- Email: [email protected]
Ventricular Remodeling
Journal of the American College of Cardiology © 2011 by the American College of Cardiology Foundation Published by Elsevier Inc.
EDITORIAL COMMENT
Ventricular Remodeling Fundamental to the Progression (and Regression) of Heart Failure* James E. Udelson, MD, Marvin A. Konstam, MD Boston, Massachusetts
The ability of the left ventricle to adapt its structure and function to prevailing conditions has long fascinated clinicians and investigators. The left ventricle has a truly remarkable plasticity, evident from stresses both physiologic and pathologic (1). The physiologic stress of high-level athletic endeavors leads to chamber dilation and a degree of hypertrophy (2), whereas more pathologic stress such as that associated with volume overload from valvular regurgitation can lead to a dramatic increase in cavity size (3). Almost as remarkable is that these processes may be reversible when the stress is removed or attenuated, with the left ventricle capable of restoration of normal size and shape. As an example, it has been well documented that after aortic valve replacement for aortic regurgitation, if performed within a certain time window, the left ventricle can demonstrate substantial reversal of the dilation over months of follow-up (4). Indeed, the concept of potential reversibility of this adaptive process underlies recommendations for “deconditioning” when a question arises about whether a hypertrophied left ventricle is secondary to athletic activity, in which case the hypertrophy should regress or is a sign of hypertrophic cardiomyopathy, in which case, it should not (5). See page 1468
Fundamental work on the changes in left ventricular (LV) structure and function after the pathologic insult of a myocardial infarction (MI) was reported by Pfeffer et al. (6) many years ago. It is thought that the process of post-MI remodeling, with chamber dilation and hypertrophy and interstitial changes in remote myocardium, is initially adaptive in an attempt to maintain stroke volume in the face of the loss of contractile elements, but becomes maladaptive
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Division of Cardiology and CardioVascular Center, Tufts Medical Center and Tufts University School of Medicine, Boston, Massachusetts. Dr. Udelson has received research funding from/served as a consultant to Otsuka, Pfizer, and Medtronic. Dr. Konstam has received moderate support from Otsuka, Pfizer, Johnson & Johnson, and Merck.
Vol. 57, No. 13, 2011 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2011.01.009
over time, driven by neurohormonal activation. The initial observations on the sequence of structural changes after an infarct in an animal model were followed soon thereafter by the demonstration that these changes were associated with the risk of mortality after the MI (7). Human studies subsequently documented many of the same findings, and over the years, the knowledge in this area has become more refined. Several studies documented that measures of LV size and function early after an MI were highly prognostic for outcomes (8,9). Moreover, particular patterns of remodeling appear to confer distinct levels of risk because post-MI patients with a pattern of concentric hypertrophy appear to be at the highest risk, as seen in an analysis from patients enrolled in a clinical trial (10). Beyond the post-MI setting, similar concepts have been demonstrated among patients with heart failure and reduced systolic function. Measures of LV size or function at 1 time point identify a group of patients at increased risk of a more unfavorable outcome (11). Longitudinal studies further illuminate the relationship between LV remodeling and outcomes. Of great interest was a secondary analysis of the SAVE (Survival and Ventricular Enlargement) trial. In this study, the change in measures of end-systolic and -diastolic volumes from baseline to a follow-up time point was associated with an unfavorable longer term course (12). This relationship persisted after adjustment for treatment assignment, that is, the data suggested that patients who remodeled while taking the angiotensin-converting enzyme inhibitor captopril were at higher risk than those taking placebo who did not remodel. The understanding that one of the main drivers of the remodeling process, either in the post-MI setting or in chronic heart failure, was neurohormonal activation, led to intense interest in and investigation of the effects of neurohormonal blockade on the processes and mechanisms of remodeling and of course also the impact of neurohormonal blockade on patient outcomes. Captopril was shown to attenuate a progressive increase in LV volumes over a year of therapy after an anterior MI (13), and enalapril was shown to reduce volumes relative to placebo over a 3-year follow-up in patients with chronic heart failure and systolic dysfunction (14). Subsequently, large randomized, placebocontrolled trials demonstrated favorable effects on longterm mortality of captopril in patients with post-MI LV dysfunction (15), and for enalapril in patients with chronic heart failure and systolic dysfunction who had mild to moderate symptoms (16). The findings that angiotensinconverting enzyme inhibitors ameliorated or reversed the remodeling process and also favorably affected mortality led to the attractive supposition that LV remodeling was a fundamental feature of the post-MI or chronic heart failure disease process and its progression and that an intervention’s effect on remodeling may act as a “surrogate” for the intervention’s potential impact on outcome.
