Reverse Cardiac Remodeling: A Marker of Better Prognosis in Heart Failure

José Rosino de Araújo Rocha Reis Filho Juliano Novaes Cardoso Cristina Martins dos Reis Cardoso Antonio Carlos Pereira-Barretto About the authors

Abstracts

In heart failure syndrome, myocardial dysfunction causes an increase in neurohormonal activity, which is an adaptive and compensatory mechanism in response to the reduction in cardiac output. Neurohormonal activity is initially stimulated in an attempt to maintain compensation; however, when it remains increased, it contributes to the intensification of clinical manifestations and myocardial damage. Cardiac remodeling comprises changes in ventricular volume as well as the thickness and shape of the myocardial wall. With optimized treatment, such remodeling can be reversed, causing gradual improvement in cardiac function and consequently improved prognosis.

Heart Failure / therapy; Ventricular Remodeling; Stroke Volume / physiology; Prognosis


Na síndrome da insuficiência cardíaca, a disfunção do miocárdio gera um aumento da atividade neuro-hormonal, que é um mecanismo adaptativo e compensatório em resposta à redução do débito cardíaco. A atividade neuro-hormonal é estimulada inicialmente na tentativa de manter o paciente compensado, mas quando permanece aumentada, contribui para a intensificação das manifestações clínicas e do dano miocárdico. A remodelação cardíaca consiste nas alterações no volume do ventrículo bem como na espessura e forma da parede do miocárdio. Com o tratamento otimizado, pode ocorrer a reversão da remodelação, com melhora gradual da função cardíaca e consequente melhora do prognóstico.

Insuficiência Cardíaca / terapia; Remodelação Ventricular; Volume Sistólico / fisiologia; Prognóstico


Introduction

When cardiac function reduces, neurohormonal activity increases. This important compensatory mechanism is a response to reduced cardiac output and also the main component in syndrome progression and in cardiac remodeling process. Neurohormonal activity is initially stimulated in an attempt to maintain compensation in patients; however, when it remains increased, it contributes to the worsening of clinical manifestations and myocardial damage. Similar to cardiac remodeling, the pathophysiological Frank-Starling mechanism is initially activated in an attempt to maintain compensation; nonetheless, when dilation is persistent, this mechanism results in the progression of myocardial damage and clinical manifestations of heart failure (HF) syndrome1Bocchi EA, Marcondes-Braga FG, Bacal F, Ferraz AS, Albuquerque D, Rodrigues Dde A, et al. Atualização das diretrizes brasileiras de insuficiência cardíaca crônica 2012. Arq Bras Cardiol. 2012;98(supl 1):1-33.

Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348(20):2007-18.

Colucci WS. Molecular and cellular mechanisms of myocardial failure. Am J Cardiol. 1997;80(11A):15L-25L.

Schrier RW, Abraham W. Hormones and hemodynamics in heart failure. N Engl J Med. 1999;341(8):577-85.
- 5Zornoff LA, Cicogna AC, Paiva SA, Spadaro J. Remodelamento e seu impacto na progressão da disfunção ventricular. Rev Soc Cardiol Estado de São Paulo. 2002;12(3):371-8..

Ventricular remodeling is the process by which ventricular size, shape, and function are regulated by mechanical, neurohormonal, and genetic factors. It can be defined by molecular, cellular, and interstitial changes in the myocardium, resulting in alterations in the size, mass, geometry, and function of the heart as a result of a myocardial injury5Zornoff LA, Cicogna AC, Paiva SA, Spadaro J. Remodelamento e seu impacto na progressão da disfunção ventricular. Rev Soc Cardiol Estado de São Paulo. 2002;12(3):371-8..-

