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  • br Introduction Sustained over activation of neurohormonal s

    2024-07-09


    Introduction Sustained over-activation of neurohormonal systems is a hallmark in the pathophysiology of cardiac dysfunction following myocardial infarction (MI) and heart failure (HF). Inhibitors of the renin-angiotensin rgs protein system (RAAS) constitute cornerstones of pharmacotherapy for HF with left ventricular (LV) reduced ejection fraction (EF), however mortality and re-hospitalization rates remain unacceptably high [1,2]. Attempts to block RAAS at multiple levels not only failed to yield additional benefit but conferred increased adverse event rates [3]. Novel strategies have attempted to further enhance valuable effects of RAAS blockade by augmenting the beneficial natriuretic peptide system [4]. Natriuretic peptides, activated in cardiac dysfunction and HF, counteract the RAAS and promote vasodilation, natriuresis, and inhibit fibrosis and hypertrophy [5]. In HF, natriuretic peptides are deficient as they become rapidly hydrolyzed by the metallopeptidase neprilysin. Concomitant RAAS blockade and inhibition of neprilysin has been advanced as a concept to augment and exploit the beneficial actions of natriuretic peptides [4]. PARADIGM-HF evaluated the dual-acting angiotensin receptor-neprilysin inhibitor (ARNi) sacubitril/valsartan (LCZ696) in HF with reduced EF. This trial was terminated early due to an overwhelming mortality and morbidity benefit of the ARNi compared to stand-alone RAAS blockade with the angiotensin converting enzyme inhibitor (ACEi) enalapril [6,7]. LCZ696 is a salt complex comprising the anionic moieties of the angiotensin type-1 receptor antagonist valsartan and of the neprilysin inhibitor sacubitril [8] a prodrug, which is converted in vivo to the active component sacubitrilat or LBQ657. We recently reported improved cardiac function and remodeling with LCZ696 compared to vehicle-treated animals following experimental MI [9]. In vitro studies using LBQ657 in the presence of increasing doses of valsartan (replicating ARNi), demonstrated more potent LV anti-hypertrophic and anti-fibrotic effects than stand-alone valsartan [4,10]. Given these mechanistic insights and the proven efficacy of ACEi in the SAVE trial, LCZ696 compared to ACEi may offer additional benefits on LV dysfunction and remodeling in a post-MI model [11]. Despite recent formal recognition of ARNi by guideline authorities, there is a striking paucity of mechanistic data on the effect of ARNi compared to stand-alone RAAS blockade on cardiac remodeling [12]. To further our current understanding of inhibiting neprilysin in addition to RAAS, head-to-head comparison between ARNi versus ACEi, the current standard of care in HF therapy, on evolving LV remodeling and dysfunction is required. Accordingly, in this study we comprehensively evaluated the functional and structural effects of ARNi versus ACEi in a post-MI model of LV remodeling and dysfunction.
    Methods
    Results
    Discussion This work provides novel mechanistic insight into the effects of ARNi (LCZ696) versus ACEi (perindopril) on cardiac function and remodeling after experimental MI. Specifically, our data show that LCZ696 compared to perindopril attenuated LV dilatation and improved LV EF, fractional shortening, indexed dP/dtmax, and end systolic pressure-volume relationship. We additionally demonstrate that LCZ696 but not perindopril attenuated the increase in lung weight, left atrial weight and LV filling pressures, i.e. surrogates of congestion. Our data also show better preservation of diastolic wall strain, a load independent marker of LV stiffness, with LCZ696 over perindopril post-MI. Finally, despite similar reductions in cardiac hypertrophy and fibrosis, myocardial expression of ANP, βMHC and TIMP2 was reduced further together with a trend toward lower collagen I in LCZ696 versus perindopril. rgs protein Taken together, our data demonstrate that LCZ696 affords improved cardioprotection after substantial MI compared to perindopril. The improvement in hemodynamic parameters observed with LCZ696 over single RAAS blockade may be attributed to higher circulating levels of natriuretic peptides. As previously reviewed, clinical and animal studies have reported cardioprotection and improved cardiac function and hemodynamic parameters afforded by the administration of natriuretic peptides [21]. Furthermore, we have previously demonstrated direct cardioprotective effects of sacubitril and valsartan beyond those of stand-alone valsartan in cardiac cells stimulated with angiotensin II, which were replicated by direct administration of natriuretic peptides [9].