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• W2077307965 abstract "Heart failure is highly influenced by heritability, and nearly 100 genes link to familial cardiomyopathy. Despite the marked genetic diversity that underlies these complex cardiovascular phenotypes, several key genes and pathways have emerged. Hypertrophic cardiomyopathy is characterized by increased contractility and a greater energetic cost of cardiac output. Dilated cardiomyopathy is often triggered by mutations that disrupt the giant protein titin. The energetic consequences of these mutations offer molecular targets and opportunities for new drug development and gene correction therapies. Heart failure is highly influenced by heritability, and nearly 100 genes link to familial cardiomyopathy. Despite the marked genetic diversity that underlies these complex cardiovascular phenotypes, several key genes and pathways have emerged. Hypertrophic cardiomyopathy is characterized by increased contractility and a greater energetic cost of cardiac output. Dilated cardiomyopathy is often triggered by mutations that disrupt the giant protein titin. The energetic consequences of these mutations offer molecular targets and opportunities for new drug development and gene correction therapies. The clinical diagnosis of heart failure (HF) arises when cardiac output is insufficient to supply demand. Acute HF can occur from abrupt occlusion of a coronary artery, catastrophic valve dysfunction, malignant hypertension, or other states that provoke an urgent mismatch between supply and demand. Chronic HF is experienced as a slow decline in function, measured over years, as fatigue, breathlessness, and often evidence of end organ vascular insufficiency. Fluid overload and arrhythmias contribute to the HF spectrum. The timeline of chronic HF is punctuated by acute HF exacerbations, and the annual costs associated with HF exceed $30 billion U.S. dollars (Heidenreich et al., 2013Heidenreich P.A. Albert N.M. Allen L.A. Bluemke D.A. Butler J. Fonarow G.C. Ikonomidis J.S. Khavjou O. Konstam M.A. Maddox T.M. et al.American Heart Association Advocacy Coordinating CommitteeCouncil on Arteriosclerosis, Thrombosis and Vascular BiologyCouncil on Cardiovascular Radiology and InterventionCouncil on Clinical CardiologyCouncil on Epidemiology and PreventionStroke CouncilForecasting the impact of heart failure in the United States: a policy statement from the American Heart Association.Circ Heart Fail. 2013; 6: 606-619Crossref PubMed Scopus (620) Google Scholar). The major costs are calculated in repeated hospitalizations, the need for medical and device intervention, and lost productivity (Dunlay et al., 2011Dunlay S.M. Shah N.D. Shi Q. Morlan B. VanHouten H. Long K.H. Roger V.L. Lifetime costs of medical care after heart failure diagnosis.Circ Cardiovasc Qual Outcomes. 2011; 4: 68-75Crossref PubMed Scopus (87) Google Scholar). Because of the chronic and progressive nature of HF, there is opportunity to intervene at early stages. HF is frequently accompanied by cardiomyopathy, defined as a morphologically abnormal heart. In vivo, echocardiography provides critical information regarding chamber dimensions and function, while magnetic resonance imaging also provides a more in-depth visualization of myocardial tissue composition (Mahrholdt et al., 2005Mahrholdt H. Wagner A. Judd R.M. Sechtem U. Kim R.J. Delayed enhancement cardiovascular magnetic resonance assessment of non-ischaemic cardiomyopathies.Eur. Heart J. 2005; 26: 1461-1474Crossref PubMed Scopus (460) Google Scholar, Rickers et al., 2005Rickers C. Wilke N.M. Jerosch-Herold M. Casey S.A. Panse P. Panse N. Weil J. Zenovich A.G. Maron B.J. Utility of cardiac magnetic resonance imaging in the diagnosis of hypertrophic cardiomyopathy.Circulation. 