Its pathophysiological importance was well-demonstrated in the experimental studies with rats, conducted by the Pfeffer and Pfeffer (initially, Marc and Janice). In the myocardial infarction model, they demonstrated that mortality in rats was strongly associated with the degree of cardiac dilation and reduced ejection fraction6Pfeffer MA, Pfeffer JM. Ventricular enlargement and reduced ventricular after myocardial infarction. Circulation. 1987;75(5 Pt 2):IV93-7. , 7Pfeffer MA, Pfeffer JM, Steinberg CR, Finn P. Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril. Circulation. 1985;72(2):406-12.. Infarcted rats with greater cardiac dilation and lower ejection fraction had poorer outcomes than those with less involvement6Pfeffer MA, Pfeffer JM. Ventricular enlargement and reduced ventricular after myocardial infarction. Circulation. 1987;75(5 Pt 2):IV93-7. , 7Pfeffer MA, Pfeffer JM, Steinberg CR, Finn P. Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril. Circulation. 1985;72(2):406-12.. The postinfarction period is conventionally divided into two phases: early (up to 72 h) and late (after 72 h)8Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction. Pathophysiology and therapy. Circulation. 2000;101(25):2981-8.. Initial remodeling involves the expansion of the infarcted area, which can result in ventricular rupture or aneurysm formation8Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction. Pathophysiology and therapy. Circulation. 2000;101(25):2981-8.. In the early stage, after a moderate to large infarction, the ventricular cavity increases in size due to expansion or to stretching and thinning of the infarcted segment8Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction. Pathophysiology and therapy. Circulation. 2000;101(25):2981-8. , 9Patten RD, Udelson JE, Konstam MA. Ventricular remodeling and its prevention in the treatment of heart failure. Curr Opin Cardiol. 1998;13(3):162-7.. Late remodeling comprises the ventricle as a whole and is associated with time-dependent dilation, ventricle shape distortion, and ventricular wall hypertrophy, which can continue for months to years8Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction. Pathophysiology and therapy. Circulation. 2000;101(25):2981-8. , 9Patten RD, Udelson JE, Konstam MA. Ventricular remodeling and its prevention in the treatment of heart failure. Curr Opin Cardiol. 1998;13(3):162-7.. Pfeffer and Pfeffer6Pfeffer MA, Pfeffer JM. Ventricular enlargement and reduced ventricular after myocardial infarction. Circulation. 1987;75(5 Pt 2):IV93-7. observed that rats with small infarctions (infarcted area < 20%) did not develop cardiac dilation and rats with moderate infarction (between 20% and 40% of infarcted area) presented progressive dilatation occurring in the noninfarcted area. The pathophysiological importance of cardiac remodeling and its role in HF prognosis have been expanded with the results of studies on ACE inhibitors in the treatment of infarcted rats. These studies have demonstrated that these drugs prevent cardiac remodeling and, in some cases, promote its reversal7Pfeffer MA, Pfeffer JM, Steinberg CR, Finn P. Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril. Circulation. 1985;72(2):406-12.. Rats treated with ACE inhibitors presenting dilation prevention or reverse remodeling had better prognosis than those that did not6Pfeffer MA, Pfeffer JM. Ventricular enlargement and reduced ventricular after myocardial infarction. Circulation. 1987;75(5 Pt 2):IV93-7. , 7Pfeffer MA, Pfeffer JM, Steinberg CR, Finn P. Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril. Circulation. 1985;72(2):406-12.. It was observed that the benefit of treatment was more significant in rats with moderate infarction7Pfeffer MA, Pfeffer JM, Steinberg CR, Finn P. Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril. Circulation. 1985;72(2):406-12..

In a subsequent study, Pfeffer et al.1010 Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial (SAVE). N Engl J Med. 1992;327(10):669-77.coordinated the SAVE study; they demonstrated that the concept of remodeling also applied to humans and that treatment with ACE inhibitors modified the natural course of myocardial infarction and myocardial infarction-associated HF. Patients with myocardial infarction and ejection fraction of <40% treated with captopril exhibited approximately 40% reduction in cardiovascular events1010 Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial (SAVE). N Engl J Med. 1992;327(10):669-77..

Other studies have demonstrated that this knowledge regarding cardiac remodeling could also be applied to patients with cardiac dilatation without myocardial infarction. Data from the Framingham study clearly documented that cardiac dilation was associated with HF1111 Vasan RS, Larson MG, Benjamin EJ, Evans JC, Levy D. Left ventricular dilatation and the risk of congestive heart failure in people without myocardial infarction. N Engl J Med. 1997;336(19):1350-5.. Patients with cardiac dilation had a 1.47-fold risk of developing heart failure compared with those without dilation1111 Vasan RS, Larson MG, Benjamin EJ, Evans JC, Levy D. Left ventricular dilatation and the risk of congestive heart failure in people without myocardial infarction. N Engl J Med. 1997;336(19):1350-5..

