Cardiomyopathy represents a group of diseases of the heart, which involve the heart muscle itself resulting in contractile and relaxation dysfunction of both ventricles leading to progressive chamber dilatation and then hypocontractile walls.
Gross pathology of a dilated cardiomyopathy depicting biventricular and biatrial dilatation and enlargement. Note the thinning of both the right ventricular and left ventricular free walls and the significant increase in ventricular volumes.
Hess, M.L., Pathak, S.K., Dilated Cardiomyopathies, Hurst's The Heart Update I, Chapter 6, p 125
Causes of Cardiomyopathy
A. Genetic Abnormalities
Anatomic features of HCM are demonstrated in the heart of a 26-year-old man. A. Exterior view; both right atrium (RA) and left atrium (LA) are dilated. Ao= aorta; PT= pulmonary trunk. B. Radiograph of specimen showing asymmetric thickening of ventricular septum (VS). C. Coronal section ; the septum is clearly thicker than left ventricular free wall (FW); an endocardial mural contact plaque (arrow) is present in the left ventricular outflow tract in apposition to the anterior mitral leaflet (AML). D. closer view of plaque and thickened anterior leaflet.
(From WC Roberts, VJ Ferrans: Hum Pathol 6:287-342, 1975.)
a. Age mainly young people
b. Abnormally thick IVS (see fig.39a, fig.39b, fig.39f, fig.40a, fig.40b, fig.40c, fig.40d, fig.40e, fig.40f, fig.41,)
c. Abnormal tissue staining properties (see fig.39c, fig.39d)
d. EKG abnormalities ( see fig.61 )
An alcohol cardiomyopathy is said to be present when other causes of a dilated cardiomyopathy have been excluded and there is a history of heavy, sustained alcohol intake. The usual requirement in terms of alcohol amount is 100 g alcohol per day, typically over several years. However, in susceptible individuals it is likely that lower amounts of intake can produce a cardiomyopathy. The histologic features of alcohol cardiomyopathy are nonspecific and do not differ from IDC. Other than history, the only potentially distinguishing feature between IDC and alcohol cardiomyopathy is that the latter may present with a relatively high cardiac output.
The pathophysiology of alcohol cardiomyopathy is thought to he related to the toxic effects of alcohol, plus in some subjects nutritional components such as thiamine deficiency.
The prognosis depends on the degree of impairment of myocardial function and the extent of abstinence from alcohol and, in an extremely compromised patient, the administration of thiamine. There is evidence that the prognosis is somewhat better for alcohol cardiomyopathy than for IDC.
The treatment of alcohol cardiomyopathy does not differ from IDC, except the inclusion of total abstinence from alcohol. Obviously, these subjects are not good candidates for cardiac transplantation because of the high relapse rate to alcoholism.
C. Adramycin, Daunorubicin, Doxorubicin Toxicity
(used in chemotheraphy for cancer )
D. Viral Infections
1. Coxsachie B
E. Chagas' Disease (Parasitic)
Chagas' disease is discussed as a cause of myocarditis. In addition, Chagas' disease is the most common cause of nonischemic cardiomyopathy in South and Central America, with over 10 million people afflicted. It is caused by a parasite, the leishmanial or tissue form of the protozoan Trypanosoma cruzi.
In settings as above where most transmissions are vectorborne, triatomine bugs defecate and inoculate trypomastigotes of the protozoan T.cruzi at mucosal surfaces or wound(bite sites).
Although in the United States the vector (triatoma, or kissing bug) is found only in the Southwest, Chagas' disease may be transmitted by blood transfusions, and as a result, it could become relatively more important in this country.
Additonal modes of transmissions have been described, including oral and vertical(transplacential) routes and organ donations. Transmissions by means of transfusions and organ donations are of growing significance in the United States and other industralied countries. As many as 20- 40% of infected persons will enter the chronic phase and have complications,primarily cardiac or gastrointestinal. Immunosuppress hosts can also have systemic parasitemia on reactivation of infection or neurologic manifestions including menigencephalitis.
The natural history consists of an initial myocarditis most commonly presenting in childhood, associated with acute myocardial infection followed by recovery and in some individuals the development of a dilated cardiomyopathy 10 to 30 years later.
In the acute phase, the diagnosis of Chagas' disease is made by visualization of parasites on thick and thin blood smears stained with Giemsa, but parasites become difficult to detect by 3 months after the infection.
The diagnosis of Chagas' cardiomyopathy is based on clinical (history, LV function, and electrocardiographic) criteria and a positive serologic test for T. cruzi.
Two tests are routinely run routinely performed: an enzyme-linked immunosorbent assay(ELISA) and an indirect immunoflourescence test for antobodies. Although the indirect immunoflourescence test is quite sensitive, cross-reactivity can be seeen with serum samples from patients with leishmaniasis.
Electrocardiographic abnormalities consist of bundle-branch or hemiblocks (indeed, hemiblocks were first described by Rosenbaum et al) in Chagas' afflicted hearts with discrete foci of involvement), LV hypertrophy, and first- or second-degree atrioventricular (AV) block.
The histologic lesion of chronic Chagas' consists of mononuclear infiltrates, fibrosis, and as shown in Fig. 74f below foci of the leishmanial form of T. cruzi in myocardial fibers.
The LV functional abnormalities initially may be segmental and may include an apical aneurysm but later become more global.
74f. Leishmanial forms of T.
cruzi within the swollen cytoplasm of a cardiac myocyte (Chagas'
&E stain, x250).
(Courtesy Dr. Elmer Koneman.)
The basis for Chagas' cardiomyopathy is unknown but may be immunologic, whereby antibodies generated against T. cruzi crossreact with cardiac "
The prognosis is relatively good for a dilated cardiomyopathy and similar toIDC; the five-year survival with heart failure is around 50 percent. Compared with IDC, death likely occurs more commonly due to an arrhythmin mechanisn. However. as for IDC and most othert dilated cardiomyopathies, mortality risk depends directly o the degrees of ventricular dysfunction and exercise intolerance.
There is no definitive treatment for Chagas' cardiomyopathy, and nonspecific treatment includes pacemaker implantation for heart block and heart failure treatment as for IDC. The one exception may be the more frequent use of amiodarone, which appears to be particularly effective in treating arrhythmias associated with Chagas' cardiomyopathy and in one study reduced mortality compared with standard treatment. The role of cardiac transplantation is still somewhat uncertain, but it can be done at acceptable risk, especially when coupled with trypanocidal
Dilated cardiomyopathies are important because they are the most common cause of heart failure, which is the single most costly medical problem in the adult U.S. population. Cardiomyopathies in general are a heterogeneous group of diseases, but they can be classified under a newly modified WHO/ISFC classification system, which, although imperfect, should he of great value in standardizing the terminology and encouraging systematic investigative and clinical approaches to diagnosis and treatment. Within this classification system, primary and secondary dilated cardiomyopathies comprise the single largest and most important group. Current diagnosis and treatment of dilated cardiomyopathies vary somewhat among the various types, but the cornerstones of medical management are similar in most cases.
Genetic causes and influences on the natural history of dilated cardiomyopathies are the new frontier in this field, and their elucidation is almost certain to lead to new therapeutic and diagnostic approaches. In the near future, molecular genetic testing will be done routinely for many cardiomyopathies that may have a single gene defect as the cause. As we learn more about the influence of polymorphic genetic variation on the natural history and selection of specific medical therapy, genetic testing will be performed in most patients with cardiomyopathy.
(Abnormal deposition of iron in heart muscle)
J. Ischemic Coronary Artery Disease
K. Arrhythmogenic RV Dysplasia
FAMILIAL ARRHYTHMOGENIC RIGHT
VENTRICULAR DYSPLASIA (ARVD)
Arrhythmogenic right ventricular dysplasia is characterized by fatty infiltration of the right ventricle, fibrosis, and ultimately thinning of the wall with chamber dilatation. It is the most common cause of sudden cardiac death in the young in Italy and is said to account for about 17 percent of sudden death in the young in the United States. Rampazzo et al. mapped this disease in two families, one to 1q42-q43, and the other on chromosome 2q32; a third locus was mapped to 14q12. A large Greek family with arrhythmogenic right ventricular dysplasia and Naxos diseasewas recently mapped to 17q. Two loci responsible for AR\'D in North America were recently mapped at 3p23 and the other at lOpl2. This is a very devastating disease, since the first symptom is often sudden death. Electrocardiographic abnormalities include inverted T waves in the right precordial leads, late potentials, and right ventricular arrhythmias with left bundle-branch block (LBBB).This is compounded by me great difficulty in making tne diagnosis even when the condition occurs in a family with a history of the disease. Since the disease affects only the right ventricle, it is difficult to detect. There is no definitive diagnostic standard. The right ventricular biopsy is definitive when positive but often produces a false-negative result, since the disease initiates in the epicardium and spreads to the endocardium of the right ventricular free wall, making it
inaccessible to biopsy. Consensus diagnostic criteria was developed that include right ventricular biopsy, magnetic resonance imaging (MRI), echo-cardiography, and electrocardiography. Identification of the gene will have tremendous diagnostic impact and hopefully will provide an explanation as to why ARVD is restricted to the right ventricle. Is it a specific right ventricular chamber gene? Is there a stimulus that is unique or predominates in the right ventricle that precipitates the phenotype? What is the stimulus? There are data suggesting that apoptosis is the process leading to the development of fat and fibrosis in ARVD. Discovery of a gene should shed light on the apoptosis pathway.
