Comprehensive Physiology Wiley Online Library

Pathophysiology of Heart Failure

Full Article on Wiley Online Library



ABSTRACT

Heart failure is considered an epidemic disease in the modern world affecting approximately 1% to 2% of adult population. It presents a multifactorial, systemic disease, in which–‐after cardiac injury‐–structural, neurohumoral, cellular, and molecular mechanisms are activated and act as a network to maintain physiological functioning. These coordinated, complex processes lead to excessive volume overload, increased sympathetic activity, circulation redistribution, and result in different, parallel developing clinical signs and symptoms. These signs and symptoms sum up to an unspecific clinical picture; thus invasive and noninvasive diagnostic tools are used to get an accurate diagnosis and to specify the underlying cause. The most important, outcome determining factor in heart failure is its constant progression. Constant optimizing of pharmatherapeutical regimes, novel targets, and fine regulation of these processes try to keep these compensatory mechanisms in a physiological range. Beside pharmacological therapy, interventional and surgical therapy options give new chances in the management of heart failure. For the optimization and establishment of these and novel therapeutical approaches, complete and comprehensive understanding of the underlying mechanisms is essentially needed. Besides diagnosis and treatment, efforts should be made for better prevention in heart failure by treatment of risk factors, or identifying and following risk groups. This summary of the pathophysiology of heart failure tries to give a compact overview of basic mechanisms and of the novel unfolding, progressive theory of heart failure to contribute to a more comprehensive knowledge of the disease. © 2016 American Physiological Society. Compr Physiol 6:187‐214, 2016.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. PV loop showing the correlation of pressure and volume alterations in physiological and pathological conditions.
Figure 2. Figure 2. Beta‐adrenergic signaling pathways and their effects in the heart.
Figure 3. Figure 3. Major effects and further metabolization of angiotensin II.
Figure 4. Figure 4. Macro‐ and microstructural changes in eccentric, concentric, and combined remodeling.
Figure 5. Figure 5. Excitation‐contraction coupling in physiological and pathological state.
Figure 6. Figure 6. Oxidative stress in heart failure.


Figure 1. PV loop showing the correlation of pressure and volume alterations in physiological and pathological conditions.


Figure 2. Beta‐adrenergic signaling pathways and their effects in the heart.


Figure 3. Major effects and further metabolization of angiotensin II.


Figure 4. Macro‐ and microstructural changes in eccentric, concentric, and combined remodeling.


Figure 5. Excitation‐contraction coupling in physiological and pathological state.


Figure 6. Oxidative stress in heart failure.
References
 1.Abbate A, Salloum FN, Vecile E, Das A, Hoke NN, Straino S, Biondi‐Zoccai GG, Houser JE, Qureshi IZ, Ownby ED, Gustini E, Biasucci LM, Severino A, Capogrossi MC, Vetrovec GW, Crea F, Baldi A, Kukreja RC, Dobrina A. Anakinra, a recombinant human interleukin‐1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction. Circulation 117: 2670‐2683, 2008.
 2.Adams KF Jr, Sueta CA, Gheorghiade M, O'Connor CM, Schwartz TA, Koch GG, Uretsky B, Swedberg K, McKenna W, Soler‐Soler J, Califf RM. Gender differences in survival in advanced heart failure: Insights from the FIRST study. Circulation 99: 1816‐1821, 1999.
 3.Ahuja P, Sdek P, MacLellan WR. Cardiac myocyte cell cycle control in development, disease, and regeneration. Physiol Rev 87: 521‐544, 2007.
 4.Al‐Hesayen AP, Parker JD. Impaired baroreceptor control of renal sympathetic activity in human chronic heart failure. Circulation 109: 2862‐2865, 2004.
 5.Ambardekar AV, Buttrick PM. Reverse remodeling with left ventricular assist devices: A review of clinical, cellular, and molecular effects. Circ Heart Fail 4: 224‐233, 2011.
 6.Amir O RO, David M, Lahat N, Wolff R, Lewis BS. Circulating Interleukin‐10: Association with higher mortality in systolic heart failure patients with elevated tumor necrosis factor‐alpha. IMAJ 12: 158‐162, 2010.