2005; 112: 855-861Crossref PubMed Scopus (327) Google Scholar). The major forms of cardiomyopathy include hypertrophic, dilated, restrictive, and arrhythmogenic (sometimes referred to as right ventricular) cardiomyopathy (Maron et al., 2006Maron B.J. Towbin J.A. Thiene G. Antzelevitch C. Corrado D. Arnett D. Moss A.J. Seidman C.E. Young J.B. American Heart AssociationCouncil on Clinical Cardiology, Heart Failure and Transplantation CommitteeQuality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working GroupsCouncil on Epidemiology and PreventionContemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.Circulation. 2006; 113: 1807-1816Crossref PubMed Scopus (1692) Google Scholar). Each of these forms of cardiomyopathy has a major heritable component, and genetic testing is now used in the evaluation of individuals with cardiomyopathy (Arndt and MacRae, 2014Arndt A.K. MacRae C.A. Genetic testing in cardiovascular diseases.Curr. Opin. Cardiol. 2014; 29: 235-240Crossref PubMed Scopus (0) Google Scholar, McNally et al., 2013McNally E.M. Golbus J.R. Puckelwartz M.J. Genetic mutations and mechanisms in dilated cardiomyopathy.J. Clin. Invest. 2013; 123: 19-26Crossref PubMed Scopus (164) Google Scholar, Teekakirikul et al., 2013Teekakirikul P. Kelly M.A. Rehm H.L. Lakdawala N.K. Funke B.H. Inherited cardiomyopathies: molecular genetics and clinical genetic testing in the postgenomic era.J. Mol. Diagn. 2013; 15: 158-170Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). The genes for which there is genetic testing are shown in Figure 1. Overall, there are nearly 100 genes linked to inherited forms of cardiomyopathy. More than 20 genes are implicated in hypertrophic cardiomyopathy (HCM), while fewer genes are linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). Dilated cardiomyopathy (DCM) is the most genetically heterogeneous. The same gene may be implicated in multiple forms of cardiomyopathy, underscoring the importance of genomic context in the pathophysiology of disease-associated variants. In addition to genetic causes, ischemia, toxic insult, and valvular defects contribute to DCM, and more than one etiology may contribute to any form of cardiomyopathy. Despite this heterogeneity, several essential classes of genetic mutations are present around which existing and novel therapies can be applied. The large number of genes responsible for cardiomyopathy, as well as the myriad of diverse mutations within each of these genes, produces remarkable heterogeneity for this complex disorder. Individual cardiomyopathy-associated genetic variants are infrequent in the general population (<1 in 500), and individual genetic variants associate with a range of expressivity causing mild and severe forms of disease. For example, deletion of arginine 14 in phospholamban (PLN gene) was described with early onset cardiomyopathy and accompanying lethal arrhythmias (Haghighi et al., 2006Haghighi K. Kolokathis F. Gramolini A.O. Waggoner J.R. Pater L. Lynch R.A. Fan G.C. Tsiapras D. Parekh R.R. Dorn 2nd, G.W. et al.A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy.Proc. Natl. Acad. Sci. USA. 2006; 103: 1388-1393Crossref PubMed Scopus (157) Google Scholar). In one population, this same mutation was found in 12% of ARVC and 15% of DCM subjects (van der Zwaag et al., 2012van der Zwaag P.A. van Rijsingen I.A. Asimaki A. Jongbloed J.D. van Veldhuisen D.J. Wiesfeld A.C. Cox M.G. van Lochem L.T. de Boer R.A. Hofstra R.M. et al.Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy.Eur. J. Heart Fail. 2012; 14: 1199-1207Crossref PubMed Scopus (121) Google Scholar), and a follow-up retrospective evaluation of 295 gene mutations carriers confirmed an earlier age of onset of both arrhythmias and cardiomyopathy (van Rijsingen et al., 2014van Rijsingen I.A. van der Zwaag P.A. Groeneweg J.A. Nannenberg E.A. Jongbloed J.D. Zwinderman A.H. Pinto Y.M. Dit Deprez R.H. Post J.G. Tan H.L. et al.Outcome in phospholamban R14del carriers: results of a large multicentre cohort study.Circ Cardiovasc Genet. 2014; 7: 455-465Crossref PubMed Google Scholar). Curiously, this same mutation was described in individuals with late-onset DCM without evidence of ventricular arrhythmias (DeWitt et al., 2006DeWitt M.M. MacLeod H.M. Soliven B. McNally E.M. Phospholamban R14 deletion results in late-onset, mild, hereditary dilated cardiomyopathy.J. Am. Coll. Cardiol. 