Arrhythmogenic right ventricular dysplasia
(ARVD) is predominantly right ventricular cardiomyopathy characterized
by fatty or fibrofatty replacement of myocardium. It is a rare
cause of sudden cardiac death except in a few endemic regions.
Recurrent ventricular tachycardia with multiple left bundle-branch
block morphologies typifies this disorder. It is a familial
disorder in approximately 30 percent of cases, with an autosomal
dominant mode of inheritance. The gene defect has been localized
to chromosomes 1, 3, and 14 In the fibrofatty variety, patchy
myocarditis, programmed cell death, and/or congenital abnormalities
of development appear to lead to myocardial atrophy and repair
by fibrofatty replacement, which may become the basis for reentrant
ventricular arrhythmia. The left ventricle and ventricular septum
can be involved in 50 to 67 percent of cases, especially later
in the course of the disease, and such involvement confers a
The electrocardiographic manifestations in sinus rhythm include T-wave inversion in V1V3 or complete or incomplete right bundle-branch block. Intraventricular conduction delay may produce a terminal notch on the QRS complex called an epsilon wave in approximately 50 percent of patients. The ventricular ectopy is usually of a left bundle-branch pattern, with a QRS axis between 90° and +110°, and generally arises from one of three sites of fatty degeneration. Called the triangle of dysplasia, these sites are the right ventricular outflow and inflow tract and apex. Any patient with frequent premature beats of a left bundle-branch morphology and left-axis deviation should be evaluated for this disorder.
In patients with ARVD, particularly at early stages of the disease, ventricular tachycardia is often precipitated by exercise, and its induction is usually found to be catecholamine sensitive at electrophysiologic study. The course and prognosis of ARVD are highly variable and difficult to predict. The annual incidence of sudden cardiac death in ARVD has been estimated to be about 2 percent despite various treatments.
Righe ventricular dysplasiais a cardiomyopathy predominantly of the right ventricle. Left ventricle involvement is usually of a lesser and variable degree. Several anomalies may be included under this general heading: Uhis anomaly, arrhythmogenic right ventricular dysplasia, and right ventricular cardiomyopathy. It is currently recognized as an important inherited cardiomyopathy and a cause of sudden death, especially in youth. Its cause is unknown, although an autosomal dominant pattern with variable expression and penetrance has been suggested, since many cases show a strong familial tendency.
Clinically patients typically present with recurrent ventricular tachycardia of left-bundle-branch-block morphology and, less commonly, CHF. Standard electrocardiography discloses incomplete or complete right-bundle-branch block in most patients or T-wave inversions in leads V1-V3 (Fig. A). These conduction or repolarization abnormalities are thought to be due to adipose infiltration of the myocardium. Clinical diagnosis is based on detection of predominantly right ventricular morphologic changes on imaging studies. Echocardiography is an effective tool to demonstrate the characteristic abnormal structure of the right ventricle, including hypokinesis, massive dilatation, and a parchment-thin wall (Fig. B). In addition, tricuspid regurgitation and paradoxic ventricular septal wall motion are common. Pathologically, there is variable infiltration or replacement of the right ventricular myocardium by adipose and fibrous tissue.
The importance of right ventricular dysplasia is its association with sudden death, with an incidence of up to 20 percent in some series.
Therapy therefore is focused on the prevention of sudden death with implantation of automatic internal cardioverter-defibrillators.
UhIs' anomaly. A. Twelve-lead electrocardiogram demonstrating characteristic right bundle branch block with T-wave inversions in leads V1-V3. B. Two-dimensional echocardiographic four-chamber view demonstrating massive right ventricular dilation "parchment-thin" wall
Gradient-echo image of a patient with arrythmogenic RV dysplasia (ARVD). Note the focal region of thinning of the right.
Ablation of Ventricular Tachycardia Foci
One of the most demanding of the catheter-ablative techniques is attempted ablation of foci initiating ventricular tachycardia. For this procedure, multipolar electrode catheters are inserted into the right ventricle, coronary sinus, and left ventricle. Ventricular tachycardia is induced by using standard stimulation protocols, and the catheters are manipulated within the ventricles to determine the earliest ventricular endocardial electrogram (during ventricular tachycardia) in relation to at least three reference orthogonal surface leads. Ventricular overdrive pacing is used in an attempt to entrain the tachycardia and to prove that the earliest endocardial potentials precede (rather than follow) the tachycardia complex. In addition, the putative focus of ventricular tachycardia is paced in an effort to determine whether the paced complexes are identical or similar to the induced tachycardia. The latter procedure is known as pace mapping. For patients with ventricular tachycardia due to coronary artery disease, concealed entrainment is manifest by a prolonged paced spike to QRS, a paced QRS identical to spontaneous tachycardia, and a post-pacing interval identical to the spontaneous ventricular tachycardia cycle length, which appears to best identify the critical slow zone for the ventricular tachycardia reentrant circuit. Once the putative isthmus is found, one or more radiofrequency applications are delivered from the distal electrode near this endocardial site to a chest-wall patch.
A subset of patients with ventricular tachycardia and structural heart disease particularly amenable to catheter ablation are those with bundle-branch reentrant arrhythmias. These patients are recognized by having a left intraventricular conduction delay or a frank pattern of left bundle-branch block. The majority have an associated cardiomyopathy, and all have prolonged infranodal conduction. In these patients, the tachycardic mechanism involves bundle-to-bundle conduction. 27 Catheter cure may be achieved by ablation of the right bundle branch. The right bundle usually is draped superficially over the right septal surface, and the right bundle potential usually is located easily. The right bundle may be ablated either by direct current or preferably by radiofrequency discharges. 27 Even after successful ablation of the right bundle branch, further electrophysiologic testing is in order to exclude ventricular tachycardia emanating from myocardial sources.
Other forms of ventricular tachycardia that may be particularly amenable to catheter ablation are those occurring in patients without structural cardiac disease. These patients present with tachycardia emanating from either the right ventricular outflow tract~ or from the inferior left septum.29 Patients with tachycardia emanating from the right ventricular outflow show a pattern of left bundle-branch block with an inferior axis. The arrhythmia is often exercise-induced and may respond to carotid massage or treatment with adenosine or beta blockers. This arrhythmia is thought to be a cyclic AMP-dependent triggered arrhythmia. The hallmark of proper ablation includes detection of early areas in the outflow tract and a precise correspondence between the paced map and spontaneous ventricular tachycardia. Another important site of ventricular tachycardia in normal hearts may emanate from the left apical septum. This arrhythmia is characterized by a pattern of right bundle-branch block associated with a left superior axis. This arrhythmia most often responds to intravenous verapamil. Ablative approaches include recording a Purkinje potential just in front of the QRS complex and/or a paced map that corresponds to the spontaneous tachycardia.
Ablation of ventricuiar tachycardia
Successful ablation was more frequent in those with ventricular tachycardia associated with no structural heart disease (85 percent), including those with right ventricular outflow tract tachycardia or left septal tachycardia, compared with ablation for ventricular tachycardia associated with coronary artery disease (58 percent) or idiopathic cardiomyopathy (62 percent).Major complications included a post-procedural death from presumed respiratory failure and cardiac tamponade, pulmonary edema, systemic emboli, AV block, and femoral artery thrombosis.
ADVANTAGES AND DISADVANTAGES of CATHETER-ABLATIVE TECHNIQUES
The use of catheter-ablative techniques has
greatly affected our approach to the management of patients
with supraventricular tachycardia. Catheter ablation of the
AV junction has replaced the need for surgical ablation of the
His bundle for patients with atrial arrhythmias refractory to
drug therapy. Furthermore, use of catheter procedures allows
cure of patients with reentrant supraventncular arrhythmias.
