The incidence of heart failure (HF) continues to increase, along with its associated
morbidity, mortality, and cost. Novel therapeutic options have been proposed to address
the needs of especially the patients who remain symptomatic despite optimal medical
therapy. A number of factors lead to ongoing symptoms in patients with chronic heart
failure (HF), including persistent abnormalities in myocardial function, neurohormonal
dysregulation, and of the peripheral vascular system.
The Phase 3 VICTORIA trial examined the efficacy of Vericiguat, a novel oral soluble
guanylate cyclase (sGC) stimulator in patients with HF and reduced ejection fraction
(HFrEF). Vericiguat enhances the cyclic guanosine monophosphate (GMP) pathway by directly
stimulating soluble guanylate cyclase independent of nitric oxide (NO). The VICTORIA
study showed that patients who received Vericiguat 2.5 mg once daily up-titrated to 10 mg
daily had a lower incidence of the primary endpoint of cardiovascular death or first HF
hospitalization compared to placebo 1.
Determining the exact mechanism, or the respective contribution of different mechanisms,
through which Vericiguat improves outcomes in HFrEF may allow for better tailoring of its
use to individual patients. The preliminary results of an echocardiography sub-study
indicate that there was no significant difference in the change of left ventricular
ejection fraction (LVEF) between baseline and study end among patients assigned to the
active drug vs placebo. We hypothesize that the beneficial effects of Vericiguat in HF
may not be linked to improvement in myocardial contractility, but rather to the effects
of sGC stimulation on the peripheral vasculature. This was not directly tested in
VICTORIA.
Studies from our group 2, 3 and others 4, 5 have collectively identified a marked
reduction in vascular function, as determined by flow-mediated vasodilation (FMD)
testing, in patients with HFrEF despite optimized pharmacotherapy, indicative of a
pervasive, disease-related reduction in endothelial health. Endothelial dysfunction is
characterized by NO dysregulation, inflammation, and oxidative stress. These factors
impair the capacity of the vascular endothelium to perform its numerous functions
including regulation of vascular tone and inflammatory processes. Importantly,
endothelial dysfunction is also associated with reduced quality of life 6 and decreased
physical capacity 7, 8 in patients with HFrEF. These studies suggest that the
consequences of vascular dysfunction are far-reaching and support the concept that
interventions targeting the peripheral vasculature to induce systemic effects could prove
beneficial in cardiovascular disease. This is particularly relevant given the known
relationship between endothelial dysfunction and mortality risk in patients with HFrEF 9,
10. Improvement in peripheral vascular function in patients with HFrEF would in turn lead
to improved physical capacity and health-related quality of life (hrQOL).
Preclinical studies provide evidence of sGC stimulation favorably affecting peripheral
vascular function. In a rat model of HF, treatment with Ataciguat normalized endothelial
function, improved sensitivity to NO, and reduced platelet activation 11. However, the
impact of Vericiguat on vascular health has not been evaluated in human HF. A recent
study also examined the effect of Vericiguat on inflammation and oxidative stress in HF
12. After 12 weeks of Vericiguat therapy, high sensitivity CRP (hsCRP) decreased
significantly, and the probability of hsCRP value being ≤3.0 mg/L at the end of the study
was higher in patients treated with Vericiguat compared to placebo. Although the impact
of Vericiguat on upstream, inflammatory cytokines such as IL-1β and IL-18 have not been
determined, there is strong evidence supporting elevation of these biomarkers that
reflect NRLP3 inflammasome activation in patients with HFrEF13, 14. Given the recent
success in clinical trials targeting the inflammasome in heart failure 15 and recent
evidence for the efficacy of sGC stimulation to mitigate NLRP3 inflammasome activity in
other organ systems 16, there is strong rationale for the expectation that Vericiguat may
favorably impact both upstream (IL-1β, IL-18, TNF-α and IL-6) and downstream (hsCRP)
inflammatory biomarkers. Importantly, an inverse correlation between biomarkers of
inflammation and endothelial function has been observed in other patient groups 13,
supporting the concept that Vericiguat treatment may result in greater improvements in
vascular function in those individuals who experience the largest reductions in vascular
inflammation.