1478
Udelson and Konstam Ventricular Remodeling
In an analysis of the existing literature on the effects of therapeutic interventions on LV remodeling and also on mortality in patients with LV dysfunction, we recently showed that there is a positive correlation between an intervention’s effect on LV volumes and function and its effect on mortality (17). The relationship does not rise to the level where remodeling benefit may be considered a surrogate for survival, as has been strictly defined for trials or for regulatory considerations. However, the data suggested that an intervention’s short-term effect on LV remodeling could be used as a probability signal for longer term therapeutic effects on outcomes, and a modest benefit on survival may be considered more conclusive when accompanied by a remodeling benefit. Recent examples of a “disconnect” in this relationship include the effect of aldosterone antagonists in patients with chronic heart failure and systolic dysfunction and mild to moderate symptoms. A trial of 9 months of therapy with eplerenone showed no effect on remodeling (18), whereas favorable outcome effects were seen in the recently published EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial (19). These data support the concept that the progression of the disease state in the post-MI setting or in chronic heart failure is unlikely to be characterized by a single parameter such as remodeling and that outcome predictions may best incorporate multiple elements. An important limitation of the literature included in our recent analysis as well as other observational data is that the studies generally report the effect of a single intervention on remodeling, whether it is a drug or a device, such as cardiac resynchronization therapy. Evidence-based treatment of patients with LV dysfunction is, of course, based on multiple therapeutic approaches used together over time to optimize outcomes. How does such a polytherapeutic approach affect the remodeling process, and what are the implications for outcomes? Into this void of information steps the study by Merlo et al. (20), reported in this issue of the Journal. At a tertiary referral center in Trieste, Italy, 361 patients with nonischemic dilated cardiomyopathy were enrolled over 10 years and were treated according to prevalent guidelines. Echocardiography was performed at baseline and again at a mean of approximately 2 years after the initial study. All patients were followed for at least 10 years, a major strength of this study. The investigators examined the relationship between baseline variables and prognosis, as well as the relationship between the change in selected variables (including the remodeling data) and outcomes, from the time point of re-evaluation onward. Reverse remodeling was arbitrarily defined as an LV ejection fraction (EF) increase of ⱖ10 EF units or an LVEF of ⱖ50% and a decrease in indexed LV end-diastolic diameter of ⱖ10% or of ⱖ33 mm/m2. Approximately one-third of the patients met this definition. Of interest was that 1 of the predictors of reverse remodeling was higher baseline systolic blood pressure, suggesting that
JACC Vol. 57, No. 13, 2011 March 29, 2011:1477–9
1 mechanism of remodeling related to a decrease in load by more intense treatment of blood pressure. Reverse remodeling was identified as an independent predictor of a composite outcome end point over the subsequent long-term follow-up after the second analysis of LV size and function. The novelty of the study revolves around this point—that the occurrence of favorable reverse remodeling in response to therapy identifies a subpopulation of patients who will have a more favorable course over many years. The strengths of the study include the seemingly homogeneous evidence-based treatment strategy at a tertiary center and the length of the follow-up, much longer than most studies. There are also some limitations. The composite end point used by Merlo et al. (20) includes the occurrence of heart transplantation, which is an event that certainly incorporates an unfavorable natural history, but is influenced by many other variables. In the multivariable model that included the occurrence of reverse remodeling at the follow-up time point, other variables were identified