin and myofilament anchoring proteins, Z-disk-associated proteins, sarcolemmal cytoskeletal proteins, nuclear envelope proteins, and intermediate proteins linking to the extracellular matrix.53 Familial DCM is genetically heterogeneous, and examples of all the Mendelian modes of inheritance exist, and mitochondrial inheritance has also been reported. In addition to primary cardiac mutations, genetic variance of other systems that influence development of cardiac failure are also important. The polymorphisms of the angiotensin-converting enzyme (ACE) gene have been well-characterized, and the presence of the DD genotype is associated with higher plasma ACE levels and an adverse prognostic outcome in DCM patients.54


A subgroup of patients with genetic causes has multisystem involvement, which may give rise to recognizable syndromes, whose genetic cause has been elucidated. Examples include Duchenne’s muscular dystrophy, myotonic dystrophy, facioscapulohumeral dystrophy, Friedrich’s ataxia, Naxos disease, and Carvajal syndrome (the last two representing the rare cardiocutaneous syndromes).


Postviral myocarditis represents a spectrum of patients, from those with classical fulminant viral myocarditis, whose ventricular function is observed to deteriorate during the course of their illness, through to the majority, who present with the features of DCM and a history of “recent viral illness.”55 The high background incidence of symptom complexes resembling viral prodromes in the general population added to the desire to identify a source or cause on the part of the patient may lead to significant overestimation of this disorder. Initially serological evidence of active viral infection was required, and can be demonstrated in up to 33% of nonfamilial DCM.56 However, the viral titres are unpredictable and are dependent on the humoral immune system. Improvement in detection of viral nucleic acids, in particular by slot-blot probe hybridization and polymerase chain reaction (PCR), has demonstrated the persistence of viral particles in cardiomyocytes after viral myocarditis in patients who subsequently develop DCM.57 Replicative activity of these viral particles is not a necessity, and their mere presence can induce DCM in patients with activated immune systems. The enteroviruses are the commonest culprit, and myosin shares approximately 40% of its amino acid sequence with the coxsackie B3 viral capsid protein.58 This provides a potent autoimmune trigger, which may also occur in response to cardiac protein epitopes exposed during membrane disruption in the acute phases of viral myocarditis. Interaction with the cellular and humoral immune systems is critical, and some DCM patients have abnormalities of the various components of the immune system. Predisposition to unregulated activation following the appropriate viral trigger may unify the viral and immunological hypotheses causing the continuing damage and deterioration of the myocardium.


The worldwide human immunodeficiency virus (HIV) epidemic has created a new category of DCM. There are a variety of cardiac complications of HIV infection and its treatment, but left ventricular enlargement and dysfunction has been demonstrated in 15% of patients, with a further 4% having isolated right ventricular impairment.59 DCM is strongly associated with markers of advanced disease, including CD4 count of <100 cells/mL, and the presence of an HIV-related encephalopathy. The underlying etiology is multifactorial, including direct myocyte infection by HIV, myocarditis secondary to opportunistic infections, autoimmune cardiac damage, nutritional deficiencies, and cardiotoxicity from both HIV therapy and illicit intravenous drug abuse (if the cause of HIV infection).