The initial reports suggest a cure rate of 90 to 100 percent
with minimal serious adverse effects. For selected patients
with ventricular tachycardia, catheter-ablative procedures may
obviate the need for surgical intervention. This is particularly
true for patients with bundle-branch reentry or for those with
right ventricular outflow tract or left septal tachycardias
The chief disadvantage of AV junctional
ablation is the need for chronic cardiac pacing after successful
ablation. Another serious adverse effect is the reported 2 to
4 percent incidence of polymorphous ventricular tachycardia
occurring in the post-ablative period. This arrhythmia is more
common in patients with severe myocardial disease, bradycardia,
and electrolyte abnormalities, and may be prevented by temporarily
pacing the heart at relatively fast rates immediately after
ablation. The chief complication reported for patients undergoing
AV modification procedures for AV nodal reentry is the risk
of complete AV block. Attempted ablation of the slow AV nodal
pathway promises to diminish or obviate this risk.
The risks of catheter ablation of accessory pathways appears to be related to the pathway site. Reported complications for left free wall pathways include the risk of systemic embolization, tamponade, or damage to the left circumflex coronary artery. Ablation of septal pathways carries the risk of causing inadvertent complete AV block. Fortunately, the risk of significant 12 complications appears to be on the order of approximately 2 percent.
Major complications have been reported in the use of catheter-ablation treatment of ventricular tachycardia. Such compli cations include the risk of cerebrovascular accidents, damage to the aortic valve, or tamponade.
Mutations in sarcomere protein genes (cardiac beta-myosin heavy chain and cardiac troponin T and actin) account for about 10 per cent of cases of familial dilated cardiomyopathy and are prevalent in families with early-onset ventricular dilatation and dysfunction resulting in congestive heart failure and sudden death in children and young adults.
Because distinct mutations in sarcomere proteins cause either dilated or hypertrophic cardiomyopathy, the effects of mutant sarcomere proteins on muscle mechanics must trigger two different series of events that remodel the heart
(see figure 126).
Reference:Kamisago,M.and Others,The New England Journal of Medicine,12/7/00,Vol.343,No.23,PP168-169
Genetic Causes of Cardiomyopathies in Humans and Animal Models
The ability to genetically manipulate the cardiovascular system has made it possible to investigate the role of a number of genes in the developing and adult mouse heart (for a review, see Robbins). The discovery that mutations in sarcomeric proteins lead to HCM has made it possible to generate ani
mal models for this disease. In the case of myosin mutations, a single genetic defect initiates a pathway that ultimately leads to hypertrophy and then in males results in late decompensation and ventricular dilatation. Multiple gene mutations have now been associated causally with familial dilated cardiomyopathies.
A serendipitous genetic model of dilated cardiomyopathy and heart failure (myf 5 mice) has been generated by activation of a skeletal muscle genetic program in the heart. These mice have a dilated cardiomyopathy phenotype characterized by progressive myocardial dysfunction and dilatation. They develop the clinical syndrome of heart failure, and they have an extraordinarily high (>90 percent at 260 days) heart failure-related mortality Another serendipitous genetic model of dilated cardiomyopathy is the muscle LIM protein (MLP) knockout mouse. 2 MLP is a positive regulator of muscle differentiation that is ordinarily expressed at high levels in the heart and which may be involved in myofibrillar protein assembly along the actin-based cytoskeleton MLP knockout mice exhibit typical features of dilated cardiomyopathy, including decreased systolic and diastolic function and /3-adrenergic
These characteristics make this model very useful in assessing the mechanisms that lead to the development and progression of myocardial failure. Thus, in transgenic mouse models, both altered expression of contractile proteins and perturbation of myocyte cytoarchitecture can lead to the dilated cardiomyopathy phenotype.
There are several additional transgenic mouse models of cardiomyopathy that may be more relevant to the production of a dilated phenotype in humans. Three of them involve overexpression of components of the adrenergic receptor pathway, the heterodimeric G-protein a, subunit (Gas)23,z4 and the /31_21,2' and /32-adrenergic receptors. These B-adrenergic pathway transgenic mouse models exhibit similar histopathology consisting of myocyte hypertrophy and increased fibrosis, evidence of apoptosis, systolic and diastolic dysfunction, and ultimately, development of LV dilatation.
Several transgenic models of concentric or symmetrical LV hypertrophy have now been reported, including overexpression of the protooncogenes ras and myc, a,-adrenergic receptors, the heterodimeric G-protein a subunit (G-alpha-4),and protein kinase C (PKC) The mechanisms for the induction of increased ventricular wall thickness are diverse, inasmuch as the ras, a,receptor, G-alpha, and PKC overexpressors exhibit true cellular hypertrophy with an increase in cell size , whereas the myc animal exhibits cardiac myocyte hyperplasia The HCM phenotypes discussed earlier illustrate the principle that apparently diverse signals can culminate in the same phenotype, presumably by converging on final common pathways.
Multiple gene defects have been identified that can produce a dilated cardiomyopathy in humans, as discussed in more detail in the section on familial forms of dilated cardiomyopathy. As listed in Table 66-2, these include mutations in the cardiac a actin, 34 desmin, 35 dystrophin, 36, 31 and lamin3s.39 genes.
Polymorphic Variation in Modifier Genes
Genes exhibit polymorphic variation; i.e., normal variants of genes exist in the population that are of slightly different size or sequence. Some gene polymorphisms are associated with differences in function of the expressed protein gene product, and some of these differences in function likely account for "biologic variation" routinely encountered in population
Examples of "modifier" genes that may have an impact on the natural history of a dilated cardiomyopathy (see Table 66-2) include the angiotensin-converting enzyme (ACE) DD genotype, where individuals are homozygous for the "deletion" variant, which is associated with increased circulating" and cardiac tissue41 ACE activity. The DD genotype appears to increase the extent of hypertrophy in HCM and may be a risk factor for early remodeling after MI and for the development
Other potentially important polymorphic variants that may influence the natural history of a cardiomyopathy involve the angiotensin AT-1 receptor and B2-adrenergic receptors.
Altered, Maladaptive Expression of a Completely Normal Gene
The third way in which altered gene expression can contribute to the development of a cardiomyopathy is altered, maladaptive expression of a completely normal "wild type" gene." This occurs most commonly in the context of progression of heart muscle disease and myocardial failure, which is the natural history of virtually all cardiomyopathies once they are established. Examples in this category include downregulation of B1-adrenergic receptors, alpha-myosin heavy chain (alpha-MHC), and sarcoplasmic reticulum Ca2+ ATPase genes and upregulation in the atrial natriuretic peptide (ANP),myosin heavy chain (B-MHC), ACE, tumor necrosis factor (TNF-alpha), endothelin, B-adrenergic receptor kinase (B-ARK) genes. These concepts are discussed
PATHOPHYSIOLOGIC PROCESSES INVOLVED IN MYOCARDIAL DYSFUNCTION, REMODELING, AND THEIR PROGRESSION
Tissue preparations and myocytes isolated from failing human hearts exhibit evidence of decreased contractile function Assuming that loading conditions and ischemia are not adversely affecting cardiac myocyte function, in the setting of chronic systolic dysfunction from a dilated cardiomyopathy, progressive myocardial failure is most likely caused by myocardial cell loss or changes in the gene expression of proteins that regulate or produce muscle contraction. Figures 126-b and 126-c summarize these general points and emphasize the central roles of the renin-angiotensin system (RAS) and the adrenergic nervous system (ANS) in promoting cell loss, growth and remodeling, and altered gene expression.
Myocardial Dysfunction and Remodeling due to Altered Expression of Contractility Regulating Genes and Changes in Sarcomeric Assembly
Gene expression can be defined, broadly, as the expression of a fully or normally functioning protein gene product or, more narrowly (and commonly), as the steady-state abundance of a gene's mRNA transcript. Using either definition, numerous
FIGURE 126-b Relationship of neurohormonal activation and production of cardiac myocyte loss due to apoptosis and necrosis and altered gene expression. Cell loss and altered gene expression result in more myocardial dysfunction, and a vicious cycle is established. RAS = renin angiotensin system; ANS = adrenergic nervous system.
FIGURE 126-c Heart failure compensatory mechanisms that are activated to support the failing heart. Light-colored areas indicate physiologic mechanisms that stabilize pump function.
abnormalities of gene expression of normal, wild-type genes have been demonstrated in the failing human heart, as discussed earlier. In order to characterize the abnormalities that may account for progressive myocardial dysfunction and remodeling, it is useful to subdivide them into two general categories,as shown in table 66-3 below.
The first category encompasses mechanisms that subserve intrinsic function, or the mechanisms responsible for contraction and relaxation of the heart in the basal or resting state. Intrinsic function is defined as myocardial contraction and relaxation in the absence of extrinsic influences, such as neurotransmitters or hormones.
