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• W2085680143 abstract "Despite significant improvements in the intraoperative management of patients undergoing cardiac surgery, postoperative left ventricular (LV) pump dysfunction occurs and often requires inotropic and/or vasodilator therapy. This LV pump dysfunction can contribute to a complex postoperative course.1Weisel RD. Myocardial stunning after coronary bypass surgery.J Card Surg. 1993; 8: 242-244PubMed Google Scholar, 2Mangano DT. Cardiovascular morbidity and CABG surgery—a perspective: epidemiology, costs, and potential therapeutic solutions.J Card Surg. 1995; 10: 366-368Crossref PubMed Google Scholar It is likely that the number of cardiac surgical procedures, such as coronary artery bypass grafting (CABG), will increase in the future due to several factors. First, the relative number of patients surviving an initial myocardial infarction and the relative proportion of elderly patients have both increased and therefore may ultimately require CABG.3Dalrymple-Hay MJ Alzetani A Aboel-Nazar S Haw M Livesey S Monro J. Cardiac surgery in the elderly.Eur J Cardiothoracic Surg. 1999; 15: 61-66Crossref PubMed Scopus (57) Google Scholar The purpose of this review is to place these conditions in the context of cardiac surgery with particular emphasis on the ischemia/reperfusion injury that may occur during the intraoperative period. Although a number of systemic and neurohormonal factors clearly influence LV pump function and hemodynamics in the postoperative setting, this review will focus on basic systems within the cardiac myocyte that are altered in hypertrophy and/or failure, which may in turn influence contractility in the perioperative setting. This review will be a structure-function presentation in which the myocyte will be dissected into key structural components that are directly related to contractile performance. The sarcolemma contains channels and energy-dependent pumps that play a fundamental role in both the generation of the action potential and excitation-contraction coupling. The most common electrophysiologic abnormality is a prolongation of the action potential. A representative action potential from a normal and failing human myocyte is shown in Fig 1. Membrane repolarization is initiated by the K+ efflux of the delayed rectifier current, which is later joined by an additional outward K+ current to return the sarcolemma to the resting membrane potential.4Katz AM. Physiology of the heart. Raven Press, New York1992Google Scholar The prolongation of the action potential with hypertrophy and/or failure is likely due to alterations in key sarcolemmal channels and currents that contribute to the action potential repolarization. Specifically, the delayed rectifier current, which is directly responsible for repolarization, is reduced in myocardial hypertrophy5Kleiman RB Houser SR. Outward currents in normal and hypertrophied feline ventricular myocytes.Am J Physiol. 1989; 256: H1450-H1461PubMed Google Scholar, 6Kleiman RB Houser SR. Outward currents in hypertrophied feline ventricular myocytes.Prog Clin Biol Res. 1990; 334: 65-83PubMed Google Scholar and has been associated with a prolongation of the action potential.7Priebe L Beuckelmann DJ. Simulation study of cellular electric properties in heart failure.Circ Res. 1998; 82: 1206-1223Crossref PubMed Google Scholar, 8Furukawa T Bassett AL Furukawa N Kimura S Myerburg RJ. The ionic mechanism of reperfusion-induced early after depolarizations in feline left ventricular hypertrophy.J Clin Invest. 1993; 91: 1521-1531Crossref PubMed Google Scholar With the use of gene transfection techniques, enhanced production of K+ channels that contribute to the delayed rectifier current has been shown to correct action potential prolongation.9Nuss HB Marban E Johns DC. Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes.J Clin Invest. 1999; 103: 889-896Crossref PubMed Google Scholar This observation supports the ionic basis for changes in action potential morphology, including defects in K+ currents that are operable during action potential repolarization. The prolongation of the action potential in hypertrophy and/or failure may result in early depolarization, which may create a re-entry circuit, thereby promoting arrhythmias.10Tomaselli GF Beuckelmann DJ Calkins HG Berger RD Kessler PD Lawrence JH et al.Sudden cardiac death in heart failure: the role of abnormal repolarization.Circulation. 