Title: Why does the myocardium fail? Insights from basic science
Abstract: Most cases of the syndrome of chronic heart failure are caused by an alteration in myocardial phenotype. Dilated cardiomyopathy is the most common myocardial phenotype associated with the syndrome;1Ho KKL Anderson KM Kannel WB Grossman W Levy D Survival after the onset of congestive heart failure in Framingham Heart Study subjects.Circulation. 1993; 88: 107-115Crossref PubMed Scopus (1600) Google Scholar its hallmarks are myocardial systolic dysfunction and chamber dilatation due to a primary or a secondary process.2Richardson P McKenna W Bristow MR et al.Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies.Circulation. 1996; 93: 841-842Crossref PubMed Scopus (2788) Google Scholar Cardiomyopathies have a molecular basis, inasmuch as altered gene expression—ie, any process that can alter the expression of a fully functional protein, which includes pretranslational, translational, and post-translational mechanisms—-is what produces disease phenotypes. I review recent progress on the molecular pathophysiology of human myocardial failure, with a focus on primary or secondary dilated cardiomyopathies. Pump dysftmction in a dilated cardiomyopathy can be caused by cardiac myocyte contractile dysfunction or by pump dysfunction in the absence of myocyte dysfunction. In either case, the alteration in phenotype is produced by altered gene expression. Although changes in the extracellular matrix contribute to changes in myocardial gene expression that may produce pump dysfunction, this review is confined to processes that affect the function of cardiac myocytes and structure. There are three general categories of mechanisms whereby altered gene expression can lead to a phenotypic change in ventricular myocardium. The first mechanism is single gene defects. For example: defects in β-myosin heavy-chain codon 403 in familial hypertrophic cardiomyopathy (HCM);3Watkins H Rosenzweig A Hwang D-S et al.Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy.N Engl J Med. 1992; 326: 1108-1114Crossref PubMed Scopus (607) Google Scholar defects in dystrophin in Becker-Duchenne familial dilated cardiomyopathy;4Milasin J Francesco M Severini GM et al.A point mutation in the 5′ splice site of the dystrophin gene first intron responsible for X-linked dilated cardiomyopathy.Hum Mol Genet. 1996; 5: 73-79Crossref PubMed Scopus (139) Google Scholar defects in cardiac actin in some autosomal dominant dilated cardiomyopathies;5Olson TM, Michels VV, Thibodeau SN, Keating MT. Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. Science (in press).Google Scholar and, as yet undetermined, gene defects in chromosome 1,6Durand J-B Bachinski LL Beiling LC et al.Localization of a gene responsible for familial dilated cardiomyopathy to chromosome 1q32.Circulation. 1995; 92: 3387-3389Crossref PubMed Scopus (123) Google Scholar 9,7Krajinovic M Pinamonti B Sinagra G et al.the Heart Muscle Disease Study GroupLinkage of familial dilated cardiomyopathy to chromosome 9.Am J Hum Genet. 1995; 57: 846-852PubMed Google Scholar or 38Olson TM Keating MT Mapping a cardiomyopathy locus to chromosome 3p22-p25.J Clin Invest. 1996; 97: 528-532Crossref PubMed Scopus (170) Google Scholar in other familial dilated cardiomyopathies. The second mechanism is polymorphic variation in modifier genes, such as in the angiotensin-converting enzyme gene and other components of the renin-angiotensin system,9Raynolds MV Bristow MR Bush E et al.Angiotensin converting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy.Lancet. 1993; 342: 1073-1075Summary PubMed Scopus (450) Google Scholar, 10Pinto YM van Gilst WH Kingma JH Schunkert H the Captopril and Thrombolysis Study Investigators Deletion-type allele of the angiotensin-converting enzyme gene is associated with progressive ventricular dilation after anterior myocardial infarction.J Am Coll Cardiol. 1995; 25: 1622-1626Summary Full Text PDF PubMed Scopus (107) Google Scholar, 11Zerjal T Vatta M Gregori D et al.Genetic polymorphisms of the renin-angiotensin system in familial dilated cardiomyopathy.J Am Coll Cardiol. 