Review Article
Reverse Remodeling in Systolic Heart Failure Tajinderpal Saraon, MD and Stuart D. Katz, MD, MS
Abstract: Left ventricular (LV) remodeling is the most common term used to describe the functional, structural, myocellular, and interstitial changes that occur in response to myocardial injury and/or chronic changes in myocardial loading conditions. Progression of LV remodeling over time in response to neurohormonal activation, increased wall stress, and inflammatory signaling pathways is associated with an increased risk of major morbidity and mortality. LV reverse remodeling describes the process by which an injured LV with a dilated spherical phenotype may return toward a normalization of ventricular structure and function, either spontaneously or in response to therapeutic interventions. LV reverse remodeling can occur in response to interventions that mitigate the source of myocardial injury, or that reduce or eliminate the neurohormonal and/or hemodynamic factors that contribute to the progression of the LV remodeling process. In this article, we review selected studies that demonstrate the LV reverse remodeling process in response to pharmacological, pacemaker device, and mechanical circulatory support device interventions. Future therapies targeting the physiological, neurohormonal, and/or molecular signaling pathways to effect reverse remodeling may further improve clinical outcomes in heart failure patients. Key Words: ventricular remodeling, neurohormonal activation, cardiac resynchronization therapy, mechanical circulatory support (Cardiology in Review 2015;23: 173–181)
DEFINITION AND USE OF THE TERM “REMODELING” Left ventricular (LV) remodeling is the most common term used to describe the functional, structural, myocellular, and interstitial changes that occur in response to myocardial injury and/or chronic changes in myocardial loading conditions. These biological changes associated with the LV remodeling process encompass both adaptive and maladaptive responses over time. The early adaptive responses serve to augment stroke volume through a combination of chamber enlargement (increased LV end-diastolic volume) and LV wall thickening. Enlargement of the ventricular cavity is associated with increased wall stress and associated changes in excitation contraction coupling, increased myocyte apoptosis, and increased interstitial fibrosis that eventually leads to further depression of myocardial pump function. The long-term result of this process is a gradual transformation from the normal elliptical shape of the LV chamber toward a more spherical and dilated geometry with reduction in cardiac output reserve and ultimately clinical symptomatic heart failure (HF).1 From the Leon H. Charney Division of Cardiology, New York University Langone Medical Center, New York, NY Disclosure: Stuart D. Katz has served as a consultant for Bristol Meyers Squibb, Amgen Inc., Merck Inc., and Luitpold Pharma. He has also served as a paid lecturer for Otsuka Pharmaceuticals. Tajinderpal Saraon discloses no conflicts of interest. Correspondence: Stuart D. Katz, MD, Helen L. and Martin S. Kimmel Professor of Advanced Cardiac Therapeutics, Leon H. Charney Division of Cardiology, New York University Langone Medical Center, 530 First Avenue, Skirball 9R, New York, NY 10016. E-mail: [email protected] Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1061-5377/15/2304-0173 DOI: 10.1097/CRD.0000000000000068
Cardiology in Review • Volume 23, Number 4, July/August 2015
HISTORY OF THE TERM “REMODELING” The term cardiac “remodeling” was first used in the medical literature in 1982 by Hochman and Bulkley2 to describe the histopathological changes (myocardial thinning, granulation tissue, and scar tissue formation) after experimental myocardial infarction (MI) in rats. In the same year, Erlebacher et al3 utilized the term “remodeling” in the description of changes in LV structure after MI in human subjects based on echocardiographic imaging. Both of these studies were primarily describing changes in LV geometry observed soon after MI; however, Erlebacher et al3 noted dilation in both the infarcted and noninfarcted territories. In 1990, Pfeffer and Braunwald4 described both acute and chronic post-MI findings of ventricular dysfunction and an increase in cavity size in the infarcted and noninfarcted regions of the LV in rats. The definition of LV remodeling was further expanded by an international forum in 2000 to encompass changes in genome expression resulting in molecular, cellular, and interstitium derangements influenced by hemodynamic load, neurohormonal activation, inflammatory signaling pathways, and other processes under investigation that are manifested in clinical settings as changes in size, shape and function of the heart.5
PHYSIOLOGY OF REMODELING The complex pathophysiology of LV remodeling is the subject of several recent reviews.6–8 The most salient aspects of the LV remodeling pathophysiology relevant to this review is that LV remodeling is modulated in part by neurohormonal and hemodynamic factors that influence myocellular and cardiac fibroblast structure and function, that progression of LV remodeling is associated with a greater risk of symptomatic HF and adverse outcomes, and that LV remodeling is a dynamic process that can be altered by therapeutic interventions over time (Fig. 1). LV reverse remodeling describes the process by which an injured LV with a dilated spherical phenotype may return toward normalization of ventricular structure and function either spontaneously or in response to a therapeutic intervention. LV reverse remodeling can occur in response to interventions that mitigate the source of myocardial injury, or reduce or eliminate the neurohormonal and/or hemodynamic factors that contribute to the progression of the LV remodeling process. In this article, we will review selected studies that demonstrate the LV reverse remodeling process in response to pharmacological, pacemaker device, and mechanical circulatory support device interventions.