 7.Anand IS, Latini R, Florea VG, Kuskowski MA, Rector T, Masson S, Signorini S, Mocarelli P, Hester A, Glazer R, Cohn JN, Val‐HeFT Investigators. C‐reactive protein in heart failure: Prognostic value and the effect of valsartan. Circulation 112: 1428‐1434, 2005.
 8.Anand I, McMurray JJ, Whitmore J, Warren M, Pham A, McCamish MA, Burton PB. Anemia and its relationship to clinical outcome in heart failure. Circulation 110: 149‐154, 2004.
 9.Andreassen AK, Nordøy I, Simonsen S, Ueland T, Müller F, Frøland SS, Gullestad L, Aukrust P. Levels of circulating adhesion molecules in congestive heart failure and after heart transplantation. Am J Cardiol 84: 604‐608, 1998.
 10.Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox WJ, Poole‐Wilson PA, Coats AJ. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. 96: 526‐534, 1997.
 11.Arakawa HUaK. Angiotensin II‐forming systems in cardiovascular diseases. Heart Fail Rev 3: 119‐124, 1998.
 12.Auer J. What does the liver tell us about the failing heart? Eur Heart J 34: 711‐714, 2013.
 13.Aukrust P, Gullestad L, Ueland T, Damås JK, Yndestad A. Inflammatory and anti‐inflammatory cytokines in chronic heart failure: Potential therapeutic implications. Ann Med 37: 74‐85, 2005.
 14.Aukrust P, Ueland T., Muller F., Andreassen AK, Nordoy I., Aas H, Kjekshus J, Simonsen S, Froland SS, Gullestad L. Elevated circulating levels of C‐C chemokines in patients with congestive heart failure. Circulation 97: 1136‐1143, 1998.
 15.Belmonte SL, Blaxall BC. G protein coupled receptor kinases as therapeutic targets in cardiovascular disease. Circ Res 109: 309‐319, 2011.
 16.Bers DM. Cardiac excitation–contraction coupling. Nature 415: 198‐205, 2002.
 17.Bers DM. Altered cardiac myocyte Ca regulation in heart failure. Physiology 21: 380‐387, 2006.
 18.Birnbaumer M. Vasopressin receptors. TEM 11: 406‐410, 2000.
 19.Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 11: 507‐15, 2014.
 20.Bortone AS HO, Chiddo A, Gaglione A, Locuratolo N, Caruso G, Rizzon P. Functional and structural abnormalities in patients with dilated cardiomyopathy. JACC 14: 613‐623, 1989.
 21.Braun J, Bax JJ, Versteegh MI, Voigt PG, Holman ER, Klautz RJ, Boersma E, Dion RA. Preoperative left ventricular dimensions predict reverse remodeling following restrictive mitral annuloplasty in ischemic mitral regurgitation. Eur J Cardiothorac Surg 27: 847‐853, 2005.
 22.Bristow MR, Ginsburg, R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, Billingham ME, Harrison DC, Stinson EB. Decreased catecholamine sensitivity and β‐adrenergic‐receptor density in failing human hearts. N Engl J Med 307: 205‐211, 1982.
 23.Carabello BA. Concentric versus eccentric remodeling. J Card Fail 8: S258‐263, 2002.
 24.Celermajer DS, Chow CK, Marijon E, Anstey NM, Woo KS. Cardiovascular disease in the developing world: Prevalences, patterns, and the potential of early disease detection. J Am Coll Cardiol 60: 1207‐1216, 2012.
 25.Cesselli D, Jakoniuk I, Barlucchi L, Beltrami AP, Hintze TH, Nadal‐Ginard B, Kajstura J, Leri A, Anversa P. Oxidative stress‐mediated cardiac cell death is a major determinant of ventricular dysfunction and failure in dog dilated cardiomyopathy. Circ Res 89: 279‐286, 2001.
 26.Chai SY, Fernando R, Peck G, Ye SY, Mendelsohn FA, Jenkins TA, Albiston AL. The angiotensin IV/AT4 receptor. Cell Mol Life Sci 61: 2728‐2737, 2004.