1998; 31: 350ACrossref Google Scholar” and in β2-adrenergic receptors.12Green SA Cole G Jacinto M Innis M Liggett SB A polymorphism of the human β2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor.J Biol Chem. 1993; 268: 23116-23121Summary Full Text PDF PubMed Google Scholar, 13Turki J Lorenz JN Green SA Donnelly ET Jacinto M Liggett SB Myocardial signaling defects and impaired cardiac function of a human β2-adrenergic receptor polymorphism expressed in transgenic mice.in: Proc Natl Acad Sci USA. 93. 1996: 10483-10488Google Scholar The third mechanism is maladaptive altered expression of completely normal genes that encode the proteins involved in the regulation of contractile function or chamber structure. I will focus on this third general means of altering gene expression because of its importance in determining the natural history of primary and secondary dilated cardiomyopathies and the potential for therapeutic targeting. Cardiac myocyte contractile function can be subdivided into two categories (panel 1).14Bristow MR Gilbert EM Improvement in cardiac myocyte function by biologic effects of medical therapy: a new concept in the treatment of heart failure.Eur Heart J. 1995; 16: 20-31Crossref PubMed Google Scholar The first is intrinsic function, which comprises the mechanisms responsible for contraction and relaxation of the heart in the basal or resting state. Intrinsic function is defined as myocardial contraction and relaxation in the absence of extrinsic influences, such as neurotransmitters or hormones. The second category is modulated function, which comprises the mechanisms responsible for the ability of the heart to rapidly increase or decrease its performance (by two-fold to ten-fold) in response to various physiological or physical stimuli. Other critical organs such as the brain, kidney, and liver do not have this quality. Modulated function is defined as stimulation of inhibition of contractile function by endogenous bioactive compounds, including neurotransmitters, cytokines, autocrine/paracrine substances, and hormones.Panel 1Categories of cardiac myocyte function and specific mechanisms that may be abnormal in the failing human heartIntrinsicFunction in the absence of neural or hormonal influence •Contractile proteins•Electrocardiogram coupling mechanisms•R-G-adenylate cyclase pathways•Bioenergetics•CytoskeletonModulatedFunction that may be stimulated or inhibited by extrinsic factors including neuretransmitters, cytokines, or hormones •R-G-adenylate cyclase pathways•R-G-phospholipase C pathways Intrinsic Function in the absence of neural or hormonal influence •Contractile proteins•Electrocardiogram coupling mechanisms•R-G-adenylate cyclase pathways•Bioenergetics•Cytoskeleton Modulated Function that may be stimulated or inhibited by extrinsic factors including neuretransmitters, cytokines, or hormones •R-G-adenylate cyclase pathways•R-G-phospholipase C pathways In the failing human heart, changes occur in the expression of those genes potentially responsible for both categories of myocardial function shown in panel 1. Abnormalities of intrinsic function include any combination of the factors responsible for an altered length-tension relation,15Ross J Braunwald E Studies of Starling's law of the heart IX. The effects of impeding venous return on performance of the normal and failing ventricle.Circulation. 1964; 30: 719-727Crossref PubMed Scopus (62) Google Scholar, 16Schwinger RHG Bohm M Koch A et al.The failing human heart is unable to use the Frank-Starling mechanism.Circ Res. 1994; 74: 959-969Crossref PubMed Scopus (195) Google Scholar, 17Holubarsch C Thorsten R Goldstein DJ et al.Existence of the Frank-Starling mechanism in the failing human heart: investigations on the organ, tissue, and sarcomere levels.Circulation. 1996; 94: 683-689Crossref PubMed Scopus (194) Google Scholar a blunted force-frequency response,18Feldman MD Gwathmey JK Phillips P Schoen F Morgan JP Reversal of the force-frequency relationship in working myocardium from patients with end-stage heart failure.J Appl Cardiol. 1988; 3: 273-283Google Scholar, 19Muleiri LA Hasenfuss G Ittleman F et al.Altered myocardial force-frequency relationship in the human heart failure.Circulation. 