2006; 48: 1396-1398Crossref PubMed Scopus (0) Google Scholar). The range of outcome with the same given variant is consistent with the presence of genetic and environmental factors that modify outcome (Arad et al., 2002Arad M. Seidman J.G. Seidman C.E. Phenotypic diversity in hypertrophic cardiomyopathy.Hum. Mol. Genet. 2002; 11: 2499-2506Crossref PubMed Google Scholar, Marian, 2000Marian A.J. Pathogenesis of diverse clinical and pathological phenotypes in hypertrophic cardiomyopathy.Lancet. 2000; 355: 58-60Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar) (Figure 2). Sex is a modifier of cardiomyopathy expression. Rare truncating mutations in TTN, the gene encoding the giant protein titin, are associated with more severe left ventricular (LV) dysfunction in males compared to females (Herman et al., 2012Herman D.S. Lam L. Taylor M.R. Wang L. Teekakirikul P. Christodoulou D. Conner L. DePalma S.R. McDonough B. Sparks E. et al.Truncations of titin causing dilated cardiomyopathy.N. Engl. J. Med. 2012; 366: 619-628Crossref PubMed Scopus (410) Google Scholar). Sex differences have also been described in HCM, where males are usually more affected, and this is recapitulated in animal models (Geisterfer-Lowrance et al., 1996Geisterfer-Lowrance A.A. Christe M. Conner D.A. Ingwall J.S. Schoen F.J. Seidman C.E. Seidman J.G. A mouse model of familial hypertrophic cardiomyopathy.Science. 1996; 272: 731-734Crossref PubMed Google Scholar, Vikstrom et al., 1996Vikstrom K.L. Factor S.M. Leinwand L.A. Mice expressing mutant myosin heavy chains are a model for familial hypertrophic cardiomyopathy.Mol. Med. 1996; 2: 556-567Crossref PubMed Google Scholar). Sex differences are attributed to a number of factors including hormone levels, gene expression differences, and basic differences in physiology, including heart size. Factors other than sex also influence the expression of genetic variants on the pathophysiology of heart disease. Secondary or additional genetic variants also contribute to severity or progression of disease. In individuals with more than one mutation, there is often earlier onset and in some cases a more rapid progression of disease (Girolami et al., 2010Girolami F. Ho C.Y. Semsarian C. Baldi M. Will M.L. Baldini K. Torricelli F. Yeates L. Cecchi F. Ackerman M.J. Olivotto I. Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations.J. Am. Coll. Cardiol. 2010; 55: 1444-1453Crossref PubMed Scopus (150) Google Scholar, Golbus et al., 2014Golbus J.R. Puckelwartz M.J. Dellefave-Castillo L. Fahrenbach J.P. Nelakuditi V. Pesce L.L. Pytel P. McNally E.M. Targeted analysis of whole genome sequence data to diagnose genetic cardiomyopathy.Circ Cardiovasc Genet. 2014; 7: 751-759Crossref PubMed Scopus (28) Google Scholar, Ingles et al., 2005Ingles J. Doolan A. Chiu C. Seidman J. Seidman C. Semsarian C. Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling.J. Med. Genet. 2005; 42: e59Crossref PubMed Google Scholar, Richard et al., 1999Richard P. Isnard R. Carrier L. Dubourg O. Donatien Y. Mathieu B. Bonne G. Gary F. Charron P. Hagege M. et al.Double heterozygosity for mutations in the beta-myosin heavy chain and in the cardiac myosin binding protein C genes in a family with hypertrophic cardiomyopathy.J. Med. Genet. 1999; 36: 542-545PubMed Google Scholar). A recent survey used whole-genome sequencing of 11 unrelated individuals to identify the spectrum of cardiomyopathy variants (Golbus et al., 2014Golbus J.R. Puckelwartz M.J. Dellefave-Castillo L. Fahrenbach J.P. Nelakuditi V. Pesce L.L. Pytel P. McNally E.M. Targeted analysis of whole genome sequence data to diagnose genetic cardiomyopathy.Circ Cardiovasc Genet. 