The role of cardiac remodeling has been highlighted in studies on HF, confirming these findings. In this context, the Val-HeFT study demonstrated that patients with the highest ventricular volumes and lowest baseline left ventricular ejection fractions presented higher mortality1212 Wong M, Staszewsky L, Latini R, Barlera S, Glazer R, Aknay N, et al. Severity of left ventricular remodeling defines outcomes and response to therapy in heart failure Val-HeFT echocardiographic data. J Am Coll Cardiol. 2004;43(11):2022-7..

Reverse ventricular remodeling

Cardiac dilation is identified as an important marker of poor prognosis. Conversely, its reversal is associated with improved prognosis. Several studies have demonstrated that drugs or procedures, which modify ventricular remodeling, preventing or delaying cardiac dilation, are associated with improved outcomes. Not all drugs used in the treatment of HF influence cardiac remodeling. Animal studies in the postinfarction period have shown that beta-blockers, aldosterone blockers, and renin–angiotensin system inhibitors prevented cardiac dilation, whereas hydralazine and digitalis did not. Thus, clinical and experimental evidence suggests that the renin–angiotensin–aldosterone system and sympathetic nervous system play an important role in the process.

ACE inhibitors, as demonstrated in the SOLVD studies, reduced the rate of cardiac dilation and, in initial forms, promoted regression in cardiac dilation1010 Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial (SAVE). N Engl J Med. 1992;327(10):669-77. , 1313 Sabbah HN, Shimoyama H, Kono T, Gupta RC, Sharov VG, Scicli G, et al. Effects of long-term monotherapy with enalapril, metoprolol, and digoxin on the progression of left ventricular dysfunction and dilatation in dogs with reduced ejection fraction. Circulation. 1994;89(6):2852-9. , 1414 Konstam MA, Pattern RD, Thomas I, Ramahi T, La Bresh K, Goldman S, et al. Effects of losartan and captopril on left ventricular volumes in elderly patients with heart failure: results of the ELITE ventricular function sub study. Am Heart J. 2000;139(6):1081-7..

Studies on angiotensin II receptor blockers demonstrated that these drugs also have a beneficial effect on ventricular remodeling. In the ELITE study, both patients receiving ACE inhibitors and those receiving angiotensin II AT1 receptor-antagonists (ARB) presented the same trend regarding ventricular remodeling, with prevention of cardiac dilation. There were no differences in response between the ACE inhibitor and ARB treatments analyzed in that study1414 Konstam MA, Pattern RD, Thomas I, Ramahi T, La Bresh K, Goldman S, et al. Effects of losartan and captopril on left ventricular volumes in elderly patients with heart failure: results of the ELITE ventricular function sub study. Am Heart J. 2000;139(6):1081-7..

Cardiac dilation is not reversed in all patients with HF and ventricular dysfunction. In patients with lesser involvement, reversal is not generally observed; it is more frequently identified in cases of moderate to intense involvement, with greater magnitude in the former7Pfeffer MA, Pfeffer JM, Steinberg CR, Finn P. Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril. Circulation. 1985;72(2):406-12. , 1010 Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial (SAVE). N Engl J Med. 1992;327(10):669-77. , 1212 Wong M, Staszewsky L, Latini R, Barlera S, Glazer R, Aknay N, et al. Severity of left ventricular remodeling defines outcomes and response to therapy in heart failure Val-HeFT echocardiographic data. J Am Coll Cardiol. 2004;43(11):2022-7. , 1414 Konstam MA, Pattern RD, Thomas I, Ramahi T, La Bresh K, Goldman S, et al. Effects of losartan and captopril on left ventricular volumes in elderly patients with heart failure: results of the ELITE ventricular function sub study. Am Heart J. 2000;139(6):1081-7.. Studies have shown reversal of cardiac dilation in approximately 30%–60% of the cases treated with neurohormonal blockers.

