Actualización en los mecanismos fisiopatológicos de la insuficiencia cardiaca
DOI:
https://doi.org/10.51481/amc.v50i1.345Palabras clave:
Insuficiencia cardiaca, remodelación cardiaca, activación neurohumoral, acople excitación-contracción, arritmias, apoptosisResumen
La insuficiencia cardiaca es uno de los síndromes clínicos más frecuentes en la práctica médica y se presenta cuando el corazón, a presiones normales de llenado, es incapaz de bombear la cantidad suficiente de sangre que requiere el metabolismo de los tejidos. Aquí se presenta una revisión de los datos más recientes sobre los mecanismos involucrados en la fisiopatología de la insuficiencia cardiaca, para que su conocimiento sea de utilidad en el manejo adecuado de esta entidad. En la insuficiencia cardiaca, como respuesta al gasto cardiaco insuficiente, se activan una serie de mecanismos neuroendocrinos sistémicos, que posteriormente, contribuyen al deterioro del cuadro clínico; es el caso del sistema simpático y el sistema renina-angiotensinaaldosterona, los cuales terminan produciendo daño endotelial, incremento de radicales libres, de la apoptosis, de la fibrosis cardiaca y generación de arritmias. También se observa un incremento en la liberación de péptidos natriuréticos, los cuales tienden a regular algunas de las respuestas neurohumorales exacerbadas, sin embargo, con el transcurso de la enfermedad su acción tiende a atenuarse. Celular y molecularmente se producen una serie de alteraciones en el manejo intracelular del Ca2+, así como en algunas de las corrientes iónicas que participan en la generación del potencial de acción de los miocitos cardiacos. La remodelación cardiaca precede al cuadro clínico de la insuficiencia y contribuye a su deterioro. Mensajeros químicos como la endotelina-1, la norepinefrina y la angiotensina II, que activan la cascada de las MAP quinasas, provocan hipertrofia cardiaca, lo que favorece la isquemia y la aparición de arritmias. El manejo farmacológico de la insuficiencia cardiaca debe dirigirse a los mecanismos fisiopatológicos afectados, es decir, al bloqueo de las acciones deletéreas de los sistemas neuroendocrinos sobreestimulados y a evitar la pérdida de miocitos, la generación de fibrosis y de arritmias cardiacas, para lo cual es indispensable el manejo apropiado de los niveles intracelulares de Ca2+.
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Minamisawa S, Sato Y, Cho MC. Calcium cycling proteins in heart failure, cardiomyopathy and arrythmias. Exp Mol Med 2004; 36: 193-203.
Braunwald E, Colucci W, Grossman W. Aspectos clínicos de la insuficiencia cardíaca: insuficiencia cardíaca de gasto alto; edema pulmonar. En: Zipes DP, Libby P, Bonow RO, Braunwald E. (Eds) Tratado de Cardiología. Madrid: Elsevier España S.A., 2005: 479-503.
Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation 2005; 112: 154-235.
Opie LH. The neuroendocrinology of congestive heart failure. Cardiovasc J South Afr 2002; 13: 171-178.
Wright DJ, Tan LB. The role of exercise testing in the evaluation and management of heart failure. Postgrad Med J 1999; 75: 453-458.
Jessup M, Brozena S. Heart Failure. N Engl J Med 2003; 348: 20072018.
Dávila DF, Núñez TJ, Odreman R, Mazzei de Dávila CA. Mechanisms of neurohormonal activation in chronic congestive heart failure: pathophysiology and therapeutic implications. Int J Cardiol 2005; 101: 343-346.
Brum PC, Rolim N, Bacurau A, Medeiros A. Neurohumoral activation in heart failure: the role of adrenergic receptors. An Acad Bras Cienc 2006; 78: 485-503.
Schrier RW, Abraham WT. Hormones and Hemodinamics in Heart Failure. N Engl J Med 1999; 341: 577-585.
Cleland JG, Khand A, Clark A. The heart failure epidemic: exactly how big is it? Eur Heart J 2001; 22: 623-626.
Farr MA, Basson CT. Sparking the Failing Heart. N Engl J Med 2004; 351: 185-187.
Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: the Framingham study. J Am Coll Cardiol 1993; 22: 6A-13A.
Goldberg LR, Jessup M. Stage B Heart Failure. Circulation 2006; 113: 2851-2860.
Harrington D, Anker SD, Coats AJ. Preservation of exercise capacity and lack of peripheral changes in asymptomatic patients with severely impaired left ventricular function. Eur Heart J 2001; 22: 392-399.