1994; 90: 2534-2539Crossref PubMed Google Scholar, 11Kuo CS Munakata K Reddy CP Surawicz B. Characteristics and possible mechanism of ventricular arrhythmia dependent on the dispersion of action potential durations.Circulation. 1983; 67: 1356-1367Crossref PubMed Google Scholar The Na+/K+ adenosine triphosphatase (ATPase), which contributes to the maintenance of the resting action potential, is altered in severe hypertrophy and/or failure12Ellingsen O Holthe MR Svindland A Aksnes G Serjersted OM Ilebekk A. Na,K-pump concentration in hypertrophied human hearts.Eur Heart J. 1994; 15: 1184-1190PubMed Google Scholar, 13Spinale FG Clayton C Tanaka R Fulbright BM Mukherjee R Schulte BA et al.Myocardial Na+,K(+)-ATPase in tachycardia induced cardiomyopathy.J Mol Cell Cardiol. 1992; 24: 277-294Abstract Full Text PDF PubMed Google Scholar, 14Schwinger RH Wang J Frank K Muller-Ehmsen J Brixius K McDonough AA et al.Reduced sodium pump alpha 1, alpha 3, and beta-1 isoform protein levels and Na+,K+-ATPase activity but unchanged Na+-Ca2+ exchanger protein levels in human heart failure.Circulation. 1999; 99: 2105-2112Crossref PubMed Google Scholar and may contribute to a more positive and unstable resting potential. These molecular defects that contribute to changes in the action potential with hypertrophy and/or failure may have particular relevance to the development of ventricular arrhythmias after cardiac operations.15Anderson DR Stephenson LW Edmunds LH. Management of complications of cardiopulmonary bypass: complications of organ systems.in: Complications in cardiothoracic surgery. Mosby-Year Book, St. Louis1991Google Scholar Normal myocyte contraction depends on a highly organized sequence of molecular and mechanical events between the sarcolemma, the sarcoplasmic reticulum (SR), and the contractile apparatus. After sarcolemmal depolarization, the L-type Ca2+ channel becomes activated, resulting in a Ca2+ current across the sarcolemma, which activates the calcium release channels of the SR, as shown in Fig 2. After calcium release channel activation, a bolus release of Ca2+ from the SR engages the myofilament apparatus, resulting in sarcomere shortening. The return to resting sarcomere length is an energy-dependent process that has been termed active relaxation.4Katz AM. Physiology of the heart. Raven Press, New York1992Google Scholar Active relaxation primarily consists of the re-uptake of intracellular Ca2+ by SR Ca2+ ATPase (SERCA-2), thus reducing the concentration of intracellular Ca2+. For the purposes of this review, specific alterations in excitation-contraction coupling that occur in hypertrophy and/or failure will be divided into two events: contraction and active relaxation. Since Ca2+ influx through the L-type Ca2+ channel is the initial trigger for excitation-contraction coupling, a defect in function and/or density will alter myocyte contractility.16Mukherjee R Hewett KW Walker JD Basler CG Spinale FG. Changes in L-type calcium channel abundance and function during the transition to pacing-induced congestive heart failure.Cardiovasc Res. 1998; 37: 432-444Crossref PubMed Google Scholar, 17Mukherjee F Spinale FG. L-type calcium channel abundance and function with cardiac hypertrophy and failure: a review.J Mol Cell Cardiol. 1998; 30: 1899-1916Abstract Full Text PDF PubMed Scopus (82) Google Scholar Accordingly, the function of the L-type Ca2+ channel has been the focus of several investigations.17Mukherjee F Spinale FG. L-type calcium channel abundance and function with cardiac hypertrophy and failure: a review.J Mol Cell Cardiol. 1998; 30: 1899-1916Abstract Full Text PDF PubMed Scopus (82) Google Scholar, 18Mewes T Ravens U. L-type calcium currents of human myocytes from ventricle of non-failing and failing hearts and from atrium.J Mol Cell Cardiol. 1994; 26: 1307-1320Abstract Full Text PDF PubMed Scopus (83) Google Scholar, 19Colston JT Kumar P Chambers JP Freeman GL. Altered sarcolemmal calcium channel density and Ca(2+)-pump ATPase activity in tachycardia heart failure.Cell Calcium. 