1992; 85: 1743-1750Crossref PubMed Scopus (459) Google Scholar or the signals responsible for abnormal cellular and chamber remodelling.20Cohn JN Structural basis for heart failure: ventricular remodeling an its pharmacological inhibition.Circulation. 1995; 91: 2504-2507Crossref PubMed Scopus (274) Google Scholar In the case of the abnormal force-frequency and length-tension responses, the evidence favours abnormal contractile function of the individual cardiac myocytes.21Davies CH Davia K Bennett JG Pepper JR Poole-Wilson PA Harding SE Reduced contraction and altered frequency response of isolated ventricular myocytes from patients with heart failure.Circulation. 1995; 92: 2540-2549Crossref PubMed Scopus (166) Google Scholar These abnormalities probably reside in the contractile proteins or their regulatory elements, various mechanisms involved in excitation-contraction coupling, alterations in β-adrenergic signal transduction,22Bristow MR Mechanism of action of beta-blocking agents in heart failure.Am J Cardiol. 1997; 80: 26L-40LSummary Full Text Full Text PDF PubMed Scopus (249) Google Scholar deficiencies in energetic mechanisms,23Nascimben L Ingwall JS Pauletto P et al.Creatine kinase system in failing and nonfailing human myocardium.Circulation. 1996; 94: 1894-1901Crossref PubMed Scopus (272) Google Scholar or perhaps in alterations in the cytoskeleton.24Tsutsui H Ishihara K Cooper IV, G Cytoskeletal role in the contractile dysfunction of hypertrophied myocardium.Science. 1993; 260: 682-687Crossref PubMed Scopus (241) Google Scholar Within these possibilities for altered intrinsic function, however, there is not currently a consensus as to which abnormalities are present in primary or secondary dilated cardiomyopathies in human beings. By contrast with abnormalities of intrinsic function, a consensus has been reached on several specific abnormalities in the stimulation component of modulated function. Most of these changes include β-adrenergic signal transduction.22Bristow MR Mechanism of action of beta-blocking agents in heart failure.Am J Cardiol. 1997; 80: 26L-40LSummary Full Text Full Text PDF PubMed Scopus (249) Google Scholar The ability of β-adrenergic stimulation to increase heart rate and contractility is substantially attenuated in the failing heart because of multiple changes at the level of receptors,29Bristow MR Anderson FL Port JD et al.Differences in β-adrenergic neuroeffector mechanisms in ischemic vs idiopathic dilated cardiomyopathy.Circulation. 1991; 84: 1024-1039Crossref PubMed Scopus (243) Google Scholar, 30Ungerer M Böhm M Elce JS Erdmann E Lohse MJ Altered expression of β-adrenergic receptor kinase and β1-adrenergic receptors in the failing human heart.Circulation. 1993; 87: 454-463Crossref PubMed Scopus (762) Google Scholar, 31Feldman AM Gates AE Veazey WB et al.Increase of the M 40 000 pertussis toxin substrate (G protein) in the failing human heart.J Clin Invest. 1988; 82: 189-197Crossref PubMed Scopus (459) Google Scholar, 32Neuman J Scholz H Doring V Schmitz W Meyerinck LV Kamar P Increase in myocardial G1-proteins in heart failure.Lancet. 1988; ii: 936-937Summary Scopus (273) Google Scholar, 33Bohm M Eschenhagen T Gierschik P et al.Radioimmunochemical quantification of Giα in right and left ventricular failure.J Mol Cell Cardiol. 1994; 26: 133-149Summary Full Text PDF PubMed Scopus (90) Google Scholar G-proteins,29Bristow MR Anderson FL Port JD et al.Differences in β-adrenergic neuroeffector mechanisms in ischemic vs idiopathic dilated cardiomyopathy.Circulation. 1991; 84: 1024-1039Crossref PubMed Scopus (243) Google Scholar, 30Ungerer M Böhm M Elce JS Erdmann E Lohse MJ Altered expression of β-adrenergic receptor kinase and β1-adrenergic receptors in the failing human heart.Circulation. 1993; 87: 454-463Crossref PubMed Scopus (762) Google Scholar, 31Feldman AM Gates AE Veazey WB et al.Increase of the M 40 000 pertussis toxin substrate (G protein) in the failing human heart.J Clin Invest. 1988; 82: 189-197Crossref PubMed Scopus (459) Google Scholar, 32Neuman J Scholz H Doring V Schmitz W Meyerinck LV Kamar P Increase in myocardial G1-proteins in heart failure.Lancet. 