2014; 7: 751-759Crossref PubMed Scopus (28) Google Scholar). In 9 of 11 individuals, the primary disease-causing variant was identified, usually because it segregated with disease. However, two cases had additional, rare, potentially pathogenic variation. Closer inspection of these families revealed that these secondary variants were segregating with a more severe phenotype, indicating that multiple rare variants may contribute to altered disease course within a family. Common or higher-frequency variation also impacts the effects of underlying pathogenic variants. Recent work has revealed an association between severity of cardiomyopathy and mitochondrial DNA haplogroup (Strauss et al., 2013Strauss K.A. DuBiner L. Simon M. Zaragoza M. Sengupta P.P. Li P. Narula N. Dreike S. Platt J. Procaccio V. et al.Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup.Proc. Natl. Acad. Sci. USA. 2013; 110: 3453-3458Crossref PubMed Scopus (37) Google Scholar). Human mitochondrial DNA can be divided into groups based on shared genealogy. Strauss and colleagues studied a large Mennonite family with autosomal recessive myopathy and cardiomyopathy caused by a frameshift mutation in the gene coding for adenine nucleotide translocator-1. The authors found considerable variability in the progression and severity of the cardiac phenotype that segregated with the maternal lineage. Sequencing showed segregation of two mitochondrial haplogroups, one of which conferred more severe cardiomyopathy (Strauss et al., 2013Strauss K.A. DuBiner L. Simon M. Zaragoza M. Sengupta P.P. Li P. Narula N. Dreike S. Platt J. Procaccio V. et al.Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup.Proc. Natl. Acad. Sci. USA. 2013; 110: 3453-3458Crossref PubMed Scopus (37) Google Scholar). These data underscore how the expressivity and penetrance of specific cardiomyopathy gene variants varies widely (Hershberger et al., 2013Hershberger R.E. Hedges D.J. Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture.Nat. Rev. Cardiol. 2013; 10: 531-547Crossref PubMed Scopus (167) Google Scholar). In silico algorithms score pathogenicity on numeric scales, relying on conservation data and less so on structural information (Ritchie and Flicek, 2014Ritchie G.R. Flicek P. Computational approaches to interpreting genomic sequence variation.Genome Med. 2014; 6: 87Crossref PubMed Google Scholar). Based on segregation with clinical phenotype, more highly penetrant mutations have been described, but even highly penetrant mutations may require the context of specific genetic backgrounds or ethnicities to fully manifest, and this “background effect” has been modeled in mice (Semsarian et al., 2001Semsarian C. Healey M.J. Fatkin D. Giewat M. Duffy C. Seidman C.E. Seidman J.G. A polymorphic modifier gene alters the hypertrophic response in a murine model of familial hypertrophic cardiomyopathy.J. Mol. Cell. Cardiol. 2001; 33: 2055-2060Abstract Full Text PDF PubMed Scopus (46) Google Scholar, Suzuki et al., 2002Suzuki M. Carlson K.M. Marchuk D.A. Rockman H.A. Genetic modifier loci affecting survival and cardiac function in murine dilated cardiomyopathy.Circulation. 2002; 105: 1824-1829Crossref PubMed Scopus (0) Google Scholar, Wheeler et al., 2009Wheeler F.C. Tang H. Marks O.A. Hadnott T.N. Chu P.L. Mao L. Rockman H.A. Marchuk D.A. Tnni3k modifies disease progression in murine models of cardiomyopathy.PLoS Genet. 2009; 5: e1000647Crossref PubMed Scopus (0) Google Scholar). With the emergence of sequence data from large numbers of ethnically diverse humans, it has become clear that “pathogenic” variation is found at a higher than expected rate. Specifically, previously described pathogenic mutations are present at a frequency higher than the prevalence of cardiomyopathy (Andreasen et al., 2013Andreasen C. Nielsen J.B. Refsgaard L. Holst A.G. Christensen A.H. Andreasen L. Sajadieh A. Haunsø S. Svendsen J.H. Olesen M.S. New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants.Eur. J. Hum. Genet. 2013; 21: 918-928Crossref PubMed Scopus (109) Google Scholar, Golbus et al., 2012Golbus J.R. Puckelwartz M.J. Fahrenbach J.P. Dellefave-Castillo L.M. Wolfgeher D. McNally E.M. Population-based variation in cardiomyopathy genes.Circ Cardiovasc Genet. 