A variety of toxins can damage the myocardium. The degree of exposure, both in dose and temporal course, together with the potency of the toxin, will determine the level of myocardial damage. Excess alcohol consumption leads to a form of DCM, and is the underlying cause in 3% cases.60 Alcohol may cause myocardial damage by various mechanisms. Ethanol and its metabolites acetaldehyde and acetate have a direct toxic effect of cardiomyocytes.61 This can cause an acute myocardial depression when ingested in large quantities, raising blood ethanol levels >1000 mg/L. Over the chronic course of excess consumption, requiring >80 g/day for >5 years, ethanol impairs excitation-contraction coupling, contractile protein and sarcolemmal function, with reduced myofibrillary protein synthesis. Like other forms of DCM, the hearts of chronic alcoholics with dilated ventricles show an excess of collagen and interstitial fibrosis. Left ventricular dilatation or dysfunction is detectable in up to 30% of chronic alcoholics, but unlike many of the other causes of DCM, these changes are reversible if abstinence is initiated early in the course of the excess consumption. In addition to the direct effects, alcohol can cause cardiac failure through a variety of other means. Thiamine deficiency associated with poor nutritional intake is common in alcoholics and causes heart failure in beriberi syndrome.62 Alcohol predisposes to atrial fibrillation and hypertension, both of which can result in heart failure. Certain toxic substances can be present in various alcoholic beverages. For example, an outbreak of DCM in Canada was traced to an excess of cobalt contaminating the brewing of a popular beer.63,64 Finally, chronic alcoholism leads to profound cognitive impairments including Korsakoff’s psychosis and dementia,65 which will result in alcoholics being less compliant with their heart failure medication, whatever the cause.


Acute cocaine abuse can cause direct myocardial depression, in addition to the ischemia induced by coronary vasospasm.66 There are reports of DCM in chronic cocaine abusers, and there is a synergistic toxic effect of taking cocaine and alcohol together, with the cometabolite cocaethylene also a potent dopamine reuptake inhibitor, which is more lethal than cocaine alone in animal models.67 Various other drugs of abuse, including amphetamines, 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy), organic solvents (toluene, kerosene, gasoline, acrylic paint sprays), and organic nitrites (e.g., amyl nitrite) have been associated with myocardial dysfunction and heart failure.


A variety of prescribed drugs have cardiac side effects, and in particular cardiotoxicity resulting in a DCM phenotype.68 The commonest culprits are the anthracycline-derived chemotherapy agents for a variety of solid and hematological malignancies.69 Soon after their introduction, late cardiac failure was reported in up to 30% patients who had received >500 mg/m2 of doxorubicin (Adriamycin). Despite limiting doses to <450 mg/m2 and excluding patients with preexisting cardiac dysfunction on screening ECG, up to 3% of patients still develop anthracycline-induced DCM. The presentation is highly variable and although the cardiac failure develops a median of 3 months after a dose of anthracycline chemotherapy, case reports presenting decades later are in the literature. The mechanism of toxicity is uncertain, and may involve free radical production and uncoupling of mitochondrial ATP synthesis by doxorubicin binding to cardiolipin in cardiac mitochondrial membranes. Trastuzumab (Herceptin) is a novel monoclonal antibody against erythroblastic leukemia viral oncogene homolog 2 (ErbB2), a coreceptor for neuroregulin signaling, and an effective chemotherapeutic agent in the treatment of breast cancer. It was initially introduced as a second-line agent to anthracyclines, but 7% of patients treated developed cardiomyopathy.70 The protective mechanism of ErbB2 signaling in the heart is still to be elucidated,71 and trials of trastuzumab monotherapy are also ongoing, but it is accepted that it lowers the threshold of anthracycline-induced cardiotoxicity. Likewise, Paclitaxel also amplifies the effect of anthracycline toxicity, up to 14% of patients receiving dual chemotherapy in a trial for metastatic breast cancer.72 Radiation therapy can rarely cause late ventricular systolic dysfunction, though modern techniques including dose fractionation and computerized blocking to reduce cardiac exposure have now limited its incidence.


Peripartum cardiomyopathy is a form of DCM, which must meet the following criteria:


(1) the development of cardiac failure in the last 4 weeks of pregnancy or within 5 months of delivery,

(2) absence of other causes of cardiac failure,

(3) absence of recognizable heart disease prior to the final 4 weeks of the pregnancy,

(4) DCM criteria for left ventricular dysfunction.73 This definition attempts to exclude preexisting but undiagnosed DCM, which will become symptomatic during pregnancy prior to the final 4 weeks of the third trimester. There is a varied course, with up to 50% cases reversible on macroscopic imaging criteria. However, it is more common in subsequent pregnancies, and is associated with other complications of pregnancy such as older maternal age, multiple pregnancy, and preeclampsia.


