THE GENETIC BASIS FOR CARDIAC REMODELING

20 Aug 2005 11:17 AR AR252-GG06-09.tex XMLPublishSM(2004/02/24) P1: KUV10.1146/annurev.genom.6.080604.162132

Annu. Rev. Genomics Hum. Genet. 2005. 6:185–216doi: 10.1146/annurev.genom.6.080604.162132

Copyright c© 2005 by Annual Reviews. All rights reserved

THE GENETIC BASIS FOR CARDIAC REMODELING

Ferhaan Ahmad1,2, J.G. Seidman2, andChristine E. Seidman2

1Cardiovascular Institute and Departments of Medicine and Human Genetics,University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 152132Department of Genetics, Harvard Medical School and Howard Hughes MedicalInstitute, Boston, Massachusetts 02115; email: [email protected]

Key Words hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictivecardiomyopathy, arrhythmogenic right ventricular dysplasia/cardiomyopathy,PRKAG2 cardiomyopathy

■ Abstract Cardiomyopathies are primary disorders of cardiac muscle associatedwith abnormalities of cardiac wall thickness, chamber size, contraction, relaxation,conduction, and rhythm. They are a major cause of morbidity and mortality at all agesand, like acquired forms of cardiovascular disease, often result in heart failure. Over thepast two decades, molecular genetic studies of humans and analyses of model organ-isms have made remarkable progress in defining the pathogenesis of cardiomyopathies.Hypertrophic cardiomyopathy can result from mutations in 11 genes that encode sar-comere proteins, and dilated cardiomyopathy is caused by mutations at 25 chromosomeloci where genes encoding contractile, cytoskeletal, and calcium regulatory proteinshave been identified. Causes of cardiomyopathies associated with clinically impor-tant cardiac arrhythmias have also been discovered: Mutations in cardiac metabolicgenes cause hypertrophy in association with ventricular pre-excitation and mutationscausing arrhythmogenic right ventricular dysplasia were recently discovered in pro-tein constituents of desmosomes. This considerable genetic heterogeneity suggests thatthere are multiple pathways that lead to changes in heart structure and function. De-fects in myocyte force generation, force transmission, and calcium homeostasis haveemerged as particularly critical signals driving these pathologies. Delineation of thecell and molecular events triggered by cardiomyopathy gene mutations provide newfundamental knowledge about myocyte biology and organ physiology that accountsfor cardiac remodeling and defines mechanistic pathways that lead to heart failure.

INTRODUCTION

The structure of the normal heart is exquisitely adapted to pump blood throughtwo independent vascular systems, the pulmonary and the systemic circulations.The thin-walled right atrium and the left atrium accept blood returning from thesystemic circulation and the pulmonary circulation, respectively. During diastole(cardiac relaxation), blood flows from the atria into the muscular ventricles. During

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20 Aug 2005 11:17 AR AR252-GG06-09.tex XMLPublishSM(2004/02/24) P1: KUV

186 AHMAD � SEIDMAN � SEIDMAN

systole (cardiac contraction), the right ventricle and the left ventricle pump bloodinto pulmonary and systemic circulations, respectively.

Heart failure is a chronic and progressive disorder characterized by impairedcardiac contraction (systolic dysfunction) and/or relaxation (diastolic dysfunction).Heart failure poses a 1 in 5 lifetime risk in both men and women (84) and is themost common cause of death in industrialized societies (101). This emergingcardiovascular epidemic imposes a significant burden on quality of life and onhealth care systems; heart failure treatments cost more than $17 billion annually,and with an aging population these socioeconomic costs will likely increase (164).

Heart failure is virtually always a secondary entity that occurs when the my-ocardial function is diminished by an underlying condition such as cardiomyopa-thy (primary or acquired from chronic ischemia, hypertension, or diabetes), valvedisease, congenital malformation, or rhythm disturbances. In response to these ini-tiating insults, the intermediate and long-term response of the heart is morphologicremodeling in association with hemodynamic changes. The two major and distinctcardiac remodeling patterns that are clinically recognized are cardiac hypertrophyor dilation. Classical definition of these morphologies is based on anatomic find-ings. However, the pervasive use of cardiac evaluation by echocardiography ormagnetic resonance imaging has changed the clinical diagnosis of cardiac hy-pertrophy or dilation from histopathologic findings to noninvasive assessment ofventricular dimensions and function.

Hypertrophy is defined by anatomic findings of increased cardiac muscle mass,which results from increased wall thickness, due to enlarged cardiac myocytesand/or increased myocardial interstitial fibrosis. When diagnosed by echocardio-graphy, hypertrophy is defined by increased ventricular wall thickness that occurswith preserved systolic but impaired diastolic function. Anatomical findings as-sociated with cardiac dilation also include increased cardiac mass, but this pri-marily reflects enlarged cardiac chamber volumes, as well as modest increasesin ventricular wall thickness, due to enlarged myocytes and increased cardiacfibrosis. Noninvasive imaging studies of dilated hearts show diminished contrac-tile performance, with primarily decreased systolic function. Although anatomicand hemodynamic parameters distinguish hypertrophic from dilated remodeling,both entities can lead to cardiac decompensation and heart failure. As this endphase emerges, hemodynamic distinctions between these pathologies become lessprominent and both systolic and diastolic defects are found in heart failure.

Hypertrophy is most often recognized as the predominant and sustained re-sponse to disorders that increase the load on the heart, such as what occurs withhypertension. Ventricular dilation is the response to disorders that produce volumeoverload, such what occurs following myocardial infarction. These distinct cardiacmorphologies also occur in primary cardiomyopathies that are caused by singlegene defects. Although the precise relationship between genetic and acquired hy-pertrophic or dilated cardiomyopathy is not completely understood, knowledgeabout the cellular and molecular pathways triggered by gene defects is expectedto be informative to remodeling that results from pressure or volume overload.

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GENETICS OF CARDIAC REMODELING 187

The morphology of the heart is predicated on cardiac myocyte number and func-tion. Terminally differentiated cardiac myocytes lack any replicative capacity, andthroughout life these cells respond to stress principally by increasing in size (my-ocyte hypertrophy) or by prematurely dying. Myocyte death triggers an increasein the number of cardiac fibroblasts as well as increases in interstitial matrix orcollectively termed cardiac fibrosis. When myocytes are hypertrophied, there is anincrease in the number of longitudinally arranged sarcomeres, the functional unitof contraction within all muscle cells (Figure 1). The sarcomere is an immense pro-tein complex that is organized into thick and thin filaments, which, in the presenceof calcium and ATP, slide past one another and thereby generate contractile force.When intracellular calcium levels rise in response to cellular electrical depolariza-tion, calcium binds to the troponin complex, composed of troponins C, I, and T,and α-tropomyosin, and releases troponin I inhibition of actin-myosin interactions.The myosin head then binds to actin, ATP binds to myosin, the myosin head isdisplaced along the thin filament, ATP hydrolysis occurs, and force is generated.During depolarization, a small amount of calcium enters the myocyte via voltage-gated L-type calcium channels and the Na+/Ca2+ exchanger. This influx of calciumtriggers greater calcium release from the stores in the sarcoplasmic reticulum viaryanodine receptors and inositol 1,4,5-trophosphate receptors in a process termedcalcium-induced calcium release. During relaxation, calcium is removed from thecytosol by the sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), the sarcolemmalNa+/Ca2+ exchanger, the sarcolemmal Ca2+-ATPase, and the mitochondrial Ca2+

uniporter. Thus, calcium is a critical molecule regulating both cardiac contractionand relaxation.

Force generated during contraction is transmitted outward to the cytoskeletonthrough a complex network of proteins that link the sarcomere to the sarcolemmaand the extracellular matrix (Figure 1). This cytoskeleton is formed from an in-termyofibrillar layer comprised of intermediate filaments, desmin, microfilaments(consisting of nonsarcomeric actin), microtubules, and subsarcolemmal compo-nents. In addition, lamin proteins comprise intermediate filaments associated withthe nucleoplasmic surface of the inner nuclear membrane.