2012; 5: 391-399Crossref PubMed Scopus (71) Google Scholar, Pan et al., 2012Pan S. Caleshu C.A. Dunn K.E. Foti M.J. Moran M.K. Soyinka O. Ashley E.A. Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation.Circ Cardiovasc Genet. 2012; 5: 602-610Crossref PubMed Scopus (0) Google Scholar). Not all genetic variants induce the same degree of cardiac dysfunction, and for primary mutation and secondary modifiers there are “mild” and “severe” mutations. Determining the expressivity of given mutations is challenging, and computational algorithms, however imperfect, emerging now serve as an adjunct to interpreting the pathogenicity of cardiomyopathy mutations. Genetic variation remains a strong predictor of risk for developing cardiomyopathy, particularly within families where a primary gene mutation has been identified. Recent work has focused on reclassifying the potential pathogenicity of variants based on frequency in the population at large, with higher-frequency variants considered less pathogenic (MacArthur et al., 2014MacArthur D.G. Manolio T.A. Dimmock D.P. Rehm H.L. Shendure J. Abecasis G.R. Adams D.R. Altman R.B. Antonarakis S.E. Ashley E.A. et al.Guidelines for investigating causality of sequence variants in human disease.Nature. 2014; 508: 469-476Crossref PubMed Scopus (470) Google Scholar). This methodology assumes that pathogenic alleles will be found in a frequency in the population less than or equal to the disease prevalence and assumes that individual variants are sufficient to cause disease. Studies of penetrance and expressivity indicate that the entire genomic context, as well as the environment, dictate the role of particular variants (Hershberger et al., 2013Hershberger R.E. Hedges D.J. Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture.Nat. Rev. Cardiol. 2013; 10: 531-547Crossref PubMed Scopus (167) Google Scholar). Pathogenicity of particular variants must be considered within the phenotype context, as many cardiomyopathic genetic variants are necessary but not sufficient to cause disease. Most large human genetic data sets include individuals who have not been specifically evaluated for subtle signs of cardiomyopathy and/or individuals who are too young to have yet developed disease. Similarly, it is expected that additional genetic and environmental stimuli are necessary to express the full phenotype of cardiomyopathy and HF. In addition to these secondary genetic and environmental modifiers, epigenetic influences may markedly alter the expression of mutant alleles or alternative genetic pathways that diminish or enhance pathogenicity. As sparks do not cause fire in the absence of oxygen, cardiomyopathy mutations require context to fully manifest. Variants are only pathogenic in a larger context that includes both the susceptible genetic and environmental conditions (Figure 2). Exploring and defining the genetic and environment stimuli necessary for cardiomyopathy expression is critical, as these modifiers influence outcome and are targets for intervention. HCM is estimated at 1:500 in younger individuals and is enriched in families. This estimate derives from a population-based survey of individuals 23–35 years of age (Maron et al., 1995Maron B.J. Gardin J.M. Flack J.M. Gidding S.S. Kurosaki T.T. Bild D.E. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults.Circulation. 1995; 92: 785-789Crossref PubMed Google Scholar). Given the broad age range of HCM and the appreciation that some genetic mutations have later onset, the overall population prevalence is higher. An Olmstead County study conducted in 1985 identified a similar prevalence for HCM (19.7 per 100,000) and a higher prevalence for DCM (36.5 per 100,000). This study and the previous one rely on older methods of detection, and as such likely underestimate the prevalence of HCM. Hypertrophy of the ventricular myocardium arises in response to physiological stimuli, such as exercise, and pathological stimuli such as hypertension