Renin Activity in Heart Failure with Reduced Systolic Function—New Insights

Abstract

Regardless of the cause, symptomatic heart failure (HF) with reduced ejection fraction (rEF) is characterized by pathological activation of the renin–angiotensin–aldosterone system (RAAS) with sodium retention and extracellular fluid expansion (edema). Here, we review the role of active renin, a crucial, upstream enzymatic regulator of the RAAS, as a prognostic and diagnostic plasma biomarker of heart failure with reduced ejection fraction (HFrEF) progression; we also discuss its potential as a pharmacological bio-target in HF therapy. Clinical and experimental studies indicate that plasma renin activity is elevated with symptomatic HFrEF with edema in patients, as well as in companion animals and experimental models of HF. Plasma renin activity levels are also reported to be elevated in patients and animals with rEF before the development of symptomatic HF. Modulation of renin activity in experimental HF significantly reduces edema formation and the progression of systolic dysfunction and improves survival. Thus, specific assessment and targeting of elevated renin activity may enhance diagnostic and therapeutic precision to improve outcomes in appropriate patients with HFrEF.

Cardiac-Specific Overexpression of Catalytically Inactive Corin Reduces Edema, Contractile Dysfunction, and Death in Mice with Dilated Cardiomyopathy

“…Attenuation of edema and pleural effusion in corin-Tg(i)/DCM mice may be associated with less volume and pressure overload and improved contractile function as a compensatory effect [53]. Reduced edema is also associated with normalization of circulating neprilysin level as reported for patients with HFrEF and in experimental HF [35,52,54] and trend toward down-regulation of renin plasma activity and aldosterone levels [44,47,55,56]. HF continues to increase in incidence and prevalence [1].…”

“…Transcript levels of GATA-4, a common transcription factor for corin, ANP, and BNP [32] remained unchanged among all three groups (Figure 5g). Systemic activation of the renin-angiotensin-aldosterone system (RAAS) occurs in HF with increased plasma renin activity, angiotensin II, and aldosterone levels [42][43][44][45][46][47]. We reported that systemic RAAS is significantly activated in female mice with DCM starting from Stage B HF [35,36].…”

“…Renin enzymatic activities in plasma samples were measured and quantified by cleavage of exogenous fluorescence resonance transfer (FRET) peptide substrates of renin FRET-QXL™520/5-FAM, optimized for mouse renin using a SensoLyte 520 mouse renin assay kit (AnaSpec, Fremont, CA, USA) as previously reported [35][36][37]47].…”

Normalizing Plasma Renin Activity in Experimental Dilated Cardiomyopathy: Effects on Edema, Cachexia, and Survival

“…Recent experimental studies have linked elevated plasma renin activity levels in female mice with DCM to accelerated, sex-related deterioration in systolic function, HF progression, and early mortality [27]. While active renin is acknowledged to initiate production of both Ang II and aldosterone [38,43], clinical studies have not rigorously examined plasma renin activity in the pathogenesis of HF [32,34,35,36,37,44]. Active renin concentration was recently suggested as a potential indicator for guiding HF with reduced EF (HFrEF) in addition to BNP and New York Heart Association classification [45].…”

“…Prior to the development of Stage C HF, which is associated with edema and other biomarker abnormalities, female mice show increased plasma renin activity concentrations [27]. Renin is an enzyme that specifically catalyzes the first and rate-limiting step in the activation of angiotensin II (Ang II) and renin enhances the secretion of aldosterone, which promotes salt and water retention and worsens the development and progression of HFrEF [29,30,31,32]. Plasma renin activity increases with HF stages and varies between patient subsets [27,33].…”