CLINICAL MEASURES OF LV REVERSE REMODELING LV reverse remodeling can be defined as the partial or full restoration of LV geometry and function toward the normal state with an improvement in HF symptoms. A meta-analysis by Udelson and Konstam9 demonstrated that the reduction in risk of adverse clinical outcomes across a wide spectrum of therapeutic interventions was associated with evidence of reverse remodeling manifested as increased LV ejection fraction (LVEF) and decreased LVEDV and LV end-systolic volume (LVESV), LV end-diastolic dimension (LVEDD), and LV end-systolic dimension (LVESD), or LV mass. In a post-MI LV dysfunction study by White et al,10 a multivariate analysis showed that LVESV had a greater predictive value for survival than LVEDV or LVEF. These studies suggest that measurements of LV volumes and EF are clinically useful surrogate markers to assess www.cardiologyinreview.com | 173
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Cardiology in Review • Volume 23, Number 4, July/August 2015
Saraon and Katz
= 0.025 and LVESV 146 ± 38 vs. 145 ± 38 mL in the enalapril group vs. 148 ± 38 to156 ± 42 mL in the placebo group, P = 0.019; Table 1).15 In the Valsartan Heart Failure (Val-HeFT) trial echocardiographic substudy, Wong et al16 reported a significant increase in LVEF and a decrease in LV internal diastolic diameter (LVIDD) in 5010 chronic systolic HF patients treated with valsartan when compared with patients treated with placebo (change in LVIDD at 18 months, −0.12 ± 0.4 vs. −0.05 ± 0.4 cm/m2, P < 0.001, and change in LVEF +4.5 ± 8.9 vs. +3.2 ± 8.6%, P < 0.001; Table 1). In a randomized, double blind, placebo-controlled study of 305 systolic HF patients with history of intolerance to angiotensin converting enzyme (ACE) inhibition, angiotensin receptor blockade with candesartan for 6 months was associated with a significant increase in LVEF when compared with placebo (% change of LVEF +23.8 ± 46% in the candesartan group vs. +8.4 ± 34.4% in the placebo group, P = 0.004; Table 1).17
Beta-Adrenergic Receptor Blockers
FIGURE 1. Schematic illustrating putative mechanisms of left ventricular remodeling and reverse remodeling and progression of heart failure. Heavy dashed lines indicate pathways that seem important in the physiology of reverse remodeling. Asterisks indicate targets for therapy. LV indicates left ventricular. the process of LV reverse remodeling in response to therapeutic intervention.11 Accordingly, studies that provide serial measures of these variables will be summarized below.