Costameres are subsarcolemmal complexes that interconnect the various in-termyofibrillar cytoskeleton networks and link them to the sarcolemma. Thereare three types of costameres—the focal adhesion-type complex, composed ofproteins such as vinculin, talin, tensin, paxillin, zyxin, and α- and β-integrins;the spectrin-based complex, composed of actin, ankyrin, and desmin; and thedystrophin-associated complex, composed of dystrophin, α- and β-dystroglycans,α-, β-, γ -, and δ-sarcoglycans, dystrobrevin, and syntrophin. Structural and func-tional integrity between adjacent myocytes is supported by desmosomes, multi-protein structures composed of cadherins, plakophilins, and plakins. In addition tosupporting organ architecture, these complexes may transmit force between cellsand participate in signal transduction pathways.

Mutations in genes that encode many of these important proteins, whichsubserve overall heart function, cause primary cardiomyopathies. Prior to the

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elucidation of underlying genetic causes, these disorders were considered “idio-pathic” because they remodel ventricular morphology in the absence of conditionsthat produce pressure or volume overload. Primary cardiomyopathies are classifiedbased on morphologic patterns of hypertrophic or dilated remodeling. Althoughthese classifications provide an appropriate anatomic label, unfortunately they failto reflect new knowledge about the molecular mechanisms that trigger changesin heart structure and function—information that ultimately should enable noveltherapeutic approaches. For example, cardiac hypertrophy can be triggered bysarcomere gene mutations (hypertrophic cardiomyopathy) or by metabolic genedefects (glycogen storage cardiomyopathies). Dilated cardiomyopathy (DCM) isused to indicate ventricular remodeling that occurs in isolation (due to gene muta-tions affecting contractile or calcium cycling proteins), in association with electro-physiologic deficits (due to gene mutations affecting a nuclear membrane proteinor desmosome proteins) or in association with skeletal muscle disease (due togene mutations in cytoskeletal proteins). Newer nomenclature that more accu-rately links morphologic subtypes of cardiac remodeling with molecular mech-anisms is needed for cardiomyopathies. The impetus for precisely defining thegenetic causes of cardiomyopathy is threefold. First, these are important medicaldisorders that produce substantial morbidity and mortality. Second, the anatomicand hemodynamic changes associated with these disorders are also observed inacquired forms of heart disease and heart failure. Improved understanding of thepathogenesis of cardiomyopathies will likely also shed light on the pathogenesis ofacquired and complex genetic cardiac disorders. Third, genetic cardiomyopathieshave enormous potential to provide new knowledge about myocyte cell biology.Insights into the mechanisms by which myocytes adapt to abnormalities in excita-tion, biomechanics of contraction and force transmission, and metabolism shouldyield clues about how exquisitely developed, ceaselessly working cells maintainlifelong capacities.

HYPERTROPHIC CARDIOMYOPATHY

With a prevalence of 200 per 100,000 individuals, hypertrophic cardiomyopathy(HCM) is the most common cardiovascular disease inherited as an autosomaldominant trait (89). The overall annual mortality rate associated with HCM is only1%, but certain subsets of patients have much higher mortality rates of 6%. Deathmay be sudden and unexpected or may occur secondary to stroke or progressiveheart failure. In the United States, HCM accounts for 36% of all sudden deaths incompetitive athletes under the age of 35 years (90).

HCM is characterized by left ventricular wall thickening, which is often asym-metric, and particularly involves the interventricular septum (Figure 2B). Histopatho-logical examination demonstrates myocytes that are hypertrophied and disar-rayed (a term indicating bizarrely shaped cells that are disoriented with respect toone another) and interspersed between increased cardiac fibrosis (Figure 2E,H).

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TABLE 1 Gene mutations in hypertrophic cardiomyopathy

Locus Symbol Disease gene Initial reports

1q32 TNNT2 Cardiac troponin T2 (172)

2q31 TTN Titin (151)

3p21 MYL3 Essential myosin light chain (131)

3p21-p14 TNNC1 Cardiac troponin C (60)

11p11.2 MYBPC3 Cardiac myosin binding protein C (179)

12q23–q24 MYL2 Regulatory myosin light chain (131)

14q12 MYH7 Beta myosin heavy chain (45)

14q12 MYH6 Alpha myosin heavy chain (114)

15q14 ACTC Cardiac actin (104)

15q22 TPM1 Alpha tropomyosin (172)

19p13.2 TNNI3 Cardiac troponin I (69)

Noninvasive imaging that reveals unexplained cardiac hypertrophy with preservedsystolic function often prompts a diagnosis of HCM. However, moleculargenetic investigations have defined several distinct causes for hypertrophicremodeling.

Hundreds of mutations in 11 genes that encode protein constituents of the sar-comere have been identified in HCM (Table 1; Figure 3) (144, 156). β-myosinheavy chain (MYH7), myosin binding protein C (MYBPC3), cardiac troponin I(TNNI3), and cardiac troponin T (TNNT2) are the most prevalent disease genes, butmutations have also been found in α-tropomyosin (TPM1), cardiac actin (ACTC),cardiac troponin C (TNNC1), essential myosin light chain (MYL3), regulatorymyosin light chain (MYL2), α-cardiac myosin heavy chain (MYH6), and titin(TTN). Comprehensive genetic analyses of these genes yield definition of a disease-causing mutation in approximately 70% of HCM cases. Although it is likely thatsome of the remaining cases are due to mutations in other sarcomere protein genes,recent data indicate that different genetic etiologies can clinically mimic HCM (2,14, 49).

Genetic heterogeneity in HCM accounts for some phenotypic diversity observedin patients (180, 181). The age at onset of clinical findings, disease penetrance,severity of cardiac hypertrophy, and risk of sudden cardiac death are in part dueto the precise disease-causing HCM mutation. An early model to account for howdifferent clinical features might result from mutations in the same gene suggestedthat defects located within the same functional protein domain would producesimilar phenotypes. However, MYH7 mutations found in the head domain thatare predicted to alter the actin-binding surface, the nucleotide-binding pocket, thehinge region, or the α-helical tail near the essential myosin light chain bindingsite (Figure 3) (141) can have either comparable or markedly different clinical

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phenotypes. For example, the Arg403Gln and Arg719Trp mutations in MYH7 areassociated with particularly severe hypertrophy and predispose to sudden deathand heart failure, whereas the Phe513Cys, Leu908Val, and Gly256Glu mutationscause less severe phenotypes (146, 147, 154). In addition, recently identified raremutations within the myosin rod (15) appear to be clinically indistinguishable fromother myosin mutations.

A more precise definition of the influence of genotype on phenotype comesfrom genetically engineered models carrying human mutations (see below). Theamount of mutant protein expressed within the heart influences clinical expression.Patients who are homozygous for a mutation (58) or are compound heterozygoteshave more hypertrophy and a poorer prognosis than do patients who have onemutant allele and one normal allele (144, 145).

Clinical variance in disease manifestations is also reflected by mutations indifferent HCM genes. MYH7 mutations usually cause more hypertrophy than otherdisease genes. TNNT2 defects that produce only mild hypertrophy are associatedwith overall higher incidences of sudden cardiac death than other HCM genes.Whereas hypertrophy in individuals with MYH7 mutations is usually present inthe first two decades of life, hypertrophic remodeling by MYBPC3 mutations canbe delayed until after the fifth or sixth decades (113). Several mutations have beenassociated with unusual patterns of cardiac hypertrophy, including left ventricularapical hypertrophy in TNNI3 mutations (69) and midcavity hypertrophy in ACTC(118) and MYL3 (131) mutations. However, these same gene mutations also causetypical patterns of hypertrophy in other members of the same family, indicatingthat genotype alone does not account for all morphologic features of ventricularremodeling (39, 69, 105).

The inter-relationship between disease-causing mutations, background geno-types, lifestyles, and hypertrophic remodeling has been investigated in animalmodels of HCM. Regular strenuous exercise augments hypertrophic remodelingand provokes sudden death in mouse models of HCM (44), thereby providingjustification for recommending avoidance of competitive athletics for affected hu-man patients. Remarkably, gender may influence disease progression in HCM.A transgenic HCM mouse model shows progressive heart failure development inmale but not female littermates (123), and clinical human studies suggest that af-fected women have less ventricular dilation and later onset of disease, but a higherincidence of stroke (34, 35, 91).