or aortic stenosis. In genetic HCM, autosomal dominant mutations in the MYH7 and MYBPC3 genes account for nearly 80% of inherited HCM (Kensler et al., 2011Kensler R.W. Shaffer J.F. Harris S.P. Binding of the N-terminal fragment C0-C2 of cardiac MyBP-C to cardiac F-actin.J. Struct. Biol. 2011; 174: 44-51Crossref PubMed Scopus (0) Google Scholar). These genes encode the sarcomere thick filament proteins β-myosin heavy chain (MYH7) and cardiac myosin binding protein-C (cMyBP-C). Although they are both highly associated with HCM, the mechanisms of the HCM-causing mutations in these two genes differ. The majority of pathogenic variants in MYH7 that cause HCM result in amino acid substitutions in critical residues and domains that adversely affect function. In contrast, the majority of pathogenic HCM-causing MYBPC3 variants are premature stop codons or frameshifting mutations, frequently resulting in absence of protein. MYBPC3 variants are thought to have a milder disease course with later onset then mutations in MYH7 (Charron et al., 1998Charron P. Dubourg O. Desnos M. Isnard R. Hagege A. Bonne G. Carrier L. Tesson F. Bouhour J.B. Buzzi J.C. et al.Genotype-phenotype correlations in familial hypertrophic cardiomyopathy. A comparison between mutations in the cardiac protein-C and the beta-myosin heavy chain genes.Eur. Heart J. 1998; 19: 139-145Crossref PubMed Scopus (0) Google Scholar, Maron et al., 2001Maron B.J. Niimura H. Casey S.A. Soper M.K. Wright G.B. Seidman J.G. Seidman C.E. Development of left ventricular hypertrophy in adults in hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations.J. Am. Coll. Cardiol. 2001; 38: 315-321Crossref PubMed Scopus (0) Google Scholar), which may be attributed to the difference in pathogenic mechanisms between mutations in these genes. MYH7 encodes β myosin heavy chain (βMHC), the thick filament protein responsible for hydrolyzing ATP to produce force. Myosin can be divided into the globular head domain and its coiled-coil rod domain. The myosin head is attached to an arm that articulates away from the rod region on a flexible hinge to extend into the interfilament space (Figure 3). The rod domain mediates the formation of the thick filament with its characteristic periodicity (Moore et al., 2012Moore J.R. Leinwand L. Warshaw D.M. Understanding cardiomyopathy phenotypes based on the functional impact of mutations in the myosin motor.Circ. Res. 2012; 111: 375-385Crossref PubMed Scopus (72) Google Scholar). Mutations in MYH7 have been identified in all regions of the protein, with more mutations concentrating in the ATPase domain, actin binding domain, and domains responsible for force transmission (Walsh et al., 2010Walsh R. Rutland C. Thomas R. Loughna S. Cardiomyopathy: a systematic review of disease-causing mutations in myosin heavy chain 7 and their phenotypic manifestations.Cardiology. 2010; 115: 49-60Crossref PubMed Scopus (63) Google Scholar). Although occurring at lower frequency, mutations in the rod domain have also been linked to HCM (Blair et al., 2002Blair E. Redwood C. de Jesus Oliveira M. Moolman-Smook J.C. Brink P. Corfield V.A. Ostman-Smith I. Watkins H. Mutations of the light meromyosin domain of the beta-myosin heavy chain rod in hypertrophic cardiomyopathy.Circ. Res. 2002; 90: 263-269Crossref PubMed Scopus (0) Google Scholar). Modeling MYH7 mutations has been achieved using materials from human tissues, in vitro or cell-based expression, or genetic engineering in mice. Each of these methods has limitations, and the results from distinct approaches have not always produced consistent findings. Mice, like other small mammals, express α-MHC as the major cardiac myosin (encoded by MYH6), rather than βMHC, like the larger human heart. αMHC, while similar in overall structure to βMHC, has an intrinsically faster rate of ATP hydrolysis and contractile kinetics (Korte et al., 2005Korte F.S. Herron T.J. Rovetto M.J. McDonald K.S. Power output is linearly related to MyHC content in rat skinned myocytes and isolated working hearts.Am. J. Physiol. Heart Circ. Physiol. 