1988; ii: 936-937Summary Scopus (273) Google Scholar, 33Bohm M Eschenhagen T Gierschik P et al.Radioimmunochemical quantification of Giα in right and left ventricular failure.J Mol Cell Cardiol. 1994; 26: 133-149Summary Full Text PDF PubMed Scopus (90) Google Scholar and adenylate cyclase.29Bristow MR Anderson FL Port JD et al.Differences in β-adrenergic neuroeffector mechanisms in ischemic vs idiopathic dilated cardiomyopathy.Circulation. 1991; 84: 1024-1039Crossref PubMed Scopus (243) Google Scholar, 34Bristow MR Minobe W Rasmussen R et al.β-adrenergic neuroeffector abnormalities in the failing human heart are produced by local, rather than systemic mechanisms.J Clin Invest. 1992; 89: 803-815Crossref PubMed Scopus (270) Google Scholar Such changes produce a major abnormality in the stimulation component of modulated function, which comprises myocardial reserve35Fowler MB Laser JA Hopkins GL Minobe W Bristow MR Assessment of the β-adrenergic receptor pathway in the intact failing human heart: progressive receptor down-regulation and subsensitivity to agonist response.Circulation. 1986; 74: 1290-1302Crossref PubMed Scopus (511) Google Scholar, 36Colucci WS Denniss AR Leatherman GF et al.Intracoronary infusion of dobutamine to patients with and without severe congestive heart failure.J Clin Invest. 1988; 81: 1103-1110Crossref PubMed Scopus (114) Google Scholar and exercise responses.37White M Yanowitz F Gilbert EM et al.Role of beta-adrenergic receptor downregulation in the peak exercise response of patients with heart failure due to idiopathic dilated cardiomyopathy.Am J Cardiol. 1995; 76: 127Google Scholar In addition, the inhibition component of modulated function is also abnormal in the failing heart, due to a reduction in parasympathetic drive.38Binkley PF Nunziata E Haas GH Nelson SD Cody RJ Parasympathetic withdrawal is an integral component of autonomic imbalance in congestive heart failure: demonstration in human subjects and verification in a paced canine model of ventricular failure.J Am Coll Cardiol. 1991; 18: 464-472Summary Full Text PDF PubMed Scopus (311) Google Scholar There is obviously overlap between these two major subdivisions of myocardial function. Data have indicated that even in the absence of adrenergic stimulation, β-adrenergic receptors have intrinsic activity—ie, a small proportion of receptors are in an activated state without agonist occupancy, and as such can support intrinsic myocardial function.39Chidiac P Hebert TE Valiquette M Dennis M Bouvier M Inverse agonist activity of β-adrengic antagonists.Mol Pharm. 1994; 45: 490-499Google Scholar, 40Milano CA Allen LF Rockman HA et al.Enhanced myocardial function in transgenic mice overexpressing the β2-adrenergic receptor.Science. 1994; 264: 562-566Crossref Scopus (661) Google Scholar Thus, overexpression of human β2-adrenergic receptors greatly increases intrinsic myocardial function,40Milano CA Allen LF Rockman HA et al.Enhanced myocardial function in transgenic mice overexpressing the β2-adrenergic receptor.Science. 1994; 264: 562-566Crossref Scopus (661) Google Scholar as does increased sarcoplasmic-reticulum calcium uptake and release by genetic ablation of the phospholamban gene.41Luo W Grupp IL Ponniah S et al.Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of β-agonist stimulation.Circ Res. 1994; 75: 401-409Crossref PubMed Scopus (629) Google Scholar The discovery that active state β-adrenergic receptors unoccupied by agonist can modulate intrinsic myocardial function is the reason the renin angiotensin-system-G-protein-(RG)-adenylate cyclase mechanism is in both categories in panel 1. The behaviour of these transgenic systems has also altered our thinking about manoeuvers to increase contractility. That is, despite maximum stimulation of contractility (to levels produced by maximum isoproterenol stimulation) both the β2-receptor cardiac overexpressor and the phospholamban knockout mouse exhibit sustained improvement in contractility without obvious evidence of desensitisation.40Milano CA Allen LF Rockman HA et al.Enhanced myocardial function in transgenic mice overexpressing the β2-adrenergic receptor.Science. 