Nitrite circumvents platelet resistance to nitric oxide in patients with heart failure preserved ejection fraction and chronic atrial fibrillation

Abstract

AimsHeart failure (HF) is a pro-thrombotic state. Both platelet and vascular responses to nitric oxide (NO) donors are impaired in HF patients with reduced ejection fraction (HFrEF) compared with healthy volunteers (HVs) due to scavenging of NO, and possibly also reduced activity of the principal NO sensor, soluble guanylate cyclase (sGC), limiting the therapeutic potential of NO donors as anti-aggregatory agents. Previous studies have shown that nitrite inhibits platelet activation presumptively after its reduction to NO, but the mechanism(s) involved remain poorly characterized. Our aim was to compare the effects of nitrite on platelet function in HV vs. HF patients with preserved ejection fraction (HFpEF) and chronic atrial fibrillation (HFpEF–AF), vs. patients with chronic AF without HF, and to assess whether these effects occur independent of the interaction with other formed elements of blood.Methods and resultsPlatelet responses to nitrite and the NO donor sodium nitroprusside (SNP) were compared in age-matched HV controls (n = 12), HFpEF–AF patients (n = 29), and chronic AF patients (n = 8). Anti-aggregatory effects of nitrite in the presence of NO scavengers/sGC inhibitor were determined and vasodilator-stimulated phosphoprotein (VASP) phosphorylation was assessed using western blotting. In HV and chronic AF, both nitrite and SNP inhibited platelet aggregation in a concentration-dependent manner. Inhibition of platelet aggregation by the NO donor SNP was impaired in HFpEF-AF patients compared with healthy and chronic AF individuals, but there was no impairment of the anti-aggregatory effects of nitrite. Nitrite circumvented platelet NO resistance independently of other blood cells by directly activating sGC and phosphorylating VASP.ConclusionWe here show for the first time that HFpEF-AF (but not chronic AF without HF) is associated with marked impairment of platelet NO responses due to sGC dysfunction and nitrite circumvents the ‘platelet NO resistance’ phenomenon in human HFpEF, at least partly, by acting as a direct sGC activator independent of NO.

EHRA/EAPCI expert consensus statement on catheter-based left atrial appendage occlusion – an update

“…In this context, lower expression of nitric oxide synthase has been shown in animals with AF 62 . The mechanisms underlying this may be multifactorial 63 .…”

Impairment of Anti-Aggregatory Responses to Nitric Oxide and Prostacyclin: Mechanisms and Clinical Implications in Cardiovascular Disease

“…CHF, a condition that is also characterized by a prothrombotic state and enhanced oxidative stress [62], provides another example of platelet resistance to NO [11,[63][64][65]. The substantial clinical evidence that CHF represents a prothrombotic disorder includes post-mortem studies showing that many such patients die of coronary thromboses [66].…”

“…Overall, it might be suggested that NO 2 − represents a practicable means for preserving sGC activation under hypoxia, or within the venous circulation, but strictly speaking, it does not circumvent NO resistance. On the other hand, a recent study reported that nitrite can at least partially circumvent platelet NO resistance independently of other blood cells by directly activating sGC and phosphorylating VASP [64]. The study assessed collagen-induced aggregation in washed platelets that were obtained from HF patients with reduced ejection fraction in comparison with healthy subjects.…”

Nitroxyl: A Novel Strategy to Circumvent Diabetes Associated Impairments in Nitric Oxide Signaling

“…Thus, in platelets from patients with ischemic heart disease, in whom NO• resistance is evident, the anti-aggregatory effects of nitrite were found also to be diminished (Dautov et al, 2014). By contrast, in heart failure patients with preserved ejection fraction (HFpEF), resistance to the anti-aggregatory actions of SNP was evident, yet the ability of nitrite to inhibit platelet aggregation was maintained (Borgognone et al, 2018). Whilst these anti-aggregatory actions of nitrite were mediated via sGC activation, they were only due, in part, to NO•.…”