CARDIOMYOPATHIESMost cardiac disease is secondary to some othercondition (e.g., coronary atherosclerosis,hypertension, or valvular heart disease). However,there are some that are attributable to intrinsicmyocardial dysfunction. Such myocardial diseasesare termed cardiomyopathies (literally, heartmuscle diseases). They are a diverse group thatincludes inflammatory disorders (myocarditis),immunologic diseases (e.g., sarcoidosis), systemicmetabolic disorders (e.g., hemochromatosis),muscular dystrophies, and genetic disorders ofcardiac muscle cells. In many cases,cardiomyopathies are of unknown etiology(termed idiopathic); however, several previously"idiopathic" cardiomyopathies have been shown tobe caused by specific genetic abnormalities incardiac energy metabolism or structural andcontractile proteins.
CARDIOMYOPATHIES classification divides cardiomyopathies into three groups : Dilated cardiomyopathy Hypertrophic cardiomyopathy Restrictive cardiomyopathy
CARDIOMYOPATHIES Among these, dilated cardiomyopathy is most common (90% of cases), and restrictive cardiomyopathy is the least frequent. Within each pattern there is a spectrum of clinical severity, and each of these three patterns can be caused by a specific identifiable cause or can be idiopathic (Table 11-5). While the recent American Heart Association classification is intellectually more satisfying, we follow here the time- honored clinicopathologic classification since, at present, it is more useful for patient management.
Before we go into further details, somecomments are in order aboutmyocarditis. They are included hereunder the umbrella ofcardiomyopathies since there isclinical overlap between some cases ofmyocarditis and dilatedcardiomyopathy and in a proportionof cases, dilated cardiomyopathy canbe shown to evolve from acutemyocarditis. Indeed, since experts atthe American Heart Association alsoinclude myocarditis amongcardiomyopathies, we seem to be ingood company
Dilated cardiomyopathy (DCM) ischaracterized by progressive cardiac dilationand contractile (systolic) dysfunction,usually with concurrent hypertrophy. It issometimes called congestivecardiomyopathy. Approximately 25% to 35%of DCM cases have a familial (genetic) basis.Others result from a variety of acquiredmyocardial insults including toxic exposures(e.g., chronic alcoholism), myocarditis, andpregnancy-associated changes (see later). Insome patients, the cause of DCM isunknown. Such cases are appropriatelycalled idiopathic dilated cardiomyopathy.Many in this category are likely to be ofgenetic origin. Regardless of the cause, allshare a similar clinicopathologic picture.
The heart in DCM is characteristicallyenlarged (two to three times itsnormal weight) and flabby, withdilation of all chambers .Because of the wall thinning thataccompanies dilation, the ventricularthickness may be less than, equal to, orgreater than normal. Mural thrombiare common and may be a source ofthromboemboli. By definition there isno primary valve pathology;consequently, any valvularinsufficiency is a secondaryconsequence of ventricular chamberdilation. The coronary arteries areusually free of significantatherosclerotic stenosis.
The histologic abnormalities inDCM are nonspecific.Microscopically most myocytes arehypertrophied with enlargednuclei, but many are attenuated,stretched, and irregular. There isvariable interstitial and endocardialfibrosis; scattered scars are also oftenpresent, probably marking previousmyocyte ischemic necrosis caused byreduced perfusion (due to poorcontractile function) and increaseddemand (due to myocytehypertrophy). The extent of thechanges frequently does not reflectthe degree of dysfunction or thepatients prognosis.
When discovered clinically, DCM is frequently at its end stage, and many hearts showonly the nonspecific findings described above. As a result the etiology can often onlybe inferred by the patients medical history, or it is based on epidemiologic evidence.The causes of DCM can be grouped into four broad categories:Viral. The nucleic acid "footprints" fromcoxsackievirus B and other enteroviruses canoccasionally be detected in the myocardium.Moreover, sequential endomyocardialbiopsies have documented cases where thereis progression from myocarditis to DCM.Consequently, some cases of DCM areattributed to myocarditis ; even withoutdirect evidence of inflammation, simplyfinding viral transcripts may be sufficient toinvoke a myocarditis that was "missed" in itsearly stages .