 27.Chemla D, Coirault C, Hébert JL, Lecarpentier Y. Mechanics of relaxation of the human heart. News Physiol Sci 15: 78‐83, 2000.
 28.Angermann CE, Frey A, Ertl G. Cognition matters in cardiovascular disease and heart failure. Eur Heart J 33: 1721‐3, 2012.
 29.Chung I, Choudhury A, Patel J, Lip GY. Soluble, platelet‐bound, and total P‐selectin as indices of platelet activation in congestive heart failure. Ann Med 41: 45‐51, 2009.
 30.Davis JO, Urquhart J, Higgins JT, Jr. Renin, angiotensin and aldosterone in experimental secondary hyperaldosteronsimus. Canad Med Assoc J 90: 245‐248, 1964.
 31.de Simone G. Concentric or eccentric hypertrophy: How clinically relevant is the difference? Hypertension 43: 714‐715, 2004.
 32.Defer N, Azroyan A, Pecker F, Pavoine C. TNFR1 and TNFR2 signaling interplay in cardiac myocytes. J Biol Chem 282: 35564‐35573, 2007.
 33.Dendorfer A, Thornagel A, Raasch W, Grisk O, Tempel K, Dominiak P. Angiotensin II induces catecholamine release by direct ganglionic excitation. Hypertension 40: 348‐354, 2002.
 34.Deschamps AM, Spinale FG. Pathways of matrix metalloproteinase induction in heart failure: Bioactive molecules and transcriptional regulation. Cardiovasc Res 69: 666‐676, 2006.
 35.Ducharme A, Frantz S, Aikawa M, Rabkin E, Lindsey M, Rohde LE, Schoen FJ, Kelly RA, Werb Z, Libby P, Lee RT. Targeted deletion of matrix metalloproteinase‐9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest 106: 55‐62, 2000.
 36.Fabiato A. Calcium‐induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol 245: C1‐14, 1983.
 37.Feldman AM CA, Wagner D, Kadakomi T, Kubota T, Li YY, McTiernan C. The Role of Tumor Necrosis Factor in the Pathophysiology of Heart Failure. J Am Coll Cardiol 35: 537‐544, 2000.
 38.Ferdinandy P, Danial H, Ambrus I, Rothery RA, Schulz R. Peroxynitrite is a major contributor to cytokine‐induced myocardial contractile failure. Circ Res 87: 241‐247, 2000.
 39.Frank JS, Langer GA. The myocardial interstitium: its structure and its role in ionic exchange. J Cell Biol 60: 586‐601, 1974.
 40.Gaasch WH, Battle WE, Oboler AA, Banas JS, Levine HJ. Left ventricular stress and compliance in man: With special reference to normalized ventricular function curves. Circulation 45: 746‐762, 1972.
 41.Gjesdal O, Bluemke DA, Lima JA. Cardiac remodeling at the population level–risk factors, screening, and outcomes. Nat Rev Cardiol 8: 673‐685, 2011.
 42.Glower DD, Spratt JA, Snow ND, Kabas JS, Davis JW, Olsen CO, Tyson GS, Sabiston DC, Rankin JS. Linearity of the Frank‐Starling relationship in the intact heart: The concept of preload recruitable stroke work. Circulation 71: 994‐1009, 1985.
 43.Gnansekaran G. Epidemiology of depression in heart failure. Heart Fail Clin 7: 1‐10, 2011.
 44.Goldsmith SR. The role of vasopressin in congestive heart failure. Cleve Clin J Med 73: S19‐S23, 2006.
 45.Gomez AM, Guatimosim S, Dilly KW, Vassort G, Lederer WJ. Heart failure after myocardial infarction: Altered excitation‐contraction coupling. Circulation 104: 688‐693, 2001.
 46.Goonasekera SA, Hammer K, Auger‐Messier M, Bodi I, Chen X, Zhang H, Reiken S, Elrod JW, Correll RN, York AJ, Sargent MA, Hofmann F, Moosmang S, Marks AR, Houser SR, Bers DM, Molkentin JD. Decreased cardiac L‐type Ca(2)(+) channel activity induces hypertrophy and heart failure in mice. J Clin Invest 122: 280‐290, 2012.
