Inhibition of Secretory Phospholipase A2 in Patients with Acute Coronary Syndromes: Rationale and Design of the Vascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 Weeks (VISTA-16) Trial

Abstract

sPLA(2) inhibition has the potential to exert a favorable effect on the artery wall. The VISTA-16 study will determine whether varespladib methyl has a beneficial impact on cardiovascular events in patients with an acute coronary syndrome.

PLA2G10 Gene Variants, sPLA2 Activity, and Coronary Heart Disease Risk

“…However, the recent results from the phase III trial of the varespladib, VISTA 16, show that in the setting of acute coronary syndrome, varespladib had no effect on the primary composite outcome (a composite of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, or unstable angina) and increased the risk of myocardial infarction. 37 These results validated our PLA2G2A Mendelian randomization. 24 One of the suggestions put forward by Nicholls et al, 37 concerning the failure of the inhibitor, was that it might not only inhibit the proatherogenic effects of sPLA2-IIA and -V. Referring to, but taking into account, the results from Ait-Oufella et al showing antiatherogenic effects of sPLA2-X, 35 the suggestion is that the inhibitor may at the same time reduce these antiatherogenic effects of sPLA2-X.…”

“…37 These results validated our PLA2G2A Mendelian randomization. 24 One of the suggestions put forward by Nicholls et al, 37 concerning the failure of the inhibitor, was that it might not only inhibit the proatherogenic effects of sPLA2-IIA and -V. Referring to, but taking into account, the results from Ait-Oufella et al showing antiatherogenic effects of sPLA2-X, 35 the suggestion is that the inhibitor may at the same time reduce these antiatherogenic effects of sPLA2-X.…”

Group X Secreted Phospholipase A2 Limits the Development of Atherosclerosis in LDL Receptor–Null Mice

“…How these sPLA2 isoforms exert such specific and opposite roles in atherosclerosis at the molecular level remains to be determined, but likely relies with their tissue and cell-specific expression, and their highly specific enzymatic properties on cells and lipoproteins. 22,48,49 Recently, a clinical trial testing the efficacy of A-002/varespladib, 20 a broadly specific inhibitor of sPLA2s GIIA, GV, and GX, 17 in patients with coronary artery disease was stopped for futility. 50 Our results may provide, at least in part, an explanation for the lack of efficacy of this inhibitor and clearly highlight the need for a specific targeting of individual sPLA2 enzymes with highly selective inhibitors that can discriminate between isoforms.…”

“…6,15,16 Moreover, treatment of animals with varespladib, a broadly specific inhibitor of various sPLA2 isoforms, reduces atherosclerosis development and aneurysm formation, 17,18 and clinical trials have been initiated to test the efficacy of this sPLA2 inhibitor in patients with coronary artery disease. 19,20 GX sPLA2 (PLA2G10) is distantly structurally related to other sPLA2 isoforms and is the most potent enzyme at hydrolyzing phosphatidylcholine, the most abundant phospholipid at the cell surface and on lipoproteins. 21,22 Gene targeting of Pla2g10 modulates lung inflammation in a mouse model of asthma 23,24 and attenuates neutrophil activity in ischemic myocardium, 25 suggesting that PLA2G10 is implicated in the modulation of innate and adaptive immune responses and may represent a novel therapeutic target for the treatment of cardiovascular diseases.…”

Varespladib and Cardiovascular Events in Patients With an Acute Coronary Syndrome

“…[12][13][14] The Vascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 Weeks (VISTA-16) study was designed to evaluate the effects of varespladib on cardiovascular risk in patients with ACS. 15 …”