Review Article
Pharmacologic and Endovascular Reversal of Left Ventricular Remodeling

https://doi.org/10.1016/j.cardfail.2016.03.017Get rights and content

Highlights

  • Pathologic LV remodeling portends a poor prognosis.

  • Improvement in LV dimensions and function may reflect improvement in loading conditions or reversal of remodeling.

  • Changes induced by true reversal of remodeling are sustained after withdrawal of therapy.

  • There is convincing evidence that beta-blockers and cardiac resynchronization therapy induce true reversal of remodeling.

Abstract

Pathologic left ventricular (LV) remodeling as described by adverse changes in LV mass, volume, geometry, and composition in response to mechanical and systemic neurohormonal activation portends a poor prognosis in patients with underlying LV systolic dysfunction. Conversely, reversal of LV remodeling is associated with improved morbidity and mortality. Improvement in LV function and size may result from either change in loading conditions or reversal of remodeling (RR). When complete normalization of LV function and geometry occurs (ejection fraction >50% and indexed LV end-diastolic dimension <33 mm/m2), true reversal of LV alteration is likely to have occurred. Sustained improvement in function and dimensions after therapy withdrawal further supports RR. In the absence of complete RR one cannot readily differentiate incomplete RR from changes in loading conditions. In this review, we evaluate the role of renin-angiotensin-aldosterone system inhibition, beta-adrenergic receptor blockade, cardiac resynchronization therapy, and endovascular mitral repair on LVRR and improvement in LV geometry and function.

Section snippets

Reversal of Left Ventricular Remodeling

LVRR is defined as improvement in LV ejection fraction (LVEF) accompanied by a decrease in LV volume and end-diastolic dimension (LVEDD). Changes in these parameters may be due to resolution of the pathologic process or to favorable effects of interventions on cardiac loading conditions. A key feature of LVRR is that the decrease in LV size and configuration persists after withdrawal of therapeutic intervention(s), suggesting that sustained changes reflect intrinsic biological reversal rather

Beta-adrenergic Receptor Blockade

The long-term effects of BARB therapy with the use of metoprolol succinate or carvedilol on LV systolic function and size have been extensively studied in patients with moderate to severe heart failure with reduced ejection fraction (HFrEF). Eichhorn et al showed improved LVEF, diastolic dimension, and myocardial efficiency after 3 months of metoprolol succinate at 50 mg twice a day.30 Several large randomized trials have demonstrated improved survival with the use of long-term BARB in

Conclusion

Changes in LVEF and LV volumes can result from alterations in cardiac loading conditions or from LVRR. Reversal of remodeling is considered to have occurred when LVEF and LV volumes normalize (LVEF ≥50% and LVEDDI ≤33 mL/m2) or when partial improvement in LVEF and LVvolumes is associated with an improvement in LV contractility. Furthermore, sustained steady-state LVEF and LV volumes after cessation of intervention provide strong evidence that LVRR has occurred. Interventions including ACEI,

Disclosures

None.

References (107)

  • P.L. Whitlow et al.

    Acute and 12-month results with catheter-based mitral valve leaflet repair: the EVEREST II (Endovascular Valve Edge-to-Edge Repair) high risk study

    J Am Coll Cardiol

    (2012)
  • D.G. Kramer et al.

    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)
  • M. Metra et al.

    Marked improvement in left ventricular ejection fraction during long-term beta-blockade in patients with chronic heart failure: clinical correlates and prognostic significance

    Am Heart J

    (2003)
  • E.J. Eichhorn et al.

    Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy: a randomized, double-blind, placebo-controlled study

    J Am Coll Cardiol

    (1994)
  • M.J. Domanski et al.

    A comparative analysis of the results from 4 trials of beta-blocker therapy for heart failure: BEST, CIBIS-II, MERIT-HF, and COPERNICUS

    J Card Fail

    (2003)
  • B.A. Groenning et al.

    Antiremodeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure

    J Am Coll Cardiol

    (2000)
  • E.J. Eichhorn

    Do beta-blockers have a role in patients with congestive heart failure?

    Cardiol Clin

    (1994)
  • R.N. Doughty et al.

    Beta-blockers in heart failure: promising or proved?

    J Am Coll Cardiol

    (1994)
  • R.N. Doughty et al.

    Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease

    J Am Coll Cardiol

    (1997)
  • B.D. Lowes et al.

    Effects of carvedilol on left ventricular mass, chamber geometry, and mitral regurgitation in chronic heart failure

    Am J Cardiol

    (1999)
  • P. Green et al.

    Long-term effects of carvedilol or metoprolol on left ventricular function in ischemic and nonischemic cardiomyopathy

    Am J Cardiol

    (2005)
  • K. Fox et al.

    Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial

    Lancet

    (2008)
  • K. Swedberg et al.

    Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study

    Lancet

    (2010)
  • J.N. Cohn et al.

