https://orcid.org/0000-0001-5017-8657
The review by Sotirakos et al. provides a comprehensive overview of new pharmacotherapies that have emerged for the treatment of heart failure with reduced ejection fraction (HFrEF). The review focuses on the development of sacubitril/valsartan, an angiotensin-neprilysin inhibitor, made up of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan [Citation1].
The authors describe how results from pivotal trials have led to the widespread use of sacubitril/valsartan in HFrEF patients. The PARADIGM-HF (Prospective comparison of ARNI [angiotensin receptor neprilysin inhibitor] with ACEI [angiotensin-converting enzyme inhibitor] to Determine Impact on Global Mortality and morbidity in Heart Failure) trial demonstrated sacubitril/valsartan superiority compared with enalapril in reducing mortality and rates of hospitalization for heart failure in HFrEF patients [Citation2]; while the EVALUATE-HF (Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction) trial demonstrated sacubitril/valsartan use resulted in a reduction in left ventricular end-systolic and end-diastolic volumes compared with enalapril, but without any significant difference in ejection fraction improvement between both groups [Citation3].
In view of these findings, it has been suggested the benefits of sacubitril/valsartan may be related to increased venous capacitance or natriuresis [Citation3,Citation4]. The reduction in congestion and favorable reverse remodeling effects may account for the early reductions in heart failure events rather than changes in afterload or contractile function. Sotirakos et al. acknowledge more research into the mechanisms of action of sacubitril/valsartan is needed [Citation1].
We would like to highlight the findings of our recent observational cohort where we compared the improvement in echocardiographic parameters of cardiac function between ischemic and non-ischemic cardiomyopathy patients receiving sacubitril/valsartan [Citation5]. Sacubitril/valsartan therapy resulted in a significant reduction in New York Heart Association (NYHA) class, left ventricular end-systolic volume and a significant increase in ejection fraction in both groups. Interestingly, the improvement in ejection fraction was significantly greater in patients with non-ischemic cardiomyopathy compared to those with ischemic cardiomyopathy [Citation5].
Our findings may help shed some light on the underlying mechanisms of sacubitril/valsartan. Non-ischemic cardiomyopathy patients have shown greater improvements in ejection fraction following renin angiotensin system inhibition and beta blockade compared with those with ischemic cardiomyopathy. The ischemic myocardium exhibits a greater degree of beta adrenoreceptor uncoupling and is therefore less likely to respond to pharmacotherapy [Citation6,Citation7]. Furthermore, the increased level of fibrosis and reduced viability of an ischemic myocardium prohibits reverse remodeling and the extent of myocardial scarring has an inverse correlation with the degree of improvement in ejection fraction. The distinct underlying pathophysiology of these two different cardiomyopathies is likely to impact on the potential for reverse remodeling, with non-ischemic patients having a better overall response to pharmacotherapy [Citation8,Citation9].
Sacubitril/valsartan is also thought to modulate cardiomyocyte mitochondrial morphology by maintaining a balance between mitochondrial fission and fusion. Increased mitochondrial fission mediated by dynamin related protein 1 (Drp1) has been proposed as a potential pathophysiological mechanism behind cardiomyocyte apoptosis in heart failure [Citation10,Citation11]. Notably, use of sacubitril/valsartan in in-vitro models of doxorubicin-induced dilated cardiomyopathy was associated with reduced levels of Drp1 and improved cardiac function [Citation12]. The protective effect of sacubitril/valsartan through the attenuation of Drp1-mediated mitochondrial apoptosis may be more pronounced in patients with non-ischemic cardiomyopathy; however, this hypothesis is extremely speculative and although interesting, requires confirmation.
The impact of sacubitril/valsartan on the prognosis of HFrEF patients is very encouraging and we agree with Sotirakos et al. that additional studies are required to fully elucidate its underlying mechanism of action. Further studies comparing the effects of sacubitril/valsartan on patients with ischemic and non-ischemic cardiomyopathies may provide new insight and a greater understanding of the mechanisms by which sacubitril/valsartan induces reverse remodeling and therefore improves prognosis in HFrEF patients.
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The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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References
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