that were associated with less favorable outcomes, including New York Heart Association functional classes III to IV and moderate to severe mitral regurgitation, both analyzed at the follow-up visit at approximately 2 years out. The latter variables may represent patients with advanced disease at baseline who did not change or patients in whom those features developed over the first 2 years of follow-up. Thus, the model is complex and included variables that reflect a change from baseline (LV remodeling), variables that reflect measures at 1 time point (baseline), and variables that reflect measures at a second time point (the New York Heart Association functional class and severity of mitral regurgitation). Perhaps more straightforward would have been to analyze all variables by the degree of change from baseline to follow-up and to have included other candidates that may provide prognostic information, such as changes in renal function. The patient population in this study included only those with nonischemic cardiomyopathy who, in most studies, tend to have more robust responses to therapies affecting remodeling (21). Thus, how these results and their implications apply to patients with ischemic cardiomyopathy is not clear. Nonetheless, there are some important messages. The data further reinforce the concept that reversal of LV remodeling in response to therapeutic intervention identifies a group of patients with heart failure and LV dysfunction who will have a more favorable long-term course. In addition, the data suggest that risk stratification in patients with heart failure is a moving target. Baseline variables on an initial visit can provide a prognostic snapshot, but many are subject to change during contemporary therapy, and significant reclassification of risk may occur. Larger databases with analysis of changes in key variables may allow creation of prognostic models that document the magnitude of reclassification.
Udelson and Konstam Ventricular Remodeling
JACC Vol. 57, No. 13, 2011 March 29, 2011:1477–9
Finally, the results also demonstrate once again the remarkable ability of the left ventricle to adapt (and readapt) to prevailing conditions and that progression and regression of the processes of LV remodeling are indeed fundamental to the disease course of patients with heart failure and systolic LV dysfunction. Reprint requests and correspondence: Dr. James E. Udelson, Tufts Medical Center, Box 70, 800 Washington Street, Boston, Massachusetts 02111. E-mail: [email protected].
REFERENCES
1. Hill JA, Olson EN. Cardiac plasticity. N Engl J Med 2008;358:1370–80. 2. Maron BJ, Pelliccia A. The heart of trained athletes: cardiac remodeling and the risks of sports, including sudden death. Circulation 2006;114:1633– 44. 3. Otto CM, Bonow RO. Valvular heart disease. In: Libby P, Bonow RO, Mann D, Zipes DP, Braunwald E, editors. Braunwald’s Heart Disease. 8th edition. Philadelphia, PA: Saunders Elsevier, 2007;1625– 712. 4. Bonow RO, Dodd JT, Maron BJ, et al. Long-term serial changes in left ventricular function and reversal of ventricular dilatation after valve replacement for aortic regurgitation. Circulation 1988;78:1108 –20. 5. Maron BJ, Pelliccia A, Spataro A, Granata M. Reduction in left ventricular wall thickness after deconditioning in highly trained Olympic athletes. Br Heart J 1993;69:125– 8. 6. Pfeffer MA, Pfeffer JM, Fishbein MC, et al. Myocardial infarct size and ventricular function in rats. Circ Res 1979;44:503–12. 7. Pfeffer MA, Pfeffer JM, Steinberg C, Finn P. Survival after an experimental myocardial infarction: beneficial effects of long term therapy with captopril. Circulation 1985;72:406 –12. 8. White HD, Norris RM, Brown MA, Brandt PW, Whitlock RM, Wild CJ. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1987;76:44 –51. 9. Migrino RQ, Young JB, Ellis SG, et al., for the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-I Angiographic Investigators. End-systolic volume index at 90 to 180 minutes into reperfusion therapy for acute myocardial infarction is a strong predictor of early and late mortality. Circulation 1997;96:116 –21. 10. Wong M, Staszewsky L, Latini R, et al. Severity of left ventricular remodeling defines outcomes and response to therapy in heart failure:
11. 12.