The second general category is modulated function, which comprises the mechanisms responsible for the remarkable ability of the heart to increase or decrease its performance dramatically (by 2- to 10-fold) and rapidly in response to various physiologic or physical stimuli. Other critical organs such as the brain, kidney, and liver do not exhibit this quality. Modulated function is defined as stimulation or inhibition of myocardial contraction or relaxation by endogenous bioactive compounds, including neurotransmitters, cytokines, autocrine/paracrine substances, and hormones.
In the failing human heart, changes are present in the expression of genes potentially responsible for both general types of myocardial function . Abnormalities of intrinsic function include the factors responsible for an altered length-tension relation a blunted force-frequency response and/or the signals responsible for abnormal cellular and chamber remodeling . In the case of the abnormal forcefrequency and length-tension responses, the evidence favors abnormal contractile function of individual cardiac myocytes.As shown in table 66-3,these abnormalities likely reside in the contractile proteins or their regulatory elements, mechanisms involved in excitation-contraction coupling, or the cytoskeleton. However, within these possibilities for altered intrinsic function, there is not currently a consensus as to which specific abnormalities are present in idiopathic dilated cardiomyopathy (IDC), the most common form of heart failure studied in humans. For cellular remodeling, in both human ventri- cles and animal models, the assembly of sarcomeres in series leads to a myocyte that is markedly increased in length but not in diameter, which contributes to remodeling at the chamber level. Such remodeling places the chamber and the myocyte at an energetic disadvantage because of the attendant increase in wall stress, which is one of the major determinants of myocardial oxygen consumption. Inadequate myocyte energy production, particularly associated with key subcellular ion flux mechanisms or the myosin ATPase cycle, in turn would contribute to myocyte contractile dysfunction. Moreover, the hypertrophy process itself leads to a qualitative change in contractile protein gene expression (induction of a "fetal" gene program) that reduces contractile function . On the other hand, cardiac myocyte contractile dysfunction likely plays a role in the remodeling process, inasmuch as medical treatment that improves intrinsic myocardial function can reverse remodeling.' Thus contractile dysfunction and remodeling at the cellular level are intimately related to the progressive contractile dysfunction and chamber enlargement that define the natural history of myocardial failure." These concepts are summarized in Fig. 126-d.
In contrast to abnormalities of intrinsic
function, a consensus has been reached on several specific abnormalities
in the stimulation component of modulated function. Most of
these changes concern B-adrenergic signal transduction. The
ability of beta adrenergic stimulation to increase heart rate
and contractility is markedly attenuated in the failing heart
due to multiple changes at the level of receptors, G-proteins,
and adenylyl cyclase. This produces a major abnormality in the
stimulation component of modulated function. In addition, the
inhibition component of modulated function is also abnormal
in the failing heart, due to a reduction in parasympathetic
There is obviously overlap between the two major subdivisions of myocardial function. Recent data indicate that even in the absence of adrenergic stimulation, beta-adrenergic receptors have intrinsic activity That is, a small number of receptors are in an activated state without agonist occupancy and as such can support intrinsic myocardial function ....ft. Thus overexpression of human B2-adrenergic receptors is able to markedly increase intrinsic myocardial function, as is enhancement of sarcoplasmic reticulum calcium uptake and release by genetic ablation of the phospholamban gene. The recent realization that active state, agonist-unoccupied beta-adrenergic receptors can modulate intrinsic myocardial function is the reason why the "R-G-adenylyl cyclase" mechanism appears in both categories in Table
ProgressiveMyocardial Dysfunction and Remodeling due to Loss of Cardiac Myocytes
The second general mechanism by which myocardial function may be adversely affected is by loss of cardiac myocytes,, which also my play a role in the progresssion of ventricular dysfunction in dilated cardiomyopathies. Cardiac myocyte loss can occur via toxic mechanisms producing necrosis or by "programmed cell death" producing apoptosis. Apoptosis, which is likely due to a combination of growth signaling and cell cycle dysregulation, has been described in end-stage IDC, as well as in the B-1,-adrenergic receptor, the G alpha- s overexpressor transgenic mice, and in models of hypertrophy. However, the human hearts with IDC or ischemic cardiomyopathy were taken from very late stage, literally dying patients maintained on multiple powerful intravenous inotropic medications,and it is not clear if apoptosis plays a significant role in remodeling and/or chamber systolic dysfunction
IMPORTANCE OF "COMPENSATORY"
As depicted in Fig. 126-b and Fig. 126-c, there is now a large body of information supporting the idea that activation of the ANS and RAS compensatory mechanisms contributes to, or is responsible for, the progressive nature of both myocardial failure and the natural history of the heart failure clinical syndrome. This evidence includes the observations that activation of both these systems is associated with progression of myocardial dysfunction and the heart failure syndrome and clinical trial data that consistently demonstrate that inhibition of these systems can prevent deterioration in or improve myocardial function as well as reduce mortality . Despite the fact that in human heart failure we now know that chronic
|TABLE 66-3 General Categorization
of Myocardial Function
Intrinsic (Function in the Absence of Neural or Hormonal Influence)
| Contractile proteins
E-C coupling mechanisms
R-G-adenylyl cyclase pathways
Sarcomere and cell remodeling
ABBREVIATIONS: E-C = excitation-contraction;
R-G = receptor-G-protein.
Modulated (Function that May Be Stimulated or Inhibited by Extrinsic Factors Including Neurotransmitters, Cytokines, or Hormone)
Fig.126-d: Relationship between progressive myocardial dysfunction and remodeling.RAS= renin angiotensin system;ANS =adrenergic nervous system.
activation of the ANS and RAS contributes to the progressive nature of myocardial dysfunction, we know virtually nothing about how these systems adversely affect the biology of the cardiac myocyte. What we do know is that mechanisms within both general categories outlined in Table 66-3 below (fig. 126-d) must be involved in the adverse myocardial effects mediated by the ANS and RAS. This is so because modulated function may be improved by treatment with ACE inhibitors or beta-blocking agents. Progressive myocardial dysfunction and remodeling are attenuated by both beta-blocking agents and ACE inhibitors, and in cardiomyopathies, intrinsic myocardial function is improved and remodeling is reversed by chronic treatment with beta-blocking agents. Additionally, mortality in chronic heart failure is directly related to activation of the ANS and RAS and may be related to activation of other neurohormonal or autocrine/paracrine systems as well.
Regardless of the type or cause of dilated cardiomyopathy, an initial myocardial insult resulting in this phenotype exhibits common pathophysiologic features that are summarized in Fig. 126-c. That is, a myocardial insult that produces systolic dysfunction will be followed by the initiation of processes designed to temporarily stabilize pump function. The possible mechanisms available for such stabilization are in fact limited. As shown in Fig. 126-b, in chronological order of their action, they are an increase in heart rate and contractility mediated by an increase in cardiac beta-adrenergic signaling (produced within seconds of the onset of pump dysfunction), volume expansion in order to use the Frank-Starling mechanism to increase stroke volume (evident within hours of the onset of pump dysfunction), and cardiac myocyte hypertrophy to increase the number of contractile elements (evident within days to weeks of the onset of pump dysfunction). As shown in Fig. 126-b, these compensatory adjustments are largely accomplished by activation of the RAS and ANS. However, despite the short-term (days to months) stability achieved via these mechanisms, they ultimately prove harmful. The best evidence that chronic, continued activation of the RAS and ANS contributes to progressive myocardial dysfunction and remodeling comes from clinical trials where both inhibitors of the RAS (ACE inhibitors) and ANS (beta adrenergic receptor-blocking agents) prevent these two phenomena, and beta-blocking agents actually may reverse remodeling and progressive systolic dysfunction, as alluded to.
Much current work is focused on the precise pathophysiologic mechanisms by which activation of the RAS and ANS produces remodeling and adverse effects on myocardial function. Some of the possibilities are given in Fig. 126-b, and they include an exacerbation of ischemia and/or energy depletion leading to cell loss via necrosis, cell loss by programmed cell death, direct promotion of hypertrophy and remodeling through stimulation of cell growth, and alterations in cardiac myocyte gene expression. A key feature of the schema shown in Fig. 126-b is the process of remodeling. Virtually all dilated cardiomyopathies undergo this process, which is characterized by progressive dilatation, progressive myocardial systolic dysfunction in viable segments, and a chamber shape change whereby the ventricle becomes less elliptical and more round 6°63 As shown in Fig. 126-d, this places the ventricle at an energetic disadvantage, which likely contributes to further myocardial dysfunction, which then contributes to progressive remodeling. The latter observation is based on data obtained with beta-adrenergic blocking agents, which produce an improvement in systolic dysfunction that can be detected prior to a reversal in remodeling .As emphasized by Fig. 126-d, each myocardial degenerative process likely begets the other, leading to an inexorably progressive deterioration in myocardial performance and clinical condition.