2005; 289: H801-H812Crossref PubMed Scopus (0) Google Scholar). The intrinsic capabilities of α-MHC versus β-MHC can lead to the same mutation demonstrating different biophysical characteristics (Lowey et al., 2008Lowey S. Lesko L.M. Rovner A.S. Hodges A.R. White S.L. Low R.B. Rincon M. Gulick J. Robbins J. Functional effects of the hypertrophic cardiomyopathy R403Q mutation are different in an alpha- or beta-myosin heavy chain backbone.J. Biol. Chem. 2008; 283: 20579-20589Crossref PubMed Scopus (44) Google Scholar). There are hundreds of distinct missense MYH7 mutations responsible for HCM, and a clear unifying hypothesis has been elusive. Clinically, HCM is often characterized by a hyperdynamic state in which there is an increase in LV ejection fraction from 60% to 70% or more. For example, the R453C MYH7 HCM mutation displays an impaired catalytic cycle of ATP hydrolysis despite few biochemical alterations in the ATPase domain, and this mutation counterintuitively results in increased contractility (Bloemink et al., 2014Bloemink M. Deacon J. Langer S. Vera C. Combs A. Leinwand L. Geeves M.A. The hypertrophic cardiomyopathy myosin mutation R453C alters ATP binding and hydrolysis of human cardiac β-myosin.J. Biol. Chem. 2014; 289: 5158-5167Crossref PubMed Scopus (17) Google Scholar, Sommese et al., 2013Sommese R.F. Sung J. Nag S. Sutton S. Deacon J.C. Choe E. Leinwand L.A. Ruppel K. Spudich J.A. Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human β-cardiac myosin motor function.Proc. Natl. Acad. Sci. USA. 2013; 110: 12607-12612Crossref PubMed Scopus (52) Google Scholar). Increasing evidence suggests that HCM mutations in MYH7 cause increased energy usage due to a less efficient myosin motor and that this energetic mismatch results in perturbed metabolic state (Crilley et al., 2003Crilley J.G. Boehm E.A. Blair E. Rajagopalan B. Blamire A.M. Styles P. McKenna W.J. Ostman-Smith I. Clarke K. Watkins H. Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy.J. Am. Coll. Cardiol. 2003; 41: 1776-1782Crossref PubMed Scopus (225) Google Scholar). 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Lammertsma A.A. et al.Gene-specific increase in the energetic cost of contraction in hypertrophic cardiomyopathy caused by thick filament mutations.Cardiovasc. Res. 2014; 103: 248-257Crossref PubMed Scopus (0) Google Scholar). Human hearts expressing the MYH7 R403Q mutation generate increased tension and faster actin sliding velocities, but at a higher energetic cost (Alpert et al., 2005Alpert N.R. Mohiddin S.A. Tripodi D. Jacobson-Hatzell J. Vaughn-Whitley K. Brosseau C. Warshaw D.M. Fananapazir L. Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations.Am. J. Physiol. Heart Circ. Physiol. 2005; 288: H1097-H1102Crossref PubMed Scopus (37) Google Scholar). Mice engineered with the R403Q HCM-associated mutation had reduced rate of relaxation and increased end diastolic pressure after inotropic stimulation (Tyska et al., 2000Tyska M.J. Hayes E. Giewat M. Seidman C.E. Seidman J.G. Warshaw D.M. Single-molecule mechanics of R403Q cardiac myosin isolated from the mouse model of familial hypertrophic cardiomyopathy.Circ. Res. 2000; 86: 737-744Crossref PubMed Google Scholar). A similar decrease in PCr and increased ADP was seen in these hearts, consistent with a higher energetic cost of contraction (Spindler et al., 1998Spindler M. Saupe K.W. Christe M.E. Sweeney H.L. Seidman C.E. Seidman J.G. Ingwall J.S. Diastolic dysfunction and altered energetics in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy.J. Clin. Invest. 1998; 101: 1775-1783Crossref PubM" @default.
• W2077307965 created "2016-06-24" @default.
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• W2077307965 date "2015-02-01" @default.
• W2077307965 modified "2023-10-12" @default.
• W2077307965 title "The Genetic Landscape of Cardiomyopathy and Its Role in Heart Failure" @default.
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