13. 14.
15.
16. 17.
18.
19. 20.
21.
1479
Valsartan heart failure trial (Val-HeFT) echocardiographic data. J Am Coll Cardiol 2004;43:2022–7. Lee TH, Hamilton MA, Stevenson LW, et al. Impact of left ventricular cavity size on survival in advanced heart failure. Am J Cardiol 1993;72:672– 6. St John Sutton M, Pfeffer MA, Plappert T, et al. Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. The protective effects of captopril. Circulation 1994;89:68 –75. Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988;319:80 – 6. Konstam MA, Rousseau MF, Kronenberg MW, et al., for the SOLVD Investigators. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dysfunction in patients with heart failure. Circulation 1992;86:431– 8. Pfeffer MA, Braunwald E, Moye LA, et al., for the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N Engl J Med 1992;327: 669 –77. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991;325:293–302. 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 metaanalytic approach. J Am Coll Cardiol 2010;56:392– 406. Udelson JE, Feldman AM, Greenberg B, et al. Randomized, doubleblind, multicenter, placebo-controlled study evaluating the effect of aldosterone antagonism with eplerenone on ventricular remodeling in patients with mild-to-moderate heart failure and left ventricular systolic dysfunction. Circ Heart Fail 2010;3:347–53. Zannad F, McMurray JJ, Krum H, et al., the EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21. Merlo M, Pyxaras SA, Pinamonti B, Barbati G, Di Lenarda A, Sinagra G. Prevalence and prognostic significance of left ventricular reverse remodeling in dilated cardiomyopathy receiving tailored medical treatment. J Am Coll Cardiol 2011;57:1468 –76. Packer M, Antonopoulos GV, Berlin JA, Chittams J, Konstam MA, Udelson JE. Comparative effects of carvedilol and metoprolol on left ventricular ejection fraction in heart failure: results of a meta-analysis. Am Heart J 2001;141:899 –907.
Key Words: idiopathic dilated cardiomyopathy y left ventricular reverse remodeling y prognosis y tailored medical treatment.
EDITORIAL COMMENT
Ventricular Remodeling Fundamental to the Progression (and Regression) of Heart Failure* James E. Udelson, MD, Marvin A. Konstam, MD Boston, Massachusetts
The ability of the left ventricle to adapt its structure and function to prevailing conditions has long fascinated clinicians and investigators. The left ventricle has a truly remarkable plasticity, evident from stresses both physiologic and pathologic (1). The physiologic stress of high-level athletic endeavors leads to chamber dilation and a degree of hypertrophy (2), whereas more pathologic stress such as that associated with volume overload from valvular regurgitation can lead to a dramatic increase in cavity size (3). Almost as remarkable is that these processes may be reversible when the stress is removed or attenuated, with the left ventricle capable of restoration of normal size and shape. As an example, it has been well documented that after aortic valve replacement for aortic regurgitation, if performed within a certain time window, the left ventricle can demonstrate substantial reversal of the dilation over months of follow-up (4). Indeed, the concept of potential reversibility of this adaptive process underlies recommendations for “deconditioning” when a question arises about whether a hypertrophied left ventricle is secondary to athletic activity, in which case the hypertrophy should regress or is a sign of hypertrophic cardiomyopathy, in which case, it should not (5). See page 1468
Fundamental work on the changes in left ventricular (LV) structure and function after the pathologic insult of a myocardial infarction (MI) was reported by Pfeffer et al. (6) many years ago. It is thought that the process of post-MI remodeling, with chamber dilation and hypertrophy and interstitial changes in remote myocardium, is initially adaptive in an attempt to maintain stroke volume in the face of the loss of contractile elements, but becomes maladaptive
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Division of Cardiology and CardioVascular Center, Tufts Medical Center and Tufts University School of Medicine, Boston, Massachusetts. Dr. Udelson has received research funding from/served as a consultant to Otsuka, Pfizer, and Medtronic. Dr. Konstam has received moderate support from Otsuka, Pfizer, Johnson & Johnson, and Merck.