SCOPE OF DILATED CARDIOMYOPATHIES
The number of cardiac or systemic processes that can produce or are associated with a dilated cardiomyopathy are plentiful and remarkably varied, as shown in Table 66-4. The dilated phenotype is by far the most common form of cardiomyopathy, comprising over 90 percent of subjects referred to specialized centers. In the United States, the most common dilated cardiomyopathy is ischemic dilated cardiomyopathy, or the cardiomyopathy that follows MI. Other common secondary dilated cardiomyopathies are hypertensive and valvular dilated cardiomyopathies, both produced in part by chronically increased wall stress. The primary cardiomyopathy, IDC, is another relatively common dilated phenotype, as discussed below.
SELECTED, COMMON TYPES OF DILATED CARDIOMYOPATHIES
Ischemic cardiomyopathy is defined as a dilated cardiomyopathy in a subject with a history of MI or evidence of clinically significant (i.e., approximately70 percent narrowing of a major epicardial artery) coronary artery disease, in whom the degree of myocardial dysfunction and ventricular dilatation is not explained solely by the extent of previous infarction or the degree of ongoing ischemic. In other words, an ischemic dilated cardiomyopathy is present when a post-MI left ventricle experiences remodeling and a drop in ejection fraction.
Dilatation of the left ventricle and a decrease in ejection fraction occurs in 15 to 40 percent of subjects within 12 to 24 months following an anterior MI and in a smaller percentage of subjects following an inferior MI. Based on limited data '41 it is tempting to speculate that the subjects who undergo the remodeling process and develop an ischemic dilated cardiomyopathy are individuals with particularly heightened compensatory mechanisms (see Fig. 126-b and Fig. 126-c), perhaps as a result in polymorphic variation in these systems. As discussed earlier, the remodeling process is an attempt by the compromised ventricle to increase its performance by increasing stroke volume, but ultimately, it correlates with an adverse outcome in the long term.
The gross pathology of ischemic cardiomyopathy includes transmural or subendocardial scarring, representing old MIs, that may comprise up to 50 percent of the LV chamber. The histopathology of the noninfarcted regions is similar to changes that occur in IDC, as discussed below.
Several studies have concluded that ischemic cardiomyopathy patients have a worse prognosis than subjects with a "nonischemic" dilated cardiomyopathy, probably because the risk of ischemic events is added to the risk of
The treatment of ischemic dilated cardiomyopathy and chronic heart failure is covered in detail in elsewhere1. In general, treatment consists of the use of ACE inhibitors in asymptomatic or symptomatic patients, the use of diuretics in volume-overloaded subjects, and the use of digoxin in subjects who remain symptomatic on the former medications. An emerging treatment strategy is the use of beta-adrenergic blocking agents in mild to moderately symptomatic subjects , whereas in both ischemic and nonischemic dilated cardiomyopathies, second- and third-generation compounds improve LV function, reduce hospitalizations, and lower mortality. Additionally, adjunctive therapy includes anticoagulation in subjects with lower LV ejection fractions to prevent thromboembolic complications, amiodarone to treat symptomatic arrhythmias, maintaining potassium levels in the high normal (4.3-5.0 meq/L) range to prevent sudden death, frequent clinic visits to adjust medications, and an aggressive approach to treating ischemia, including revascularization.
A hypertensive dilated cardiomyopathy is diagnosed when myocardial systolic function is depressed out of proportion to the increase in wall stress. In other words, a subject presenting in heart failure with a hypertensive crisis would not carry this diagnosis unless ventricular dilatation and depressed systolic function remained after correction of the hypertension. In addition to producing a "pure" form of hypertensive cardiomyopathy, hypertension is a major risk factor for heart failure from any cause.Within the WHO/ISFC classification, "hypertensive heart disease" may present in the "dilated'' ,"restrictive'', or "unclassified" categories.
The most important pathophysiologic element in hypertension in dilated cardiomyopathy is sustained increased systolic wall stress. Interestingly, in both systolic pressure overloaded right and left ventricles, phenotypic expression is qualitatively variable and can include dilatation and systolic dysfunction without increased wall thickness, increased wall thickness, concentric hypertrophy with or without systolic dysfunction, and systolic dysfunction without concentric hypertrophy. Other contributors to the pathophysiology of hypertensive cardiomyopathies are local neurohormonal mechanisms.
The prognosis depends on the presence of other comorbid conditions such as diabetes mellitus and coronary artery disease, as well as the extent of control of afterload. Compared with other forms of cardiomyopathy, in the absence of comorbid conditions, the prognosis of hypertensive cardiomyopathy in subjects whose afterload is controlled is probably better than for most other types of dilated cardiomyopathy.
The treatment is as for ischemic dilated cardiomyopathy, except that afterload must be vigorously controlled. This consists of the addition of pure antihypertensive vasodilators such as amlodipine or a-blocking agents to standard heart failure therapy.
A valvular cardiomyopathy occurs when a valvular abnormality is present and myocardial systolic function is depressed out of proportion to the increase in wall stress. This most commonly occurs with left-sided regurgitant lesions (mitral regurgitation and aortic regurgitation), less commonly occurs with aortic stenosis, and never occurs as a consequence of pure mitral stenosis.
The classic explanation for the typical phenotypes observed in valvular cardiomyopathies relates to exposure to different types of wall stress."' Within this construct, the pattern of eccentric hypertrophy derives from increased diastolic wall stress.Thus long-standing mitral regurgitation most commonly results in compensated eccentric hypertrophy that can progress to a dilated failing phenotype. Aortic regurgitation is a particularly poorly tolerated hemodynamic insult because wall stress is increased in both systole and diastole, and when decompensation occurs, ventricular volume will be increased with or without increased wall thickness. Aortic stenosis classically results in compensated concentric hypertrophy, but when decompensation occurs, a variety of phenotypes can be observed that are similar to hypertensive cardiomyopathies. A disturbing and fairly commonly observed phenomenon is the development of a dilated cardiomyopathy after surgical correction of mitral and sometimes aortic valve disease in subjects who preoperatively had only mild LV dysfunction. These cases are likely due to the superimposition of myocardial damage resulting from open heart surgery and/or underlying dysfunction
The prognosis is variable and depends on the number of associated conditions, the nature and extent of the valvular abnormality, and most important, the severity of the cardiomyopathy at the time of surgical correction (see below). In general, severely depressed myocardial function will not improve much with surgical repair of aortic regurgitation or mitral regurgitation, but the prognosis is likely to be improved because of elimination of some of the hemodynamic insult. Replacement of the mitral valve should not be attempted in the majority of subjects with severe mitral regurgitation and LV ejection fractions less than 25 percent because of prohibitively high operative/perioperative mortality rates. On the other hand, there is no impairment of LV systolic function severe enough to preclude valve replacement of severe aortic stenosis, since function invariably will improve on relief of the hemodynamic insult, and the prognosis is relatively good.
The treatment of a valvular dilated cardiomyopathy is surgical valve replacement or repair as soon as the cardiomyopathy is detected. Catheter valvuloplasty may be an option for severe aortic stenosis (AS) patients who are not good surgical candidates for reasons other than heart failure. Medical treatment may be the only option in subjects with aortic insufficiency or mitral regurgitation whose LV function is severely impaired. The medical treatment of either disorder should be as mentioned earlier for ischemic cardiomyopathy plus aggressive afterload reduction, usually hydralazine/nitrates on top of ACE inhibitors. The calcium channel blocker amlodipine is another option for afterload reduction, particularly for aortic insufficiency, where calcium channel blocker therapy has been shown to improve survival.