THERAPEUTIC INTERVENTIONS ASSOCIATED WITH REVERSE REMODELING Modifiable Forms of Myocardial Injury Natural history studies demonstrate that LV remodeling in response to modifiable forms of myocardial injury, such as alcoholrelated cardiomyopathy and tachycardia-induced cardiomyopathy can reverse after withdrawal of the offending insult. La Vecchia et al12 reported that 48% of 19 study subjects had improved LVEF of >15% from baseline (from mean of 29 ± 9% at baseline to a mean of 54 ± 10% at follow-up, P < 0.001) at 2 years with abstinence of alcohol and the addition of HF therapy. Watanabe et al13 reported recovery of LV systolic function in 12 patients with tachycardia-induced cardiomyopathy [mean LVEF of 0.32 ± 0.10 (range, 17–51%)] by rate control, cardioversion, or ablation of the tachyarrhythmia [LVEF recovered to 0.54 ± 0.10% (range, 50–67%, P < 0.001) during a mean of 53.5 ± 61.3 days].
Renin Angiotensin Aldosterone System Inhibition Pharmacological inhibition of the Renin–Angiotensin Aldosterone System has been shown to be associated with a significant reduction in major morbidity and mortality risk and associated evidence of reverse remodeling.14–18 Early data from Cannon et al in 1983 demonstrated that captopril therapy was associated with an increased LVEF over 12 weeks (LVEF % change of 16.2% in the captopril group vs. −1.8% change in the placebo group, P < 0.05) and improved exercise capacity [24% mean increase in exercise time with captopril (495 ± 22 to 614 ± 27 s) when compared with 0.4% with placebo (480 ± 28 to 483 ± 43 s, P < 0.01)].14 Data from the Studies on Left Ventricular Dysfunction (SOLVD) trial echocardiographic substudy (n = 301, 153 in placebo group and 148 in enalapril group) demonstrated that enalapril therapy attenuated progressive increases in LV dilatation from baseline to 12 months of therapy (LVEDV 196 ± 41 to 197 ± 39 mL in the enalapril group vs. 200 ± 42 to 210 ± 46 mL in the placebo group, P 174 | www.cardiologyinreview.com
Several trials have shown the morbidity and mortality benefits associated with beta-adrenergic receptor blocker (carvedilol, bisoprolol, and metoprolol succinate) therapy in patients with chronic systolic HF (Table 2).19–31 A meta-analysis of beta-adrenergic receptor blocker trials in systolic HF has shown that this class of medications provides the highest relative improvement in LVEF in response to therapy when compared with other neurohormonal antagonists.11 The Carvedilol Post Infarction Survival Control In LV Dysfunction (CAPRICORN) trial was a randomized, controlled trial of the beta-adrenergic receptor blocker carvedilol versus placebo in 1959 patients with acute MI and LVEF ≤40%, which demonstrated a significant reduction in all-cause mortality risk in the carvedilol group compared with placebo [116 (12%) vs. 151 (15%), 95% confidence interval (CI), 0.60–0.98; P = 0.03].21 The CAPRICORN echo substudy of 127 patients demonstrated a significant decrease in LVESV of 9.2 mL (95% CI, −17.1 to −1.3 mL, P = 0.023) and a significant increase in LVEF of 3.9% (95% CI, +0.8 to +7.1%, P = 0.015) between the carvedilol and placebo groups after 6 months.19 A comparable benefit was reported in 48 older chronic systolic HF patients (LVEF 70 years) in a randomized, placebo-controlled, double-blind study comparing carvedilol versus placebo over a period of 12 months.22 When compared with placebo, carvedilol was associated with a significant reduction in LVEDD (40 ± 4 to 41 ± 4 mm/ m2 placebo vs. 38 ± 5 to 36 ± 4 mm/m2 carvedilol, P = 0.001), LVESD (75 ± 9 to 76 ± 5 mm/m2 placebo vs. 81 ± 13 to 68 ± 18 mm/m2 carvedilol, P = 0.03), and LVEF (29 ± 5 to 30 ± 6% placebo vs. 27 ± 8 to 35 ± 6% carvedilol, P = 0.01). Senior et al23 also reported beneficial effects of carvedilol on LV remodeling in 49 post-MI patients with a predischarge LVEF
Reverse Remodeling in Systolic Heart Failure Tajinderpal Saraon, MD and Stuart D. Katz, MD, MS
Abstract: Left ventricular (LV) remodeling is the most common term used to describe the functional, structural, myocellular, and interstitial changes that occur in response to myocardial injury and/or chronic changes in myocardial loading conditions. Progression of LV remodeling over time in response to neurohormonal activation, increased wall stress, and inflammatory signaling pathways is associated with an increased risk of major morbidity and mortality. LV reverse remodeling describes the process by which an injured LV with a dilated spherical phenotype may return toward a normalization of ventricular structure and function, either spontaneously or in response to therapeutic interventions. LV reverse remodeling can occur in response to interventions that mitigate the source of myocardial injury, or that reduce or eliminate the neurohormonal and/or hemodynamic factors that contribute to the progression of the LV remodeling process. In this article, we review selected studies that demonstrate the LV reverse remodeling process in response to pharmacological, pacemaker device, and mechanical circulatory support device interventions. Future therapies targeting the physiological, neurohormonal, and/or molecular signaling pathways to effect reverse remodeling may further improve clinical outcomes in heart failure patients. Key Words: ventricular remodeling, neurohormonal activation, cardiac resynchronization therapy, mechanical circulatory support (Cardiology in Review 2015;23: 173–181)
