Passive smoking is associated with dose-related impairment of endothelium-dependent dilatation in healthy young adults, suggesting early arterial damage.

Although carotid IMT is significantly correlated with extent and severity of CAD, the relationship is weak. This relatively poor correlation (r2 < .10) should be considered in the interpretation of clinical trials that use carotid IMT as a surrogate end point for coronary atherosclerosis.

In hypercholesterolemic rabbits, oral L -arginine (the substrate for endothelium derived nitric oxide) attenuates endothelial dysfunction and atheroma formation, but the effect in hypercholesterolemic humans is unknown. Using high resolution external ultrasound, we studied arterial physiology in 27 hypercholesterolemic subjects aged 29 Ϯ 5 (19-40) years, with known endothelial dysfunction and LDL-cholesterol levels of 238 Ϯ 43 mg/dl. Each subject was studied before and after 4 wk of L -arginine (7 grams ϫ 3/ day) or placebo powder, with 4 wk washout, in a randomized double-blind crossover study. Brachial artery diameter was measured at rest, during increased flow (causing endothelium-dependent dilation, EDD) and after sublingual glyceryl trinitrate (causing endothelium-independent dilation). After oral L -arginine, plasma L -arginine levels rose from 115 Ϯ 103 to 231 Ϯ 125 mol/liter ( P Ͻ 0.001), and EDD improved from 1.7 Ϯ 1.3 to 5.6 Ϯ 3.0% ( P Ͻ 0.001). In contrast there was no significant change in response to glyceryl trinitrate. After placebo there were no changes in endothelium-dependent or independent vascular responses. Lipid levels were unchanged after L -arginine and placebo.

The vasodilator response to exogenous NO is impaired in asymptomatic subjects with reduced EDD, consistent with smooth muscle dysfunction in adults at risk for atherosclerosis.

Vascular reactivity is impaired in the systemic arteries of asymptomatic young adults with insulin-dependent diabetes and may represent early large-vessel disease. The degree of impairment is related to the duration of diabetes, and these patients appear particularly vulnerable to damage from LDL cholesterol, even at levels considered acceptable in nondiabetic subjects.

Male gender is an independent risk factor for coronary artery disease, and androgen administration has been associated with increased atherosclerosis in experimental animals. Since endothelial dysfunction is an important event in the atherogenic process, we hypothesized that androgen deprivation in adult men might be associated with enhanced arterial endothelial function. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (causing endothelium-dependent dilatation) and after nitroglycerin (an endothelium-independent dilator). We studied 30 adult males aged 40 to 70 years: 10 had had bilateral orchidectomy and/or maximal androgen blockade for > or = 6 months for treatment of prostate cancer, and all were in complete remission (group 1). Ten healthy controls (group 2) and 10 controls who had remission from nonprostate cancers (group 3) were matched for age and smoking history. Testosterone levels were lower in men in group 1 versus groups 2 or 3 (0.8 +/- 0.1 versus 19.2 +/- 8.4 or 16.1 +/- 4.9 nmol/L, P < .001). By contrast, endothelium-dependent dilatation was markedly higher in group 1 than in groups 2 or 3 (6.2 +/- 3 versus 2.7 +/- 2 or 2.0 +/- 1.9%, P < .001). The nitroglycerin response was similar in all three groups (P = .92). On multivariate analysis, increased endothelium-dependent dilatation was significantly associated with low serum testosterone levels (P = .001) but not with cholesterol levels or with a past history of malignancy (P > .25). The withdrawal of male sex hormones may be associated with enhanced endothelial function in adult men. This is consistent with a deleterious effect of physiologic levels of male sex steroids on the arterial wall.

Oxidative stress is implicated in atherogenesis, yet most clinical trials with antioxidants, particularly vitamin E, have failed to protect against atherosclerotic diseases. A striking exception is probucol, which retards atherosclerosis in carotid arteries and restenosis of coronary arteries after angioplasty. Because probucol has in vitro cellular-protective effects independent of inhibiting lipid oxidation, we investigated the mode of action of probucol in vivo. We used three models of vascular disease: apolipoprotein E–deficient mice, a model of atherosclerosis; rabbit aortic balloon injury, a model of restenosis; and carotid injury in obese Zucker rats, a model of type 2 diabetes. Unexpectedly, we observed that the phenol moieties of probucol were insufficient, whereas its sulphur atoms were required for protection. Probucol and its sulphur-containing metabolite, but not a sulphur-free phenolic analogue, protected via cell-specific effects on inhibiting macrophage accumulation, stimulating reendothelialization, and inhibiting vascular smooth muscle cell proliferation. These processes were mediated via induction of heme oxygenase-1 (HO-1), an activity not shared by vitamin E. Our findings identify HO-1 as the molecular target of probucol. They indicate 2-electron rather than radical (1-electron) oxidants as important contributors to atherogenesis, and point to novel lead compounds for therapeutic intervention against atherosclerotic diseases.

BackgroundPrograms targeting the standard modifiable cardiovascular risk factors (SMuRFs: hypertension, diabetes mellitus, hypercholesterolemia, smoking) are critical to tackling coronary heart disease at a community level. However, myocardial infarction in SMuRF‐less individuals is not uncommon. This study uses 2 sequential large, multicenter registries to examine the proportion and outcomes of SMuRF‐less ST‐segment–elevation myocardial infarction (STEMI) patients.Methods and ResultsWe identified 3081 STEMI patients without a prior history of cardiovascular disease in the Australian GRACE (Global Registry of Acute Coronary Events) and CONCORDANCE (Cooperative National Registry of Acute Coronary Syndrome Care) registries, encompassing 42 hospitals, between 1999 and 2017. We examined the proportion that were SMuRF‐less as well as outcomes. The primary outcome was in‐hospital mortality, and the secondary outcome was major adverse cardiovascular events (death, myocardial infarction, or heart failure, during the index admission). Multivariate regression models were used to identify predictors of major adverse cardiovascular events. Of STEMI patients without a prior history of cardiovascular disease 19% also had no history of SMuRFs. This proportion increased from 14% to 23% during the study period (P=0.0067). SMuRF‐less individuals had a higher in‐hospital mortality rate than individuals with 1 or more SMuRFs. There were no clinically significant differences in major adverse cardiovascular events at 6 months between the 2 groups.ConclusionsA substantial and increasing proportion of STEMI presentations occur independently of SMuRFs. Discovery of new markers and mechanisms of disease beyond standard risk factors may facilitate novel preventative strategies. Studies to assess longer‐term outcomes of SMuRF‐less STEMI patients are warranted.