1994; 5: 349-356Crossref Google Scholar, 20Wagner JA Sax FL Weisman HF Porterfield J McIntosh C Weisfeldt ML et al.Calcium-antagonist receptors in the atrial tissue of patients with hypertrophic cardiomyopathy.N Engl J Med. 1989; 320: 755-761Crossref PubMed Google Scholar The majority of these studies have reported a reduction in L-type Ca2+ current and/or channel density in hypertrophied and/or failing myocytes. For example, Mukherjee and associates16Mukherjee R Hewett KW Walker JD Basler CG Spinale FG. Changes in L-type calcium channel abundance and function during the transition to pacing-induced congestive heart failure.Cardiovasc Res. 1998; 37: 432-444Crossref PubMed Google Scholar reported a decrease in L-type Ca2+ current that was associated with intrinsic defects in contractile function with the development of pacing-induced heart failure. The peak levels of Ca2+ released into the cytosolic compartment have been demonstrated to be decreased in severe hypertrophy and/or failure.21Beuckelmann DJ Naubauer M Erdmann E. Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure.Circulation. 1992; 85: 1046-1055Crossref PubMed Google Scholar The Ca2+ discharged from the SR binds to troponin C, resulting in conformation changes of the contractile apparatus. These changes allow for myofilament cross-bridge formation and, thus, myocyte shortening. A decrease in SR Ca2+ release would inhibit the ability of the myofilament apparatus to undergo the conformational changes necessary for cross-bridge formation. Second, the absolute reduction of Ca2+ will result in a diminished number of cross-bridges formed during a contractile cycle, leading to diminished contractile force generation. Several mechanisms may be responsible for the reduced release of Ca2+. First, there appears to be a reduction in the trigger Ca2+ current marked by L-type Ca2+ channel dysfunction. Second, SR calcium release channels appear to be reduced22Brillantes AM Allen P Takahashi T Izumo S Marks AR. Differences in cardiac calcium release channel (ryanodine receptor) expression in myocardium from patients with end-stage heart failure caused by ischemic versus dilated cardiomyopathy.Circ Res. 1992; 71: 18-26Crossref PubMed Google Scholar, 23Go LO Moschella MC Watras J Handa KK Fyfe BS Marks AR. Differential regulation of two types of intracellular calcium release channels during end-stage heart failure.J Clin Invest. 1995; 96: 888-894Crossref Google Scholar or dysfunctional24D’Agnolo A Luciani GB Mazzucco A Gallucci V Salviati G. Contractile properties and Ca2+ release activity of the sarcoplasmic reticulum in dilated cardiomyopathy.Circulation. 1992; 85: 518-525Crossref PubMed Google Scholar, 25Nimer LR Needleman DH Hamilton SL Krall J Movsesian MA. Effect of ryanodine on sarcoplasmic reticulum Ca2+ accumulation in nonfailing and failing human myocardium.Circulation. 1995; 92: 2504-2510Crossref PubMed Google Scholar in severe hypertrophy and/or failure. A summary of the alterations in Ca2+ dynamics that occur in myocyte hypertrophy and/or failure appears in Fig 2. The fundamental contractile unit of the myocyte is the sarcomere. The sarcomere is composed of actin and myosin filaments, tropomyosin, and the troponin complex: troponin C, troponin I, and troponin T. Although a myosin isoform switch was previously considered to occur only in animal models of failure,26Lompre AM Schwartz K d’Albis A Lacombe G Van Thiem N Swynghedauw B. Myosin isoenzyme redistribution in chronic heart overload.Nature. 1979; 282: 105-107Crossref PubMed Scopus (138) Google Scholar, 27Nadal-Ginard B Mahdavi V. Molecular basis of cardiac performance: plasticity of the myocardium generated through protein isoform switches.J Clin Invest. 1989; 84: 1693-1700Crossref PubMed Google Scholar, 28Dorn II, GW Robbins J Ball N Walsh RA. Myosin heavy chain regulation and myocyte contractile depression after LV hypertrophy in aortic-banded mice.Am J Physiol. 1994; 267: H400-H405PubMed Google Scholar, 29Yelmarty RV Moore RL Yu FT Elensky M Semanchick AM Cheung JY. Relaxation abnormalities in single cardiac myocytes from renovascular hypertensive rats.Am J Physiol. 