1994; 264: 562-566Crossref Scopus (661) Google Scholar, 41Luo W Grupp IL Ponniah S et al.Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of β-agonist stimulation.Circ Res. 1994; 75: 401-409Crossref PubMed Scopus (629) Google Scholar The second way in which myocardial contractile funtion can be altered in a dilated cardiomyopathy is by changes that affect the ability of the chamber to contract as normal despite preserved myocyte contractile function. For example, in pump dysfunction secondary to remodelling of cardiac myocytes,42Anand IS Liu D Chugh SS et al.Isolated myocyte contractile function is normal in postinfarct remodeled rat heart with systolic dysfunction.Circulation. 1997; 96: 3974-3984Crossref PubMed Scopus (106) Google Scholar the myocytes become greatly lengthened relative to any increase in transverse diameter in dilated cardiomyopathies.43Gerdes AM Kellerman SE Moore JA et al.Structural remodeling of cardiac myocytes from patients with chronic ischemic heart disease.Circulation. 1992; 86: 426-430Crossref PubMed Scopus (243) Google Scholar This type of remodelling places the chamber and the myocyte at an energetic disadvantage because of the attendant increase in wall stress,44Zhang J McDonald KM Bioenergetic consequences of left ventricular remodeling.Circulation. 1995; 92: 1011-1019Crossref PubMed Scopus (58) Google Scholar which is one of the major determinants of myocardial oxygen consumption. Inadequate production of myocyte energy, particularly associated with key subcellular ion flux mechanisms or the myosin ATPase cycle,45Sata M Sugiura S Yamashita H Momomura S Serizawa T Coupling between myosin ATPase cycle and creatine kinase cycle facilitates cardiac actomyosin sliding in vitro: a clue to mechanical dysfunction during myocardial ischemia.Circulation. 1996; 93: 310-317Crossref PubMed Scopus (32) Google Scholar would in turn contribute to myocyte contractile dysfunction. A second example is pump dysfunction related to loss of cardiac myocytes. Another feature of the remodelling process, at least in some settings, is loss of cardiac myocytes within the context of chamber hypertrophy and dilatation.46Narula J Haider N Virmani R et al.Apoptosis in myocytes in end-stage heart failure.N Engl J Med. 1996; 335: 1182-1189Crossref PubMed Scopus (1245) Google Scholar There are two ways in which cells of any type, including cardiac myocytes, die: necrosis and apoptosis. Necrosis typically occurs in the setting of some catastrophic pathological process, such as severe inflammation or interruption of blood supply, and is accompanied by release of cell breakdown products, which attract a polymorphonuclear infiltrate. Apoptosis is the natural way cells die, and the dying cell is usually phagocytosed without evidence of an inflammatory response. Since cardiac myocytes do not generally divide (or divide infrequently), cardiac cell loss threatens the integrity of myocardial performance. When cell loss occurs in the setting of dilated cadiomyopathy46Narula J Haider N Virmani R et al.Apoptosis in myocytes in end-stage heart failure.N Engl J Med. 1996; 335: 1182-1189Crossref PubMed Scopus (1245) Google Scholar or ageing,47Olivetti G Melissari M Capasso JM Anversa P Cardiomyopathy of the aging human heart: myocyte loss and reactive cellular hypertrophy.Circ Res. 1991; 68: 1560-1568Crossref PubMed Scopus (594) Google Scholar the major means of compensation is hypertrophy of the remaining myocytes, which in turn may be accompanied by alterations in gene expression leading to contractile dysfunction. Left-ventricular dysfunction generally leads to overt heart failure, and once overt heart failure occurs myocardial failure and remodelling are likely to be progressive. What are the mechanisms responsible for this inexorable deterioration in chamber phenotype? Figure 1 shows that when the heart is damaged by an insult, compensatory mechanisms are activated to stabilise myocardial performance. These mechanisms, through increases in heart rate, contractility, volume expansion, and hypertrophy (panel 2), stabilise myocardial performance for a short time. However, continued chronic use of these compensatory mechanisms to support the failing heart