 47.Griselli M, Herbert H, Hutchinson WL, Taylor KM, Sohail M, Krausz T, Pepys MB. C‐reactive protein and complement are important mediators of tissue damage in acute myocardial infarction. J Exp Med 190: 1733‐1739, 1999.
 48.Halade GV, Jin YF, Lindsey ML. Matrix metalloproteinase (MMP)‐9: A proximal biomarker for cardiac remodeling and a distal biomarker for inflammation. Pharmacol Ther 139: 32‐40, 2013.
 49.Heinrich PC BI, Müller‐Newen G, Schaper F, Graeve L. Interleukin‐6‐type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334: 297‐314, 1998.
 50.Iribarren C, Karter AJ, Go AS, Ferrara A, Liu JY, Sidney S, Selby JV. Glycemic control and heart failure among adult patients with diabetes. Circulation 103: 2668‐2673, 2001.
 51.Ishikawa Y, Sorota S, Kiuchi K, Shannon RP, Komamura K, Katsushika S, Vatner DE, Vatner SF, Homcyl CJ. Downregulation of adenylylcyclase types V and VI mRNA levels in pacing‐induced heart failure in dogs. J Clin Invest 93: 2224‐2229, 1994.
 52.Jensen BC, O'Connell TD, Simpson PC. Alpha‐1–adrenergic receptors in heart failure: The adaptive arm of the cardiac response to chronic catecholamine stimulation. J Cardivasc Phar 63: 291‐301, 2014.
 53.Kameda K. Correlation of oxidative stress with activity of matrix metalloproteinase in patients with coronary artery disease: Possible role for left ventricular remodelling. Eur Heart J 24: 2180‐2185, 2003.
 54.Kanellakis P, Ditiatkovski M, Kostolias G, Bobik A. A pro‐fibrotic role for interleukin‐4 in cardiac pressure overload. Cardiovasc Res 95: 77‐85, 2012.
 55.Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA 241: 2035‐2038, 1979.
 56.Kardys I, Knetsch AM, Bleumink GS, Deckers JW, Hofman A, Stricker BH, Witteman JC. C‐reactive protein and risk of heart failure. The Rotterdam Study. Am Heart J 152: 514‐520, 2006.
 57.Kaschina E, Unger T. Angiotensin AT1/AT2 receptors: Regulation, signalling and function. Blood Press 12: 70‐88, 2003.
 58.Kehat I, Molkentin JD. Molecular pathways underlying cardiac remodeling during pathophysiological stimulation. Circulation 122: 2727‐2735, 2010.
 59.Kim HNJ, J. L., Jr. Natriuretic peptide testing in heart failure. Circulation 123: 2015‐2019, 2011.
 60.Kim J, Eckhart AD, Eguchi S, Koch WJ. Beta‐adrenergic receptor‐mediated DNA synthesis in cardiac fibroblasts is dependent on transactivation of the epidermal growth factor receptor and subsequent activation of extracellular signal‐regulated kinases. J Biol Chem 277: 32116‐32123, 2002.
 61.Konstam MA, Kramer DG, Patel AR, Maron MS, Udelson JE. Left ventricular remodeling in heart failure: Current concepts in clinical significance and assessment. JACC Cardiovasc Imaging 4: 98‐108, 2011.
 62.Kubo H, Jaleel N, Kumarapeli A, Berretta RM, Bratinov G, Shan X, Wang H, Houser SR, Margulies KB. Increased cardiac myocyte progenitors in failing human hearts. Circulation 118: 649‐657, 2008.
 63.Lane RE, Cowie MR, Chow AW. Prediction and prevention of sudden cardiac death in heart failure. Heart 91: 674‐680, 2005.
 64.Lazzarini V, Mentz RJ, Fiuzat M, Metra M, O'Connor CM. Heart failure in elderly patients: Distinctive features and unresolved issues. Eur J Heart Fail 15: 717‐723, 2013.
 65.Lefkowitz RJ, Rockman HA, Koch WJ. Catecholamines, cardiac‐adrenergic receptors, and heart failure. Circulation 101: 1634‐1637, 2000.