1992; 262: C980-C990PubMed Google Scholar a recent study has identified that it occurs in the failing human myocyte. Specifically, Lowes and associates30Lowes BD Minobe W Abraham WT Rizeq MN Bohlmeyer TJ Quaife RA et al.Changes in gene expression in the intact human heart: downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium.J Clin Invest. 1997; 100: 2315-2324Crossref PubMed Google Scholar have reported a reduction in the expression of the cardiac specific α-myosin heavy chain coupled with a reciprocal increase in the expression of the β-myosin heavy chain in severe hypertrophy and failure.30Lowes BD Minobe W Abraham WT Rizeq MN Bohlmeyer TJ Quaife RA et al.Changes in gene expression in the intact human heart: downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium.J Clin Invest. 1997; 100: 2315-2324Crossref PubMed Google Scholar The β isoform of the myosin heavy chain causes a slower velocity of shortening when compared with the α-myosin heavy chain.31Weiss A Leinwand LA. The mammalian myosin heavy chain gene family.Ann Rev Cell Dev Biol. 1996; 12: 417-439Crossref PubMed Scopus (176) Google Scholar Therefore, these changes in myosin heavy chain expression with severe hypertrophy and/or failure may directly contribute to alterations in LV ejection performance. Although there appears to be no change in cardiac troponin I in the setting of hypertrophy and/or failure, its presence in the serum has been used as a marker for acute myocardial ischemia.32Adams III, JE Bodor GS Davalia-Roman VG Delmez JA Apple FS Ladenson JH et al.Cardiac troponin I: a marker with high specificity for cardiac injury.Circulation. 1993; 88: 101-106Crossref PubMed Google Scholar Interestingly, it appears that CABG coupled with cardiopulmonary bypass can be associated with the release of cardiac troponin I.33Ascione R Lloyd CT Gomes WJ Caputo M Bryan AJ Angelini GD. Beating verses arrested heart revascularization: evaluation of myocardial function in a prospective randomized study.Eur J Cardiothorac Surg. 1999; 15: 685-690Crossref PubMed Scopus (196) Google Scholar The transient loss of troponin I in cardiac myocytes after CABG may further exacerbate contractile dysfunction in the setting of hypertrophy and/or failure. While studies regarding the contractile apparatus in the setting of severe hypertrophy and/or failure are currently ongoing, in general terms the myofilament apparatus appears to be structurally intact. In contrast, the intracellular environment that surrounds the contractile elements is substantially abnormal in the setting of hypertrophy and/or failure and is likely to be a major contributory cause of LV contractile dysfunction. The resequestration of Ca2+ into the SR occurs primarily through the actions of SERCA-2 and the influence of the regulatory protein phospholamban. The regulatory influence of phospholamban on SERCA-2 is dependent on the phosphorylation state. When phosphorylated, phospholamban enhances SERCA-2 Ca2+ affinity and uptake, whereas dephosphorylated phospholamban diminishes SERCA-2 Ca2+ function. Defects in the resequestration of Ca2+ into the SR have been clearly identified in severe hypertrophy and/or failure, which is manifested by increased intracellular diastolic Ca2+.34Lindner M Erdmann E Beuckelmann DJ. Calcium content of the sarcoplasmic reticulum in isolated ventricular myocytes from patients with terminal heart failure.J Mol Cell Cardiol. 1998; 30: 743-749Abstract Full Text PDF PubMed Scopus (106) Google Scholar, 35Gwathmey JK Copelas L MacKinnon R Schoen FJ Feldman MD Grossman W et al.Abnormal intracellular calcium handling in myocardium from patients with end-stage heart failure.Circ Res. 1987; 61: 70-76Crossref PubMed Google Scholar, 36Wexler LF Lorell BH Momomura S Weinberg EO Ingwall JS Apstein CS. Enhanced sensitivity to hypoxia-induced diastolic dysfunction in pressure-overload left ventricular hypertrophy in the rat: role of high-energy phosphate depletion.Circ Res. 1988; 62: 766-775Crossref PubMed Google Scholar, 37Huddleston CB Wareing TH Boucek RJ Hammon Jr., JW Response of the hypertrophied left ventricle to global ischemia: comparison of hyperkalemic cardioplegic solution with and without verapamil.J Thorac Cardiovasc Surg. 1992; 103: 919-926PubMed Google Scholar At the myocardial level, defects in Ca2+ homeostasis will result in a slowed LV myocardial relaxation. Furthermore, defects in SR Ca2+ re-uptake would result in increased diastolic Ca2+ concentrations, which, in turn, cause decreased sensitivity of the contractile apparatus to intracellular Ca2+ concentrations. Alterations in Ca2+ resequestration that occur in severe hypertrophy and/or failure are likely due to several factors. The majority of studies have reported decreased protein expression and/or function of SERCA-2 in severe hypertrophy and/or failure.38de la Bastie D Levitsky D Rappaport L Mercadier JJ Marotte F Wisnewsky C et al.Function of the sarcoplasmic reticulum and expression of its Ca2(+)-ATPase gene in pressure overload-induced cardiac hypertrophy in the rat.Circ Res. 1990; 66: 554-564Crossref PubMed Google Scholar, 39Schwinger RH Bohm M Schmidt U Karczewski P Bavendiek U Flesch M et al.Unchanged protein levels of SERCA II and phospholamban but reduced Ca2+ uptake and Ca(2+)-ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts.Circulation. 1995; 92: 3220-3228Crossref PubMed Google Scholar, 40Meyer M Schillinger W Peiske B Holubarsch C Heilmann C Poisval H et al.Alterations of sarcoplasmic reticulum proteins in failing dilated cardiomyopathy.Circulation. 1995; 92: 778-784Crossref PubMed Google Scholar, 41Hasenfuss G Reinecke H Struder R Meyer M Pieske B Holtz J et al.Relation between myocardial function and expression of sarcoplasmic reticulum Ca(2+)-ATPase in failing and nonfailing human myocardium.Circ Res. 1994; 75: 434-442Crossref PubMed Google Scholar, 42Struder R Reinecke H Bilger J Eschenhagen T Bohm M Hasenfuss G Gene expression of the cardiac Na(+)-Ca(2+) exchanger in end-stage human heart failure.Circ Res. 1994; 75: 443-453Crossref PubMed Google Scholar For example, Hasenfuss and associates41Hasenfuss G Reinecke H Struder R Meyer M Pieske B Holtz J et al.Relation between myocardial function and expression of sarcoplasmic reticulum Ca(2+)-ATPase in failing and nonfailing human myocardium.Circ Res. 1994; 75: 434-442Crossref PubMed Google Scholar reported a 36% reduction in SERCA-2 protein levels in the failing human myocardium. In a recent study by Dillman,43Dillman WH. Regulation of expression of cardiac sarcoplasmic reticulum proteins under pathophysiological conditions.Mol Cell Biochem. 1996; 157: 125-128Crossref PubMed Google Scholar cardiac myocytes were transfected with DNA for SERCA-2, which resulted in increased synthesis and protein levels. The enhanced protein expression of SERCA-2 in this study increased Ca2+ re-uptake.43Dillman WH. Regulation of expression of cardiac sarcoplasmic reticulum proteins under pathophysiological conditions.Mol Cell Biochem. 1996; 157: 125-128Crossref PubMed Google Scholar This in vitro study emphasizes the importance of the loss of expression and function of SERCA-2 on Ca2+ homeostasis. Although it appears that SERCA-2 is reduced in severe hypertrophy and/or failure, the changes in the regulatory protein phospholamban appear to be more complex. In animal models of hypertrophy and failure, a reduction in the expression of phospholamban has been documented.44Kiss E Ball NA Kranias EG Walsh RA. Differential changes in cardiac phospholamban and sarcoplasmic reticular Ca(2+)-ATPase protein levels: effects on Ca2+ transport and mechanics in compensated pressure-overload hypertrophy and congestive heart failure.Circ Res. 1995; 77: 759-764Crossref PubMed Google Scholar In human studies, a reduction in messenger RNA (mRNA) phospholamban levels has been reported,39Schwinger RH Bohm M Schmidt U Karczewski P Bavendiek U Flesch M et al.Unchanged protein levels of SERCA II and phospholamban but reduced Ca2+ uptake and Ca(2+)-ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts.Circulation. 1995; 92: 3220-3228Crossref PubMed Google Scholar, 45Flesch M Schwinger RH Schnabel P Schiffer F van Gelder I Bavendiek U et al.Sarcoplasmic reticulum Ca2+-ATPase and phospholamban mRNA and protein levels in end-stage heart failure due to ischemic or dilated cardiomyopathy.J Mol Med. 1996; 74: 321-332Crossref PubMed Google Scholar, 46Linck B Boknik P Eschenhagen T Muller FU Neumann J Nose M et al.Messenger RNA expression and immunological quantification of phospholamban and SR-Ca(2+)-ATPase in failing and nonfailing human hearts.Cardiovasc Res. 1996; 31: 625-632Crossref PubMed Scopus (140) Google Scholar but absolute protein levels appear to be unchanged in severe hypertrophy and/or failure.39Schwinger RH Bohm M Schmidt U Karczewski P Bavendiek U Flesch M et al.Unchanged protein levels of SERCA II and phospholamban but reduced Ca2+ uptake and Ca(2+)-ATPase activity of cardiac sarcoplasmic reticulum from dilated cardiomyopathy patients compared with patients with nonfailing hearts.Circulation. 