DEFINITION AND USE OF THE TERM “REMODELING” Left ventricular (LV) remodeling is the most common term used to describe the functional, structural, myocellular, and interstitial changes that occur in response to myocardial injury and/or chronic changes in myocardial loading conditions. These biological changes associated with the LV remodeling process encompass both adaptive and maladaptive responses over time. The early adaptive responses serve to augment stroke volume through a combination of chamber enlargement (increased LV end-diastolic volume) and LV wall thickening. Enlargement of the ventricular cavity is associated with increased wall stress and associated changes in excitation contraction coupling, increased myocyte apoptosis, and increased interstitial fibrosis that eventually leads to further depression of myocardial pump function. The long-term result of this process is a gradual transformation from the normal elliptical shape of the LV chamber toward a more spherical and dilated geometry with reduction in cardiac output reserve and ultimately clinical symptomatic heart failure (HF).1 From the Leon H. Charney Division of Cardiology, New York University Langone Medical Center, New York, NY Disclosure: Stuart D. Katz has served as a consultant for Bristol Meyers Squibb, Amgen Inc., Merck Inc., and Luitpold Pharma. He has also served as a paid lecturer for Otsuka Pharmaceuticals. Tajinderpal Saraon discloses no conflicts of interest. Correspondence: Stuart D. Katz, MD, Helen L. and Martin S. Kimmel Professor of Advanced Cardiac Therapeutics, Leon H. Charney Division of Cardiology, New York University Langone Medical Center, 530 First Avenue, Skirball 9R, New York, NY 10016. E-mail: [email protected] Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1061-5377/15/2304-0173 DOI: 10.1097/CRD.0000000000000068
Cardiology in Review • Volume 23, Number 4, July/August 2015
HISTORY OF THE TERM “REMODELING” The term cardiac “remodeling” was first used in the medical literature in 1982 by Hochman and Bulkley2 to describe the histopathological changes (myocardial thinning, granulation tissue, and scar tissue formation) after experimental myocardial infarction (MI) in rats. In the same year, Erlebacher et al3 utilized the term “remodeling” in the description of changes in LV structure after MI in human subjects based on echocardiographic imaging. Both of these studies were primarily describing changes in LV geometry observed soon after MI; however, Erlebacher et al3 noted dilation in both the infarcted and noninfarcted territories. In 1990, Pfeffer and Braunwald4 described both acute and chronic post-MI findings of ventricular dysfunction and an increase in cavity size in the infarcted and noninfarcted regions of the LV in rats. The definition of LV remodeling was further expanded by an international forum in 2000 to encompass changes in genome expression resulting in molecular, cellular, and interstitium derangements influenced by hemodynamic load, neurohormonal activation, inflammatory signaling pathways, and other processes under investigation that are manifested in clinical settings as changes in size, shape and function of the heart.5
PHYSIOLOGY OF REMODELING The complex pathophysiology of LV remodeling is the subject of several recent reviews.6–8 The most salient aspects of the LV remodeling pathophysiology relevant to this review is that LV remodeling is modulated in part by neurohormonal and hemodynamic factors that influence myocellular and cardiac fibroblast structure and function, that progression of LV remodeling is associated with a greater risk of symptomatic HF and adverse outcomes, and that LV remodeling is a dynamic process that can be altered by therapeutic interventions over time (Fig. 1). LV reverse remodeling describes the process by which an injured LV with a dilated spherical phenotype may return toward normalization of ventricular structure and function either spontaneously or in response to a therapeutic intervention. LV reverse remodeling can occur in response to interventions that mitigate the source of myocardial injury, or reduce or eliminate the neurohormonal and/or hemodynamic factors that contribute to the progression of the LV remodeling process. In this article, we will review selected studies that demonstrate the LV reverse remodeling process in response to pharmacological, pacemaker device, and mechanical circulatory support device interventions.
