Author + information
- ↵⁎Reprint requests and correspondence:
Dr. Dominick J. Angiolillo, University of Florida College of Medicine–Jacksonville, 655 West 8th Street, Jacksonville, Florida 32209
In the HOPE (Heart Outcomes Prevention Evaluation) trial, the angiotensin-converting enzyme (ACE) inhibitor ramipril reduced the incidence of major cardiovascular events, including cardiovascular death, stroke, and myocardial infarction, in patients who had clinical evidence of vascular disease or diabetes mellitus plus 1 additional cardiovascular risk factor but presented without heart failure or low left ventricular ejection fraction (1). In a population at lower cardiovascular risk than that enrolled in the HOPE trial and similarly presenting without apparent heart failure, the EUROPA (European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease) investigators found that perindopril was likewise effective in reducing the rates of cardiovascular death and myocardial infarction (2). Overall, these studies have provided a solid basis for secondary prevention guidelines to assert that all patients with coronary and other atherosclerotic vascular disease manifestations, regardless of left ventricular function and in the absence of contraindications, should be treated with ACE inhibitors in addition to aspirin, beta-blockers, statins, and aggressive risk-factor modification (3). Because the HOPE and EUROPA populations did not include patients with hypertension unless blood pressure was already sufficiently controlled with other treatments, ACE inhibitors are likely to exert direct actions beyond their hemodynamic effects. The results of these 2 trials have therefore stimulated research toward understanding how modulating the renin-angiotensin system protects blood vessels and possibly contributes to atherothrombotic risk reduction.
In this issue of the Journal, Willoughby et al. (4) add another piece to the puzzle that elucidates putative effects of ramipril beyond previously documented beneficial changes to vasomotor function. The investigators addressed the question of whether inhibiting the ACE with ramipril results in more potent platelet responsiveness to the disaggregating effects of nitric oxide (NO) and thus beneficially affect the so-called NO resistance phenomenon. NO is formed from l-arginine by a 2-step oxidation to l-citrulline catalyzed by the enzyme NO synthase (NOS). One of the 3 isoforms of NOS identified to date (NOS3) is expressed constitutively in endothelial cells, which represent the main source of vascular NO under physiological conditions. Newly synthetized NO prompts a vasodilator effect by diffusing from the endothelial cells to the subjacent vascular smooth muscle cells, where it activates in a paracrine manner the production of the second messenger cyclic guanosine monophosphate (cGMP) by soluble heme-containing enzyme guanylyl cyclase. Other cells expressing NOS3 in the cardiovascular system include cardiac myocytes, red blood cells, megakaryocytes, and platelets. Platelets produce smaller amounts of NO than endothelial cells, and NO generated from platelets exerts its effects in an autocrine manner (Fig. 1). Stimulation of platelets by aggregating agents activates platelet NOS3 and generates NO as a negative feedback mechanism regulating platelet recruitment, adhesion, and activation. NO generation is impaired in cardiovascular disease and in the presence of coronary risk factors and therefore might contribute to the occurrence of thrombotic complications in combination with the well-documented decrease in endothelium-derived NO in these conditions (5).
In the study by Willoughby et al. (4), HOPE-like patients (n = 119) were randomized in a double-blind fashion to receive ramipril (n = 60) or placebo (n = 59). At 12 weeks, there were no significant changes in the extent of adenosine diphosphate–induced aggregation or in platelet responsiveness to the antiaggregatory effects of NO-donor sodium nitroprussiate in both groups. However, when analyzing changes in sodium nitroprussiate response relative to those in adenosine diphosphate response to address their physiological antagonism, an increase in NO responsiveness was found in the ramipril group (p = 0.001), with onset of the effect within 4 weeks. Intriguingly, the increase in responsiveness with ramipril was confined mostly to patients with baseline severe NO resistance (p = 0.03), while no effect was noted over placebo in patients with normal baseline platelet response. Ramipril marginally reduced blood pressure but positively affected surrogate clinical markers for arterial stiffness and endothelial dysfunction. In a further mechanistic study of a less NO responsive cohort (n = 19), ramipril was found to ameliorate NO resistance as early as at 2 weeks, with parallel increases in cGMP generation in response to sodium nitroprussiate and no changes in plasma levels of thrombospondin-1, a modulator of soluble guanylyl cyclase activity, thereby implying that ramipril reduces NO resistance by facilitation of thrombospondin-1–independent cGMP generation.
The investigators should be commended for an elegantly performed study, which indeed provides potential mechanistic explanations for the reduction in cardiovascular ischemic events observed with ACE inhibitors in the HOPE and EUROPA trials. However, a number of unsolved questions remain. First, platelet NO responsiveness is a relatively narrow characteristic of platelet physiology, and the contribution of differences in platelet NO responsiveness to atherothrombotic risk in vivo remains unclear. By promoting the activation of the cGMP-dependent protein kinase, NO causes inhibition of platelet activation through several pathways, including synergistic mechanisms to reduce cytosolic Ca2+ levels and indirect inhibition of thromboxane A2 and glycoprotein IIb/IIIa receptors. However, NO can regulate platelet function independently of cGMP, such as by inhibiting exocytosis of platelet granules and recruitment of platelets to the growing thrombus. Further studies are clearly needed to clarify the magnitude and contribution of both cGMP-dependent and cGMP-independent pathways through which NO may exert its effects on platelets. Second, the pathophysiological basis (i.e., reduction in guanylate cyclase sensitivity to NO and/or scavenging of the released NO by O2-), as well as the predictive factors and clinical implications of changes in NO responsiveness, are uncertain. Therefore, linking findings from mechanistic studies to large trials with cardiovascular endpoints may sound speculative, when evidence of a direct relationship with clinical outcomes is lacking. Indeed, the possible association between ACE inhibitors and platelet function may have been strengthened by investigating other aspects of platelet physiology that have been more clearly correlated with clinical cardiovascular outcomes, such as light transmittance aggregometry (rather than whole-blood impedance aggregometry) in response to adenosine diphosphate and other agonists, and flow cytometry–determined markers of platelet activation (i.e., P-selectin, fibrinogen). It should be noted that the reported effects of ACE inhibitors on platelets as well as thrombotic markers have been quite marginal to date. Finally, with only 19 “extreme” patients with impaired platelet NO responsiveness and no placebo comparator arm, the mechanistic substudy remains at best hypothesis generating, and the contribution of the platelet cGMP pathway in the ACE inhibitor effect should be further reinforced and investigated.
Dr. Angiolillo has received honoraria for lectures from AstraZeneca, Abbott Vascular, Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, and Daiichi Sankyo; consulting fees from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Daiichi Sankyo, The Medicines Company, Portola, Novartis, Medicure, Accumetrics, Arena Pharmaceuticals, Merck, Abbott Vascular, Evolva, and AstraZeneca; and research grants from Bristol-Myers Squibb, Sanofi-Aventis, GlaxoSmithKline, Otsuka, Boston Scientific, Eli Lilly, Daiichi Sankyo, The Medicines Company, Portola, Accumetrics, Merck/Schering-Plough, AstraZeneca, Eisai, and Johnson & Johnson. Dr. Capodanno has received honoraria from Eli-Lilly, AstraZeneca, and Boston Scientific.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
- American College of Cardiology Foundation
- Fox K.M.,
- European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease Investigators
- Smith S.C. Jr.,
- Benjamin E.J.,
- Bonow R.O.,
- et al.
- Willoughby S.R.,
- Rajendran S.,
- Chan W.P.,
- et al.
- Gkaliagkousi E.,
- Ritter J.,
- Ferro A.