Modifying genes also may affect phenotypic expression of HCM mutations.A tentative association was reported between the DD variant of angiotensin-1converting enzyme and the extent of hypertrophy and sudden cardiac death (78,87). However, analyses of polymorphisms in genes encoding other components ofthe renin-angiotensin system, aldosterone, endothelin, and tumor necrosis factor,have been inconclusive (22, 32, 125, 126, 128, 171). The presence of a modify-ing genetic locus that attenuates hypertrophic remodeling was also demonstratedin a murine model of HCM due to the Myh6 Arg403Gln mutation (158), butthe gene remains unknown. Identifying this modifying factor and others may be

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important for defining opportunities to ameliorate hypertrophic remodeling inHCM patients.

Cellular and molecular events triggered by sarcomere protein gene mutationsthat lead to HCM remain incompletely defined. Dominant gene mutations generallyproduce disease by inactivating an allele, resulting in a diminution of functionalprotein (haploinsufficiency), or alternatively by creating a mutant protein that eitherinterferes with normal function (dominant negative) or assumes a new function.Evidence from genetically engineered animal models that carry human mutationsprimarily support the latter mechanisms for causing remodeling in HCM. Bio-physical studies of HCM mutant proteins discovered altered crossbridge kineticsof thin and thick filaments in the sarcomere and differences in actomyosin inter-actions. These studies demonstrate an increase in calcium sensitivity resulting inproportional increases in tension generation and ATPase activity at a given calciumconcentration in HCM mutations affecting myosin, troponin T, C, and I or myosinlight chain proteins (13, 33, 37, 55–57, 71, 72, 76, 99, 106, 127, 142, 149, 167, 168,170, 182). HCM mutations may also lead to inefficient use of ATP at the myofila-ment level, a result that suggests that energy requirements of HCM myocytes maybe greater than normal cells. In addition, some myosin mutations exhibit increasesin maximum power output, enhanced ATPase activity, and increased actin slidingvelocities—all suggesting that these defects create a gain in myosin function.

Several models predict how altered, and potentially enhanced, biophysical prop-erties of individual sarcomere proteins cause hypertrophic remodeling. First, het-erogeneity of mutant and wild-type proteins within the sarcomere may disruptcoordination of the intricate association between individual myosins and actin,and inhomogeneous mechanical events may compromise overall sarcomere func-tion. Second, either because a mutation directly affects ATPase activity or becauseof indirect mechanisms, energy requirements of myocytes containing sarcomeremutations will likely increase. Furthermore, once remodeling occurs at the cellularlevel (with increased sarcomere content) energy demands by the whole organ alsoincrease. Because such myocytes within the hypertrophied heart are at consider-able risk for ischemia, unmet metabolic demands can result in premature myocytedeath and replacement fibrosis within the heart. Studies of cardiac muscle fromseveral murine HCM models are consistent with this hypothesis. Mutations inMhy6, Mybp3, Tnnt2, or Tnni3 demonstrated that enhanced contractile functionoccurs at the cost of increased work (16, 23, 102, 176). Nuclear magnetic res-onance studies of the murine model of the Arg403Gln mutation in Mhy6 havereduced basal energy stores and unfavorable ATP/ADP ratios, which may furtherdecrease free energy release from ATP hydrolysis (127, 143, 163, 176).

Engineered animal models carrying a sarcomere protein gene mutation haveprovided reagents to discover the mechanisms by which mutant sarcomeres pro-duce signals that result in hypertrophic remodeling. Although there may be distinctsignals triggered by different mutant sarcomere proteins with different biophysicalfunctions during contraction and relaxation, calcium has emerged as a critical andcommon key agent implicated in this process.

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Calcium cycling between the sarcomere and sarcoplasmic reticulum is alteredin HCM. The maximum calcium released from sarcoplasmic reticulum stores issignificantly diminished in myocytes with the Arg403Gln Mhy6 mutation (41). Inaddition, the levels of the calcium-binding sarcoplasmic reticulum proteins calse-questrin and junctin, and of the ryanodine receptor calcium channel, are decreasedin these mice (157). When HCM mice are treated with the L-type calcium chan-nel inhibitor diltiazem in advance of an established hypertrophic myocardium,normal levels of calsequestrin, junctin, and ryanodine receptor are restored, anddevelopment of the histopathologic changes of HCM is diminished.

Changes in myocyte calcium cycling can help to explain the pathophysiology ofhuman HCM (110). Patients with MYH7 and MYBPC3 mutations exhibit decreaseddiastolic velocities compared with control subjects even prior to the developmentof left ventricular hypertrophy (111). Impaired diastolic relaxation is likely due tothe increase in calcium sensitivity observed at the cellular and the molecular levelsin animal models. Whether calcium cycling also contributes to changes in systolicfunction observed in hypertrophic remodeling is unknown.

Only a few of the downstream events occurring in response to calcium signalsand increased energy demands have been identified. Several transcription factorsincluding myocyte enhancer factor-2 (MEF2), GATA4, and serum response factor(SRF) interact to control stress-induced fetal gene reactivation, which character-izes hypertrophy in the adult heart (117). The activity of these transcription factorsdepends on their ability to associate with histone acetyltransferases (HATs). TheseHATs transfer acetyl groups from acetyl CoA to ε−amino groups of lysine residuesin nucleosomal histone tails, which promote chromatin relaxation and facilitate lo-cal gene transcription. Histone deacetylases (HDACs) are endogenous inhibitorsof HATs. Class II HDACs inhibit MEF2 activity and appear to repress cardiachypertrophy. When phosphorylated, they are exported from the nucleus, allowingMEF2 to activate downstream genes that drive hypertrophy. Mice lacking class IIHDACs demonstrate exaggerated cardiac hypertrophy in response to various stres-sors (24, 187). In contrast, class I HDACs appear to inhibit SRF activity, therebyinhibiting its repression of cardiac hypertrophy. Although a role for HDACs hasbeen established in load-induced cardiac hypertrophy (94), the relevance of thesetranscriptional modulators in hypertrophy due to sarcomere gene mutations re-mains to be determined.

On the basis of early insights into the pathogenesis of HCM, a few noveltherapeutic agents have been tested in animal models. As noted above, the cal-cium channel blocker diltiazem attenuated myocardial hypertrophy and fibrosisin mice with an Arg403Gln mutation in Myh6 (157). Angiotensin II has been im-plicated in both promoting myocyte hypertrophy and increasing cardiac fibrosis.The angiotensin II receptor antagonist losartan (83) and the HMG-CoA reductaseinhibitor simvastatin, which both inhibit load-induced cardiac hypertrophy, mayameliorate HCM by reducing the activity of the angiotensin converting enzyme(129) through reduction of levels of activated ERK1/2, a prominent cardiac stress-response kinase. Therapeutic interventions in the various mouse models of HCM

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suggest possible novel avenues for reducing hypertrophic development in humanswith sarcomere gene mutations.

GLYCOGEN CARDIOMYOPATHY

A distinct subset of cardiomyopathies occurs due to mutations in genes encodingmetabolic proteins. Glycogen deposition is a shared feature of these metaboliccardiomyopathies. Prior to elucidation of the genetic etiology of these disorders,many of the glycogen cardiomyopathies were mistakenly classified as HCM. How-ever, unlike cardiomyopathies due to sarcomere gene mutations, glycogen storagedisorders usually present with electrophysiologic deficits, and chronically affectedindividuals develop more systolic dysfunction than occurs with sarcomere genemutations. Histopathologic findings also distinguish these two genetic forms ofcardiac hypertrophy. Whereas myocyte and myofibrillar disarray, myocyte hyper-trophy, and cardiac fibrosis are characteristic of mutations in sarcomeric proteins,these features are notably absent in glycogen storage cardiomyopathies. Rather,myocyte vacuoles containing glycogen are found in hypertrophied hearts withmetabolic gene mutations (Figure 2J) (4).