Idiopathic Dilated Cardiomyopathy, Including Familial Forms
IDC is diagnosed by excluding significant coronary artery disease, valvular abnormalities, and other causes. IDC is a relatively common cause of heart failure, with an estimated prevalence rate of 0.04 percent and incidence rates varying from 0.005 to 0.006 percent . The true incidence of IDC is undoubtedly higher, owing to the fact that subjects may remain asymptomatic until marked ventricular dysfunction has occurred. The incidence of IDC increases with age, and males are afflicted at a higher rate than are females. As discussed below, histologic features are nonspecific and consist of myocardial cell hypertrophy and varying amounts of increased interstitial fibrosis. Although the diagnosis is not difficult, problems arise when an apparent IDC presents in someone with a history of hypertension or excessive alcohol intake. In such cases, it is best to reassign the etiology to alcohol only when the intake has exceeded 80 g/day for males and 40 g/day for females for more than 5 years and to hypertensive heart disease when blood pressure has been uncontrolled and high (>160/100 mmHg), as well as sustained (for years). All subjects with an unexplained dilated cardiomyopathy need a thyroid-stimulating hormone (TSH) determination done to exclude hypo- or hyperthyroidism, and subjects with diastolic dysfunction need to have an infiltrative process excluded. As discussed below, this is best done by performing
IDC may be familial in as many as 35 to 50 percent of the patients when first-degree relatives are carefully screened.' The analysis of the phenotype identifies a wide range of clinical and pathologic forms indicating genetic heterogeneity. Accordingly, several chromosomal assignments for gene location have been made, and recently, as shown in Table 66-2, several genes have been identified . The majority of familial patients present with autosomal dominant inheritance and a phenotype characterized by low and age-related penetrance (which is the proportion of carriers who manifest the disease). It is estimated that only 20 percent of gene carriers under the age of 20 display the disease phenotype. Autosomal dominant dilated cardiomyopathy can be due to mutations of the cardiac actin or desmin gene, but in the majority of cases the disease gene is still unknown. The detection of an altered creatine kinase level can indicate the existence of a subclinical skeletal muscle disease. In these patients, an X-linked inheritance suggests mutations in the dystrophin gene whereas an autosomal dominant transmission and the presence of conduction defects and arrhythmia suggests mutations in the lamin A/C gene . In laminopathy, the phenotype of the affected relatives can be very variable, from a pure IDC to a mild Emery-Dreifuss-like or limb-girdle-like muscle dystrophy . Skeletal muscle and endomyocardial biopsy are diagnostic in X-linked dilated cardiomyopathy, showing abnormalities of dystrophin protein expression by immunocytochemistry. Finally, autosomal recessive transmission of dilated cardiomyopathy occurs in mutations of sarcoglycan genes, which encode for dystrophin complex-associated proteins.
Dystrophin, sarcoglycans, desmin, and lamin are cytoskeletal proteins. The contractile protein cardiac a-actin also has a forcetransmission or cytoskeletal role. Other data support the hypothesis that IDC could represent, in the majority of cases, a disease of the cytoskeleton; absence of the protein metavinculin in the myocardium was reported in one IDC patient, and as discussed earlier, a dilated cardiomyopathy can be created in mice22 or is present in a hamster line related to mutations in cytoskeletal genes. However, as discussed earlier, it appears that other genetic abnormalities such as mutations in contractile proteins and overexpression of beta-adrenergic receptors or Gas24 also can produce a dilated phenotype.
In children, X-linked familial IDC suggests mutation in the G4.5 or tafazzin gene, particularly if associated with certain other signs (such as endocardial fibroelastosis, neutropenia, short stature, or skeletal muscle abnormalities). The function of tafazzin is still unknown. In mitochondrial DNA (mtDNA) mutations, myocardial dysfunction usually is associated with multiorgan involvement (encephalopathy, lactic acidosis, skeletal muscle abnormalities, retinitis pigmentosa, etc.). It is still unclear whether a mtDNA mutation can lead to an isolated IDC phenotype in adults.
Although still incomplete, new knowledge on the genetics of IDC has important clinical implications. The frequency of familial forms indicates the need of family screening in IDC, which can allow genetic counseling, an early detection of the disease, and early therapeutic interventions in affected relatives. The complexity of the phenotype requires an accurate skeletal muscle investigation, which can direct the diagnosis toward a specific type of familial myopathy. Finally, family investigations require more sensitive diagnostic criteria 131 that are able to detect minor cardiac abnormalities as initial signs of the disease. These include initial dilatation without marked systolic dysfunction, arrhythmia, and isolated wall and other abnormalities.
The major morphologic feature of IDC on postmortem examination is dilatation of the cardiac chambers . One ventricle (usually the left) may be more dilated than the other ventricle. The weight of the heart is increased in IDC, with a mean cardiac weight of 551 g for women and 632 g for men. Although there is an increase in muscle mass and myocyte cell volume in IDC, LV wall thickness is usually not increased because of the marked dilatation of the ventricular cavities. Grossly visible scars may be present in either ventricle, and while most scars are small, some may be large and transmural. Scarring occurs in the absence of significant narrowing of the epicardial coronary arteries. In most cases, the degree of fibrosis does not appear to be extensive enough to cause changes in systolic or diastolic function. Intracardiac thrombi and mural endocardial plaques (from the organization of thrombi) are present at necropsy in more than 50 percent of patients with IDC. The effect of anticoagulation on the incidence of thrombi has not been studied carefully, but systemic and pulmonary emboli are more frequent in patients with ventricular thrombi or plaques.
The characteristic findings of IDC on microscopy are marked myocyte hypertrophy, very large, bizarrely shaped nuclei (Fig. 126-e) , increased interstitial fibrosis (see Fig. 126-e), myocyte atrophy, and myofilament loss. In isolated cardiac myocytes, the major cellular phenotypic change is marked increase in cell length without a concomitant increase in diameter. As described earlier, this cellular lengthening or remodeling contributes to the chamber remodeling/dilatation that characterizes IDC and other cardiomyopathies. These morphologic changes in IDC are not specific and are generally found in secondary cardiomyopathies such as in the noninfarcted regions of ischemic dilated cardiomyopathy. Also, the morphometric changes in IDC do not correlate with the severity of illness. Ultrastructural abnormalities such as mitochondrial changes, T-tubular dilatation, and intracellular lipid droplets may be observed in IDC but also can be observed in other forms of heart disease . There may be interstitial parenchymal and perivascular focal infiltrates of small lymphocytes. The lymphocytic infiltrates that are present on histologic examination in IDC are not associated with adjacent myocyte damage, in contrast to myocarditis where adjacent myocyte necrosis is observed. Fibrosis is nearly always present in IDC, and its pattern is quite variable from a fine perimyocytic distribution to coarse scars indistinguishable from those present in chronic ischemia. However, small intramural arteries and capillaries are structurally normal in IDC.
A number of immune regulatory abnormalities have been identified in IDC, including humoral and cellular autoimmune reactivity against myocytes, decreased natural killer cell activity, and abnormal suppressor cell activity.These abnormalities suggest that immune defects may be important etiologic factors in the development of IDC. These findings, however, are not universally present in patients with IDC, and some abnormalities are also present in other types of heart muscle disease. For example, an increase in the cardioselective M7 antimitochondrial antibodies is found in both IDC and hypertrophic cardiomyopathy but not in heart failure from coronary artery disease. The incidence of some autoreactive antibodies, such as antinuclear and antifibrillary antibodies, increases with the severity of heart failure. It is likely that many of the antibodies detected in IDC and other myocardial diseases do not have pathogenic relevance, but rather are secondary to the primary degenerative process. However, it is possible that certain antibodies present in IDC may have important functional implications. For example, anti-beta1-adrenergic receptor antibodies could modify beta-adrenergic receptor activity and produce chronic increases in signal transduction that are harmful to the failing heart. Disturbed energy metabolism from antibodies to the ADP/ATP carrier of the inner mitochondrial membrane is another potential pathogenetic autoimmune mechanism ; these antibodies are present in some individuals with IDC and have been shown to impair metabolism and myocardial function.
There has been great interest in histocompatibility locusantigens (HLAs) in IDC because these antigens are knownto be associated with immune regulatory functions, and manyautoimmune diseases are found to have positive HLA antigenicassociations. HLA associations also have been identified in IDC;the frequency of HLA-B27, HLA-A2, HLA-DR4, and HLADQ4 is increased compared with controls, and the frequencyof HLA-DRw6 is decreased compared with controls. Geneticabnormalities in the HLA region potentially could alter immuneresponse and thereby increase disease susceptibility to infectious agents such as enteroviruses. Thus the association in IDCwith specific HLAs suggest a possible immunologic etiology for thisdisease. However, these specificHLAs are present in less than 50percent of patients with IDC, andthe heterogeneity of these antigens does not point to a uniquesite for a putative disease-associated gene. Thus, while the autoimmune hypothesis is an attractivecandidate for the etiology of somecases of IDC, it remains unproved.
A clinical and pathologic syndrome that is similar to IDC may develop after resolution of viral myocarditis in animal models and biopsy-proven myocarditis in human subjects. This has led to speculation that IDC may develop in some individuals as a result of subclinical viral myocarditis. Theoretically. an episode of myocarditis could initiate a number of autoimmune reactions that injure the myocardium and ultimately result in the development of IDC. The
FIGURE 126-e: Right ventricular endomyocardial biopsy from a subject with IDC. Note the increased nuclear size (arrow) and the increased interstitial fibrosis.
abnormalities in immune regulation and the variety of antimyocardial antibodies present in IDC are consistent with this hypothesis. However, it is generally not possible to isolate an infectious virus or to demonstrate the presence of viral antigens in the myocardium of patients with IDC.'S4 Enteroviral RNA sequences are found in heart biopsy samples in IDC, but only in approximately one-third of patients. Furthermore, active myocardial inflammation is usually not detected in IDC. However, in controlled trials, corticosteroid therapy of patients with IDC does not result in significant clinical improvements . Importantly, recent experimental data have shown in vitro and in vivo that the enteroviral protease 2A is able to cleave dystrophin and disrupt the cytoskeleton in cardiac myocytes, providing a potential link between viral infection and a genetic model of the disease. Furthermore, analysis of human viruses other than enteroviruses suggests that adenoviruses, herpesvirus, and cytomegalovirus also can cause myocarditis and potentially IDC, particularly in children and young subjects. Further investigation will be necessary to understand the significance of these findings, particularly in the adult population.