    Cardiac remodeling—concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an international forum on cardiac remodeling

    J Am Coll Cardiol

    (2000)
  • M.R. Gold et al.

    The effect of reverse remodeling on long-term survival in mildly symptomatic patients with heart failure receiving cardiac resynchronization therapy: results of the REVERSE study

    Heart Rhythm

    (2015)
  • B.H. Trichon et al.

    Relation of frequency and severity of mitral regurgitation to survival among patients with left ventricular systolic dysfunction and heart failure

    Am J Cardiol

    (2003)
  • T. Feldman et al.

    Percutaneous approaches to valve repair for mitral regurgitation

    J Am Coll Cardiol

    (2014)
  • R.J. Siegel et al.

    The acute hemodynamic effects of Mitraclip therapy

    J Am Coll Cardiol

    (2011)
  • J.J. Silbiger

    A novel mechanism by which Mitraclip implantation may favorably alter the natural history of left ventricular remodeling in patients with mitral regurgitation: proposed role of the ventricular-valvular loop

    J Am Soc Echocardiogr

    (2013)
  • L. Mauri et al.

    4-Year results of a randomized controlled trial of percutaneous repair versus surgery for mitral regurgitation

    J Am Coll Cardiol

    (2013)
  • F. Maisano et al.

    Percutaneous mitral valve interventions in the real world: early and 1-year results from the ACCESS-EU, a prospective, multicenter, nonrandomized post-approval study of the Mitraclip therapy in Europe

    J Am Coll Cardiol

    (2013)
  • ZouC.H. et al.

    Frequency and predictors of normalization of left ventricular ejection fraction in recent-onset nonischemic cardiomyopathy

    Am J Cardiol

    (2014)
  • P.K. Bhat et al.

    Usefulness of left ventricular end-systolic dimension by echocardiography to predict reverse remodeling in patients with newly diagnosed severe left ventricular systolic dysfunction

    Am J Cardiol

    (2012)
  • G. Cioffi et al.

    Prevalence, predictors and prognostic implications of improvement in left ventricular systolic function and clinical status in patients >70 years of age with recently diagnosed systolic heart failure

    Am J Cardiol

    (2003)
  • S.O. Marx et al.

    PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts

    Cell

    (2000)
  • S. Iyengar et al.

    Effect of cardiac resynchronization therapy on myocardial gene expression in patients with nonischemic dilated cardiomyopathy

    J Card Fail

    (2007)
  • M. Vanderheyden et al.

    Myocardial gene expression in heart failure patients treated with cardiac resynchronization therapy: responders versus nonresponders

    J Am Coll Cardiol

    (2008)
  • D.A. Kass et al.

    Reverse remodeling from cardiomyoplasty in human heart failure. External constraint versus active assist

    Circulation

    (1995)
  • G. Cioffi et al.

    Pharmacological left ventricular reverse remodeling in elderly patients receiving optimal therapy for chronic heart failure

    Eur J Heart Fail

    (2005)
  • F. Waagstein et al.

    Increased exercise ejection fraction and reversed remodeling after long-term treatment with metoprolol in congestive heart failure: a randomized, stratified, double-blind, placebo-controlled trial in mild to moderate heart failure due to ischemic or idiopathic dilated cardiomyopathy

    Eur J Heart Fail

    (2003)
  • J.L. Januzzi et al.

    Reversed reverse remodeling: can biomonitoring solve the clinical conundrum of the 3Rs?

    Circ Heart Fail

    (2014)
  • M. St John Sutton et al.

    Left ventricular reverse remodeling with biventricular versus right ventricular pacing in patients with atrioventricular block and heart failure in the BLOCK HF trial

    Circ Heart Fail

    (2015)
  • D.P. Kao et al.

    Therapeutic molecular phenotype of beta-blocker–associated reverse-remodeling in nonischemic dilated cardiomyopathy

    Circ Cardiovasc Genet

    (2015)
  • P.J. Hauptman et al.

    Reversal of ventricular remodeling: important to establish and difficult to define

    Eur J Heart Fail

    (2007)
  • J.E. Udelson et al.

    Randomized, double-blind, 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)
  • R.N. Doughty et al.

    Effects of carvedilol on left ventricular remodeling after acute myocardial infarction: the CAPRICORN echo substudy

    Circulation

    (2004)
  • M.A. Konstam 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)
  • M. St John Sutton 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)
  • E. Foster et al.

    Percutaneous mitral valve repair in the initial EVEREST cohort: evidence of reverse left ventricular remodeling

    Circ Cardiovasc Imaging

    (2013)
  • S. Kainuma et al.

    Restrictive mitral annuloplasty with or without surgical ventricular reconstruction in ischaemic cardiomyopathy: impacts on neurohormonal activation, reverse left ventricular remodelling and survival

    Eur J Heart Fail

    (2014)
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    Funding: None.

    Conflicts of interest: none.

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