Human mutations in three lysosome proteins produce cardiac hypertrophy:Pompe disease [recessively inherited lysosomal acid α 1,4−glucosidase (GAA) de-ficiency], Danon disease [X-linked lysosome-associated membrane protein(LAMP2) deficiency], and Fabry disease [X-linked lysosomal hydrolase α galac-tosidase A (GLA) deficiency]. Pompe and Danon diseases are rare systemic disor-ders with prominent cardiac hypertrophy and electrophysiologic defects. Encodedon chromosome 17q25.2–q25.3, GAA mutations occur in fewer than 0.2 of 100,000live births (96) and cause classical infantile Pompe, which is usually fatal within thefirst year of life, or a less common viable juvenile or adult form, characterized bycardiac hypertrophy and skeletal myopathy (93). The same mutation can occasion-ally produce different forms of the disease. Cardiac hypertrophy associated withelectrophysiologic defects can also indicate LAMP2 mutations. Initially recognizedin the context of X-linked Danon disease, LAMP2 mutations cause hypertrophyand skeletal myopathy, with neurologic and hepatic findings. Affected males of-ten die during the second decade of life but females survive decades longer (36).Recent human molecular genetic data indicate that some LAMP2 mutations pre-dominantly cause cardiac disease with mild or subclinical systemic manifestations(3). The mechanisms by which these lysosomal proteins cause hypertrophy andelectrophysiologic dysfunction remain incompletely understood. Although glyco-gen accumulation probably contributes in part to the observed cardiac pathology,more global changes in myocardial metabolism are also likely. These human mu-tations point to critical roles of lysosomes in the working myocyte and specializedelectrical cells of the heart.

Mutations in AMP-activated protein kinase (AMPK) also cause a glycogenstorage cardiomyopathy. AMPK is a heterotrimeric protein composed of α, β,

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and γ subunits, each of which has several isoforms. The enzyme functions asa metabolite-sensing protein kinase that is activated under conditions of energydepletion manifested by increased cellular AMP levels. The kinase regulates en-ergy metabolism by various mechanisms, including activation of glucose transport,stimulation of β-oxidation of fatty acids, inactivation of cholesterol synthesis, inhi-bition of creatine kinase, and transcriptional regulation of several genes (68). Mu-tations in exon 5 of PRKAG2, encoding the γ 2 subunit of AMPK produce a distinctcardiomyopathy characterized by ventricular hypertrophy, ventricular preexcita-tion, and progressive conduction system disease (2, 14, 49). PRKAG2 cardiomy-opathy is not characterized by myofibrillar disarray or cardiac fibrosis. Rather,the hypertrophied myocytes contain vacuoles filled with glycogen and glycogen-protein complexes (amylopectin) (4). Because the γ 2 subunit has cardiac-specificexpression, extracardiac manifestations do not occur in PRKAG2 cardiomyopathy,distinguishing this from other forms of glycogen storage cardiomyopathies.

In vitro studies suggest that γ subunit mutations cause a gain of function ofAMPK. Introducing the Thr400Asn and Asn488Ile mutations into the yeast homo-logue of the γ 2 subunit, Snf4, resulted in constitutive activation of the Snf1/Snf4kinase (2). Expression of recombinant AMPK COS7 cells and pulmonary fibro-blasts with the Arg70Gln introduced into the γ 1 subunit demonstrated markedly in-creased AMPK activity, associated with increased phosphorylation of the α subunitThr172 and increased phosphorylation of one of its major substrates, acetyl-CoAcarboxylase (54).

Animal models of AMPK mutations also have provided insight into the patho-genesis (12, 66, 136). An Arg200Gln mutation in the Hampshire pig Prkag3 gene,encoding the skeletal muscle γ 3 subunit, produces high glycogen content in skele-tal muscle (100). Transgenic mice expressing the Asn488Ile mutation (4) haveelevated AMPK activity, a 30-fold increase in glycogen deposition in cardiac my-ocytes (Figure 2J), dramatic left ventricular hypertrophy, ventricular preexcitation,and sinus node dysfunction. Disruption of the annulus fibrosus by glycogen-filledmyocytes was the anatomic substrate for preexcitation, which is frequently presentin glycogen storage cardiomyopathies. Markedly elevated AMPK α2, but not α1,activity is present in one-week-old transgenic Asn488Ile mice (4).

Features of PRKAG2 cardiomyopathy found in the Asn488Ile transgenic mouseare reversed by expression of a dominant negative transgenic mutation in the α2subunit of AMPK (PRKAA2), which almost abolishes AMPK activity (183). Thehistological abnormalities, cardiac hypertrophy, glycogen content, and ventricularpreexcitation are reduced or normalized in the double transgenic mice (F. Ahmad,M. Arad, N. Musi, H. He, C. Wolf, D. Branco, A. Perez-Atayde, Y. Xing, R. Tian,L. Goodyear, C. Berul, J. Ingwall, C. Seidman, J. Seidman, unpublished observa-tions). Collectively, these data indicate that several PRKAG2 mutations produce again of function in the catalytic α2 subunit.

With aging, Asn488Ile transgenic mice develop ventricular dilation and sys-tolic dysfunction—disease progression that is also found in human patients (4,49). The processes leading to this end-stage phenotype remain largely unknown.

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Defining the cellular events involved in this process should provide informa-tion about both acquired and inherited hypertrophic heart disorders that presentinitially with cardiac hypertrophy and ultimately evolve into a decompensatedphenotype.

The demonstration that human PRKAG2 mutations cause constitutive activity ofAMPK implicates its downstream targets as possibly being involved in the patho-genesis of the hypertrophic cardiac remodeling. Glucose may be inappropriatelytaken up by cardiomyocytes and converted to glycogen because transporters aretargets of AMPK. The excess glycogen deposition leads to cardiac hypertrophy,ventricular preexcitation, and impaired exercise capacity. Of note, transgenic miceexpressing a dominant negative α2 subunit demonstrate blunted cellular glucoseuptake in the setting of myocardial ischemia (183). It is possible that the atten-uation of the phenotype of the Asn488Ile mutation in double transgenic mice issecondary to a similar reduction in excessive glucose uptake.

Other targets of AMPK activity may also contribute to hypertrophic remodeling.Only a fraction of the proteins that undergo phosphorylation by AMPK are known,and for most of these, their roles in the heart are unexplored. For example, AMPKcan phosphorylate TSC2, a kinase encoded by a tuberous sclerosis disease gene(81). Rhabdomyomas, which arise frequently in patients with tuberous sclerosis,are vacuolated muscle tumors that contain abundant amounts of glycogen (62).TSC2 phosphorylates mTOR (mammalian target of rapamycin), a molecule thatparticipates in the degradation of IRS-1 (insulin receptor substrate). Thus, AMPKappears to participate in the regulation of muscle cell growth, and may function ina similar fashion in cardiac myocytes.

DILATED CARDIOMYOPATHY

Dilated cardiomyopathy (DCM) is characterized by left or bi-ventricular dilation inassociation with depressed myocardial contractility (Figure 2C). Although patho-logic study reveals distended chambers of the heart, the histopathology of DCMis often unremarkable with only nonspecific evidence of myocyte hypertrophy,myocyte degeneration, and increased interstitial fibrosis (Figure 2F,I ).

DCM is a prevalent cardiomyopathy affecting 36.5 out of 100,000 individu-als and is associated with a poor clinical prognosis. Affected individuals exhibitprogressive symptoms of easy fatigability, exertional dyspnea, or palpitations, andgradually develop heart failure, often in association with life-threatening atrial orventricular arrhythmias. The mortality of individuals with symptomatic DCM ishigh, approaching 25% at one year and 50% at five years (19).