Endomyocardial biopsy of the right or left ventricle may be a valuable diagnostic adjunct for diagnosing specific myocardial processes that can produce a dilated phenotype, such as myocarditis and infiltrative cardiomyopathies. Since several of these other dilated cardiomyopathies may have specific treatments and/or a different prognosis than IDC, endomyocardial biopsy may be warranted in many individuals presenting with a dilated cardiomyopathy. In the future, biopsy may be used more frequently to identify genetic disorders resulting in abnormal gene or protein expression, such as now can be done to diagnose Becker-Duchenne cardiomyopathy. Since special staining, electron microscopy, or molecular analysis of the biopsy material may be necessary, endomyocardial biopsy is best performed in specialized cardiomyopathy/heart failure centers.
Several studies of the natural history of IDC have been conducted . The prognosis is generally better than for ischemic cardiomyopathy, and prior to the routine use of ACE inhibitors, survival was approximately 50 percent in 5 years. The prognosis has been improved substantially since then, inasmuch as ACE inhibition, cardiac transplantation and beta-adrenergic blockade are all effective treatments in this cardiomyopathy.
The treatment of IDC is similar to that discussed earlier for ischemic cardiomyopathy, except that there is no issue of revascularization. The risk of thromboembolic complications may be higher than in ischemic cardiomyopathy, resulting in a lower threshhold for anticoagulation. Beta-Adrenergic blockade produces a quantitatively greater degree of improvement in LV function compared with ischemic cardiomyopathy either because there is a greater degree of adrenergic activation or there is more viable myocardium to work with in IDC. Approximately 10 percent of IDC subjects treated with beta-adrenergic blockade will normalize their myocardial function, and this form of treatment should be offered to all IDC patients who do not have a contraindication before considering cardiac transplantation.
SELECTED SPECIFIC DILATED CARDIOMYOPATHIES
WITH UNIQUE MANAGEMENT ISSUE
The commonly used and highly efficacious anthracycline antibiotic anticancer agents doxorubicin and daunorubicin produce a dose-related cardiomyopathy that may limit their clinical application. Within the WHO/ISFC classification, an anthracycline cardiomyopathy would most likely be in the "dilated" category, but because the extent of dilatation initially may be minimal (see below), it also could be in the "unclassified" category. The cardiomyopathy produced by these agents depends on the total cumulative dose, and for the more widely used compound doxorubicin (Adriamycin), the incidence of heart failure due to cardiomyopathy dramatically increases above total cumulative doses of 450 mg/m2 in subjects without underlying cardiac problems or other risk factors.Prior mediastinal radiation involving the heart is a powerful risk factor for anthracycline cardiomyopathy, and the risk is also evident i f radiation treatment follows chemotherapy. In subjects with risk factors, anthracycline cardiomyopathy
Although the diagnosis of anthracycline cardiomyopathy can be made clinically, the definitive diagnosis depends on the demonstration of a substantial number of cardiac myocytes exhibiting the characteristic anthracycline effect. Tissue sampling is best done by endomyocardial biopsy, which allows for "thin section" electron microscopic processing of the sample and more definitive resolution of the anthracycline effect with
In the absence of a tissue diagnosis, anthracycline cardiomyopathy may be diagnosed clinically by exclusion of other causes of cardiomyopathy in a subject who has had at least 350 mg/m2 of doxorubicin or the equivalent amount of another anthracycline. As shown in Fig. 126-f , the anthracycline cardiac myocytic lesion consists of cell vacuolization progressing to cell dropout, and when 16 to 25 percent of the total number of sampled cells exhibit this morphology, myocardial dysfunction results.
There are some distinguishing clinical features of anthracycline cardiomyopathy that may relate to its pathophysiology. These include a relative absence of hypertrophy and dilatation and a higher heart rate (110-130 beats per minute) than is usually encountered in ambulatory heart failure. The reasons for these features are that the onset of symptoms may be relatively acute (remodeling takes time to develop), and the anthracycline inhibits contractile protein synthesis, reducing the amount of compensatory dilatation and remodeling. In this situation, the only option available for stabilizing cardiac output is increasing the heart rate, since increasing stroke volume via a larger end-diastolic volume has been precluded. The increased heart rate is produced by a greater than expected hyperadrener-gic state,and so these subjects may be exceptionally dependent on adrenergic support.
FIGURE 126-f Cardiac myocyte vacuolization in cases of Adriamycin cardiomyopathy classified on endomyocardial biopsy as grade 3 by the Billingham classification.
The prognosis of anthracycline cardiomyopathy is variable and depends on numerous factors, including the age and underlying prechemotherapy cardiac status of the patient and the time of presentation relative to the last dose of drug. Subjects who present late (several months) or very late (years) after the last dose have a better prognosis because the anthracycline myocardial effect takes at least 60 days to become fully manifest. That is, subjects who develop heart failure within a few days of the last dose of drug have an additional cardiomyopathic burden to face, since the last one to two doses produce their full morphologic effect over the next 1 to 2 months.
Subjects who develop anthracycline cardiomyopathy should be treated aggressively with conventional heart failure treatment, since some degree of reversibility is likely. Conventional treatment consists of ACE inhibitors, digoxin, and diuretics. Beta-Adrenergic blockade has been used successfully in some subjects, but because of the high adrenergic drive, it may be difficult to administer. On the other hand, the heightened adrenergic mechanism may be producing a commensurate amount of adverse effect on the myocardium, and so the potential for a favorable response may be even greater than in other kinds of cardiomyopathy. In severe refractory cases, cardiac transplantation may be performed provided that the patient's cancer is in complete remission and is not likely to recur (approximately70 percent chance of cure).
Several strategies have been shown to lower the risk of developing anthracycline cardiomyopathy without compromising the chemotherapy response rate. These include using endomyocardial biopsy and right-sided heart catheterization with exercise to assess risk, which virtually eliminates clinical cardiomyopathy and allows more anthracycline to be administered to less susceptible subjects; using serial radionuclide angiography with or without exercise as a monitoring strategy, which may be somewhat helpful but because of a low specificity reduces the total amount of chemotherapy that can be administered safely to some subjects; giving the agents as low-dose weekly or as 48- to 72-h infusions rather than as every 3- to 4-week boluses; using a liposomal formulation ; or concomitantly administering a second agent that reduces toxicity. Unfortunately, none of these strategies completely eliminates the risk of developing a clinical cardiomyopathy.
Postpartum or peripartum cardiomyopathy is defined as the presentation of systolic dysfunction and clinical heart failure during the last trimester of pregnancy or within 6 months of delivery. Given the extreme hemodynamic load produced by pregnancy, it is perhaps surprising that postpartum cardiomyopathy is not more common.
Postpartum cardiomyopathy most likely will be classified within the "dilated" WHO/ISFC category but occasionally will be "unclassified" because dilatation and remodeling have not had time to occur. Postpartum cardiomyopathy is likely a heterogeneous group of disorders consisting of the addition of the hemodynamic load of pregnancy to a variety of underlying myocardial processes, including hypertensive heart disease, familial or idiopathic
Approximately half of subjects who develop postpartum cardiomyopathy will recover completely, and the majority of the rest will improve. Subjects who have developed a postpartum cardiomyopathy should never become pregnant again, even if myocardial function has recovered fully.
Treatment should be aggressive and as for IDC. Cardiac transplantation may be required in severely compromised patients who do not improve.
N. Friedreich Ataxia
Sarcoidosis is a systemic granulomatous disease of unknown etiology characterized by enhanced cellular immune responses. The patholo
gic hallmark of this disease is the noncaseating granuloma (figure 77 c).The initial lesion is an inflammatory infiltrate consisting of activated helper-induced T lymphocytes and abundant macrophages that secrets cytokines. The macrophages aggregates and the differentiate into epitheliod and multinuclear giant cells. Fibroblasts, mast cells, collagen fibers and proteoglycans encase the inflammatory cells into a ball-like cluster. The fibrotic response results in end-organ damage.
Clusters of cases have been observed, suggesting
spread by person to person-to-person exposure or environmental
Genetic factors may also play a role in the development of the disease as an exaggerated cellular immune response and information of granulomas may develop in genetically predisposed hosts after exposure to the offending antigen.