Vol. 57, No. 13, 2011 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2011.01.009
over time, driven by neurohormonal activation. The initial observations on the sequence of structural changes after an infarct in an animal model were followed soon thereafter by the demonstration that these changes were associated with the risk of mortality after the MI (7). Human studies subsequently documented many of the same findings, and over the years, the knowledge in this area has become more refined. Several studies documented that measures of LV size and function early after an MI were highly prognostic for outcomes (8,9). Moreover, particular patterns of remodeling appear to confer distinct levels of risk because post-MI patients with a pattern of concentric hypertrophy appear to be at the highest risk, as seen in an analysis from patients enrolled in a clinical trial (10). Beyond the post-MI setting, similar concepts have been demonstrated among patients with heart failure and reduced systolic function. Measures of LV size or function at 1 time point identify a group of patients at increased risk of a more unfavorable outcome (11). Longitudinal studies further illuminate the relationship between LV remodeling and outcomes. Of great interest was a secondary analysis of the SAVE (Survival and Ventricular Enlargement) trial. In this study, the change in measures of end-systolic and -diastolic volumes from baseline to a follow-up time point was associated with an unfavorable longer term course (12). This relationship persisted after adjustment for treatment assignment, that is, the data suggested that patients who remodeled while taking the angiotensin-converting enzyme inhibitor captopril were at higher risk than those taking placebo who did not remodel. The understanding that one of the main drivers of the remodeling process, either in the post-MI setting or in chronic heart failure, was neurohormonal activation, led to intense interest in and investigation of the effects of neurohormonal blockade on the processes and mechanisms of remodeling and of course also the impact of neurohormonal blockade on patient outcomes. Captopril was shown to attenuate a progressive increase in LV volumes over a year of therapy after an anterior MI (13), and enalapril was shown to reduce volumes relative to placebo over a 3-year follow-up in patients with chronic heart failure and systolic dysfunction (14). Subsequently, large randomized, placebocontrolled trials demonstrated favorable effects on longterm mortality of captopril in patients with post-MI LV dysfunction (15), and for enalapril in patients with chronic heart failure and systolic dysfunction who had mild to moderate symptoms (16). The findings that angiotensinconverting enzyme inhibitors ameliorated or reversed the remodeling process and also favorably affected mortality led to the attractive supposition that LV remodeling was a fundamental feature of the post-MI or chronic heart failure disease process and its progression and that an intervention’s effect on remodeling may act as a “surrogate” for the intervention’s potential impact on outcome.
1478
Udelson and Konstam Ventricular Remodeling
In an analysis of the existing literature on the effects of therapeutic interventions on LV remodeling and also on mortality in patients with LV dysfunction, we recently showed that there is a positive correlation between an intervention’s effect on LV volumes and function and its effect on mortality (17). The relationship does not rise to the level where remodeling benefit may be considered a surrogate for survival, as has been strictly defined for trials or for regulatory considerations. However, the data suggested that an intervention’s short-term effect on LV remodeling could be used as a probability signal for longer term therapeutic effects on outcomes, and a modest benefit on survival may be considered more conclusive when accompanied by a remodeling benefit. Recent examples of a “disconnect” in this relationship include the effect of aldosterone antagonists in patients with chronic heart failure and systolic dysfunction and mild to moderate symptoms. A trial of 9 months of therapy with eplerenone showed no effect on remodeling (18), whereas favorable outcome effects were seen in the recently published EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial (19). These data support the concept that the progression of the disease state in the post-MI setting or in chronic heart failure is unlikely to be characterized by a single parameter such as remodeling and that outcome predictions may best incorporate multiple elements. An important limitation of the literature included in our recent analysis as well as other observational data is that the studies generally report the effect of a single intervention on remodeling, whether it is a drug or a device, such as cardiac resynchronization therapy. Evidence-based treatment of patients with LV dysfunction is, of