Preclinical study suggests that ARNI reduces cardiac remodelling and dysfunction
The Angiotensin-Receptor Neprilysin Inhibitor LCZ696 Attenuates Cardiac Remodeling and Dysfunction After Myocardial Infarction by Reducing Cardiac Fibrosis and Hypertrophy
von Lueder T, Wang B, Kompa A, et al.
Circ Heart Fail. Oct. 31 2014. Published online. DOI: 10.1161/CIRCHEARTFAILURE.114.001785
BackgroundAngiotensin receptor neprilysin inhibitors (ARNi) form a novel drug class in the treatment of heart failure. They suppress angiotensin II and augment natriuretic peptides (NPs) by inhibiting their breakdown by neprilysin (NEP). Presumably, they also yield a lower risk of bradykinin induced angioedema [1,2].
LCZ696 is the first-in-class ARNi that was evaluated in patients with hypertension and heart failure [3,4,5]. Recently, the PARADIGM-HF trial demonstrated that patients with heart failure and a reduced ejection fraction randomised to the LCZ696 group show lower mortality and morbidity rates than patients treated with enalapril, a gold standard ACE-inhibitor [5,6].
Although the efficacy and safety of LCZ696 has been demonstrated, myocardial effects are unknown. The present preclinical study, therefore, investigates whether LCZ696 has beneficial effects on left ventricular cardiac remodelling and cardiac fibrosis after induction of myocardial infarction (MI) in rats. One week after MI, rats were randomised to four-week treatment with either LCZ696 (68 mg/kg body weight; n=11) or placebo (n=6). Cardiac function was assessed by echocardiography and invasive LV catheterisation. Cellular cardiac hypertrophy and fibrosis were assessed in vitro after Angiotensin II stimulation of myocytes and fibroblasts.
- The LCZ696 group (compared to placebo) demonstrated lower cardiac weights (P<0.01), and markedly reduced fibrosis in peri-infarct and remote myocardium.
- Compared to placebo, rats in the LCZ696 group showed a lower LV end-diastolic diameter (LVEDD measured by echocardiography; 9.7±0.2 vs 10.5±0.3 mm), higher LV ejection fraction (LVEF, 60±2 vs 47±5%), higher diastolic wall strain (0.23±0.02 vs 0.13±0.02), and higher circular strain (-9.8±0.5 vs -7.3±0.5%; all P<0.05).
- GFR decreased significantly in both groups over the study period. While the decrease was larger in vehicle-treated rats, no significant differences in renal function were seen between treatments.
- In cultured cells, the NEP-inhibitor component (LBQ657) of LCZ696 inhibited hypertrophy but not fibrosis. Valsartan (VAL), the angiotensin receptor blocker (ARB) component of LCZ696, inhibited both hypertrophy and fibrosis. Inhibitory properties of VAL were augmented by dual VAL+LBQ and the highest doses completely cancel Angiotensin II-mediated effects.
ConclusionsThis study showed that LCZ696 reduces cardiac remodelling and dysfunction following experimental MI in rats. Post-MI, it inhibited cardiac fibrosis and cardiac hypertrophy in vivo as well as in vitro. Furthermore, LCZ696 may yield a superior inhibition on fibrosis and hypertrophy than either a stand-alone NEP-inhibitor or ARB. The present findings may provide mechanistic insight into the benefits that have been attributed to LCZ696 from clinical studies. For instance, the present findings may also apply to the many patients in the PARADIGM-HF trial who have an ischemic basis to their LV dysfunction . By combining RAAS blockade with augmentation of beneficial NP effects, LCZ696 may have potential as a novel therapeutic agent post-MI or for other cardiovascular disorders.
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1. Kjeldsen SE, Hedner T, Narkiewicz K, et al. Angiotensin receptor-neprilysin inhibiton (ARNI)-a novel therapeutic concept for management of hypertension and heart failure. Blood Press. 2012;21:329-330.
2. von Lueder TG, Sangaralingham SJ, Wang BH, et al. Renin-Angiotensin blockade combined with natriuretic peptide system augmentation: novel therapeutic concepts to combat heart failure. Circ Heart Fail. 2013;6:594-605.
3. Ruilope LM, Dukat A, Bohm M, et al. Bloodpressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. Lancet. 2010;375:1255-1266.
4. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380:1387-1395.
5. McMurray JJ, Packer M, Desai AS, et al. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail. 2013;15:1062-1073.
6.Novartis. PARADIGM-HF trial of Novartis’ LCZ696 for chronic heart failure closes early based on strength of interim results. Novartis media release.2014; http://www.novartis.com/newsroom/media-releases/en/2014/1772754.shtml.
7. McMurray JJ, Packer M, Desai AS, et al. Baseline characteristics and treatment of patients in Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail. 2014;16:817-825.