Angiotensin receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction by reducing cardiac fibrosis and hypertrophy

Thomas G von Lueder; Bing H Wang; Andrew R Kompa; Li Huang; Randy Webb; Pierre Jordaan; Dan Atar; Henry Krum

doi:10.1161/CIRCHEARTFAILURE.114.001785

Angiotensin receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction by reducing cardiac fibrosis and hypertrophy

Circ Heart Fail. 2015 Jan;8(1):71-8. doi: 10.1161/CIRCHEARTFAILURE.114.001785. Epub 2014 Oct 31.

Authors

Thomas G von Lueder¹, Bing H Wang¹, Andrew R Kompa¹, Li Huang¹, Randy Webb¹, Pierre Jordaan¹, Dan Atar¹, Henry Krum²

Affiliations

¹ From the Department of Epidemiology and Preventive Medicine, Monash Center of Cardiovascular Research and Education in Therapeutics, Monash University, Alfred Hospital, Melbourne, Australia (T.G.v.L., B.H.W., A.R.K., L.H., H.K.); Department of Cardiology B, Oslo University Hospital Ullevål, Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (T.G.v.L., D.A.); Department of Medicine, University of Melbourne, St Vincent's Hospital, Fitzroy, Australia (A.R.K.); Development Franchise-Critical Care, Novartis Pharma, East Hanover, NJ (R.W., P.J.); and Oncology and Drug Safety & Epidemiology, Novartis Pharma, Basel, Switzerland (P.J.).
² From the Department of Epidemiology and Preventive Medicine, Monash Center of Cardiovascular Research and Education in Therapeutics, Monash University, Alfred Hospital, Melbourne, Australia (T.G.v.L., B.H.W., A.R.K., L.H., H.K.); Department of Cardiology B, Oslo University Hospital Ullevål, Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (T.G.v.L., D.A.); Department of Medicine, University of Melbourne, St Vincent's Hospital, Fitzroy, Australia (A.R.K.); Development Franchise-Critical Care, Novartis Pharma, East Hanover, NJ (R.W., P.J.); and Oncology and Drug Safety & Epidemiology, Novartis Pharma, Basel, Switzerland (P.J.). henry.krum@med.monash.edu.au.

PMID: 25362207
DOI: 10.1161/CIRCHEARTFAILURE.114.001785

Abstract

Background: Angiotensin receptor neprilysin inhibitors (ARNi), beyond blocking angiotensin II signaling, augment natriuretic peptides by inhibiting their breakdown by neprilysin. The myocardial effects of ARNi have been little studied until recently. We hypothesized that LCZ696 attenuates left ventricular (LV) remodeling after experimental myocardial infarction (MI), and that this may be contributed to by inhibition of hypertrophy and fibrosis in cardiac cells.

Methods and results: One week after MI, adult male Sprague-Dawley rats were randomized to treatment for 4 weeks with LCZ696 (68 mg/kg body weight perorally; MI-ARNi, n=11) or vehicle (MI-vehicle, n=6). Five weeks after MI, MI-ARNi versus MI-vehicle demonstrated lower LV end-diastolic diameter (by echocardiography; 9.7±0.2 versus 10.5±0.3 mm), higher LV ejection fraction (60±2 versus 47±5%), diastolic wall strain (0.23±0.02 versus 0.13±0.02), and circular strain (-9.8±0.5 versus -7.3±0.5%; all P<0.05). LV pressure-volume loops confirmed improved LV function. Despite similar infarct size, MI-ARNi versus MI-vehicle had lower cardiac weights (P<0.01) and markedly reduced fibrosis in peri-infarct and remote myocardium. Angiotensin II-stimulated incorporation of 3[H]leucine in cardiac myocytes and 3[H]proline in cardiac fibroblast was used to evaluate hypertrophy and fibrosis, respectively. The neprilysin inhibitor component of LCZ696, LBQ657, inhibited hypertrophy but not fibrosis. The angiotensin receptor blocker component of LCZ696, valsartan inhibited both hypertrophy and fibrosis. Dual valsartan+LBQ augmented the inhibitory effects of valsartan and the highest doses completely abrogated angiotensin II-mediated effects.

Conclusions: LCZ696 attenuated cardiac remodeling and dysfunction after MI. This may be contributed to by superior inhibition of LCZ696 on cardiac fibrosis and cardiac hypertrophy than either stand-alone neprilysin inhibitor or angiotensin receptor blocker.

Keywords: angiotensins; brain natriuretic peptide; cardiac hypertrophy; left ventricular remodeling; myocardial infarction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminobutyrates / therapeutic use*
Angiotensin Receptor Antagonists / therapeutic use*
Animals
Biphenyl Compounds
Cardiomyopathy, Hypertrophic / etiology
Cardiomyopathy, Hypertrophic / physiopathology
Cardiomyopathy, Hypertrophic / prevention & control*
Disease Models, Animal
Drug Combinations
Fibrosis / complications
Fibrosis / drug therapy
Fibrosis / pathology
Male
Myocardial Infarction / complications*
Myocardial Infarction / therapy
Myocardium / pathology*
Neprilysin / antagonists & inhibitors
Rats
Rats, Sprague-Dawley
Tetrazoles / therapeutic use*
Treatment Outcome
Valsartan
Ventricular Function, Left / drug effects*
Ventricular Remodeling / drug effects*

Substances

Aminobutyrates
Angiotensin Receptor Antagonists
Biphenyl Compounds
Drug Combinations
Tetrazoles
Valsartan
Neprilysin
sacubitril and valsartan sodium hydrate drug combination