Berk BC, Fujiwara K, Lehoux S. ECM remodeling in hypertensive heart disease. J Clin Invest 2007; 117: 568-575.
Weir R, Mcmurray J, Taylor J, Brady A. Heart Failure in Older Patients. Br J Cardiol 2006; 13: 257-266.
Birkeland JA, Sejersted OM, Taraldsen T, Sjaastad I. EC-coupling in normal and failing hearts. Scand Cardiovasc J 2005; 13-23.
Leite-Moreira AF. Current perspectives in diastolic dysfunction and diastolic heart failure. Heart 2006; 92: 712-718.
Zile, MR. Brutsaert D. New concepts in diastolic dysfunction and diastolic heart failure: part I: diagnosis, prognosis and measurements of diastolic function. Circulation 2002; 105: 1387-1393.
Clark AL. Origin of symptoms in chronic heart failure. Heart 2006; 92: 12-16.
Ulate G, Ulate A. El calcio en los miocitos cardiacos y su papel en las miocardiopatías. Rev Costarr Cardiol 2006; 8: 19-25.
Benjamin IJ, Schneider MD. Learning from failure: congestive heart failure in the postgenomic age. J Clin Invest 2005; 115: 495-499.
Iwanaga Y, Hoshijima M, Gu Y, Iwatate M, Dieterle T, Ikeda Y, et al. Chronic phospholamban inhibition prevents progressive cardiac dysfunction and pathological remodeling alter infarction in rats. J Clin Invest 2004; 113: 727-736.
Sande JB, Sjaastad I, Hoen IB, Bokenes J, Tonnessen T, Holt E, et al. Reduced level of serine1 phosphorylated phospholambn in the failing rat myocardium: A major contributor to reduced SERCA2 activity. Cardiovasc Res 2002; 53: 382-91.
Tappia PS. Phospholipid-mediated signaling systems as novel targets for treatment of heart disease. Can J Physiol Pharmacol 2007; 85: 2541.
Hunter JJ, Chien KR. Signaling pathways for cardiac hypertrophy and failure. N Eng J Med 1999; 341: 1276-1283.
Swynghedauw B. Phenotypic plasticity of adult myocardium: molecular mechanisms. J Exp Biol 2006; 209: 2320-2327.
Berenji K, Drazner MH, Rothermel BA, Hill JA. Does load-induced ventricular hypertrophy progress to systolic heart failure? Am J Physiol Heart Circ Physiol 2005; 289: H8-H16.
Teunissen BE, Jongsma HJ, Bierhuizen MF. Regulation of myocardial connexins during hypertrophic remodeling. Eur Heart J 2004; 25: 1979-1989.
Watanabe T, Barker TA, Berk BC. Angiotensin II and the endothelium: diverse signals and effects. Hypertension 2005; 45: 163-169.
Dorn GW, Force T. Protein kinase cascades in the regulation of cardiac hypertrophy. J Clin Invest 2005; 115: 527-537.
Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang CS. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Ventricular Dysfunction (SOLVD). Circulation 1990; 82: 1724-1729.
Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and the relation to mortality. CONSENSUS Trial Study Group. Circulation 1990; 82: 1730-1736.
Francis GS, McDonald KM, Cohn JN. Neurohumoral activation in preclinical heart failure: remodeling and the potential for intervention. Circulation 1993; 87: IV-90-96.
Post SR, Hammond HK, Insel PA. Beta-adrenergic receptors and receptor signaling in heart failure. Annu Rev Pharmacol Toxicol 1999; 39: 343-360.
Port JD, Bristow MR. Altered beta-adrenergic receptor gene regulation and signaling in chronic heart failure. J Mol Cell Cardiol 2001; 33: 887-905.
Brum PC, Kosek J, Patterson A, Bernstein D, Kobilka B. Abnormal cardiac function associated with sympathetic nervous system hyperactivity in mice. Am J Physiol Heart Circ Physiol 2002; 283: H1838-H1845.
Lohse MJ, Engelhardt S, Eschenhagen T. What is the role of betaadrenergic signaling in heart failure? Circ Res 2003; 93: 896-906.
Communal C, Singh K, Sawyer DB, Colucci WS. Opposing effects of beta(1)-and beta(2)-adrenergic receptors on cardiac myocyte apoptosis: role of a pertussis toxin-sensitive G protein. Circulation 1999; 100: 2210-2212.
Xiao RP, Zhu W, Zheng M, Chakir K, Bond R, Lakatta EG, et al. Subtype-specific beta-adrenoceptor signaling pathways in the heart and the potential clinical implications. Trends Pharmacol Sci 2004; 25: 358-365.
