The Role of sGC Stimulators and Activators in Heart Failure With Reduced Ejection Fraction

Abstract

Over the past decade, soluble guanylate cyclase (sGC) activators and stimulators have been developed and studied to improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF). The sGC enzyme plays an important role in the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway, that has been largely untargeted by current guideline directed medical therapy (GDMT) for HFrEF. Disruption of the NO-sCG-cGMP pathway can be widely observed in patients with HFrEF leading to endothelial dysfunction. The disruption is caused by an oxidized state resulting in low bioavailability of NO and cGMP. The increase in reactive oxygen species can also result in an oxidized, and subsequently heme free, sGC enzyme that NO is unable to activate, furthering the endothelial dysfunction. The novel sGC stimulators enhance the sensitivity of sGC to NO, and independently stimulate sGC, while the sGC activators target the oxidized and heme free sGC to stimulate cGMP production. This review will discuss the pathophysiologic basis for sGC stimulator and activator use in HFrEF, review the pre-clinical and clinical data, and propose a place in the HFrEF armamentarium for this novel pharmacotherapeutic class.

The treatment with sGC stimulator improves survival of hypertensive rats with volume-overload induced heart failure and cardio-renal syndrome

“…The discovery of orally active sGC stimulators and sGC activators was a breakthrough in the pharmacology of NO/sGC/cGMP eld and seems to have an extensive therapeutic potential. Hence, there is still a great need for pre-clinical and clinical research to fully understand the mode of action and to explore their bene cial activity in cardiovascular and cardio-renal diseases in special patient populations (Cordwin et al 2021;Sandner et al 2021b).…”

“…nitroglycerine) or PDE5 inhibitors (e.g. sildena l) (Roberto B. Evora et al 2012) and more recently sGC stimulators and sGC activators were introduced (Cordwin et al 2021). The sGC activators (e.g.…”

“…The sGC activators (e.g. cinaciguat) activate both the oxidized and heme-free sGC, while sGC stimulators increase cGMP production independently of NO by activating the reduced heme moiety (Cordwin et al 2021). sGC stimulators, such as riociguat and vericiguat, exhibit also synergistic activity with NO, because they sensitize sGC to low levels of endogenous NO by stabilizing NO-sGC binding (Stasch et al 2001; Liu et al 2021).…”

New Opportunities in Heart Failure with Preserved Ejection Fraction: From Bench to Bedside… and Back

“…sGC direct stimulators, such as vericiguat and riociguat, act on the NO-sensitive form of sGC and stimulate the enzyme directly by mimicking NO in its absence and sensitizing sGC to low levels of NO [117,118].…”

Combination Sodium Nitrite and Hydralazine Therapy Attenuates Heart Failure With Preserved Ejection Fraction Severity in a “2‐Hit” Murine Model

“… 8 , 9 In the setting of HFrEF, therapeutics that positively modulate NO and downstream NO signaling have been shown to improve outcomes in patients with HFrEF including isosorbide dinitrate (ISDN)/hydralazine, soluble guanylyl cyclase stimulators and phosphodiesterase inhibitors. 10 , 11 , 12 , 13 However, unlike HFrEF, attempts to treat this NO deficiency in patients with HFpEF with nitrite therapy, nitrate, or phosphodiesterase‐5 inhibitors in the clinic have failed to improve patient outcomes. 14 , 15 , 16 , 17 , 18 …”