Uncontrolled tachycardia, predominantly atrial fibrillation, is now recognized as a cause of left ventricular dilation and failure in a pattern mimicking DCM. It has been called tachycardia-induced cardiomyopathy, and generally requires heart rates of >120 beats/min to be present for at least 3 months.74 The continuous excess metabolic demand creates an insidious oxygen supply-demand mismatch, and the ventricular dysfunction is reversible once adequate rate control has been established. As the alternative clinical diagnosis is arrhythmia driven by the primary DCM, the diagnosis can only be made in retrospect after rate control has allowed the ventricle to recover. However, is it likely that this subtype of cardiac failure can be superimposed on other causes of left ventricular dysfunction, emphasizing the importance of rate control in heart failure patients.


Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a relatively common cardiac condition, affecting 1 in 500 of the general population.75 It is characterized by the presence of cardiac hypertrophy with a hyperdynamic left ventricle, in the absence of the other causes of LVH, systemic hypertension or aortic stenosis, or of magnitude beyond that expected by mild forms of these conditions. The hypertrophy is typically asymmetrical, although concentric HCM does occur, and the usual diagnostic cutoff is a wall thickness of ≥15 mm. However, genotype-phenotype correlations demonstrate that almost any wall thickness is compatible with the presence of an HCM mutation. The interventricular septum is predominantly affected, but advances in imaging technology have revealed a variety of other forms including isolated midventricular, apical, and right ventricular HCM. In addition to causing heart failure, many forms predispose to malignant ventricular arrhythmias, and HCM is the commonest cause of sudden death in the young adult population.76


In patients with significant septal or midventricular hypertrophy, obstruction of the left ventricular ejection may occur. This usually involves the left ventricular outflow tract, and results from the systolic anterior movement of the mitral valves leaflets leading to midsystolic contact with the septum. This causes a dynamic obstruction, and may be persistent (detectable in every cardiac cycle), labile (variable) or latent, but provocable by exercise, standing, postectopic response, the Valsalva maneuver, or amyl nitrite inhalation. The presence or absence of a gradient is important as it has prognostic significance, although the magnitude of the gradient does not.77 In addition, the treatment options are different in obstructive disease.


Mitral valve regurgitation, caused by the systolic anterior movement, concomitant mitral valve prolapse, anterior mitral valve leaflet (AMVL) damage from repeated traumatic contact with the septum, and/or involvement of the papillary muscles in the fibrotic disease process, also exacerbates heart failure in HCM patients.


The hypertrophied left ventricle is hyperdynamic with good systolic function early in disease, often with generation of high intraventricular pressures in obstructive disease. However, the left ventricle in HCM has reduced compliance, and is dependent on atrial systole for adequate filling. These diastolic abnormalities are independent of the degree or geometry of the hypertrophy, suggesting a more widespread microscopic disease process. The increased atrial pressures required lead to atrial distension and enlargement, and significant deterioration accompanies conversion of rhythm to atrial fibrillation. Progressive myocardial fibrosis from ischemia and myocyte degeneration eventually leads to wall thinning and progressive dilatation of the left ventricle in a subgroup of HCM patients, and if they survive free of malignant arrhythmias, then they can convert from a hypertrophic to a dilated left ventricular phenotype with severe systolic dysfunction and outflow obstruction disappears.78


Apical HCM was first described in the Japanese population in the 1970s, but is now increasingly recognized globally.79 It characteristically presents with chest pain in the young adult with anterior T-wave inversion in addition to voltage criteria for LVH. Ventriculography reveals a spade-shaped left ventricle at end diastole and the diagnosis is confirmed by cardiac magnetic resonance (MR). The prognosis with apical HCM is better than other forms.