Zhao XL, Gutierrez LM, Chang CF, Hosey MM. The alpha 1-aubunit of skeletal muscle L-type Ca channels is the key target for regulation by A-kinase and protein phosphatase-1C. Biochem Biophys Res Commun 1994; 198: 166-173.
Gerhardstein BL, Puri TS, Chien AJ, Hosey MM. Identification of the sites phosphorylated by cyclic AMP-dependent protein kinase on the beta 2 subunit of L-type voltage-dependent calcium channels. Biochemistry 1999; 38: 10361-10370.
Simmerman HK, Jones LR. Phospholamban: protein structure, mechanism of action, and role in cardiac function. Physiol Rev 1998; 78: 921-947.
Sulakhe PV, Vo XT. Regulation of phospholamban and troponin-I phosphorylation in the intact rat cardiomyocytes by adrenergic and cholinergic stimuli: roles of cyclic nucleotides, calcium, protein kinases and phosphatases and depolarization. Mol Cell Biochem 1995; 149-150: 103-126.
Kunst G, Kress KR, Gruen M, Uttenweiler D, Gautel M, Fink RH. Myosin binding protein C, a phosphorylation-dependent force regulator in muscle that controls the attachment of myosin heads by its interaction with myosin S2. Circ Res 2000; 86: 51-58.
Xiao RP. Cell logic for dual coupling of a single class of receptors to G(s) and G(i) proteins. Circ Res 2000; 87: 635-637.
Sibley DR, Strasser RH, Benovic JL, Daniel K, Lefkowitz RJ. Phosphorylation / dephosphorylation of the beta–adrenergic receptor regulates its functional coupling to adenylate cyclase and subcellular distribution. Proc Natl Acad Sci USA 1986; 83: 94-08-9412.
Hausdorff WP, Lohse MJ, Bouvier M, Liggett SB, Caron MG, Lefkowitz RJ. Two kinases mediate agonist-dependent phosphorylation and desensitization of the beta 2-adrenergic receptor. Symp Soc Exp Biol 1990; 44: 225-240.
Ungerer M, Bohm M, Elce JS, Erdmann E, Lohse MJ. Altered expression of beta-adrenergic receptor kinase and beta1-adrenergic receptors in the failing human heart. Circulation 1993; 87: 454-463.
Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, et al. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 2000; 101: 365-376.
Reiken S, Gaburjakova M, Guatimosim S, Gomez AM, D′Armiento J, Burkhoff D, et al. Protein kinase A phosphorylation of the cardiac calcium release channel (ryanodine receptor) in normal and failing hearts. Role of phosphatases and response to isoproterenol. J Biol Chem 2003; 278: 444-453.
Wehrens XH, Lehnart SE, Marks AR. Intracellular calcium release and cardiac disease. Annu Rev Physiol 2005; 67: 69-98.
Wehrens XH, Marks AR. Altered function and regulation of cardiac ryanodine receptors in cardiac disease. Trends Biochem Sci 2003; 28: 671-678.
Schwinger RH, Munch G, Bolck B, Karczewski P, Krause EG, Erdmann E. Reduced Ca(2+)-sensitivity of SERCA2a in failing human myocardium due to reduced serin-16 phospholamban phosphorylation. J Mol Cell Cardiol 1999; 31: 479-491.
Hajjar RJ, Muller FU, Schmitz W, Schnabel P, Bohn M. Molecular aspects of adrenergic signal transduction in cardiac failure. J Mol Med 1998; 76: 747-755.
Roma G. Catecholamine cardiotoxicity. J Mol Cell Cardiol 1985; 17: 291-306.
Mann DL, Kent RL, Parsons B, Cooper GT. Adrenergic affects on the biology of the adult mammalian cardiocyte. Circulation 1992; 85: 790-804.
Levine TB, Francis GS, Goldsmith SR, Simon AB, Cohn JN. Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure. Am J Cardiol 1982; 49: 1659-1666.
Hensen J, Abraham WT, Dürr J, Schrier RW. Aldosterone in congestive heart failure: analysis of determinants and role in sodium retention. Am J Nephrol 1991; 11: 441-446.
Chun TY, Bloem LJ, Pratt JH. Aldosterone inhibits inducible nitric oxide synthase in neonatal rat Cardiomyocytes. Endocrinology 2003; 144: 1712-1717.
Fuller PJ, Young MJ. Mechanisms of mineralocorticoid action. Hypertension 2005; 46: 1227-1235.
Ouvrard-Pascaud A, Sainte-Marie Y, Benitah JP, Perrier R, Soukaseum C, Cat AN, et al. Conditional mineralocorticoid receptor expression in the heart leads to life-threatening arrhythmias. Circulation 2005; 111: 3025-3033.