In half of all individuals with DCM there is no recognized antecedent cardiovas-cular disorder (31). Furthermore, 35% of DCM patients have affected first-degreerelatives (51), indicating a considerable role for genetics in disease pathogenesis.Longitudinal family studies also demonstrate several distinct clinical phenotypesof DCM. Some DCM occurs after years of cardiac conduction system disease:

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progressive delays in atrioventricular conduction may be evident decades beforeventricular dilation and systolic dysfunction. Other genetic forms of DCM occurwith extracardiac manifestations, most often skeletal muscle disease, but also withhematologic, skin, or hearing disorders. Deciphering how particular mutationscausing DCM disrupt the function of other organs will provide new informationregarding shared properties among various highly specialized cells.

Inherited DCM is most commonly transmitted as an autosomal dominant trait,but autosomal recessive, X-linked, or matrilinear (mitrochondrial) inheritancesalso occur. Initial progress in deciphering the genetic causes of DCM was slow dueto the considerable morbidity and mortality of the disease, which limited the avail-ability of large families suitable for genetic linkage studies, the late onset of thisdisease, and the incomplete penetrance of expression of disease. With the availabil-ity of high-density polymorphic genomic markers and the increasingly successfulstrategy of selecting candidate genes based on biological function, the number ofhuman DCM gene mutations identified (Table 2) has dramatically increased.

Two models may account for cardiac remodeling that results in DCM. The finalcommon pathway model suggests that DCM reflects a nonspecific degenerativestate, which occurs by any of a variety of different stimuli: a gene mutation, viralinfection, or volume overload. An alternative model is that several independentpathways can remodel the heart and cause DCM. A corollary to this second modelis the prediction that despite shared histopathology, the cell biology of differentcauses of DCM will be distinct. Deciphering genetic causes of DCM has helpedto inform these models. Based on a still-incomplete repertoire of known humanDCM genes, it is apparent that mutations affect proteins with a wide range ofunrelated functions. Models that recapitulate human gene mutations have begun todecipher their biologic consequences, revealing distinct DCM pathways. Whetherthe myriad of DCM mutations will ultimately converge on a few or many DCMpathways remains under active investigation.

Disruption of myocyte cytoarchitecture, the protein scaffold that connects thenucleus to the extracellular matrix through the sarcolemma, is one pathway lead-ing to DCM. Human mutations (Table 2) have been identified in multiple compo-nents of the myocyte cytoskeleton, including cardiac muscle LIM protein (CLP),cypher/ZASP (LBD3), δ-sarcoglycan (SGCD), desmoplakin (DSP) desmin (DES),dystrophin (DMD), telethonin (TCAP), and vinculin (VCL). Mutations in manyproteins of the dystrophin-associated complex that cause skeletal muscular dys-trophies frequently also cause DCM. However, some mutations produce primarilycardiac disease with little or no skeletal muscle dysfunction. The DMD mutationThr279Ala in humans (124) and a deletion in the δ sarcoglycan gene (Sgcd ) inthe hamster lead to DCM. The Thr279Ala mutation results in a change in polarityin the first hinge region (H1) of the protein and substitution of a beta-sheet foralpha-helix in this portion of the protein, thus destabilizing it. One of the ma-jor functional consequences predicted to arise from these cytoskeletal mutationsis impaired transmission of contractile force generated by the sarcomere to theextracellular matrix.

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TABLE 2 Chromosomal loci and gene mutations in dilated cardiomyopathy

Locus Symbol Disease gene Additional phenotype Initial reports

1p1–q21 LMNA Lamin A/C Conduction disease,skeletal myopathy

(40, 67)

1q32 TNNT2 Cardiac troponin T2 None (65)

2q14–q22 Unknown Conduction disease (64)

2q31 TTN Titin None (46, 162)

2q35 DES Desmin Skeletal myopathy (48)

3p22–p25 Unknown Conduction disease (120)

5q33 SGCD Delta sarcoglycan Skeletal myopathy (175)

6p23–p4 DSP Desmoplakin Woolly hair,keratoderma, recessivetransmission

(116)

6q12–q16 Unknown None (166)

6q22.1 PLN Phospholamban None (152)

6q23–q24 EYA4 Skeletal myopathy,sensorineural hearingloss

(98, 153)



10q22–q23

MVCL Metavinculin Mitral valve prolapse (18, 119)

10q22.3–q23.2

LDB3 Cypher/ZASP Left ventricularnoncompaction

(177)

11p11.2 MYBPC3 Cardiac myosin bindingprotein C

None (30)

11p15.1 CLP Cardiac muscle LIMprotein

None (70)

12p12.1 ABCC9 ATP-sensitive K channel Arrhythmias (11)

14q12 MYH7 Beta myosin heavy chain None (65)

15q14 ACTC Cardiac actin None (122)

15q22 TPM1 Alpha tropomyosin None (121)

16p11 CTF1 Cardiotrophin 1 None (38)

19q13.2 Unknown Conduction disease (21)

Xp21 DMD Dystrophin Skeletal myopathy (174)

Xq28 TAZ Tafazzin Skeletal myopathy (29)

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Animal models of other human cytoskeletal protein mutations indicate ad-ditional potential disease mechanisms. Mice deficient in α-sarcoglycan exhibitaltered integrity of the cytoskeleton of coronary artery vascular smooth musclecells as well as cardiac myocytes. Notably, these mice develop coronary arteryvasospasm and myocardial ischemia, indicating that vascular insufficiency maycompound deficits in force transmission in this form of DCM (26).

A human mutation in the cytoarchitecture protein desmin may cause DCMthrough complex mechanisms involving the formation of electron-dense bodies,known as aggresomes, containing amyloid proteins. In transgenic mice designed tomodel desmin-related DCM, prevalent cytoplasmic aggresomal bodies were foundin the heart, which contained amyloid oligomers (150). Accumulation of aggre-somes hint that pathways involved in amyloidosis, protein misfolding disorders,and neurodegenerative diseases also contribute to DCM.

The pathophysiologic mechanism of human DCM mutations that affect the nu-clear envelope protein lamin A/C (LMNA) remains enigmatic, although recent dataimplicate deficits in the myocyte cytoskeleton. Ubiquitously expressed in all cells,lamin A/C participates in nuclear dissociation and reassembly during mitosis, butthe relevance of this function to terminally differentiated cardiac myocytes, and tomutations that cause DCM, is unclear. Recent analyses of cardiac myocytes andfibroblasts isolated from Lmna−/− deficient mice demonstrate deformities of thenucleus and the desmin cytoskeletal network, impaired mechanotransduction, di-minished viability during periods of mechanical strain, and impaired activation oftranscriptional programs in response to mechanical strain (75, 115). Deformitiesof the nuclear envelope have also been observed in the skin fibroblasts of patientswith LMNA mutations (108). As such, LMNA mutations may limit the adaptivemechanisms of myocyte. Several features of human lamin A/C mutations remainunexplained. Why do defects in the protein cause progressive electrophysiologicabnormalities decades before signs or symptoms of DCM? The considerable phe-notypic diversity associated with lamin A/C mutations remains poorly understood.Some mutations lead to DCM and conduction disease in the absence of skeletalmyopathy (40); other mutations, particularly those affecting the central helical roddomain, cause juvenile-onset skeletal muscular dystrophies (17, 107); still oth-ers affecting carboxyl terminal residues cause familial partial lipodystrophy withinsulin-resistant diabetes (160).

Discovering that genetic defects in the myocyte cytoskeleton can cause DCMprovided a clue as to the mechanism responsible for acquired DCM, specificallythat following viral infection of the heart (myocarditis) (5, 184). Enteroviruses pro-duce protease 2A, which can specifically cleave the hinge 3 region of dystrophin.Mice infected with Coxsackie-B3 have decreased levels of dystrophin-associatedsarcoglycans within the sarcolemma, and dystrophin-deficient mice develop moresevere DCM when infected with enterovirus. One patient with DCM caused byCoxsackie-B2 myocarditis showed reduced dystrophin and beta-sarcoglycan stain-ing of the sarcolemma of cardiac tissue. Collectively, these data suggest that

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enteroviral infections, like some DCM gene mutations, may cause disease byaffecting the integrity of the dystrophin-sarcoglycan complex.