has a definite downside, summarised in panel 2 and figure 2.Panel 2Signalling pathways involved in progressive myocardial dysfunction and remodelling Tabled 1Signalling pathwayCompensatory effectAdverse biological effect(s)• AdrenergicIncrease heart rate, contractility, volume expansion, hypertrophyMyocyte toxic effects, apoptosis, growth and remodelling, altered gene expression• Angiotensin IIVolume expansion, hypertrophyApoptosis, growth and remodelling, altered gene expression, collagen deposition• EndothelinHypertrophyGrowth and remodelling, altered gene expression• TNFÄ-aHypertrophyApoptosis, inflammation, growth and remodelling, altered gene expression, metalloproteinase activation• Stretch/wall stressVolume expansion, hypertrophyApoptosis, growth and remodelling, altered gene expression Open table in a new tab Figure 2Central role of neurohormonal, cytokine, and mechanical (increased wall stress) signalling pathways in production of adverse biological effects that lead to progressive myocardial dysfunction and remodellingView Large Image Figure ViewerDownload Hi-res image Download (PPT) Tabled 1Signalling pathwayCompensatory effectAdverse biological effect(s)• AdrenergicIncrease heart rate, contractility, volume expansion, hypertrophyMyocyte toxic effects, apoptosis, growth and remodelling, altered gene expression• Angiotensin IIVolume expansion, hypertrophyApoptosis, growth and remodelling, altered gene expression, collagen deposition• EndothelinHypertrophyGrowth and remodelling, altered gene expression• TNFÄ-aHypertrophyApoptosis, inflammation, growth and remodelling, altered gene expression, metalloproteinase activation• Stretch/wall stressVolume expansion, hypertrophyApoptosis, growth and remodelling, altered gene expression Open table in a new tab Activaton of neurohormonal, cytokine, and mechanical stretch signalling pathways alters gene expression, cardiac myocyte loss, and cell remodelling, which all contribute to the progression in myocardial dysfunction and remodelling that is part of the natural history of heart failure (panel 2, figure 2). Activation of the adrenergic and renin-angiotensin systems contributes to the multiple adverse biological effects shown in panel 2, which combine to produce progressive myocardial dysfunction and remodelling.48Eichhorn EJ Bristow MR Medical therapy can improve the biologic properties of the chronically failing heart: a new era in the treatment of heart failure.Circulation. 1996; 94: 2285-2296Crossref PubMed Scopus (441) Google Scholar The cytokines endothelin-149Mulder P Richard V Derumeaux G et al.Role of endogenous endothelin in chronic heart failure: effect of long-term treatment with an endothelin antagonist on survival, hemodynamics, and cardiac remodeling.Circulation. 1997; 96: 1976-1982Crossref PubMed Scopus (347) Google Scholar and tumour-necrosis factor-α50Bryant D Becker L Richardson J et al.Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-α.Circulation. 1998; 97: 1375-1381Crossref PubMed Scopus (544) Google Scholar have also been implicated in many of these effects. Finally, increased wall stress or mechanical signalling itself is a potent mediator of alterations in gene expression in model systems,51Komuro I Yazaki Y Control of cardiac gene expression by mechanical stress.Ann Rev Physiol. 1993; 55: 55-75Crossref PubMed Scopus (300) Google Scholar, 52Sadosha J Izumo S Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mehanism.EMBO J. 1993; 12: 1681-1692PubMed Google Scholar and may also produce apoptosis.53Teiger E Dam T-V Richard L Wisnewsky C et al.Apoptosis in pressure overload-induced heart hypertrophy in the rat.J Clin Invest. 