1995; 92: 3220-3228Crossref PubMed Google Scholar, 46Linck B Boknik P Eschenhagen T Muller FU Neumann J Nose M et al.Messenger RNA expression and immunological quantification of phospholamban and SR-Ca(2+)-ATPase in failing and nonfailing human hearts.Cardiovasc Res. 1996; 31: 625-632Crossref PubMed Scopus (140) Google Scholar, 47Movsesian MA Karimi M Green K Jones LR. Ca(2+)-transporting ATPase, phospholamban, and calsequestrin levels in nonfailing and failing human myocardium.Circulation. 1994; 90: 653-657Crossref PubMed Google Scholar This may represent an imbalance in the transcription and/or translation rates of phospholamban in severe hypertrophy and/or failure. Nevertheless, if SERCA-2 levels decrease without a comparable change in phospholamban expression, alterations in the stoichiometry between these proteins can result. Using transfection techniques, Hajjar and colleagues48Hajjar RJ Schmidt U Kan JX Matsui T Rosenweig A. Adenoviral gene transfer of phospholamban in isolated rat cardiomyocytes: rescue effects of concomitant gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase.Circ Res. 1997; 81: 145-153Crossref PubMed Google Scholar overexpressed the phospholamban protein in cardiac myocytes. The increased ratio of phospholamban to SERCA-2 resulted in slowed Ca2+ re-uptake into the SR and increased resting Ca2+ concentrations. These studies demonstrate the importance of the phospholamban/SERCA-2 stoichiometric relationship in maintaining SR Ca2+ re-uptake and intracellular Ca2+ concentrations, a relationship that may be altered in the setting of severe hypertrophy and/or failure. The slower Na+/Ca2+ exchanger also participates in the extrusion of cytosolic Ca2+ during active relaxation. There appears to be up-regulation of the Na+/Ca2+ exchanger gene expression and activity in hypertrophy and/or failure.49Reinecke H Struder R Vetter R Just H Holtz J Drexler H. Role of the cardiac sarcolemmal Na(+)-Ca2+ exchanger in end-stage human heart failure.Ann N Y Acad Sci. 1996; 779: 543-545Crossref PubMed Google Scholar, 50Reinecke H Struder R Vetter R Holtz J Drexler H. Cardiac Na+/ Ca2+ exchange activity in patients with end-stage heart failure.Cardiovasc Res. 1996; 31: 48-54PubMed Google Scholar, 51Flesch M Schwinger RH Schiffer F Frank R Sudkamp M Kuhn-Regnier F et al.Evidence for functional relevance of an enhanced expression of the Na(+)-Ca2+ exchanger in failing human myocardium.Circulation. 1996; 94: 992-1002Crossref PubMed Google Scholar, 52Yashar PR Fransua M Frishman WH. The sodium-calcium ion membrane exchanger: physiologic significance and pharmacologic implications.J Clin Pharmacol. 1998; 38: 393-401Crossref PubMed Google Scholar The up-regulation of this protein may initially serve as a compensatory mechanism resulting from the reduction of SERCA-2 function. This may eventually result in an overall reduction in the amount of cytosolic Ca2+ available for SR uptake and subsequent release for excitation-contraction coupling. SR re-uptake of cytosolic Ca2+ is an energy-dependent process.4Katz AM. Physiology of the heart. Raven Press, New York1992Google Scholar Therefore increased intracellular Ca2+ levels will require increased hydrolysis of ATP for resequestration and maintenance of a normal resting cytosolic Ca2+ concentration. In hypertrophied myocardium, reduced basal levels of high-energy phosphates such as ATP have been reported.53Attarian DE Jones RN Currie WD Hill RC Sink JD Olsen CO et al.Characteristics of chronic left ventricular hypertrophy induced by subcoronary valvular aortic stenosis. I. Myocardial blood flow and metabolism.J Thorac Cardiovasc Surg. 1981; 81: 382-388PubMed Google Scholar This reduction in intrinsic levels of high-energy phosphates will also impede energy-dependent resequestration of Ca2+ and thereby cause increased cytosolic Ca2+ levels in hypertrophy and/or failure.54Menasche P Tronc F Nguyen A Veyssie L Demirag M Lariviere J et al.Retrograde warm blood cardioplegia preserves hypertrophied myocardium: a clinical study.Ann Thorac Surg. 1994; 57: 1429-1434Abstract Full Text PDF PubMed Google Scholar Hypothermic, hyperkalemic cardioplegic arrest is associated with an increase in intracellular Ca2+.55Dorman BH Hebbar L Clair MJ Hinton RB Roy RC Spinale FG. Potassium channel opener–augmented cardioplegia: protection of myocyte contractility with chronic left ventricular dysfunction.Circulation. 