In a study of outpatients over 70 years of age, Cioffi et al.1515 Cioffi G, Stefenelli C, Tarantini L, Opasich C. Prevalence, predictors and prognostic implications of improvement in left ventricular systolic function and clinical status in patients > 70 years of age with recently diagnosed sustolic heart failure. Am J Cardiol. 2003;92(2):166-72. observed an improvement in the ejection fraction in 36% during a mean follow-up of 17 months. Predictors for this improvement were absence of diabetes, history of hypertension, and treatment with beta-blockers; treatment with beta-blockers increased the chance of reversal by 3.4 times1515 Cioffi G, Stefenelli C, Tarantini L, Opasich C. Prevalence, predictors and prognostic implications of improvement in left ventricular systolic function and clinical status in patients > 70 years of age with recently diagnosed sustolic heart failure. Am J Cardiol. 2003;92(2):166-72.. In the V-HeFT I and II studies, reverse remodeling was also observed both in the group treated with hydralazine and nitrate and that treated with enalapril1616 Cintron G, Johson G, Francis G, Cobb F, Cohn JN. Prognostic significance of serial changes in left ventricular ejection fraction in patients with congestive heart failure. Circulation. 1993;87(6 Suppl):VI17-23.. A 5-unit increase in ejection fraction was the best predictor of mortality among the studied variables1616 Cintron G, Johson G, Francis G, Cobb F, Cohn JN. Prognostic significance of serial changes in left ventricular ejection fraction in patients with congestive heart failure. Circulation. 1993;87(6 Suppl):VI17-23.. Approximately 30% of the patients had an increase in ejection fraction greater than 5 units; 50% of these presented an increase of more than 10 units.

The improvement in cardiac remodeling has also been observed. In the IMPROVE-HF registry, which examined 3,994 patients hospitalized for compensation, ejection fraction increased over 10% in 28.6% of patients1717 Wilcox JE, Fonarow GC, Yancy CW, Albert NM, Curtis AB, Heywood JT, et al. Factors associated with improvement in ejection fraction in clinical practice among patients with heart failure: findings from IMPROVE-HF. Am Heart J. 2012;163(1):49-56.e2..

Increased adrenergic activity appears to have a greater role in ventricular remodeling. Studies have demonstrated that beta-blockers promoted a more intense reversal of cardiac dilation than ACE inhibitors (Figure 1). ACE inhibitors prevent ventricular dilation and promote small increases in ejection fraction, but reduction in ventricular diameter and increase in ejection fraction are more significant with beta-blockers1313 Sabbah HN, Shimoyama H, Kono T, Gupta RC, Sharov VG, Scicli G, et al. Effects of long-term monotherapy with enalapril, metoprolol, and digoxin on the progression of left ventricular dysfunction and dilatation in dogs with reduced ejection fraction. Circulation. 1994;89(6):2852-9. , 1818 Hoshikawa E, Matsumura Y, Kubo T, Okawa M, Yamasaki N, Kitaoka H, et al. Effect of left ventricular reverse remodeling on long-term prognosis after therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and betablockers in patients with idiopathic dilated cardiomyopathy. Am J Cardiol. 2011;107(7):1065-70..

Figure 1
ACE inhibitors prevent cardiac dilation and beta-blockers reverse it. Coh JN et al JACC 2000; 35: 569-82.

The current literature documents that adrenergic activity actually plays an important role in ventricular remodeling, greater than that of the renin–angiotensin system, at least in the most symptomatic forms of the disease. Conversely, the adrenergic system may not be greatly stimulated in the initial phases of ventricular dysfunction because blockage of this system in asymptomatic forms of ventricular dysfunction does not result in a very significant reduction in mortality, as demonstrated in the CAPRICORN study1919 Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left ventricular dysfunction: the CAPRICORN randomized trial. Lancet. 2001;357(9266):1385-90..

Prognosis and remodeling

There is a growing body of evidence on the importance of reverse ventricular remodeling in HF prognosis1919 Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left ventricular dysfunction: the CAPRICORN randomized trial. Lancet. 2001;357(9266):1385-90.

20 Steimle AE, Stevenson LW, Fonarow GC, Hamilton MA, Moriguchi JD. Prediction of improvement in recent onset cardiomyopathy after referral heart transplantation. J Am Coll Cardiol. 1994;23(3):553-9.

21 Kawai K, Takaoka H, Hata K, Yokota Y, Yokoyama M. Prevalence, predictors, and prognosis of reversal of maladaptive remodeling with intensive medical therapy in idiopathic dilated cardiomyopathy. Am J Cardiol. 1999;84(6):671-6.