 66.Lieber C, Mohsenin V. Cheyne‐Stokes respiration in congestive heart failure. Yale J Biol Med 65: 39‐50, 1992.
 67.Lijnen PJ, Petrov VV, Fagard RH. Induction of cardiac fibrosis by transforming growth factor‐beta(1). Mol Genet Metab 71: 418‐435, 2000.
 68.Lombardo TA, Harrison TR. Cardiac asthma. Circulation 4: 920‐929, 1951.
 69.Lorell BH, Carabello BA. Left ventricular hypertrophy: Pathogenesis, detection, and prognosis. Circulation 102: 470‐479, 2000.
 70.Lu J, Holmgren A. The thioredoxin antioxidant system. Free Radic Biol Med 66: 75‐87, 2014.
 71.Luchner A, Henqstenberg C, Lowel H, Riegger GA, Schunkert H, Holmer S. Effect of compensated renal dysfunction on approved heart failure markers: Direct comparison of brain natriuretic peptide (BNP) and N‐terminal pro‐BNP. Hypertension 46: 118‐123, 2005.
 72.MacLennan DH, Kranias EG. Phospholamban: A crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol 4: 566‐577, 2003.
 73.Madamanchi A. β‐Adrenergic receptor signaling in cardiac function and heart failure. MJM 10: 99‐107, 2007.
 74.Maekawa Y, Anzai T, Yoshikawa T, Asakura Y, Takahashi T, Ishikawa S, Mitamura H, Ogawa S. Prognostic significance of peripheral monocytosis after reperfused acute myocardial infarction: A possible role for left ventricular remodeling. J Am Coll Cardiol 39: 241‐246, 2002.
 75.Maisel A, Mueller C, Adams K Jr, Anker SD, Aspromonte N, Cleland JG, Cohen‐Solal A, Dahlstrom U, DeMaria A, Di Somma S, Filippatos GS, Fonarow GC, Jourdain P, Komajda M, Liu PP, McDonagh T, McDonald K, Mebazaa A, Nieminen MS, Peacock WF, Tubaro M, Valle R, Vanderhyden M, Yancy CW, Zannad F, Braunwald E. State of the art: Using natriuretic peptide levels in clinical practice. Eur J Heart Fail 10: 824‐839, 2008.
 76.Marantz PR, Tobin JN, Wassertheil‐Smoller S, Steingart RM, Wexler JP, Budner N, Lense L, Wachspress J. The relationship between left ventricular systolic function and congestive heart failure diagnosed by clinical criteria. Circulation 77: 607‐612, 1988.
 77.Maron BJ. Distinguishing hypertrophic cardiomyopathy from athlete's heart: A clinical problem of increasing magnitude and significance. Heart 91: 1380‐1382, 2005.
 78.Maron BJ, Pelliccia A. The heart of trained athletes: Cardiac remodeling and the risks of sports, including sudden death. Circulation 114: 1633‐1644, 2006.
 79.Martin M, Requero JJ, Castro MG, Coto E, Hernandez E, Carro A, Calvo D, de la Tassa CM. Hypertrophic cardiomyopathy and athlete's heart: A tale of two entities. Eur J Echocardiogr 10: 151‐153, 2009.
 80.McDonagh TA. Asymptomatic left ventricular dysfunction in the community. Curr Cardiol Rep 2: 470‐474, 2000.
 81.McEwan PE, Gray GA, Sherry L, Webb DJ, Kenyon CJ. Differential effects of angiotensin II on cardiac cell proliferation and intramyocardial perivascular fibrosis in vivo. Circulation 98: 2765‐2773, 1998.
 82.McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez‐Sanchez MA, Jaarsma T, Kober L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Ronnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A, ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 33: 1787‐1847, 2012.
 83.Mehta PA, Dubrey SW. High output heart failure. QJM 102: 235‐241, 2009.
 84.Mehta J, Dinerman J, Mehta P, Saldeen TG, Lawson D, Donnelly WH, Wallin R. Neutrophil function in ischemic heart disease. Circulation 79: 549‐556, 1989.
 85.Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart 93: 1137‐1146, 2007.