Human sarcomere protein gene mutations cause DCM as well as HCM (155).Titin (TTN) mutations and some mutations in cardiac actin (ACTC), tropomyosin(TPM1), and myosin heavy chain (MYH7) are located in functional domains in-volved in force propagation, suggesting that these defects may share a pathophys-iologic mechanism with mutations in the myocyte cytoskeleton. However, othersarcomere gene mutations (TNNT2) may directly diminish the capacity of the sar-comere to produce force, thereby triggering DCM. A mutation in myosin heavychain mutation that alters a residue essential for tight actin interactions likelyfunctions in a similar manner. In addition, DCM mutations in troponin T (TNNT2)appear to affect sarcomere response to calcium. Cardiac muscle fibers and isolatedmyocytes into which DCM cardiac troponin T (cTnT) mutation Lys210� was in-troduced showed calcium desensitization and decreased maximal force comparedto wild type (85, 106, 148, 178).

Calcium is implicated in the pathology of another DCM due to mutations inphospholamban (PLN), the reversible inhibitor of the cardiac sarcoplasmic reticularCa2+-ATPase (SERCA2) that regulates basal cardiac contractility (52, 152). Phos-phorylation of phospholamban following β-adrenergic stimulation of the heartreleases inhibition of SERCA2. One DCM mutation in PLN prevents phosphory-lation by trapping protein kinase A (PKA). Consequently, calcium reuptake fromthe cytosol into the sarcoplasmic reticulum (SR) is delayed and DCM ensues. Miceengineered to carry the human PLN mutations develop fulminant DCM and heartfailure, whereas mice deficient in phospholamban have minor cardiac abnormal-ities (reviewed in 86). When PLN is ablated by mutation from mice with DCMthat lack the actin-associated cytoskeletal muscle LIM protein, cardiac functionimproves (103). These data indicate that precisely regulating calcium is centralto normal cardiac function; when calcium functions or cycling is directly (viatroponin or phospholamban mutation, respectively) or indirectly (via myosin mu-tation) disturbed cellular events ensue that lead to HCM or DCM.

Altered energetic and metabolic processes of the myocyte can cause DCM. Car-diomyopathy is a well recognized feature of mitochondrial syndromes (20). Re-cently, DCM mutations were identified in the regulatory SUR2A subunit (encodedby ABCC9) of KATP channels (11), a multimeric protein complex that containsa potassium pore and enzyme system that participates in decoding metabolic sig-nals during stress adaptation of cells (189). The causative mutations render KATPchannels insensitive to ADP-induced conformation changes; these defects affectchannel opening and closure and are predicted to make hearts more susceptible tocalcium overload (59).

Additional mechanisms for DCM will likely be discovered. Mutations in tafazin(TAZ), a molecule with unknown biologic functions, have been identified as thecause of X-linked childhood-onset DCM associated with short stature and immuno-logic deficiency (6). A mutation in EYA4, encoding a transcriptional coactivator

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that may function as a nuclear phosphatase, causes DCM with sensorineural hear-ing loss (153). In addition, many more DCM loci have been mapped for which thedisease gene remains unknown.

Whether there are interactions among the multiple pathways triggered by humangene mutations that cause DCM is unclear. Study of the transcriptional responses todifferent DCM gene mutations is one methodology that may address this question.To date, only a few studies (82, 186) have been performed, which have identifiedaltered levels of several functional groups (cytoskeletal and myofibrillar genes,proteins with degradation or synthesis functions, metabolic and stress-responseproteins). Whether these altered expression profiles are specific to the incitingmolecular defects remains to be determined. To date, these studies have failed toidentify signaling molecules that contribute to the observed changes in levels ofstructural protein. More knowledge of cellular and molecular events triggered byDCM mutations is needed to elucidate the pathways by which the human heartremodels and ultimately fails.

Clinical evaluations of families with DCM gene mutations often reveal theabsence of disease in individuals carrying disease-causing mutations. As withHCM, modifier genes likely significantly affect the phenotypic severity of DCM.Loci for several modifier genes have been mapped in a murine model of DCMsecondary to cardiac-specific expression of calsequestrin (77).

RESTRICTIVE CARDIOMYOPATHY

Restrictive cardiomyopathy (RCM) is a rare form of cardiac remodeling character-ized by decreased myocardial compliance and elevated diastolic filling pressures.Diastolic dysfunction is prominent and leads to atrial enlargement, elevated sys-temic and pulmonary venous pressures, and heart failure. Systolic function andmyocardial wall thickness remain normal. The prevalence and the incidence ofRCM have not been assessed accurately, but estimates indicate that restrictiveremodeling occurs in less than 5% of all cardiomyopathies (42).

The extremely low prevalence of RCM combined with the need for catheteriza-tion-based diagnostic procedures has limited the identification of kindreds appro-priate for linkage and mutation analysis. Hence, advances in the molecular geneticsof RCM have been limited to candidate gene studies. Zhang and colleagues identi-fied a four-generation family with RCM pathophysiology due to desmin depositionin cardiac myocytes (188). Sequence analyses of desmin and of other candidategenes failed to define the responsible mutation. Mogensen and colleagues identi-fied a single family in which some members exhibited RCM whereas others hadclassic findings of HCM (105). A cardiac troponin I (TNNTI3) mutation was foundin all family members with either form of cardiomyopathy, RCM or HCM. Analy-ses of TNNTI3 sequences in other unrelated RCM patients led to the identificationof additional mutations by these investigators. All RCM mutations in TNNTI3 werelocated in domains involved in actomyosin ATPase inhibitory function.

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These data suggest that although HCM, DCM, and RCM are often considereddistinct clinical entities, they may be genetically and pathologically related. Pro-gressive accumulation of cardiac fibrosis triggered by gene mutations that causeeither HCM or DCM can affect hemodynamic parameters (in particular impaireddiastolic relaxation) so as to superimpose restrictive physiology onto remodelingprograms. This mechanism may account for why an identical mutation causeseither HCM or RCM in the same family. Additional genetic and environmentalfactors, in addition to the primary mutation, may modify the disease phenotype.

ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA/CARDIOMYOPATHY

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD or ARVC)is an intriguing inherited disorder characterized by replacement of the right ven-tricular myocardium by adipose and fibrous tissue and is associated with suddencardiac death. Research to elucidate ARVD disease manifestations, pathogenesis,and genetics has been impeded by several factors, including technical difficultiesin imaging the right ventricle and, until recently, limited clinical awareness of thisdisorder. Rampazzo and colleagues estimate the prevalence of ARVD in the Venetoregion of Italy to be 6/10,000 and, in certain subpopulations, 44/10,000 (137). InItaly, 12.5% to 25% of sudden death events in both sedentary individuals andyoung athletes under the age of 35 years were caused by undiagnosed ARVD (7,43). These findings have been corroborated elsewhere in the world. In the UnitedStates, 17% of sudden death victims between the ages of 20 and 40 years had ARVD(161). In addition, ARVD was found in 18 of 50 cases of sudden unexpected peri-operative death (169), affecting a wide variety of ethnic groups. Associated withclinically important ventricular arrhythmias, ARVD has a high annual mortalityrate of 3%, which may be reduced to 1% by medical therapy (130).

The histopathology of ARVD is characterized by progressive replacement ofthe right ventricular myocardium by adipose and fibrous tissue (Figure 2K ) (28).Affected myocardial tissue demonstrates sparse myocytes interspersed amongadipocytes and fibrous tissue, a process that appears to begin at the epicardiumand gradually extends through the myocardium toward the subendocardium. Theanterior right ventricular outflow tract (RVOT), the apex, and the inferoposteriorwall are most frequently affected, but eventually the entire right ventricle becomesdiffusely involved (109, 112). Adipocytes and fibrous tissue are found in the leftventricle in 76% of patients (28). The interventricular septum is affected in only20% of patients (8), which contributes to the underdiagnosis of ARVD becausethe septum is the routine site for endomyocardial biopsies.

Descriptive studies suggest that loss of myocardium and replacement by adiposeand fibrous tissue in ARVD result from excessive and inappropriate apoptosis ofcardiac myocytes. Investigators have observed apoptosis in myocardial samplesfrom patients with ARVD (185).