22 Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger RE, et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation. 1996;94(11):2807-16.
- 2323 Levine TB, Levine AB, Keteyian SJ, Narins B, Lesch M. Reverse remodeling in heart failure with intensification of vasodilator therapy. Clin Cardiol. 1997;20(8):697-702.. Patients who present regression of ventricular dilation or increased ejection fraction after treatment have better quality of life.

At follow-up, Cioffi et al.1515 Cioffi G, Stefenelli C, Tarantini L, Opasich C. Prevalence, predictors and prognostic implications of improvement in left ventricular systolic function and clinical status in patients > 70 years of age with recently diagnosed sustolic heart failure. Am J Cardiol. 2003;92(2):166-72. demonstrated that patients with reverse cardiac remodeling had lower mortality (3%) compared with those who did not present reversal (22%). In the V-HeFT I study, mortality in the first year of follow-up for patients who had a reduction in ejection fraction greater than 6 units, an alteration in ejection fraction ranging between −5 and 5 units, and those who had an increase in ejection fraction greater than five units was 29%, 16%, and 6%, respectively1616 Cintron G, Johson G, Francis G, Cobb F, Cohn JN. Prognostic significance of serial changes in left ventricular ejection fraction in patients with congestive heart failure. Circulation. 1993;87(6 Suppl):VI17-23..

Hoshikawa et al.1818 Hoshikawa E, Matsumura Y, Kubo T, Okawa M, Yamasaki N, Kitaoka H, et al. Effect of left ventricular reverse remodeling on long-term prognosis after therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and betablockers in patients with idiopathic dilated cardiomyopathy. Am J Cardiol. 2011;107(7):1065-70. observed that prognosis is related to the reversal of cardiac dilation. They divided their patients into three groups: those with full reverse cardiac remodeling, with LV diameter < 55 mm and Delta D fraction > 25%; those with partial reversal; and those who did not present reversal. The authors observed that all patients with no reversal of cardiac dilation died during the follow-up, which lasted an average of 5 years1818 Hoshikawa E, Matsumura Y, Kubo T, Okawa M, Yamasaki N, Kitaoka H, et al. Effect of left ventricular reverse remodeling on long-term prognosis after therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and betablockers in patients with idiopathic dilated cardiomyopathy. Am J Cardiol. 2011;107(7):1065-70.. All patients who presented some reversal survived. In that study population, all patients were treated with neurohormonal blockers; 78% showed a reversal of cardiac dilatation and, of these, 57% showed complete reversal1818 Hoshikawa E, Matsumura Y, Kubo T, Okawa M, Yamasaki N, Kitaoka H, et al. Effect of left ventricular reverse remodeling on long-term prognosis after therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and betablockers in patients with idiopathic dilated cardiomyopathy. Am J Cardiol. 2011;107(7):1065-70..

This same group reassessed their patients. Furthermore, Matsumura et al.2424 Matsumura Y, Hoshikawa-Nagai E, Kubo T, Yamasaki N, Furuno T, Kitaoka H, et al. Left ventricular reverse remodeling in long-term (>12 years) survivors with idiopathic dilated cardiomyopathy. Am J Cardiol. 2013;111(1):106-10. demonstrated the role of reverse remodeling in long-term prognosis. This study revealed that in 12 years of follow-up, all patients who had regression of cardiac dilation survived; however, those presenting increased dilation died or required transplantation. In this population of patients with dilated cardiomyopathy, it was observed that 35.6% of patients had some reversal; 37% of these presented normal diameters and ejection fractions2424 Matsumura Y, Hoshikawa-Nagai E, Kubo T, Yamasaki N, Furuno T, Kitaoka H, et al. Left ventricular reverse remodeling in long-term (>12 years) survivors with idiopathic dilated cardiomyopathy. Am J Cardiol. 2013;111(1):106-10.. All patients with some reversal remained alive at the end of 12 years, demonstrating that even small reversals indicate a good response to treatment2424 Matsumura Y, Hoshikawa-Nagai E, Kubo T, Yamasaki N, Furuno T, Kitaoka H, et al. Left ventricular reverse remodeling in long-term (>12 years) survivors with idiopathic dilated cardiomyopathy. Am J Cardiol. 2013;111(1):106-10..

