Statins, in addition to their beneficial lipid modulation effects, exert a variety of several so-called "pleiotropic" actions that may result in clinical benefits. Rosuvastatin, the last agent of the class to be introduced, has proved remarkably potent in reducing low-density lipoprotein cholesterol levels. At present, no large-scale primary or secondary prevention clinical trials document either its long-term safety or its effectiveness in preventing cardiovascular events. A substantial number of experimental and clinical studies have indicate favorable effects of rosuvastatin on endothelial function, oxidized low-density lipoprotein, inflammation, plaque stability, vascular remodeling, hemostasis, cardiac muscle, and components of the nervous system. Available data regarding the effects of rosuvastatin on renal function and urine protein excretion do not seem to raise any safety concerns. Whether the established "pleiotropy" and/or lipid-lowering efficacy of rosuvastatin may translate into reduced morbidity and mortality remains to be shown in ongoing clinical outcome trials.

Reduced cigarette smoke exposure in adult smokers switching from a conventional cigarette (CC) to a potential exposure-reduced electrically heated cigarette smoking system (EHCSS) and no smoking (NS) improved exercise performance. The effects of reduced smoke exposure on the prognostic parameters heart rate (HR) and rate—pressure-product (RPP) were investigated. A total of 18 male adult CC-smokers were randomized in a 3-period cross-over study to CC, EHCSS, or to NS for 3 days each before performing spiroergometry. Exposure parameters declined from CC to EHCSS and to NS. Resting HR and RPP increased from NS to EHCSS and to CC. Chronotropic response/HR recovery were more pronounced in NS than in EHCSS and CC. RPPmax was similar in NS and EHCSS and lowest during CC. Reduced tobacco smoke exposure for 3 days improved the prognostic parameters HR and RPP in an apparently dose-dependent manner.

We analyzed the feasibility of an intensive lipid-lowering strategy based on a starting dose of atorvastatin according to baseline and target low-density lipoprotein cholesterol (LDL-C) level (<2.6 mmol/L) in 202 statin-naïve patients with type 2 diabetes within 24 weeks. They were assigned to receive a daily dosage of atorvastatin based on their initial LDL-C levels. The primary endpoint was the proportion of patients achieving the LDL-C goal after 24 weeks of treatment. No changes were made in prescribed atorvastatin dosage. At the study end, 66.5% of the 188 patients completing the trial reached the LDL-C target (75%, 67%, 58% and 59% with 10, 20, 40 and 80 mg per day of atorvastatin, respectively) reached LDL-C target. Atorvastatin reduced the levels of total cholesterol, LDL-C, high density lipoprotein cholesterol (HDL-C) and tryglicerides by 29%, 35%, 3% and 22%, respectively, and all statin doses were well tolerated. Thus, individualizing the starting dose of atorvastatin according to baseline and target LDL-C levels, allowed a high proportion of type 2 diabetic patients to achieve the target within 24 weeks.

It is hypothesized that preexisting cardiovascular disease could affect the susceptibility to direct and acute cardiotoxic effects of ultrafine air pollutants. Ultrafine particles (UFP) isolated from 12.5 mg of diesel particulate matter (National Institute of Standards and Technology) were infused into isolated Langendorffperfused hearts obtained from spontaneously hypertensive rats (SHR) and normotensive control Wistar— Kyoto rats (WKY). Perfusion for 30 minutes with UFP reduced cardiac function in both groups—but to a greater extent in WKY. In SHR, developed pressure was reduced by 24.1 ± 4.4% of baseline and maximal dP/dt was reduced by 19.8 ± 4.9%; in WKY, developed pressure was reduced by 43.5 ± 7.3% and maximal dP/dt by 41.8 ± 8.2% (P < .05 for maximal dP/dt in SHR vs WKY). Coronary flow was decreased by 30.3% versus 53.7% in SHR versus WKY ( P < .05). The results of this study suggest that although UFP depress myocardial contractile response and coronary flow in both SHR and WKY the underlying hypertension does not necessarily worsen the response.