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TABLE 3 Chromosomal loci and gene mutations in arrhythmia right ventricular dysplasia

Locusname

Chromosomallocation

Flankingmarkers Size (cM) Disease gene

Distinguishingclinical features

Initialreports

ARVD2 1q42–q43 SurroundingD1S163

Cardiacryanodinereceptor(RYR2)

Associated withcatecholaminergicpolymorphic VT

(9, 138,173)

ARVD4 2q32.1–q32.3 D2S152—D2S389

5.4 Unknown Associated withlocalized leftventricularinvolvement

(140)

ARVD5 3p23 D3S1293—D3S3659

3.8 Unknown (1)

ARVD8 6p24 D6S1574—D6S259

18.5 Desmoplakin(DSP)

(10, 139)

ARVD6 10p12–p14 D10S547—D10S1653

10.6 Unknown Early onset, highpenetrance

(80)

ARVD7 10q22 D10S605—D10S215

9.3 Unknown Associated withmyofibrillarmyopathy

(97)

12p11 Plakophilin-2(PKP2)

(47)

ARVD3 14q12–q22 D14S262—D14S69

14.5 Unknown (159)

ARVD1 14q23–q24 SurroundingD14S42

Unknown (137)

Naxos 17q21 D17S800—D17S1789

0.7 Junctionalplakoglobin(JUP)

Autosomalrecessivetransmission,associated withdiffusenonepidermolyticpalmoplantarkeratoderma andwoolly hair

(25, 95)

In almost all families, ARVD is transmitted in an autosomal dominant pattern.Nine genetic loci associated with this disease have been ascertained by genetic link-age analysis or candidate gene analysis, and mutations in genes at three loci havenow been discovered (Table 3). ARVD mutations have been identified in genes thatencode protein components of cardiac desmosomes: plakophilin-2 (PKP2) (47),desmoplakin (DSP) (139), and junctional plakoglobin (JUP) (95). Plakophilin-2,an armadillo-repeat protein encoded on chromosome 12p11, is abundantly ex-pressed in cardiac muscle. Located on the outer domain of desmosomes, it linkscadherins with desmoplakin and the intermediate filaments within myocytes. Mice

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deficient in Pkp2 die during mid-gestation with morphologic defects and abnormalarchitecture of myocyte junctions. Plakoglobin is a cytoplasmic protein, which isa submembranous constituent of both kinds of cell-cell adhering junctions, thedesmosomal and the adherens junctions. Plakoglobin participates in bridging theintermediate filament and the intracellular actin cytoskeletal networks to the trans-membrane complexes connecting adjacent cells (50). Desmoplakin is a constituentof the desmosomal plaque, anchoring intermediate filaments to the plasma mem-brane and forming a scaffold that is essential for maintaining tissue integrity. Inmyocardial and Purkinje fiber cells, it also binds to desmin (79). These proteins,therefore, serve a structural function similar to other proteins implicated in DCM.

A variety of PKP2 mutations have been identified, including missense, smallinsertions and deletions, and splice site defects. Whether these defects result infunctionally null alleles or cause ARVD by a dominant negative mechanism isunknown. One DSP mutation, Ser299Arg (139), disrupts a protein kinase C (PKC)phosphorylation site that is involved in plakoglobin binding and in clusteringdesmosomal cadherin-plakoglobin complexes.

Naxos disease is clinically related to ARVD but with notable differences, in-cluding an autosomal recessive inheritance pattern, diffuse nonepidermolytic pal-moplantar keratoderma, and woolly hair (25), in addition to the cardiac manifes-tations. A frameshift mutation in the gene encoding plakoglobin (JUP) that altersfive amino acids and then prematurely terminates translation was the first mutationidentified to cause Naxos disease. Emphasizing even further the parallels betweenARVD and DCM, a single base pair deletion (7991delG) in DSP was found in afamily with autosomal recessive DCM associated with keratoderma and woollyhair (116). Thus, in some patients with ARVD, a degenerative mechanism similarto that observed in DCM appears to be involved. Altered integrity at cardiac my-ocyte cell-cell junctions may promote myocyte degeneration and death, with therepair process consisting of adipose and fibrous tissue replacing myocardium. Inaddition, plakoglobin plays a direct role in regulating apoptotic cell death (53).

The basis for the striking predilection of pathology in the right ventriclewith ARVD remains unclear despite the identification of causative mutations.Plakophilin, plakoglobin, and desmoplakin are expressed in both ventricles and,as noted above, a mutation in DSP that results in left ventricular DCM was re-ported (116). The striking asymmetric ventricular involvement in ARVD may bedue to the relative thinness of the right ventricular free wall, which makes it moresusceptible to mechanical stress.

Another breakthrough in understanding the molecular genetics of ARVD oc-curred with the identification of mutations in the cardiac ryanodine receptor gene(RYR2) leading to ARVD (173). RYR2, which contains 105 exons, encodes a565-kDa product containing 4967 amino acids. This polypeptide monomer ispart of a homotetrameric membrane-spanning calcium channel on the sarcoplas-mic reticulum and interacts with four regulatory 12-kDa FK-506 binding pro-teins (FKBP12.6). This channel serves critical functions in excitation-contraction(EC) coupling and intracellular calcium homeostasis within the cardiac myocyte.

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Stimulating voltage-sensitive L-type calcium channels (dihydropyridine receptors)on the outer myocardial cell membrane allows the entry of small amounts of cal-cium ions, which in turn activate release of larger amounts of calcium from thesarcoplasmic reticulum lumen into the cytoplasm via RyR2.

The carboxyl end of the RyR2 channel is anchored to the sarcoplasmic reticulumby 4 to 10 membrane-spanning hydrophobic motifs and a large cytoplasmic domainthat is proximate to the outer cell membrane L-type calcium channels (27). Criticalelements of the channel include the pore and sites for ATP binding, calmodulinbinding, and FKBP12.6 binding. Sites for binding of two other major proteinphosphatases in cardiac muscle, protein phosphatase 1, and protein phosphatase2A are also present (92).

Several RYR2 channel mutations that cause ARVD have been identified (9,173). Three missense mutations appear to cluster at the amino end of the protein,and three appear to cluster in the center of the protein at its FKIBP12.6 bindingdomain. As indicated in Table 3, families with ARVD secondary to mutationsin RYR2 are distinguished by an unusual propensity to catecholaminergic poly-morphic ventricular tachycardia (CPVT) (9). Mutations in the FKBP12.6 bindingdomain, or at the carboxyl end of the transmembrane domain RYR2 gene havealso been identified in families with isolated CPVT transmitted in an autosomaldominant pattern (74, 135). These families had no evidence of structural heartdisease (165). Thus, two disorders, ARVD and CPVT, can result from mutationsin the same gene, as observed with other disorders such as HCM, DCM, and RCM.An intriguing question is why different mutations in the RYR2 gene lead to twodistinct phenotypes. Mutations in the amino terminal cluster have been reportedonly in families demonstrating ARVD and, conversely, mutations in the carboxylcluster have been reported only in families with CPVT. Although the functionof the RyR2 polypeptide domain at the amino cluster is unclear, it is located inthe cytoplasm whereas the carboxyl cluster contains the transmembrane domains.Mutations in the central cluster lead to both phenotypes. Perhaps each group ofamino acids, when mutated, alters the function or structure of the polypeptide in adistinct manner so that both groups of mutations produce the CPVT, but only onegroup is associated with the structural changes characteristic of ARVD. An alter-native hypothesis is that mutations in the same gene produce different phenotypesbecause of differing genetic backgrounds in each family. Different alleles of mod-ifier genes in each family may attenuate or promote the development of ARVDin addition to CPVT. A third possibility is that families with ARVD and withCPVT are exposed to different environmental influences, which lead to differentphenotypes. The mechanisms leading to distinct phenotypes should be elucidatedas further mutations are identified.