In addition to the analysis of clinical trials and small group studies, reverse cardiac remodeling was assessed in a meta‑analysis involving 69,766 patients in 30 randomized trials2525 Kramer DG, Trikalinos TA, Kent DM, Antonopoulos GV, Konstam MA, Udelson JE. Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction: a Meta-Analytic approach. J Am Coll Cardiol. 2010;56(5):392-406., which showed a strong relationship between improved ejection fraction and reduced mortality. Overall, mortality significantly decreased by 49% in patients presenting improved ejection fraction compared with those who did not2525 Kramer DG, Trikalinos TA, Kent DM, Antonopoulos GV, Konstam MA, Udelson JE. Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction: a Meta-Analytic approach. J Am Coll Cardiol. 2010;56(5):392-406.. Based on the regression analysis, a 5% increase in mean ejection fraction corresponded to a relative reduction of 14% in mortality (OR, 0.86; 95% CI, 0.77–0.96; p = 0.013). For each 5% absolute increase in ejection fraction, patients who presented reversals had a 4.9-fold higher chance of not dying compared with those showing no reversal. Similar results were described for the change in left ventricular volume2525 Kramer DG, Trikalinos TA, Kent DM, Antonopoulos GV, Konstam MA, Udelson JE. Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction: a Meta-Analytic approach. J Am Coll Cardiol. 2010;56(5):392-406..

Treatment and reverse remodeling

Because prognosis is better in patients with reversed cardiac dysfunction, at least partially, reversal should be considered a primary treatment goal. Patients not presenting this reversal should have their treatment regimen reassessed. In the absence of reversal, they should be more carefully followed up because they are at risk for a poorer outcome. Effective treatment should reverse cardiac remodeling2626 Oliveira GH, Mukerji S, Hernandez AV, Qattan MY, Banchs J, Durand JB, et al. Incidence, predictors, and impact on survival of left ventricular systolic dysfunction and recovery in advanced cancer patients. Am J Cardiol. 2014;113(11):1893-8.

27 Kramer DG, Trikalinos TA, Kent DM, Antonopoulos GV, Konstam MA, Udelson JE. Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction. J Am Coll Cardiol. 2010;56(5):392-406.
- 2828 de Groote P, Delour P, Mouquet F, Lamblin N, Dagorn J, Hennebert O, et al. The effects of b-blockers in patients with stable chronic heart failure: predictors of left ventricular ejection fraction improvement and impact on prognosis. Am Heart J. 2007;154(3):589-95.. Notably, all effective drugs and procedures, such as cardiac resynchronization, promote the reversal of cardiac dilation1818 Hoshikawa E, Matsumura Y, Kubo T, Okawa M, Yamasaki N, Kitaoka H, et al. Effect of left ventricular reverse remodeling on long-term prognosis after therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and betablockers in patients with idiopathic dilated cardiomyopathy. Am J Cardiol. 2011;107(7):1065-70. , 2929 Cioffi G, Stefenelli C, Tarantini L, Opasich C. Chronic left ventricular failure in the community: prevalence, prognosis and predictors of the complete clinical recovery with return of cardiac size and function to normal in patients undergoing optimal therapy. J Card Fail. 2004;10(3):250-7.

30 Konstam MA, Rousseau MF, Kronemberg MW, Udelson JE, Melin J, Stewart D, et al. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dysfunction in patients with heart failure. Circulation. 1992;86(2):431-8.

31 Chan AK, Sanderson JE, Wang T, Lam W, Yip G, Wang M, et al. Aldosterone receptor antagonism induces reverse remodeling when added to angiotensin receptor blockade in chronic heart failure. J Am Coll Cardiol. 2007;50(7):591-6.
- 3232 Cioffi G, Tarantini L, de Feo S, Pulignano G, Del Sindaco D, Stefenelli C, et al. Pharmacological left ventricular reverse remodeling in elderly patients receiving optimal therapy for chronic heart failure. Eur J Heart Fail. 2005;7(6):1040-8.. Nonreversal may be a sign that the doses of prescribed medications are inadequate or that the disease severity is high, resulting in a failure to obtain desired response to a proposed treatment.