 86.Movsesian MA, Karimi M, Green K, Jones LR. Ca(2+)‐transporting ATPase, phospholamban, and calsequestrin levels in nonfailing and failing human myocardium. Circulation 90: 653‐657, 1994.
 87.Murphy MP. How mitochondria produce reactive oxygen species. Biochem J 417: 1‐13, 2009.
 88.Nahrendorf M, Pittet MJ, Swirski FK. Monocytes: Protagonists of infarct inflammation and repair after myocardial infarction. Circulation 121: 2437‐2445, 2010.
 89.Naughton MT. Pathophysiology and treatment of Cheyne‐Stokes respiration. Thorax 53: 514‐518, 1998.
 90.Nojiri N, Shimizu T, Funakoshi M, Yamaguchi O, Zhou H, Kawakami S, Ohta Y, Sami M, Tachibana T, Ishikawa H, Kurosawa H, Kahn RC, Otsu K, Shirasawa T. Oxidative stress causes heart failure with impaired mitochondrial respiration. J Biol Chem 281: 33789‐33801, 2006.
 91.O'Connell TD, Jensen BC, Baker AJ, Simpson PC. Cardiac alpha1‐adrenergic receptors: Novel aspects of expression, signaling mechanisms, physiologic function, and clinical importance. Pharmacol Rev 66: 308‐333, 2014.
 92.Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, Oyabu J, Murakawa T, Nakayama H, Nishida K, Akira S, Yamamoto A, Komuro I, Otsu K. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature 485: 251‐255, 2012.
 93.Ouzounian M, Lee DS, Liu PP. Diastolic heart failure: Mechanisms and controversies. Nat Clin Pract Cardiovasc Med 5: 375‐386, 2008.
 94.Ozawa Y, Smith D, Craige E. Origin of the third heart sound. II. Studies in human subjects. Circulation 67: 399‐404, 1983.
 95.Pacher P, Kecskemeti V. Cardiovascular side effects of new antidepressants and antipsychotics: New drugs, old concerns? Curr Pharm Des 10: 2463‐2475, 2004.
 96.Palace VP, Hill MF, Farahmand F, Singal PK. Mobilization of antioxidant vitamin pools and hemodynamic function after myocardial infarction. Circulation 99: 121‐126, 1999.
 97.Park JH, Negishi K, Grimm RA, Popovic Z, Stanton T, Wilkoff BL, Marwick TH. Echocardiographic predictors of reverse remodeling after cardiac resynchronization therapy and subsequent events. Circ Cardiovasc Imaging 6: 864‐872, 2013.
 98.Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, Hawkins PN, Myers RM, Smith MD, Polara A, Cobb AJ, Ley SV, Aquilina JA, Robinson CV, Sharif I, Gray GA, Sabin CA, Jenvey MC, Kolstoe SE, Thompson D, Wood SP. Targeting C‐reactive protein for the treatment of cardiovascular disease. Nature 440: 1217‐1221, 2006.
 99.Periasamy M, Huke S. SERCA pump level is a critical determinant of Ca(2+)homeostasis and cardiac contractility. J Mol Cell Cardiol 33: 1053‐1063, 2001.
 100.Piepoli M. Diagnostic and prognostic indicators in chronic heart failure. Eur Heart J 20: 1367‐1369, 1999.
 101.Pieske B. Reverse remodeling in heart failure – fact or fiction? Eur Heart J Suppl 6: D66‐D78, 2004.
 102.Rathi SS, Dhalla NS. Mechanism of cardioprotective action of TNF‐α in the isolated rat heart. Exp Clin Cardiol 6: 146‐150, 2002.
 103.Reaux A, Iturrioz X, Vazeux G, Fournie‐Zaluski MC, David C, Roques BP, Corvol P, Llorens‐Cortes C. Aminopeptidase A, which generates one of the main effector peptides of the brain renin‐angiotensin system, angiotensin III, has a key role in central control of arterial blood pressure. Biochem Soc Trans 28: 435‐440, 2000.
 104.Richards AM. The renin‐angiotensin‐aldosterone system and the cardiac natriuretic peptides. Heart 76: 36‐44, 1996.