Alcohol or other toxic exposure. Alcoholabuse is strongly associated withdevelopment of DCM. Alcohol and itsmetabolites, especiallyacetaldehyde, have a direct toxic effecton myocardium. Moreover, chronicalcoholism can be associated withthiamine deficiency, introducing anelement of beriberi heart disease.Nevertheless, the cause-and-effectrelationship with alcohol alone isdebated, and no morphologic featuresserve to distinguish alcoholiccardiomyopathy from DCM of any othercause. Nonalcoholic toxic insultsinclude certain chemotherapeuticagents, particularly doxorubicin(Adriamycin), and cobalt
Genetic influences. Familial forms of DCM account for 25% to 35% ofcases; autosomal dominant inheritance is the predominant pattern; X-linked, autosomal recessive, and mitochondrial inheritances are lesscommon.Most of the genetic abnormalities seem to involve the myocytecytoskeleton. Although not the most common form, X-linked DCMcaused by mutation in the dystrophin gene is the best understood.Dystrophin is an intracellular structural protein that plays a critical role inlinking the cytoskeleton of striated muscle with the extracellular matrix;indeed, dystrophin is mutated in the most common muscular dystrophies.Interestingly, some patients with dystrophin gene mutations have DCM asthe primary clinical feature. Other cytoskeletal proteins involved in DCMinclude α-cardiac actin (links the sarcomere with dystrophin), desmin (theprincipal intermediate-filament protein in cardiac myocytes), and thenuclear lamins A and C. Mitochondrial gene deletions and mutations ingenes encoding enzymes involved in fatty acid beta-oxidation canpresumably cause DCM by altering myocardial ATP generation
Peripartum cardiomyopathy occurs late in gestation or severalweeks to months postpartum. Theetiology is multifactorial, includingpregnancy-associated hyper-tension, volume overload, nutritionaldeficiency, other metabolicderangement, and/or an immunologicresponse (e.g., abnormal cytokineproduction).Fortunately, approximately half ofthese patients spontaneously recovernormal function
Clinical FeaturesDCM can occur at any age, including inchildhood, but it most commonly occursbetween ages 20 and 50 years. It typicallypresents with slowly progressing (e.g.,shortness of breath and poor exertionalcapacity), but patients can slip precipitouslyfrom a compensated to a decompensatedstate. The fundamental defect in DCM isineffective contraction. Hence in end-stageDCM, the cardiac ejection fraction istypically less than 25%. Secondary mitralregurgitation and abnormal cardiac rhythmsare common, and embolism fromintracardiac thrombi can occur. Fifty percentof patients die within 2 years, and only 25%survive longer than 5 years;Death is usually due to progressive cardiacfailure or arrhythmia. In most cases cardiactransplantation is the only definitivetreatment.
Hypertrophic cardiomyopathy (HCM)(also known as idiopathichypertrophic subaortic stenosis) ischaracterized by myocardialhypertrophy, abnormal diastolic filling,and-in a third of cases-ventricularoutflow obstruction. As discussedbelow, the obstruction, in some cases,is dynamic, caused by the anteriorleaflet of the mitral valve. The heart isthick-walled, heavy, and hypercontracting, in striking contrast to theflabby, poorly contractile heart inDCM. Systolic function is usuallypreserved in HCM, but themyocardium does not relax andtherefore shows primary diastolicdysfunction.
The essential gross feature of HCM ismassive myocardial hypertrophy withoutventricular dilation .The classic pattern ofHCM involves disproportionate thickeningof the ventricular septum relative to the leftventricle free wall (so-called asymmetricalseptal hypertrophy); nevertheless, inabout 10% of cases there is concentrichypertrophy. On longitudinal sectioning,the ventricular cavity loses its usual round-to-ovoid shape and is compressed into a"banana-like" configuration .Often presentis an endocardial plaque in the leftventricular outflow tract, as well as athickening of the anterior mitral leaflet.Both findings reflect contact of the anteriormitral leaflet with the septum duringventricular systole and correlate withfunctional left ventricular outflow tractobstruction.
The characteristichistologic features inHCM are severemyocytehypertrophy,myocyte (andmyofiber) disarray,and interstitial andreplacement fibrosis
Almost all cases of HCM are caused Although it is clear that theseby missense point mutations in one genetic defects underlie HCM,of several genes encoding the the sequence of events leadingsarcomeric proteins that form the from mutations to disease is stillcontractile apparatus of striated poorly understood. A currentmuscle .In most cases, the pattern of proposal suggests that HCMtransmission is autosomal dominant represents a compensatorywith variable expression. Greater change in response to impairedthan 100 causal mutations have been contractility. In this model,identified in at least 12 sarcomeric ineffective myocyte contractiongenes , with the β-myosin heavy triggers exuberant growth factorchain being most frequently release with subsequent intenseaffected, followed by myosin- compensatory hypertrophybinding protein C and troponin T. (causing myofiber disarray) andThese three genes account for 70% fibroblast proliferation (causingto 80% of all cases of HCM. interstitial fibrosis).
