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

Figures

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  Figure 1. Schematic representation of the potential role of renin activity in the modulation of heart failure with reduced ejection fraction (HFrEF) via direct and indirect effects: Further complicating the physiology of renin is that it has systemic and local effects within the heart. The green arrows represent proteolytic and non-proteolytic conversions of prorenin to enzymatically active renin. Enzymatically active renin has the potential to directly modulate HFrEF progression through binding with receptors such as the (pro)renin receptor and/or IGF-2/M6P receptor. It can also act indirectly through the generation of Angiotensin I (Ang I), which acts through the angiotensin converting enzyme (ACE)-angiotensin II (Ang II)/Ang II type I receptor (AT1) and neprilysin (NEP)/Angiotensin Converting Enzyme 2 (ACE2)-Angiotensin (1–7) (Ang (1–7))/Mas axes or possibly Ang II type 2 receptor (AT2) (*).

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  Figure 2. Schematic presentation of assay principles used to measure enzymatic renin activity in plasma samples: Plasma renin activity (PRA); active renin concentration (ARC)/active plasma renin concentration (APRC); and plasma renin activity concentration (PRAC).

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  Figure 3. Plasma renin activity concentration (PRAC) in healthy control and heart failure (HF) patients with systolic dysfunction: (A) Plasma samples of healthy control patients (normal ejection fraction, EF) and patients with reduced (rEF) with and without symptomatic HFrEF. (B) Spearman correlation of PRAC to plasma N-terminal pro-atrial natriuretic peptide (N-ANP). All patients were males and 50–70 years old. Groups were healthy control subjects (n = 16), HF with reduced ejection fraction (HFrEF) asymptomatic (n = 16), and HFrEF symptomatic (n = 15). Venous blood samples were collected using EDTA-aprotinin tubes. This investigation was a part of our previously reported study [25]. This study was approved by the Institutional Review Board, and all subjects gave their informed consent for inclusion before they participated in this study [25]. Data represent mean ± SEM. ++ p < 0.01, (red, Control vs. Asymptomatic) +++ p < 0.0001 (black, Control vs. Symptomatic), * p < 0.05 (Asymptomatic vs. Symptomatic HFrEF). AU = arbitrary units. Comparisons between groups were calculated using the Mann–Whitney test. Statistical analysis was performed with GraphPad Prism 8.0.2 (GraphPad Software, San…

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  Figure 4. PRAC increases in a sex-dependent manner throughout the course of HFrEF progression in male and female mice with dilated cardiomyopathy (DCM). This figure combines published and unpublished data from our previously reported study [145]. Wild type males (WT-M): n = 5–8/age group; WT females (WT-F): n = 6–7/age group; DCM males (DCM-M): n = 7–8/age group; DCM females (DCM-F): n = 6–8/age group. +/red—Difference between WT and DCM females: ++ p < 0.01, +++ p < 0.001; +/black—Difference between WT and DCM males: +++ p < 0.001; */black—Difference between DCM females and DCM males: *** p < 0.001. Time-dependent differences between sexes (male vs. female) and differences between genotypes (WT vs. DCM) were analyzed by two-way ANOVA with the Bonferroni posttest correction using GraphPad Prism 8.0.2 (GraphPad Software, San Diego, CA, USA). Data are expressed as mean ± SEM. All animal study activities were approved [145].