1997; 96: II253-II259Google Scholar, 56Jovanovic A Lopez JR Alekseev AE Shen WK Terzic A. Adenosine prevents K+-induced Ca2+ loading: insight into cardioprotection during cardioplegia.Ann Thorac Surg. 1998; 65: 586-591Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 57Cyran SE Ditty SE Baylen BG Cheung J LaNoue KF. Developmental differences in the response of cytosolic free calcium to potassium depolarization and cardioplegia in cardiac myocytes.J Mol Cell Cardiol. 1992; 24: 1167-1177Abstract Full Text PDF PubMed Scopus (8) Google Scholar For example, in an in vitro model of cardioplegic arrest and rewarming, increased intracellular Ca2+ levels have been recorded, which persisted in the early reperfusion period (Fig 3).55Dorman BH Hebbar L Clair MJ Hinton RB Roy RC Spinale FG. Potassium channel opener–augmented cardioplegia: protection of myocyte contractility with chronic left ventricular dysfunction.Circulation. 1997; 96: II253-II259Google ScholarFurthermore, additional studies with cardioplegic arrest and rewarming have reported a prolongation of the isovolumic pressure decline,58Schaff HV Dombroff R Flaherty JT Bulkley BH Hutchins GM Goldman RA et al.Effect of potassium cardioplegia on myocardial ischemia and post arrest ventricular function.Circulation. 1978; 58: 240-249Crossref PubMed Google Scholar, 59Flaherty JT Schaff HV Goldman RA Gott VL. Metabolic and functional effects of progressive degrees of hypothermia during global ischemia.Am J Physiol. 1979; 236: H839-H845PubMed Google Scholar indicative of abnormalities in myocyte active relaxation. Thus conventional cardioplegic arrest may alter Ca2+ homeostatic mechanisms, which can persist in the early reperfusion period. These alterations in Ca2+ homeostasis may exacerbate pre-existing abnormalities in severe hypertrophy and/or failure which, in turn, would contribute to LV dysfunction in the early postoperative period. A number of sarcolemmal receptor systems are affected with the development of hypertrophy and/or failure.60Castellano M Bohm M. The cardiac beta-adrenoceptor–mediated signaling pathway and its alterations in hypertensive disease.Hypertension. 1997; 29: 715-722Crossref PubMed Google Scholar, 61Leier CV Binkley PF Cody RJ. Alpha-adrenergic component of the sympathetic nervous system in congestive heart failure.Circulation. 1990; 82: I68-I76PubMed Google Scholar, 62Schriffin EL Intengan HD Thibault G Touyz RM. Clinical significance of endothelin in cardiovascular disease.Curr Opin Cardiol. 1997; 12: 354-367PubMed Google Scholar This review will focus on the prototypical β-adrenergic receptor (β-AR) system as it is the receptor system most often pharmacologically manipulated in the early postoperative setting. Under ideal circumstances, intracellular phosphorylation targets after β-AR stimulation are the L-type Ca2+ channel, phospholamban, and troponin I of the contractile apparatus. Thus alteration in the expression, function, and/or activation of the β-AR system will influence key components of the excitation-contraction coupling process, thereby affecting myocyte contractile function. In hypertrophy and/or failure, a decrease in β-AR density has been reported. For example, Bristow and associates63Bristow MR Ginsburg R Umans V Fowler M Minobe W Rasmussen R et al.Beta-1 and beta-2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes" @default.
• W2085680143 created "2016-06-24" @default.
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• W2085680143 date "2000-02-01" @default.
• W2085680143 modified "2023-10-16" @default.
• W2085680143 title "Myocyte contractile dysfunction with hypertrophy and failure: Relevance to cardiac surgery" @default.
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