The mechanism whereby the mutations identified in the RYR2 gene lead toARVD remains enigmatic. One of the identified mutations, Arg176Gln, corre-sponds to a mutation in the skeletal muscle isoform of the ryanodine receptor,Arg163Gln, for which functional studies are available (61). This mutation resultsin hyperactivation and hypersensitivity of the channel, leading to excessive cal-cium ion release from the sarcoplasmic reticulum. The mutations in the vicinity

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of an FKBP12.6 binding domain may attenuate the negative regulatory effect ofFKBP12.6 (133) and thus similarly lead to hyperactivation and hypersensitivityof the RyR2 channel. Cytoplasmic calcium overload resulting from these muta-tions can cause delayed afterdepolarizations, which in turn produce ventriculartachycardia (134). Delayed afterdepolarizations are enhanced by adrenergic stim-ulation. Thus, elevating ambient catecholamine levels during exertion or stress,in the setting of a hyperactivated or hypersensitive mutant RYR2 allele, may leadto the arrhythmias that are clinically apparent. The mechanism of the histologi-cal changes is less obvious. Ryanodine receptor (RyR1 and RyR2) activation bycaffeine stimulates apoptosis in prostate cancer (LNCaP) cells, whereas inhibitionby ryanodine inhibits apoptosis (88). Thus, there may be a relationship betweenRyR2 and apoptosis.

CONCLUSIONS

Remarkable strides have been made in elucidating the molecular genetics of car-diomyopathies, considering that they were deemed “idiopathic” less than twodecades ago. A large proportion of HCM is secondary to mutations in sarcom-eric proteins. PRKAG2 cardiomyopathy was unknown as a distinct entity and hadbeen grouped with HCM on the basis of noninvasive clinical testing. Identify-ing causative mutations and modeling these mutations in yeast and mice haveelucidated the pathogenesis of diseases that are completely divergent from HCM.

DCM occurs as a result of mutations in genes encoding a variety of proteins,including sarcomeric and structural proteins, and may result from activation of sev-eral different independent mechanisms. Although progress has been slower in thestudy of RCM and ARVD, causative mutations are being identified with increasingspeed. These disorders indicate ventricular dilation and systolic dysfunction maybe the end result of various insults, initiated by mutations with many differenteffects on myocytes.

Identifying the causative mutation in patients with cardiomyopathies by ge-netic diagnosis facilitates early recognition of individuals at risk for arrhyth-mias and sudden death. In addition to the important clinical information thisprovides to patients, families, and physicians, longitudinal investigation of in-dividuals with gene mutations provides an opportunity further to expand data onmyocyte and myocardial response to gene mutations. Better information of thecell and molecular signals triggered by gene mutations should continue to providenew knowledge about myocyte biology as well as foster development of ratio-nale therapy for cardiomyopathies that may ultimately reduce progression to heartfailure.

ACKNOWLEDGMENT

The Howard Hughes Medical Institute supported this work. We thank SteveDePalma, Ph.D., for constructing Figure 3.

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The Annual Review of Genomics and Human Genetics is online athttp://genom.annualreviews.org

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GENETICS OF CARDIAC REMODELING C-1

Figure 1 The structure of the cardiac myocyte, showing the sarcomere, the cytoskeletalnetwork, calcium channels, nuclear proteins, lysosomes, mitochondria, and AMP-activat-ed protein kinase (AMPK). Mutations in the genes encoding most of the protein compo-nents of these structures lead to cardiomyopathies. Copyright © 1999 MassachusettsMedical Society. All rights reserved.

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C-2 AHMAD ■ SEIDMAN ■ SEIDMAN

Figure 2 Anatomic and histological remodeling in cardiomyopathies. Morphologic fea-tures of the normal heart (A), compared to hypertrophic (B) and dilated (C) cardiomyopa-thy. The normal myocardial histology (D) is distorted by myocyte hypertrophy, disarray,and fibrosis in hypertrophic cardiomyopathy (HCM) (E), and myocyte loss and fibrosis indiluted cardiomyopathy (DCM) (F). Compared with normal tissue (G), increased intersti-tial fibrosis (blue) is evident by the Masson trichrome stain in both HCM (H) and DCM (I).Cardiac tissue from mice with a human PRKAG2 mutation demonstrates glycogen car-diomyopathy (J). Note the vacuoles within the myocytes. Arrhythmogenic right ventricu-lar dysplasia (K) demonstrates dramatic increases in adipose (A) and fibrous tissue (F) thatreplace normal myocytes. (D–F, J, and K represent the hematoxylin and eosin stain.)


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GENETICS OF CARDIAC REMODELING C-3

Figure 3 A three-dimensional representation of the actin-myosin complex, showing positions of known cardiomyopathy mutations. One myosin heavy chain (white), oneessential myosin light chain (orange), one regulatory myosin light chain (purple), and fiveactin monomers (shades of green) are displayed. Residues in actin and myosin that aremutated in HCM are indicated in blue, and residues mutated in DCM are indicated in red.


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P1: KUV

July 27, 2005 13:16 Annual Reviews AR252-FM

Annual Review of Genomics and Human GeneticsVolume 6, 2005

CONTENTS

A PERSONAL SIXTY-YEAR TOUR OF GENETICS AND MEDICINE,Alfred G. Knudson 1

COMPLEX GENETICS OF GLAUCOMA SUSCEPTIBILITY, Richard T. Libby,Douglas B. Gould, Michael G. Anderson, and Simon W.M. John 15

NOONAN SYNDROME AND RELATED DISORDERS: GENETICS AND

PATHOGENESIS, Marco Tartaglia and Bruce D. Gelb 45

SILENCING OF THE MAMMALIAN X CHROMOSOME, Jennifer C. Chow,Ziny Yen, Sonia M. Ziesche, and Carolyn J. Brown 69

THE GENETICS OF PSORIASIS AND AUTOIMMUNITY, Anne M. Bowcock 93

EVOLUTION OF THE ATP-BINDING CASSETTE (ABC) TRANSPORTER

SUPERFAMILY IN VERTEBRATES, Michael Dean and Tarmo Annilo 123

TRADE-OFFS IN DETECTING EVOLUTIONARILY CONSTRAINED SEQUENCE

BY COMPARATIVE GENOMICS, Eric A. Stone, Gregory M. Cooper,and Arend Sidow 143

MITOCHONDRIAL DNA AND HUMAN EVOLUTION, Brigitte Pakendorfand Mark Stoneking 165

THE GENETIC BASIS FOR CARDIAC REMODELING, Ferhaan Ahmad,J.G. Seidman, and Christine E. Seidman 185

HUMAN TASTE GENETICS, Dennis Drayna 217

MODIFIER GENETICS: CYSTIC FIBROSIS, Garry R. Cutting 237

ADVANCES IN CHEMICAL GENETICS, Inese Smuksteand Brent R. Stockwell 261

THE PATTERNS OF NATURAL VARIATION IN HUMAN GENES,Dana C. Crawford, Dayna T. Akey, and Deborah A. Nickerson 287

A SCIENCE OF THE INDIVIDUAL: IMPLICATIONS FOR A MEDICAL SCHOOL

CURRICULUM, Barton Childs, Charles Wiener, and David Valle 313

COMPARATIVE GENOMIC HYBRIDIZATION, Daniel Pinkeland Donna G. Albertson 331

SULFATASES AND HUMAN DISEASE, Graciana Diez-Rouxand Andrea Ballabio 355

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July 27, 2005 13:16 Annual Reviews AR252-FM

vi CONTENTS

DISEASE GENE DISCOVERY THROUGH INTEGRATIVE GENOMICS, CosmasGiallourakis, Charlotte Henson, Michael Reich, Xiaohui Xie,and Vamsi K. Mootha 381

BIG CAT GENOMICS, Stephen J. O’Brien and Warren E. Johnson 407

INDEXES

Subject Index 431Cumulative Index of Contributing Authors, Volumes 1–6 453Cumulative Index of Chapter Titles, Volumes 1–6 456

ERRATA

An online log of corrections to Annual Review of Genomicsand Human Genetics chapters may be foundat http://genom.annualreviews.org/

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Documents

THE GENETIC BASIS FOR CARDIAC REMODELING