HCM is characterized by a massively hypertrophied leftventricle that paradoxically provides a markedly reducedstroke volume. This pathophysiologic effect is a directconsequence of impaired diastolic filling and overall smallerchamber size. In addition, roughly 25% of patients havedynamic obstruction to the left ventricular outflow by theanterior leaflet of the mitral valve. Reduced cardiac outputand a secondary increase in pulmonary venous pressurecause exertional dyspnea, and there is a harsh systolicejection murmur. A combination of massive hypertrophy,high left ventricular pressures, and compromisedintramural coronary arteries frequently leads to myocardialischemia (with angina), even in the absence of concomitantcoronary artery disease. Major clinical problems includeatrial fibrillation with mural thrombus formation, IE of themitral valve, CHF, arrhythmias, and sudden death. Mostpatients are improved by therapy that promotes ventricularrelaxation; occasionally, partial surgical excision of septalmuscle is necessary to relieve the outflow tract obstruction.
Restrictive cardiomyopathy ischaracterized by a primary decrease inventricular compliance, resulting inimpaired ventricular filling during diastole(simply put, the wall is stiffer). Thecontractile (systolic) function of the leftventricle is usually unaffected. Thus, thefunctional state can be confused with thatof constrictive pericarditis or hypertrophiccardiomyopathy. Restrictivecardiomyopathy can be idiopathic orassociated with systemic diseases that alsohappen to affect the myocardium-forexample, radiationfibrosis, amyloidosis, hemochromatosis, sarcoidosis, or products of inborn errors ofmetabolism. For each of these causes, thecurious reader is referred to the morecomplete discussion in the relevantchapters. Genetic factors are less clearlydefined in restrictive cardiomyopathy.
In idiopathic restrictive cardiomyopathythe ventricles are of approximatelynormal size or slightly enlarged, thecavities are not dilated, and themyocardium is firm. Biatrial dilation iscommonly observed.Microscopically there is interstitialfibrosis, varying from minimal andpatchy to extensive and diffuse.Restrictive cardiomyopathy of disparatecauses may have similar grossmorphology. However, endomyocardialbiopsy can reveal disease-specificfeatures (e.g., amyloid, ironoverload, sarcoid granulomas).
In myocarditis there isinflammation of the myocardiumwith resulting injury. It isimportant, however, to emphasizethat the presence of inflammationalone is not diagnostic ofmyocarditis; for example,inflammatory infiltrates can alsooccur as a secondary response toischemic injury. In myocarditis, theinflammatory process is the causeof-rather than a response to-myocardial injury.
During active myocarditis the heart mayappear normal or dilated. Theventricular myocardium is typicallyflabby and often mottled by patchy ordiffuse foci of pallor and/orhemorrhage. Mural thrombi can bepresent.Microscopically, active myocarditisshows an interstitial inflammatoryinfiltrate, with focal necrosis ofmyocytes adjacent to the inflammatorycells
Lymphocytic myocarditis is mostcommon .If the patient survives the acutephase of myocarditis, the inflammatorylesions either resolve, leaving no residualchanges, or heal by progressive fibrosis. Lymphocytic myocarditis
Hypersensitivity myocarditis hasinterstitial and perivascular infiltratescomposed of lymphocytes, macrophages,and a high proportion of eosinophils Hypersensitivity myocarditis
Giant-cell myocarditis is amorphologically distinctive entitycharacterized by widespreadinflammatory cellular infiltratescontaining multinucleate giant cells(formed by macrophage fusion)interspersed with lymphocytes,eosinophils, and plasma cells. Giant-cellmyocarditis probably represents theaggressive end of the spectrum oflymphocytic myocarditis, and there is atleast focal-and frequently extensive-necrosis .This variant carries a poorprognosis Giant-cell myocarditis
Chagas myocarditis is distinctive byvirtue of the parasitization of scatteredmyofibers by trypanosomesaccompanied by an inflammatoryinfiltrate of neutrophils, lymphocytes,macrophages, and occasionaleosinophils Chagas myocarditis
The clinical spectrum of myocarditis isbroad. At one end, the disease isasymptomatic and patients recoverwithout sequelae, and at the other end isthe precipitous onset of heart failure orarrhythmias, occasionally with suddendeath. Between these extremes are themany forms of presentation, associatedwith a variety of symptoms(e.g., fatigue, dyspnea, palpitations, pain,and fever). The clinical features ofmyocarditis can even mimic those ofacute MI. Occasionally, over manyyears, patients can progress frommyocarditis to DCM.
Metastatic NeoplasmsThe most common tumor of theheart is a metastatic tumor; tumormetastases to the heart occur inabout 5% of patients dying ofcancer. Although any malignancycan secondarily involve the heart,certain tumors have a higherpredilection to spread to the heart.In descending order these tumorsare carcinoma of the lung,lymphoma, breast cancer,leukemia, melanoma, carcinomasof the liver, and colon.
Primary NeoplasmsPrimary cardiac tumors are uncommon; inaddition, most primary cardiac tumors arealso (thankfully) benign. The five mostcommon have no malignant potential andaccount for 80% to 90% of all primary hearttumors. In descending order of frequency(adults) the primary cardiac tumors are:myxomas, fibromas, lipomas, papillaryfibroelastomas, rhabdomyomas, andangiosarcomas (this last one is malignant).Only the myxomas and rhabdomyomas willreceive any significant attention here.
