Soluble guanylate cyclase: a potential therapeutic target for heart failure

Abstract

The number of annual hospitalizations for heart failure (HF) and the mortality rates among patients hospitalized for HF remains unacceptably high. The search continues for safe and effective agents that improve outcomes when added to standard therapy. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway serves an important physiologic role in both vascular and non-vascular tissues, including regulation of myocardial and renal function, and is disrupted in the setting of HF, leading to decreased protection against myocardial injury, ventricular remodeling, and the cardio-renal syndrome. The impaired NO-sGC-cGMP pathway signaling in HF is secondary to reduced NO bioavailability and an alteration in the redox state of sGC, making it unresponsive to NO. Accordingly, increasing directly the activity of sGC is an attractive pharmacologic strategy. With the development of two novel classes of drugs, sGC stimulators and sGC activators, the hypothesis that restoration of NO-sGC-cGMP signaling is beneficial in HF patients can now be tested. Characterization of these agents in pre-clinical and clinical studies has begun with investigations suggesting both hemodynamic effects and organ-protective properties independent of hemodynamic changes. The latter could prove valuable in long-term low-dose therapy in HF patients. This review will explain the role of the NO-sGC-cGMP pathway in HF pathophysiology and outcomes, data obtained with sGC stimulators and sGC activators in pre-clinical and clinical studies, and a plan for the further clinical development to study these agents as HF therapy.

Novel Therapies for Heart Failure – Where Do They Stand? –

“…56-59 Agents that stimulate or activate sGC directly offer a novel strategy for increasing cGMP levels that does not depend on NO availability. 60 Riociguat, a sGC stimulator already approved by the US FDA for treating chronic thromboembolic pulmonary hypertension and pulmonary artery hypertension, 58,61 was studied in HF patients in the LEPHT (Left ventricular systolic dysfunction associated with Pulmonary Hypertension riociguat Trial) study. 62, 63 This phase 2 study enrolled 201 symptomatic HFrEF with pulmonary hypertension (mean PAP ≥25 mmHg at rest).…”

Impact of Comorbidities on Myocardial Remodeling and Dysfunction In Heart Failure with Preserved Ejection Fraction

“…Recently, two classes of drugs have been discovered, the sGC activators and sGC stimulators, which target two different redox states of sGC: the NO-sensitive reduced (ferrous) sGC and NOinsensitive oxidized (ferric) sGC respectively [217]. Oxidative stress favours heme-free sGC, which is unresponsive to NO.…”

“…Oxidative stress favours heme-free sGC, which is unresponsive to NO. Hence, oxidative stress synergistically hampers NO-cGMP signaling through sGC oxidation and through ROS-mediated scavenging of NO [218,219], thereby compromising NO-sGC-cGMP mediated signaling [217,220]. The sGC stimulators have a dual mode of action; they sensitize sGC to low levels of NO and can stimulate sGC directly in the absence of endogenous NO.…”

Progress or lack of progress in hospitalized heart failure

“…Accordingly, short-term use was no longer investigated [39]. The chronic use of this agent is currently under active investigation and may reveal more favorable results [40]. The addition of a renin inhibitor (aliskiren) to standard therapy had no effect in overall post-discharge mortality and rehospitalization but was associated with a marked decrease in a number of biomarkers including troponin, aldosterone and natriuretic peptides [3].…”