The impact of soluble guanylate cyclase stimulator on cardiac and venous return characteristics: a framework analysis using generalized circulatory equilibrium

Background Vericiguat, a soluble guanylate cyclase (sGC) stimulator, is a guideline-recommended therapy for worsening heart failure. Although hypotension has been reported in some patients, the underlying physiological mechanisms remain poorly understood. Because arterial pressure (AP) is tightly regulated by the arterial baroreflex, we investigated the hemodynamic effects of vericiguat with particular focus on baroreflex-mediated AP regulation. Purpose To evaluate the acute hemodynamic effects of vericiguat under baroreflex-intact and -denervated conditions using the generalized circulatory equilibrium framework. Methods Twenty-one anesthetized open-chest dogs (9.6 ± 0.7 kg) were studied. AP, right atrial pressure (RAP), left atrial pressure (LAP), pulmonary arterial pressure, and cardiac output (CO) were recorded simultaneously. Arterial baroreflex denervation was achieved by bilateral stripping of the perivascular nerves around the carotid sinus and transection of the aortic depressor nerves. In the generalized circulatory equilibrium framework, the hemodynamic operating point is defined by the intersection of the integrated cardiac output curve and the venous return surface (Fig. 1A). Arterial pressure is determined by the product of systemic vascular resistance (SVR) and CO. Venous return function was assessed as stressed blood volume (SBV): SBV (mL/kg) = (CO + 19.61 × RAP + 3.49 × LAP) × 0.129. After stabilization, vericiguat (30 µg/kg/min) was infused for 10 minutes. Hemodynamic variables at baseline were compared with those at 10 minutes after infusion in both baroreflex-intact and -denervated animals. The same protocol was performed using nitroglycerin (NTG, 5 µg/kg/min) in baroreflex-intact condition. Results In baroreflex-intact conditions, vericiguat significantly reduced SVR (68.5 ± 14.9 vs. 54.2 ± 11.5 mmHg·min/L, P=0.013) and AP (90.2 ± 6.6 vs. 77.3 ± 6.5 mmHg, P=0.002), while increasing CO (145.1 ± 22.2 vs. 155.3 ± 23.4 mL/min/kg, P=0.044). Vericiguat did not significantly change SBV (29.4 ± 2.9 vs. 30.5 ± 2.8 mL/kg, P=0.28). In contrast, NTG significantly decreased SBV (35.2 ± 1.1 vs. 31.5 ± 1.2 mL/kg, P = 0.007) and CO (165.2 ± 9.2 vs. 147.5 ± 11.3 mL/min/kg, P = 0.002) without significant change in SVR (58.9 ± 10.2 vs. 58.7 ± 9.8 mmHg·min/L, P=0.90). In baroreflex-denervated conditions, vericiguat reduced SVR more markedly while SBV remained unchanged and CO was not significantly altered (Fig. 1B). Conclusions Vericiguat increased CO primarily through LV afterload reduction without altering SBV. SBV responses differed significantly between vericiguat and NTG. Baroreflex impairment amplified vericiguat-induced reductions in SVR and AP. These findings suggest an increased risk of hypotension and underscore the importance of individualized therapy in heart failure patients with impaired baroreflex function.