course, based on multiple therapeutic approaches used together over time to optimize outcomes. How does such a polytherapeutic approach affect the remodeling process, and what are the implications for outcomes? Into this void of information steps the study by Merlo et al. (20), reported in this issue of the Journal. At a tertiary referral center in Trieste, Italy, 361 patients with nonischemic dilated cardiomyopathy were enrolled over 10 years and were treated according to prevalent guidelines. Echocardiography was performed at baseline and again at a mean of approximately 2 years after the initial study. All patients were followed for at least 10 years, a major strength of this study. The investigators examined the relationship between baseline variables and prognosis, as well as the relationship between the change in selected variables (including the remodeling data) and outcomes, from the time point of re-evaluation onward. Reverse remodeling was arbitrarily defined as an LV ejection fraction (EF) increase of ⱖ10 EF units or an LVEF of ⱖ50% and a decrease in indexed LV end-diastolic diameter of ⱖ10% or of ⱖ33 mm/m2. Approximately one-third of the patients met this definition. Of interest was that 1 of the predictors of reverse remodeling was higher baseline systolic blood pressure, suggesting that
JACC Vol. 57, No. 13, 2011 March 29, 2011:1477–9
1 mechanism of remodeling related to a decrease in load by more intense treatment of blood pressure. Reverse remodeling was identified as an independent predictor of a composite outcome end point over the subsequent long-term follow-up after the second analysis of LV size and function. The novelty of the study revolves around this point—that the occurrence of favorable reverse remodeling in response to therapy identifies a subpopulation of patients who will have a more favorable course over many years. The strengths of the study include the seemingly homogeneous evidence-based treatment strategy at a tertiary center and the length of the follow-up, much longer than most studies. There are also some limitations. The composite end point used by Merlo et al. (20) includes the occurrence of heart transplantation, which is an event that certainly incorporates an unfavorable natural history, but is influenced by many other variables. In the multivariable model that included the occurrence of reverse remodeling at the follow-up time point, other variables were identified that were associated with less favorable outcomes, including New York Heart Association functional classes III to IV and moderate to severe mitral regurgitation, both analyzed at the follow-up visit at approximately 2 years out. The latter variables may represent patients with advanced disease at baseline who did not change or patients in whom those features developed over the first 2 years of follow-up. Thus, the model is complex and included variables that reflect a change from baseline (LV remodeling), variables that reflect measures at 1 time point (baseline), and variables that reflect measures at a second time point (the New York Heart Association functional class and severity of mitral regurgitation). Perhaps more straightforward would have been to analyze all variables by the degree of change from baseline to follow-up and to have included other candidates that may provide prognostic information, such as changes in renal function. The patient population in this study included only those with nonischemic cardiomyopathy who, in most studies, tend to have more robust responses to therapies affecting remodeling (21). Thus, how these results and their implications apply to patients with ischemic cardiomyopathy is not clear. Nonetheless, there are some important messages. The data further reinforce the concept that reversal of LV remodeling in response to therapeutic intervention identifies a group of patients with heart failure and LV dysfunction who will have a more favorable long-term course. In addition, the data suggest that risk stratification in patients with heart failure is a moving target. Baseline variables on an initial visit can provide a prognostic snapshot, but many are subject to change during contemporary therapy, and significant reclassification of risk may occur. Larger databases with analysis of changes in key variables may allow creation of prognostic models that document the magnitude of reclassification.
Udelson and Konstam Ventricular Remodeling
JACC Vol. 57, No. 13, 2011 March 29, 2011:1477–9
Finally, the results also demonstrate once again the remarkable ability of the left ventricle to adapt (and readapt) to prevailing conditions and that progression and regression of the processes of LV remodeling are indeed fundamental to the disease course of patients with heart failure and systolic LV dysfunction. Reprint requests and correspondence: Dr. James E. Udelson, Tufts Medical Center, Box 70, 800 Washington Street, Boston, Massachusetts 02111. E-mail: [email protected].