CLINICAL MEASURES OF LV REVERSE REMODELING LV reverse remodeling can be defined as the partial or full restoration of LV geometry and function toward the normal state with an improvement in HF symptoms. A meta-analysis by Udelson and Konstam9 demonstrated that the reduction in risk of adverse clinical outcomes across a wide spectrum of therapeutic interventions was associated with evidence of reverse remodeling manifested as increased LV ejection fraction (LVEF) and decreased LVEDV and LV end-systolic volume (LVESV), LV end-diastolic dimension (LVEDD), and LV end-systolic dimension (LVESD), or LV mass. In a post-MI LV dysfunction study by White et al,10 a multivariate analysis showed that LVESV had a greater predictive value for survival than LVEDV or LVEF. These studies suggest that measurements of LV volumes and EF are clinically useful surrogate markers to assess www.cardiologyinreview.com | 173
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Cardiology in Review • Volume 23, Number 4, July/August 2015
Saraon and Katz
= 0.025 and LVESV 146 ± 38 vs. 145 ± 38 mL in the enalapril group vs. 148 ± 38 to156 ± 42 mL in the placebo group, P = 0.019; Table 1).15 In the Valsartan Heart Failure (Val-HeFT) trial echocardiographic substudy, Wong et al16 reported a significant increase in LVEF and a decrease in LV internal diastolic diameter (LVIDD) in 5010 chronic systolic HF patients treated with valsartan when compared with patients treated with placebo (change in LVIDD at 18 months, −0.12 ± 0.4 vs. −0.05 ± 0.4 cm/m2, P < 0.001, and change in LVEF +4.5 ± 8.9 vs. +3.2 ± 8.6%, P < 0.001; Table 1). In a randomized, double blind, placebo-controlled study of 305 systolic HF patients with history of intolerance to angiotensin converting enzyme (ACE) inhibition, angiotensin receptor blockade with candesartan for 6 months was associated with a significant increase in LVEF when compared with placebo (% change of LVEF +23.8 ± 46% in the candesartan group vs. +8.4 ± 34.4% in the placebo group, P = 0.004; Table 1).17
Beta-Adrenergic Receptor Blockers
FIGURE 1. Schematic illustrating putative mechanisms of left ventricular remodeling and reverse remodeling and progression of heart failure. Heavy dashed lines indicate pathways that seem important in the physiology of reverse remodeling. Asterisks indicate targets for therapy. LV indicates left ventricular. the process of LV reverse remodeling in response to therapeutic intervention.11 Accordingly, studies that provide serial measures of these variables will be summarized below.