Lalevee N, Rebsamen MC, Barrere-Lemaire S, Perrier E, Nargeot J, Benitah JP, et al. Aldosterone increases T-type calcium channel expression and in vitro beating frequency in neonatal rat cardiomyocytes. Cardiovasc Res. 2005; 67: 216-224.
Schrier RW. Pathogenesis of sodium and water retention in highoutput and low-output cardiac failure, nephrotic syndrome, cirrhosis, and pregnancy. N Engl J Med 1988; 319: 1065-1072.
Raine AEG, Eme P, Burgisser E, Muller FB, Bolli P, Burkart F, et al. Atrial natriuretic peptide and atrial pressure in patients with congestive heart failure. N Engl J Med 1986; 315: 533-537.
Saito Y, Nakao K, Arai H, Sugawara A, Morii N, Yamada T, et al. Atrial natriuretic polypeptide (ANP) in human ventricle: increased gene expression of ANP in dilated cardiomyopathy. Biochem Biophys Res Commun 1987; 148: 211-217.
Ferrari R, Agnoletti G. Atrial natriuretic peptide: its mechanism of release from the atrium. Int J Cardiol 1989; 24: 137-149.
Tsutamoto T, Wada A, Maeda K, Hisanaga T, Maeda Y, Fukai D. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation 1997; 96: 509-516.
Olivetti G, Abbi R, Quani F, Kajstura J, Cheng W, Nitahara JA, et al. Apoptosis in the failing heart. N Engl J Med 1997; 336: 1131-1141.
Saraste A, Pulkki K, Kallajoki M, Heikkila P, Laine P, Mattila S, et al. Cardiomyocyte apoptosis and progression of heart failure to transplantation. Eur J Clin Invest 1999; 29: 380-386.
Guerra S, Leri A, Wang X, Finato N, DiLoreto C, Beltrami CA, et al. Myocyte death in the failing human heart is gender dependent. Circ Res 1999; 85: 856-866.
Crow MT, Mani K, Nam YJ, Kitsis RN. The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res 2004; 95: 957-970.
Wencker D, Chandra M, Nguyen K, Miao W, Garantziotis S, Factor SM, et al. A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest 2003; 111: 1497-1504.
Zaugg M, Xu W, Lucchinetti E, Shafiq SA, Jamali NZ, Siddiqui MA. Beta-adrenergic receptor subtypes differentially affect apoptosis in adult rat ventricular myocytes. Circulation 2000; 102: 344-350.
Zhu WZ, Zheng M, Koch WJ, Lefkowitz RJ, Kobilka BK, Xiao RP. Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes. Proc Natl Acad Sci USA 2001; 98: 1607-1612.
Chesley A, Lundberg MS, Asai T, Xiao RP, Ohtani S, Lakatta EG, et al. The beta(2)-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through G(i)-dependent coupling to phosphatidylinositol 3-kinase. Circ Res 2000; 87: 1172-1179.
Hayakawa Y, Chandra M, Miao W, Shirani J, Brown JH, Dorn GW, et al. Inhibition of cardiac myocyte apoptosis improves cardiac function and abolishes mortality in the peripartum cardiomyopathy of Galpha(q) transgenic mice. Circulation 2003; 108: 3036-3041.
Adams JW, Sakata Y, Davis MG, Sah VP, Wang Y, Liggett SB, et al. Enhanced Galpha(q) signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure. Proc Natl Acad Sci USA 1998; 95: 10140-10145.
Tomaselli GF, Marban E. Electrophysiological remodeling in hypertrophy and heart failure. Cardiovasc Res 1999; 42: 270-283.
Wehrens XH, Lehnart SE, Reiken SR, Deng SX, Vest JA, Cervantes D, et al. Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Science 2004; 304: 292-296.
Tomaselli GF, Zipes DP. What causes sudden death in heart failure? Circ Res 2004; 95: 754-763.
Bristow M. Beta-adrenergic receptor blockade in chronic heart failure. Circulation 2000; 101: 558-569.
Groenning BA, Nilsson JC, Sondergaard L, Fritz-Hansen T, Larsson HB, Hildebrandt PR. Antiremodeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure. J Am Coll Cardiol 2000; 36: 2072-2080.
Weber KT. Aldosterone in congestive heart failure. N Engl J Med 2001; 345: 1689-1697.
Gheorghiade M, Teerlink JR, Mebazaa A. Pharmacology of new agents for acute heart failure syndromes. Am J Cardiol 2005; 96[suppl]: 68G-73G.
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