Fifty percent of patients have demonstrable genetic causes (Table 3-13), which are predonichantly transmitted in a Mendelian autosomal dominant inheritance.80 All the mutations known to cause HCM affect 1 of 13 genes, all which encode sarcomeric proteins involved in the structure, regulation and contraction of the thick and thin filaments. Over 200 different mutations have been found, with varying degrees of penetrance, even for the same mutation within a family cohort. This genetic heterogeneity added to the clinical heterogeneity ranging from benign to malignant forms with a high rate of sudden death, varying ages of presentation, and symptom profiles leads unfortunately to the current scenario where identifying the mutant protein does not have sufficient positive or negative predictive power for prognosis. The link between genotype and pathophysiology is not clearly elucidated, and most cases show significant myocyte disarray, with disruption of myocardial bundles into a characteristic whorled pattern. Some myocytes are hypertrophied but otherwise appear normal, whereas others have grossly disorganized intracellular architecture. Extensive fibrosis is evident, and abnormal intramural coronary arteries with wall thickening and lumen reduction are present.


Restrictive Cardiomyopathy

The third group of cardiomyopathies is the restrictive cardiomyopathies (Table 3-13).81,82 The main feature of restrictive cardiomyopathy is abnormal diastolic function. The ventricular walls become rigid and noncompliant, usually due to either an infiltrative or fibrotic pathology. This impedes ventricular filling leading to high atrial pressures with associated atrial distension, and the characteristic tall, peaked “restrictive” E wave on trans-mitral and/or transtricuspid Doppler ECG. It is important to recognize that the term restrictive when applied to transmitral filling represents abnormally high atrial pressure with rapid early filling, which may occur in many other conditions causing heart failure, and the diagnosis of restrictive cardiomyopathy depends upon exclusion of these other causes, certain characteristic features, and identification of the cause. Depending upon the underlying pathology, the ventricles are either normal size or only slightly enlarged due to thickening of the ventricular wall. This increased thickness is due to infiltrative deposits or fibrosis, and not myocyte hypertrophy. Systolic function may initially appear normal, but usually deteriorates as the disease advances.


The causes of restrictive cardiomyopathy compromise a variety of conditions listed in Table 3-13. The main causes vary according to geographical location. In Europe, United States, and Australasia, cardiac amyloid is the commonest form of RCM whereas in the equatorial regions of Africa, the Indian subcontinent, and parts of South America, endomyocardial fibrosis (EMF) is one of the commonest overall causes of cardiac failure. The commonest causes will be briefly discussed.


Amyloidosis is a heterogeneous collection of systemic disorders, which are characterized by the extracellular deposition of autologous proteins, which form twisted sheets of b-pleated fibrils in various tissues including the heart. A simple stratification of these conditions is as follows:


1. A small excess in synthesis of a normal protein results in slow deposition, which takes decades to develop, for example, wild-type transthyretin giving rise to “senile amyloidosis.”


2. A significant excess of a normal protein results in rapid deposition and a faster clinical time course presenting at a younger age. Various mutations of transthyretin have been described, and this form is familial amyloidosis, inherited in an autosomal dominant fashion, and is more common in the Afro-Caribbean population.


3. A rapid synthesis of an abnormal protein, for example, the immunoglobulin light chain produced by the plasma cells of multiple myeloma, traditionally referred to as amyloid light-chain (AL) amyloidosis.


4. The slower synthesis of an abnormal protein, such as the acute phase reactant Serum amyloid A, which accumulates in chronic inflammatory conditions such as rheumatoid arthritis and tuberculosis.


Sheets of the b-pleated fibrils deposit between myocardial fibers and may occur in the ventricles, atria, on the cardiac valves, and in the aortic and coronary artery walls. The classical presentation is with heart failure dominated by right-sided findings, low voltage complexes on the ECG, and a characteristic appearance on ECG of granular, speckled, or sparkling myocardium, which is thick, but does not thicken during systole.83 The thickening may be nonuniform and resemble HCM, and the characteristic restrictive transmitral filling pattern is present. In the absence of systemic evidence of multiple myeloma, endomyocardial biopsy may confirm diagnosis demonstrating the presence of cardiac amyloid on Congo red staining, and a typical appearance on cardiac MR with a characteristic pattern of global subendocardial late enhancement coupled with abnormal myocardial and blood-pool gadolinium kinetics has been described.84