REFERENCES
1. Hill JA, Olson EN. Cardiac plasticity. N Engl J Med 2008;358:1370–80. 2. Maron BJ, Pelliccia A. The heart of trained athletes: cardiac remodeling and the risks of sports, including sudden death. Circulation 2006;114:1633– 44. 3. Otto CM, Bonow RO. Valvular heart disease. In: Libby P, Bonow RO, Mann D, Zipes DP, Braunwald E, editors. Braunwald’s Heart Disease. 8th edition. Philadelphia, PA: Saunders Elsevier, 2007;1625– 712. 4. Bonow RO, Dodd JT, Maron BJ, et al. Long-term serial changes in left ventricular function and reversal of ventricular dilatation after valve replacement for aortic regurgitation. Circulation 1988;78:1108 –20. 5. Maron BJ, Pelliccia A, Spataro A, Granata M. Reduction in left ventricular wall thickness after deconditioning in highly trained Olympic athletes. Br Heart J 1993;69:125– 8. 6. Pfeffer MA, Pfeffer JM, Fishbein MC, et al. Myocardial infarct size and ventricular function in rats. Circ Res 1979;44:503–12. 7. Pfeffer MA, Pfeffer JM, Steinberg C, Finn P. Survival after an experimental myocardial infarction: beneficial effects of long term therapy with captopril. Circulation 1985;72:406 –12. 8. White HD, Norris RM, Brown MA, Brandt PW, Whitlock RM, Wild CJ. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1987;76:44 –51. 9. Migrino RQ, Young JB, Ellis SG, et al., for the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-I Angiographic Investigators. End-systolic volume index at 90 to 180 minutes into reperfusion therapy for acute myocardial infarction is a strong predictor of early and late mortality. Circulation 1997;96:116 –21. 10. Wong M, Staszewsky L, Latini R, et al. Severity of left ventricular remodeling defines outcomes and response to therapy in heart failure:
11. 12.
13. 14.
15.
16. 17.
18.
19. 20.
21.
1479
Valsartan heart failure trial (Val-HeFT) echocardiographic data. J Am Coll Cardiol 2004;43:2022–7. Lee TH, Hamilton MA, Stevenson LW, et al. Impact of left ventricular cavity size on survival in advanced heart failure. Am J Cardiol 1993;72:672– 6. St John Sutton M, Pfeffer MA, Plappert T, et al. Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. The protective effects of captopril. Circulation 1994;89:68 –75. Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988;319:80 – 6. Konstam MA, Rousseau MF, Kronenberg MW, et al., for the SOLVD Investigators. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dysfunction in patients with heart failure. Circulation 1992;86:431– 8. Pfeffer MA, Braunwald E, Moye LA, et al., for the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N Engl J Med 1992;327: 669 –77. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991;325:293–302. 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 metaanalytic approach. J Am Coll Cardiol 2010;56:392– 406. Udelson JE, Feldman AM, Greenberg B, et al. Randomized, doubleblind, multicenter, placebo-controlled study evaluating the effect of aldosterone antagonism with eplerenone on ventricular remodeling in patients with mild-to-moderate heart failure and left ventricular systolic dysfunction. Circ Heart Fail 2010;3:347–53. Zannad F, McMurray JJ, Krum H, et al., the EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21. Merlo M, Pyxaras SA, Pinamonti B, Barbati G, Di Lenarda A, Sinagra G. Prevalence and prognostic significance of left ventricular reverse remodeling in dilated cardiomyopathy receiving tailored medical treatment. J Am Coll Cardiol 2011;57:1468 –76. Packer M, Antonopoulos GV, Berlin JA, Chittams J, Konstam MA, Udelson JE. Comparative effects of carvedilol and metoprolol on left ventricular ejection fraction in heart failure: results of a meta-analysis. Am Heart J 2001;141:899 –907.
Key Words: idiopathic dilated cardiomyopathy y left ventricular reverse remodeling y prognosis y tailored medical treatment.