To assess the role of the renin—angiotensin (RAS) and adrenergic systems in the development and progression of dilated cardiomyopathy in the Syrian cardiomyopathic hamster (SCH), echocardiographic parameters were evaluated in 6-month-old animals after 5 months of treatment with enalapril (25 mg/kg/day) plus losartan (10 mg/kg/day), or with carvedilol (1 mg/kg/day). Cardiac output indexes (COI) increased by 53% after RAS blockade and by 20% after β-blockade in SCH. Moreover, LVEDV and LVESV decreased 30% and 62%, respectively (P < .05) during RAS blockade, whereas ejection fraction (EF) increased by 48%. By contrast, carvedilol reduced LVESV by only 28% (P < .05) and increased EF by only 15% (P < .05). These results suggest that RAS activation plays a critical role in the development of cardiac dysfunction in SCH and that suppression of RAS may be more effective than β-blockade in retarding the development of cardiomyopathy in SCH. Owing to timing (pre—heart failure stage) and to the single dose protocol, the implications of this study for human subjects remain to be clarified.

Rosuvastatin was tested on rat aortic rings in the presence and absence of K⁺ channel blockers, mevalonic acid, and inhibitors of nitric oxide, prostaglandins, or endothelial-derived hyperpolarizing factor synthesis. The direct vascular effects of rosuvastatin were then evaluated by obtaining dose—response curves. Rosuvastatin relaxed aortic rings with and, to a lesser degree, without endothelium. Under both these conditions this effect was partially inhibited by L-NAME, tetraethylammonium, apamin + charybdotoxin (only administered together), or mevalonic acid. The combination of L-NAME with any of the other 3 treatments completely inhibited the effect of rosuvastatin, but indomethacin, clotrimazol, glibenclamide, charybdotoxin, or apamin alone had no effect. Therefore, the relaxation induced by rosuvastatin, even in the absence of endothelium, is partially related to 2 different mechanisms, one that is isoprenoid dependent and NO mediated and the other that is tied to the opening of Ca ²⁺-dependent K⁺ channels of the slow subfamily.

Endothelial dysfunction (ED) is characterized by impaired nitric oxide (NO) signaling, decreased NO-dependent vasodilatation, increased vascular inflammation, and diminished response to angiogenic factors. TP508 (Chrysalin^®), an angiogenic tissue repair peptide, was tested for potential effects on myocardial revascularization and ED using a porcine model of chronic myocardial ischemia. TP508 increased perfusion in ischemic regions up to16-fold (P < .02) and doubled myocardial wall thickening (P < .02) relative to placebo controls. Ischemic arterioles exhibited impaired NO-mediated vasodilation and diminished NO production. TP508 reversed ischemic effects, increasing NO-mediated vasodilation (P < .05), endothelial nitric oxide synthase (eNOS) expression, and NO production. In human endothelial cells, TP508 stimulated eNOS activation (1.84 ± 0.2-fold; P < .02), increased NO production (85 ± 18%; P < .02), and prevented hypoxia-induced eNOS downregulation (P < .01). Thus, TP508 reverses ED both in porcine ischemic hearts and cultured human endothelial cells. These results suggest potential therapeutic benefit of TP508 in myocardial revascularization and treatment of ED-related diseases.

It has been suggested that ranolazine protects the ischemic/reperfused heart by reducing diastolic wall pressure during ischemia. However, there is limited information regarding the effect of ranolazine on the anatomic zone of no-flow in a model of acute myocardial occlusion/reperfusion. Before coronary artery occlusion (CAO), open-chest anesthetized rabbits were assigned to vehicle or ranolazine. Hearts received 60 minutes of CAO and 3 hours reperfusion. Ischemic risk zone was comparable in the 2 groups. Ranolazine significantly reduced infarct size. There was a non-significant trend for the no-reflow defect to be smaller in the ranolazine group. Regional myocardial blood flow was similar in both groups in the risk zone during ischemia and at 3 hours reperfusion. Heart rates were similar in both groups, whereas mean arterial pressure was reduced in the ranolazine group. While ranolazine was effective in reducing myocardial infarct size, the mechanism by which it did this was independent of improving perfusion during either ischemia or reperfusion, suggesting that ranolazine's effect of reducing infarct size involves alternative mechanisms.