 105.Riegger GA, Liebau G, Kochsiek K. Antidiuretic hormone in congestive heart failure. Am J Med 72: 49‐52, 1982.
 106.Sabbah HN, Sharov VG, Lesch M, Goldstein S. Progression of heart failure: A role for interstitial fibrosis. Mol Cell Biochem 147: 29‐34, 1995.
 107.Schrier RW. Cardiorenal versus renocardiac syndrome: Is there a difference? Nat Clin Pract Nephrol 3: 637, 2007.
 108.Sharma S. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J 18: 1692‐1700, 2004.
 109.Sharma R, Coats AJ, Anker SD. The role of inflammatory mediators in chronic heart failure: Cytokines, nitric oxide, and endothelin‐1. Int J Cardiol 72: 175‐186, 2000.
 110.Sinning D, Kasner M, Westermann D, Schulze K, Schultheiss HP, Tschope C. Increased left ventricular stiffness impairs exercise capacity in patients with heart failure symptoms despite normal left ventricular ejection fraction. Cardiol Res Pract 2011: 692862, 2011.
 111.Slavikova J, Kuncova J, and Topolcan O. Plasma catecholamines and ischemic heart disease. Clin Cardiol 30: 326‐330, 2007.
 112.Smallie T, Ricchetti G, Horwood NJ, Feldmann M, Clark AR, Williams LM. IL‐10 inhibits transcription elongation of the human TNF gene in primary macrophages. J Exp Med 207: 2081‐2088, 2010.
 113.Steinberg SF. Oxidative stress and sarcomeric proteins. Circ Res 112: 393‐405, 2013.
 114.Suskin N MR, Burns RJ, Latini R, Pericak D, Probstfield J, Rouleau JL, Sigouin C, Solymoss CB, Tsuyuki R, White M, Yusuf S. Glucose and insulin abnormalities relate to functional capacity in patients with congestive heart failure. Eur Heart J 16: 1368‐1375, 2000.
 115.Sutton MS, Keane MG. Reverse remodelling in heart failure with cardiac resynchronisation therapy. Heart 93: 167‐171, 2007.
 116.Takimoto E, Kass DA. Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension 49: 241‐248, 2007.
 117.Tang YD, Katz SD. Anemia in chronic heart failure: Prevalence, etiology, clinical correlates, and treatment options. Circulation 113: 2454‐2461, 2006.
 118.Tarzami ST. Chemokines and inflammation in heart disease: Adaptive or maladaptive? Int J Clin Exp Med 4: 74‐80, 2011.
 119.Thibodeau JT, Turer AT, Gualano SK, Ayers CR, Velez‐Martinez M, Mishkin JD, Patel PC, Mammen PP, Markham DW, Levine BD, Drazner MH. Characterization of a novel symptom of advanced heart failure: Bendopnea. JACC Heart failure 2: 24‐31, 2014.
 120.Tousoulis D, Homaei H, Ahmed N, Asimakopoulos G, Zouridakis E, Toutouzas P, Davies GJ. Increased plasma adhesion molecule levels in patients with heart failure who have ischemic heart disease and dilated cardiomyopathy. Am Heart J 141: 277‐280, 2001.
 121.Udelson JE. Heart failure with preserved ejection fraction. Circulation 124: e540‐543, 2011.
 122.Unger T CO, Csikos T, Culman J, Gallinat S, Gohlke P, Höhle S, Meffert S, Stoll M, Stroth U, Zhu YZ. Angiotensin receptors. J Hypertens Suppl 14: S95‐104, 1996.
 123.Ungerer M, Bohm M, Elce JS, Erdmann E, Lohse MJ. Altered expression of beta‐adrenergic receptor kinase and beta 1‐ adrenergic receptors in the failing human heart. Circulation 87: 454‐463, 1993.
 124.van Empel VP, Bertrand AT, Hofstra L, Crijns HJ, Doevendans PA, De Windt LJ. Myocyte apoptosis in heart failure. Cardiovasc Res 67: 21‐29, 2005.
 125.van Empel VP, De Windt LJ. Myocyte hypertrophy and apoptosis: A balancing act. Cardiovasc Res 63: 487‐499, 2004.