MyxomasMyxomas are the most commonprimary tumor of the adult heart.Roughly 90% are located in theatria, with the left atriumaccounting for 80% of those.Myxomas are almost always single and aremost commonly located at the fossa ovalis(atrial septum). They range from small (<1cm) to impressive (≤10 cm), sessile orpedunculated masses .and can vary fromglobular hard masses to soft, translucent,villous lesions with a gelatinous appearance.Pedunculated forms are often sufficientlymobile to swing into the mitral or tricuspidvalves during systole, causing intermittentobstruction. Sometimes such mobility exertsa "wrecking-ball" effect, causing damage tothe valve leaflets.
Histologically myxomas arecomposed of stellate,multinucleated myxoma cellswith hyperchromatic nuclei,admixed with cells showingendothelial, smooth muscle,and/or fibroblasticdifferentiation, all embedded inan abundant acidmucopolysaccharide groundsubstance .Hemorrhage, poorlyorganizing thrombus, andmononuclear inflammation arealso usually present.
Clinical FeaturesThe major clinical manifestations aredue to valvular "ball-valve"obstruction, embolization, or asyndrome of constitutionalsymptoms, such as fever and malaise.Constitutional symptoms areprobably due to the elaboration ofinterleukin-6, a major mediator of theacute-phase response.Echocardiography is the diagnosticmodality of choice, and surgicalresection is almost uniformlycurative.
RhabdomyomasRhabdomyomas are the most frequentprimary tumor of the heart in infantsand children; they are frequentlydiscovered because of an obstruction ofa valvular orifice or cardiac chamber.Cardiac rhabdomyomas occur with highfrequency in patients with tuberoussclerosis .Rhabdomyomas are probablybetter classified as hamartomas ormalformations rather than trueneoplasms; recent work suggests thatthese lesions may be caused bydefective apoptosis duringdevelopmental remodeling.
MorphologyRhabdomyomas are generally small,gray-white myocardial masses up toseveral centimeters in diameter thatprotrude into the ventricular chambers.Histologically they have a mixedpopulation of cells; the mostcharacteristic of which are large,rounded, or polygonal cells containingnumerous glycogen-laden vacuolesseparated by strands of cytoplasmrunning from the plasma membrane tothe more or less centrally locatednucleus. These are the so-called spidercells.
An estimated five million people in theUnited States have heart failure, and 300,000die each year as a direct consequence.Cardiac transplantation is increasingly anoption for these patients (mostly for IHD anddilated cardiomyopathy), with roughly 2000performed annually in the U.S. (3000 a yearworldwide). A brief look at the numberssuggests that many more patients die whileon a waiting list (estimated at 50,000 peryear) than are successfully transplanted.Indeed, even though the demand for heartshas doubled in the last decade, largely as aresult of better ways to support patients insevere failure, the actual supply has droppedBeyond the issues of supply and demand, themajor complications of cardiactransplantation are acute cardiac rejectionand graft coronary arteriosclerosis
Rejection is typically diagnosed byendomyocardial biopsy of thetransplanted heart; it is characterizedby an interstitial lymphocyticinflammation with associated myocytedamage .The histology is similar to thatseen in viral myocarditis .In bothinstances, T-cell-mediated killing andlocal cytokine production canmaterially compromise cardiacfunction. When myocardial injury is notextensive, the "rejection episode" can bereversed by immunosuppressivetherapy. Advanced rejection can beirreversible and fatal.
Cardiac allograft rejection typified by lymphocytic infiltrate, withassociated damage to cardiac myocytes. Note the similarity betweenrejection and typical viral myocarditis
Graft coronary arteriosclerosis, demonstrating severe diffuseconcentric intimal thickening producing critical stenosis. Theinternal elastic lamina (arrow) and media are intact .
Graft coronary arteriosclerosis (GCA) is the Despite these problems,single most important long-term limitation the outlook forfor cardiac transplantation. It is a late, transplanted patients isprogressive, diffusely stenosing intimal generally good, with a 1-proliferation in the coronary arteries, year survival of 80% andleading to ischemic injury. Within 5 years 5-year survivals of moreof transplantation, 50% of patients have than 60% (comparedsignificant GCA, and virtually all patients with 50% and <10%,have lesions within 10 years. The respectively, in medicallypathogenesis of GCA involves immunologic managed end-stageresponses that induce local production of heart failure).growth factors that promote intimalsmooth muscle cell recruitment andproliferation with extracellular matrixsynthesis. GCA is a particularly vexingproblem, because it can lead to silent MI(transplant patients have denervatedhearts and do not experience angina),progressive CHF, or SCD.