THERAPEUTIC INTERVENTIONS ASSOCIATED WITH REVERSE REMODELING Modifiable Forms of Myocardial Injury Natural history studies demonstrate that LV remodeling in response to modifiable forms of myocardial injury, such as alcoholrelated cardiomyopathy and tachycardia-induced cardiomyopathy can reverse after withdrawal of the offending insult. La Vecchia et al12 reported that 48% of 19 study subjects had improved LVEF of >15% from baseline (from mean of 29 ± 9% at baseline to a mean of 54 ± 10% at follow-up, P < 0.001) at 2 years with abstinence of alcohol and the addition of HF therapy. Watanabe et al13 reported recovery of LV systolic function in 12 patients with tachycardia-induced cardiomyopathy [mean LVEF of 0.32 ± 0.10 (range, 17–51%)] by rate control, cardioversion, or ablation of the tachyarrhythmia [LVEF recovered to 0.54 ± 0.10% (range, 50–67%, P < 0.001) during a mean of 53.5 ± 61.3 days].
Renin Angiotensin Aldosterone System Inhibition Pharmacological inhibition of the Renin–Angiotensin Aldosterone System has been shown to be associated with a significant reduction in major morbidity and mortality risk and associated evidence of reverse remodeling.14–18 Early data from Cannon et al in 1983 demonstrated that captopril therapy was associated with an increased LVEF over 12 weeks (LVEF % change of 16.2% in the captopril group vs. −1.8% change in the placebo group, P < 0.05) and improved exercise capacity [24% mean increase in exercise time with captopril (495 ± 22 to 614 ± 27 s) when compared with 0.4% with placebo (480 ± 28 to 483 ± 43 s, P < 0.01)].14 Data from the Studies on Left Ventricular Dysfunction (SOLVD) trial echocardiographic substudy (n = 301, 153 in placebo group and 148 in enalapril group) demonstrated that enalapril therapy attenuated progressive increases in LV dilatation from baseline to 12 months of therapy (LVEDV 196 ± 41 to 197 ± 39 mL in the enalapril group vs. 200 ± 42 to 210 ± 46 mL in the placebo group, P 174 | www.cardiologyinreview.com
Several trials have shown the morbidity and mortality benefits associated with beta-adrenergic receptor blocker (carvedilol, bisoprolol, and metoprolol succinate) therapy in patients with chronic systolic HF (Table 2).19–31 A meta-analysis of beta-adrenergic receptor blocker trials in systolic HF has shown that this class of medications provides the highest relative improvement in LVEF in response to therapy when compared with other neurohormonal antagonists.11 The Carvedilol Post Infarction Survival Control In LV Dysfunction (CAPRICORN) trial was a randomized, controlled trial of the beta-adrenergic receptor blocker carvedilol versus placebo in 1959 patients with acute MI and LVEF ≤40%, which demonstrated a significant reduction in all-cause mortality risk in the carvedilol group compared with placebo [116 (12%) vs. 151 (15%), 95% confidence interval (CI), 0.60–0.98; P = 0.03].21 The CAPRICORN echo substudy of 127 patients demonstrated a significant decrease in LVESV of 9.2 mL (95% CI, −17.1 to −1.3 mL, P = 0.023) and a significant increase in LVEF of 3.9% (95% CI, +0.8 to +7.1%, P = 0.015) between the carvedilol and placebo groups after 6 months.19 A comparable benefit was reported in 48 older chronic systolic HF patients (LVEF 70 years) in a randomized, placebo-controlled, double-blind study comparing carvedilol versus placebo over a period of 12 months.22 When compared with placebo, carvedilol was associated with a significant reduction in LVEDD (40 ± 4 to 41 ± 4 mm/ m2 placebo vs. 38 ± 5 to 36 ± 4 mm/m2 carvedilol, P = 0.001), LVESD (75 ± 9 to 76 ± 5 mm/m2 placebo vs. 81 ± 13 to 68 ± 18 mm/m2 carvedilol, P = 0.03), and LVEF (29 ± 5 to 30 ± 6% placebo vs. 27 ± 8 to 35 ± 6% carvedilol, P = 0.01). Senior et al23 also reported beneficial effects of carvedilol on LV remodeling in 49 post-MI patients with a predischarge LVEF
