Baroreflex activation therapy (BAT), which electrically stimulates carotid sinus baroreceptors to modulate autonomic tone, has emerged as a novel adjunct to guideline-directed medical therapy for resistant hypertension and heart failure. Beyond its established cardiovascular benefits, emerging preclinical and early-phase clinical data suggest that BAT may favorably influence renal function and cardiorenal interactions. By suppressing sympathetic nervous system activity and downregulating the renin-angiotensin-aldosterone system, BAT improves renal hemodynamics and may counteract key mechanisms leading to diuretic resistance. The latter represents a common and clinically significant challenge in patients with advanced heart failure, in whom impaired renal perfusion, neurohormonal activation, and tubular remodeling all contribute to reduced diuretic responsiveness and worsening kidney function. Early evidence indicates that BAT may preserve glomerular filtration rate, reduce proteinuria and improve urinary sodium excretion, suggesting potential renoprotective effects and a therapeutic role in mitigating diuretic resistance. However, these findings remain limited by small sample sizes, short follow-up periods, and heterogenous study populations across diverse clinical settings. This review synthesizes key physiologic mechanisms linking baroreflex signal modulation to renal outcomes and evaluates available clinical data. While BAT offers established cardiovascular benefits in heart failure, its renoprotective and diuretic-sparing potential remains investigational and lacks validation from randomized clinical trials. Dedicated prospective large-scale randomized studies are essential to establish long-term renal efficacy across the cardiorenal disease spectrum.
Targeted protein degradation is an active area of pharmaceutical research and development with the promise to increase the potential number of druggable targets across numerous therapeutic areas. One challenge in their current development has been unexpected cardiovascular findings that have been reported during clinical trials with some degraders, primarily delayed ventricular repolarization manifested as longer corrected QT (QTc) intervals and potential for increased arrhythmic risk. The objective of this study was to investigate whether guinea pigs might be a suitable small animal model to characterize potential cardiovascular effects earlier in degrader development in alignment with 3R principles. The pharmacokinetics and cardiovascular effects were measured in naïve guinea pigs using 4 distinct degraders previously tested in non-human primates. We found exposures were broadly lower in guinea pigs than non-human primates, and dose-limiting toxicity was observed with some degraders after increasing the dose (mg/kg) in guinea pigs to account for the lower exposures. No consistent CV changes were observed across all 4 degraders, which was not translatable to the QTc interval prolongation observed in non-human primates administered the same degraders. Lastly, an anesthetized guinea pig model was investigated to evaluate acute cardiovascular changes at elevated in vivo exposures beyond those achieved in the conscious preparations. However, no consistent changes were observed in QTc intervals. In this context of this preliminary investigation of 4 degraders, the guinea pig model was not a suitable option for evaluating cardiovascular liabilities.
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance. Sotatercept, an activin-signaling inhibitor, is a novel therapy targeting this pathology. We conducted a systematic review and meta-analysis to assess its efficacy and safety in PAH. A systematic search of PubMed, Cochrane CENTRAL, Scopus, and Web of Science was conducted, to identify randomized controlled trials (RCTs) evaluating Sotatercept in adults with PAH. Data were pooled using random-effects models to estimate mean differences (MDs) and risk ratios (RRs) with 95% confidence intervals (CIs). Four RCTs enrolling 921 patients were included. Compared with placebo, Sotatercept significantly improved 6-minute walk distance (MD 30.54 m, 95% CI 4.05–57.04, P=0.02), WHO functional class (RR 1.71, 95% CI 1.37–2.15, P<0.00001), multicomponent improvement (RR 2.77, 95% CI 1.45–5.29, P=0.002), pulmonary vascular resistance (MD −197.01 dyn⋅s⋅cm −5 , 95% CI −213.16 – −180.86, P<0.00001), and reduced clinical worsening events (RR 0.28, 95% CI 0.21–0.38, P<0.00001). There were no significant differences in NT-proBNP levels or all-cause mortality. Safety analysis showed lower risks of serious adverse events (AEs), peripheral edema, and right ventricular failure, but higher rates of bleeding, epistaxis, and drug-related AEs. Sotatercept demonstrated meaningful clinical benefits in exercise capacity, hemodynamics, and disease progression among patients with PAH, with a generally acceptable safety profile. These findings support Sotatercept as a promising adjunct to standard therapy, though longer-term trials are needed to confirm durability and survival impact.