1996; 97: 2891-2897Crossref PubMed Scopus (394) Google Scholar Understanding the abnormalities in gene expression that produce contractile dysfunction is critical to the development of treatment to delay or even reverse progression of myocardial dysfunction and remodelling. In end-stage failing human dilated cardiomyopathies and in animal models, multiple changes have been described in the expression of structurally normal genes that encode proteins that regulate intrinsic systolic function. Many of these changes involve the reactivation of developmentally regulated genes that are usually expressed in fetal or neonatal periods, but other changes in gene regulation are also present in hypertrophy and myocardial failure. The three mechanisms that have been most scrutinised in animal models and the failing human heart are underlined in panel 1. Although in advanced end-stage failure abnormalities in all these mechanisms may contribute to myocardial dysfunction, it is more relevant to ask which of them affect earlier stages of the disease process and contribute to the progressive natural history of dilated cardiomyopathies. Myosin—-the thick filament contractile protein (figure 3)—is a hexamer comprised of two heavy-chain molecules (myosin heavy chain, MyHC) and four light-chain molecules. In cardiac myocytes, there are two isoforms of MyHC: α and β. These isoforms are the products of separate isogenes located in series on chromosome 14 in human beings.54Saez LJ Gianola KM McNally EM Feghali A Eddy A Shows TB et al.Human cardiac myosin heavy chain genes and their linkage in the genome.Nucleic Acids Res. 1987; 15: 5443-5459Crossref PubMed Scopus (127) Google Scholar MyHC isoforms are critical enzymatic and structural proteins in the heart. α-MyHC and β-MyHC are homologous at the aminoacid (96%) and cDNA (95%) levels,55Kurabayashi M Tsuchimochi H Komuro I Takaku F Yazaki Y Molecular cloning and characterization of human cardiac α- and β-form myosin heavy chain complementary cDNA clones.J Clin Invest. 1988; 82: 524-531Crossref PubMed Scopus (67) Google Scholar and in certain species, such as the guineapig, cow, and human beings, the isoforms are difficult to separate by gel electrophoresis.56Clark WA Chizzonite RA Everett AW Rabinowitz M Zak R Species correlations between cardiac isoenzymes: a comparison of electrophoretic and immunologic properties.J Biol Chem. 1982; 257: 5449-5554Summary Full Text PDF PubMed Google Scholar The ATPase activity of MyHC resides in the globular, 5′ end of the molecule, where most of the hypertrophic cardiomyopathy-producing mutations in β-MyHC occur.57Marian AJ Roberts R Recent advances in the molecular genetics of hypertrophic cardiomyopathy.Circulation. 1995; 92: 1336-1347Crossref PubMed Scopus (203) Google Scholar This ATPase activity produces the energy for muscle contraction, and the amount of myosin ATPase activity is directly related to velocity of shortening.58Barany M ATPase activity of myosin correlated with speed of muscle shortening.J Gen Physiol. 1967; 50: 197-218Crossref PubMed Scopus (1385) Google Scholar Myosin ATPase activity can also be regulated by the associated light chains, of which there are two (essential [LC1] and regulatory [LC2]), with atrial and ventricular isoforms of each. Myosin or myofibrillar ATPase may also be regulated by troponin T isoforms. Troponin T is a regulatory thin filament protein that binds troponin I and C to tropomyosin and is important in the regulation of calcium sensitivity of myofibrillar ATPase. In the failing human heart, alterations in expression of myosin light chain59Morano M Zacharzowski U Maier M et al.Regulation of human heart contractility by essential myosin light chain isoforms.J Clin Invest. 1996; 98: 467-473Crossref PubMed Scopus (114) Google Scholar and troponin T isoform60Anderson PAW Malouf NN Oakley AE Pagani ED Allen PD Troponin T isoform expression in humans: a comparison among normal and failing adult heart, fetal heart, and adult and fetal skeletal muscle.Circ Res. 1991; 69: 1226-1233Crossref PubMed Scopus (309) Google Scholar are correlated with myofbrillar ATPase activity59Morano M Zacharzowski U Maier M et al.Regulation of human heart contractility by essential myosin light chain isoforms.J Clin Invest. 1996; 98: 467-473Crossref PubMed Scopus (114) Google Scholar or velocity of muscle shortening.60Anderson PAW Malouf NN Oakley AE Pagani ED Allen PD Troponin T isoform expression in humans: a comparison among normal and failing adult heart, fetal heart
Publication Year: 1998
Publication Date: 1998-08-01
Language: en
Type: review
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 177
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