 126.Ventura‐Clapier R, Garnier A, Veksler V. Energy metabolism in heart failure. J Physiol 555: 1‐13, 2004.
 127.Ventura‐Clapier R, Garnier A, Veksler V, Joubert F. Bioenergetics of the failing heart. Biochim Biophys Acta 1813: 1360‐1372, 2011.
 128.Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD, Meldrum DR, Dupuis J, Long CS, Rubin LJ, Smart FW, Suzuki YJ, Gladwin M, Denholm EM, Gail DB, National Heart, Lung, and Blood Institute Working Group on Cellular Molecular Mechanisms of Right Heart, Failure. Right ventricular function and failure: Report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation 114: 1883‐1891, 2006.
 129.Waldum B, Stubnova V, Westheim AS, Omland T, Grundtvig M, Os I. Prognostic utility of B‐type natriuretic peptides in patients with heart failure and renal dysfunction. Clin Kidney J 6: 55‐62, 2013.
 130.Weber KT. Cardiac interstitium in health and disease: The fibrillar collagen network. J Am Coll Cardiol 13: 1637‐1652, 1989.
 131.Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium. Fibrosis and renin‐angiotensin‐aldosterone system. Circulation 83: 1849‐1865, 1991.
 132.Weirather J, Hofmann UD, Beyersdof N, Ramos GC, Vogel B, Frey A, Ertl G, Kerkau T, Frantz S. Foxp3 +CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation. Circ Res 115: 55‐67, 2014.
 133.Westermann D, Kasner M, Steendijk P, Spillmann F, Riad A, Weitmann K, Hoffmann W, Poller W, Pauschinger M, Schultheiss HP, Tschope C. Role of left ventricular stiffness in heart failure with normal ejection fraction. Circulation 117: 2051‐2060, 2008.
 134.Winslow RL, Rice J, Jafri S, Marban E, O'Rourke B. Mechanisms of altered excitation‐contraction coupling in canine tachycardia‐induced heart failure, II: Model studies. Circ Res 84: 571‐586, 1999.
 135.Wisneski JA, Bristow JD. Left vetricular stiffness. Ann Rev Med 29: 475‐483, 1978.
 136.Wollert KC, Drexler H. The role of interleukin‐6 in the failing heart. Heart Fail Rev 6: 95‐103, 2001.
 137.Wu X‐Y, Luo AY, Zhou YR, Ren JH. Nacetylcysteine reduces oxidative stress, nuclear factorkappaB activity and cardiomyocyte apoptosis in heart failure. Mol Med Rep 10: 615‐624, 2014.
 138.Yi XP, Gerdes AM, Li F. Myocyte redistribution of GRK2 and GRK5 in hypertensive, heart‐failure‐prone rats. Hypertension 39: 1058‐1063, 2002.
 139.Young ME, Guthrie PH, Razeghi P, Leighton B, Abbasi S, Patil S, Taegtmeyer H. Impaired long chain fatty acid oxidation and contractile dysfunction in the obese Zucker rat heart. Diabetes 51: 2587‐2595, 2002.
 140.Liu Y, Leri A, Li B, Wang X, Cheng W, Kajstura J, Anversa P. Angiotensin II stimulation in vitro induces hypertrophy of normal and postinfarcted ventricular myocytes. Circ Res 82: 1145‐1159, 1998.
 141.Zhang D, Fan GC, Zhou X, Zhao T, Pasha Z, Xu M, Zhu Y, Ashraf M, Wang Y. Over‐expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium. J Mol Cell Cardiol 44: 281‐292, 2008.
 142.Zouggari Y. B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction. Nat Med 19: 1273‐1280, 2013.

Related Articles:

A Modern View of Heart Failure: Practical Applications of Cardiovascular Physiology
Electrophysiology and Excitation‐Contraction Coupling
Systolic and Diastolic Function (Mechanics) of the Intact Heart
Ultrastructure of the Heart

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Edit Tanai, Stefan Frantz. Pathophysiology of Heart Failure. Compr Physiol 2015, 6: 187-214. doi: 10.1002/cphy.c140055