The clinical manifestations of sarcoidosis are protean. The disease may be widespread or limited to a single organ. Virtually any organ except the adrenal gland may be involved. The lymphoid , pulmonary, cardiovascular, hepatobiliary, and hematologic systems are the most commonly involved, with the lungs being affected in over 90 percent of patients.
Cardiac sarcoid is more common than previously recognized. In a recent autopsy study of 38 patients with sarcoidosis, 76 percent had cardiac involvement, accounting for 50 percent of the deaths. In other series, sarcoidosis affected the heart in 25 to 50 percent of autopsy cases with fatality in 50 percent of the cases with cardiac involvement. Cardiac sarcoid is more likely fatal and less likely to be diagnosed antemortem than pulmonary sarcoid,. Cardiac sarcoid is more commmonly than previously recognized. In arecent autopsy of 38 patients with sarcoid, 76 % had cardiac involvement accounting for 50% of the deaths. In other series,,sarcoidosisaffeccted the heartt in 25 to 50% of autopsy cases with fatality i 50% of hte cases with cardica involvment.Cardiacx sarcoid is more likey fatal and less likely to be diagnosed antemortem than pulmonary sarcoid.. Frequently the initial presentation is that a sudden death. Myocardial involvement peaks between the third and sixth decades of life. Less than 10 per cent of patients with sarcoid have symptoms referable to the cardiovascular system.
In myocardial sarcoid, portions of the myocardial
wall are replaced by sarcoid granulomas, which preferentially
involve the cephalad portion of the ventricular septum or the
left ventricular papillary muscles. Myocardial involvement is
much more common than pericardial involvement. Cor pulmonale
due extensive pulmonary sarcoidosis with interstitial fibrosis
Because of the varied extent of the myocardial granulomas, presenting signs and symptoms range from first degree heart block to fulminant heart failure. First degree AV block, bundle -branch block, complete heart block,ventricular arrhythmias ,sudden death, and heart failure occur with a frequency of 10 to 20 per cent. Heart failure can present as s cardiomyopathy with restrictive hemodynamics.Some 25 percent of the deaths due to cardiac sarcoid are from heart failure, while sudden death accounts for one-third to one-half of the deaths.
In diagnosing cardiac sarcoid, evidence of
other organ system involvement including lymphadenopathy, hepatomegaly,
splenomegaly, or pulmonary findings should be sought. In cases
where the heart is involved to a much greater degree than are
other organs little or no evidence of extra cardiac sarcoidosis
may be found. Chest x-ray, ECG and echocardiography findings
will depend on the extent and location of involvement .
Due to the scattered nature of the granulomas, endomyocardial biopsy lacks sensitivity and seldom makes the diaognosis despite high specificity. Magnetic resonance imaging has been useful in diagnosing scars or lesions in the myocardium due to sarcoid.
Although no controlled trials have been performed, high dose corticosteroids are usually given in the hope that the course of the disease may be altered. Administration of corticosteroids can improve cardiac symptoms and reverse ECG changes in over half of treated patients. Antiarrhythmic drugs should be used as necessary, although drug therapy of ventricular tachycardia in patients with sarcoidosis, even when guided with program ventricular stimulation, is associated with a high rate of arrhythmia reoccurrence or sudden death. Automatic internal cardioverter-defibrillators have been advocated. Prognosis after the diagnosis of cardiac sarcoid is variable but can the poor. In one series of 247 patients, survival was 41 percent at five years and fifteen percent at ten years. Transplantation is also a successful treatment, as recurrences of sarcoid in the allograft is low, possibly due to post transplants steroid therapy.
Q. Noncompaction Syndrome of the Left Ventricle, Endocardial Fibroelastosis(EFE), Barth Syndrome
Noncompaction of the left ventricular myocardium is characterized by numerous, prominent ventricular trabeculations, deep intertrabecular recesses (areas of abnormal blood lakes within the endocardium), arrhythmias and a distinctive facial dysmorphism. The right ventricle may be similarly involved with these markedly abnormal trabeculations. There is no abnormal wall thickening. Wall thickness is normal.
There is endocardial thickening in cases of endocardial fibroelastosis, leading to decreased compliance and impaired diastolic function.Primary forms are typically unassociated with other cardiac anomalies. It usually presents in infancy and early childhood with signs and symptoms of congestive heart failure. The diagnosis is made by biopsy. Treatment with anticongestive and inotropic measures have been ineffective, and the clinical course usually results in death or transplantation. Histopathology reveals extensive deposition of extracellular matrix (collagen and elasticfibers)
Three inherited forms have been described. The majority of cases occur sporadically. The X-linked form shows miitochondrial abnormalities similar to Barth syndrome with the exception that EFE patients have endocardial scarring. It is likely that this form is caused by mutations in the G4.5 gene found in Barth syndrome and LV noncompaction.
The incidence of the sporadic form has diminished markedly in the U.S. with the giving of vaccine (mumps-measles-rubella) to many in the population.
The Barth syndrome has skeletal muscle involvement and white cell abnormalities as well as cardiac abnormalities.
But all three have mutations in the G4.5,
as does dilated hypertrophic cardiomyopathy (see above)..
Cardiac arrhythmias including ventricular tachycardia are common in these cases, and hence implantable cardiac defibrillators are advised.
At times, as the problem progresses and cardiac failure occurs,there has been the need to do heart transplants when medication fails.
Non-compaction of Myocardium Cardiomyopathy
Non-compaction of the ventricular myocardium ("spongy myocardium") is a rare congenital cardiomyopathy of children and adults resulting from arrested myocardial development during embryogenesis. Prior to formation of the epicardial coronary circulation at about 8 weeks of life, the myocardium is a meshwork of interwoven myocardial fibers that form trabeculae and deep trabecular recesses. That increased surface area permits perfusion of the myocardium by direct communication with the left ventricular cavity. Normally,as the myocardium undergoes gradual compaction, the epicardial
In this disorder, echocardiography demonstrates a thin epicardium with extremely hypertrophied endocardium and prominent trabeculations with deep recesses. These features tend to be apically localized since compaction would normally proceed from base to apex, and from epicardium to endocardium.
Clinical presentation consists of congestive heart failure with depressed left ventricular systolic function, ventricular arrhythmias, arterial thromboemboli from thrombus formation within the inter - trabecular recesses, as well as restrictive physiology from endocardial fibrosis.
INCIDENCE AND NATURAL HISTORY OF LEFT VENTRICULAR NON-COMPACTION PRESENTING DURING CHILDHOOD.
P. Daubeney, A. Nugent, P. Chondros, L. Wilkinson, A.M. Davis, S. Kleinert, C.W. Chow, J.L. Wilkinson, R. Weintraub.
Departments of Cardiology, Clinical Epidemiology & Biostatistics, and Anatomic Pathology, Royal Children's
Left-ventricular non-compaction (LVNC) has previously been considered a rare medical curiosity whose cause and outcome are unknown. This review examines the clinical features and outcomes for children with LVNC who were enrolled in the National Australian Childhood Cardiomyopathy Study. This is an ongoing population-based study which includes all children within Australia with primary cardiomyopathy who presented at 0-10 years of age.
The diagnosis was based on the presence of characteristic honeycomb or spongiform appearance of ventricular myocardium on echocardiography, angiography, cardiac MRI or direct examination. The prognostic factors sought included age at presentation, gender, dominant pathophysiology (DCM or RCM), ventricular systolic dysfunction at presentation, number of affected myocardial segments and presence of Barth syndrome. A total of 21 patients were identified, representing 6.5% of the NACCS study population. The diagnosis was made from echocardiography in 21, ventricular angiography in 11, cardiac MRI in 1 and direct examination (transplant/post-mortem) in 4.
The median age at presentation was 0.4 years (range 1 day - 9.7 years). CHF was the presenting symptom in 17/21 (81%) and 14 patients (67%) presented prior to 12 months of age. Barth syndrome was present in 5/21 (24%). The dominant pathophysiology was DCM in 16 (76%), RCM in 4 (19%) with one child (5%) having normal cardiac function.
Survival free from cardiac transplantation was 55% at 10 years of age and 30% after 15 years. Survival free from late cardiac dysfunction (defined by death, transplant, FS<25% or arrhythmias requiring therapy) was 35% at 10 years and 15% at 16 years. Barth syndrome was the only variable related to outcome. Children with Barth syndrome had a superior 10 year survival (100% vs 25%) and freedom from cardiac dysfunction (75% vs 12%; P<.02 for both) compared to the remaining study
We conclude that LVNC is more frequent than previously recognised. Patients without Barth syndrome have a poor prognosis and merit early consideration of cardiac transplantation.