Fabry’s disease, also known as angiokeratoma corporis diffusum universale, has recently been identified as a common cause of cardiomyopathy with features of HCM and RCM.85 It is an X-linked disorder due to lysosomal a-galactosidase A deficiency, leading to the intracellular accumulation of glycosphingolipids (especially globo-triaosylceramide), which causes increased ventricular wall thickness, restrictive diastolic filling, conduction tissue disease, and abnormalities of the mitral valve.86 Endomyocardial biopsy may reveal low a-galactosidase A activity. The skin and kidneys may also be involved.


Sarcoidosis is a granulomatous disorder of unknown etiology, which may involve the myocardium in up to 5% patients. This leads to stiffening of the ventricular myocardium, conduction abnormalities, ventricular arrhythmias, and rarely myocardial infarction due to coronary involvement. The commonest cardiac problem in sarcoidosis is right ventricular failure secondary to the diffuse pulmonary fibrosis seen in advanced cases.87


EMF occurs in equatorial regions as noted earlier, with the highest incidence in Uganda, Rwanda, and Nigeria.81 There is extensive fibrosis, particularly affecting the endocardium, and involves the inflow tracts of the right and/or left ventricles, often involving the atrioventricular valves and subvalvular apparatus. Both apices are also frequently affected. Combined right and left ventricular involvement occurs in 50% cases, with 40% left-sided, and the remaining 10% right-sided. Endocardial fibrosis acts as a substrate for intracavity thrombus formation, leading to cavity obliteration, pulmonary and systemic emboli. The underlying etiology is not known, and the presence of eosinophilia in some, but not all, series has led to speculation of an eosinophil-triggered damage, perhaps initiated by parasitic infection. However, this has not been confirmed. Eosinophils release a number of molecular mediators, which are toxic to the myocardium, and patients with marked eosinophilia may develop endomyocardial involvement. This is most striking in patients with the hypereosinophilic syndrome (Löffler’s endocarditis), who have persistent eosinophilia of >1500/mm3. The circulating eosinophils invade the endocardium, release their toxins (e.g., eosinophil cationic protein), and trigger an intense myocarditis and endocarditis.88 Mural thrombosis and fibrosis may result, and coronary artery involvement may lead to superimposed myocardial ischemia.


The above pathological categories are a useful classification to approach the broad clinical entity of cardiac failure. In the clinical scenario, patients present with variable constellations of symptoms, signs, and findings, and cardiac failure has been divided into a variety of categories as described above. Patients’ symptoms are highly subjective, and are based on both cardiac and noncardiac factors such as muscle tone, anemia, concomitant respiratory or renal disease, cultural and society issues, and there is no significant correlation between symptom severity and objective measurements of cardiac function, although there is some value in prognostic determination.


The authors advocate the practical approach of subclassification based upon the clinical time course and etiology (Tables 3-1, 3-2, 3-3). However, as molecular and genetic diagnostic techniques improve and become more widely available, newer classification may become based on the particular protein, which is affected.


There is already a move to rename familial HCM and DCM in this way, with the new categories listed in Table 3-9. Finally the development of the field of stem cell biology has revealed new insights into cardiac physiology. The demonstration of resident cardiac stem cells with mitotic activity in the adult human heart,89 and the possible derivation of cardiac cells during repair from circulating bone marrow-derived cells,90,91 has disbanded the view of the heart as a postmitotic organ of fixed cell number. This dynamic turnover appears to decrease with age, and we believe that the development of cardiac failure is in part due the overwhelming of the aging, inadequate repair processes by the insults of acquired heart disease, which are far greater than those experienced previously in evolution when the repair systems were created and selected. The supplementation of these reparative processes with novel cellular and molecular therapies may hopefully swing the balance away from cardiac failure, whatever its label or cause.


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