In the treatment of HF, dosage is extremely important. Reverse remodeling is often not observed because the treatment drugs are administered at low doses. The importance of dosage can be observed in the FAST–Carvedilol study3333 Melo D, Pereira-Barretto AC, Ramires JA. The impact of rapid use of beta-blockers on ventricular remodeling and mortality in end-stage heart failure. J Am Coll Cardiol. 2011;57(Suppl A):17.. In this study, half of patients were discharged after using this drug at a dose of 3.125 mg or 6.25 mg twice daily, whereas the dosage for the remaining was rapidly increased during hospitalization and was the highest tolerated dose during discharge. At the outpatient clinic, dosage of carvedilol was not increased by the physicians for various reasons; this was most frequently because of borderline blood pressure. Thus, the average carvedilol dose was 6.99 mg/day in the control group and 16.19 mg/day in the intervention group. At follow-up, the intervention group presented a reversal of cardiac dilation; this reduction was already evident at 3 months of treatment (Figure 2)3333 Melo D, Pereira-Barretto AC, Ramires JA. The impact of rapid use of beta-blockers on ventricular remodeling and mortality in end-stage heart failure. J Am Coll Cardiol. 2011;57(Suppl A):17.. The group treated with low doses did not present reversal. At follow-up, in the first year, the survival rate was 43.5% in the control group versus 65.2% in the intervention group. The data draw attention to the importance of dosage both in reversing cardiac dilatation and reducing mortality and show that both are probably interconnected3333 Melo D, Pereira-Barretto AC, Ramires JA. The impact of rapid use of beta-blockers on ventricular remodeling and mortality in end-stage heart failure. J Am Coll Cardiol. 2011;57(Suppl A):17..

Figure 2
Beta-blockers used at the correct dosage reverses cardiac dilation; this reduction is already evident at 3 months of treatment. Melo D et al. JACC 2011; 57 (supl A): 17.

The authors of the present study have used these guidelines in clinical practice, increasing the dosage (particularly for beta-blockers) in patients who did not present reverse cardiac remodeling, thereby achieving a reversal of the dilation not obtained with the usual dosage. In patients whose heart rate is consistently above 70 bpm during optimized treatment, ivabradine has been effective in reversing cardiac dilation3434 Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, Dubost-Brama A, et al; SHIFT investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized placebo-controlled study. Lancet. 2010;376(9744):875-85. Erratum in: Lancet. 2010;376(9757):1988..

Conclusion

Cardiac dilation is a marker of poorer prognosis in patients with HF. The drugs used to treat HF, particularly beta-blockers, ACE inhibitors, and ARBs, promote reverse remodeling. Patients who present reverse remodeling during treatment have better outcomes and lower mortality than those who do not present it.

  • Sources of Funding
    There were no external funding sources for this study.
  • Study Association
    This study is not associated with any thesis or dissertation work.

References

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    Bocchi EA, Marcondes-Braga FG, Bacal F, Ferraz AS, Albuquerque D, Rodrigues Dde A, et al. Atualização das diretrizes brasileiras de insuficiência cardíaca crônica 2012. Arq Bras Cardiol. 2012;98(supl 1):1-33.
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    Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348(20):2007-18.
  • 3
    Colucci WS. Molecular and cellular mechanisms of myocardial failure. Am J Cardiol. 1997;80(11A):15L-25L.
  • 4
    Schrier RW, Abraham W. Hormones and hemodynamics in heart failure. N Engl J Med. 1999;341(8):577-85.
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    Zornoff LA, Cicogna AC, Paiva SA, Spadaro J. Remodelamento e seu impacto na progressão da disfunção ventricular. Rev Soc Cardiol Estado de São Paulo. 2002;12(3):371-8.
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    Pfeffer MA, Pfeffer JM. Ventricular enlargement and reduced ventricular after myocardial infarction. Circulation. 1987;75(5 Pt 2):IV93-7.
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    Pfeffer MA, Pfeffer JM, Steinberg CR, Finn P. Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril. Circulation. 1985;72(2):406-12.
  • 8
    Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction. Pathophysiology and therapy. Circulation. 2000;101(25):2981-8.
  • 9
    Patten RD, Udelson JE, Konstam MA. Ventricular remodeling and its prevention in the treatment of heart failure. Curr Opin Cardiol. 1998;13(3):162-7.
  • 10
    Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial (SAVE). N Engl J Med. 1992;327(10):669-77.
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Publication Dates

  • Publication in this collection
    27 Mar 2015
  • Date of issue
    June 2015

History

  • Received
    18 Oct 2014
  • Reviewed
    05 Jan 2015
  • Accepted
    07 Jan 2015
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