UPEI-100, a conjugate of lipoic acid and apocynin, mediates neuroprotection in a rat model of ischemia/reperfusion.

Previous work in our laboratory has provided evidence that preadministration of apocynin and lipoic acid at subthreshold levels for neuroprotection enhanced the neuroprotective capacity when injected in combination. Therefore, the present investigation was designed to determine whether a co-drug consisting of lipoic acid and apocynin functional groups bound by a covalent bond, named UPEI-100, is capable of similar efficacy using a rodent model of stroke. Male rats were anesthetized with Inactin (100 mg/kg iv), and the middle cerebral artery was occluded for 6 h or allowed to reperfuse for 5.5 h following a 30-min occlusion (ischemia/reperfusion, I/R). Preadministration of UPEI-100 dose-dependently decreased infarct volume in the I/R model (P < 0.05), but not in the middle cerebral artery occlusion model of stroke. Using the optimal dose, we then injected UPEI-100 during the stroke or at several time points during reperfusion, and significant neuroprotection was observed when UPEI-100 was administered up to 90 min following the start of reperfusion (P < 0.05). A time course for this neuroprotective effect showed that UPEI-100 resulted in a decrease in infarct volume following 2 h of reperfusion compared with vehicle. The time course of this neuroprotective effect was also used to study several mediators along the antioxidant pathway and showed that UPEI-100 increased the level of mitochondrial superoxide dismutase and oxidized glutathione and decreased a marker of lipid peroxidation due to oxidative stress (HNE-His adduct formation). Taken together, the data suggest that UPEI-100 may utilize similar pathways to those observed for the two parent compounds; however, it may also act through a different mechanism of action.

Protected carotid artery stenting in patients at high risk for carotid endarterectomy.

OBJECTIVES: To compare the 30-day, six-month, and one-year outcomes of carotid artery stenting (CAS) and carotid endarterectomy (CEA) in male veterans, and to identify any predictors of adverse outcomes. CAS has been shown to be non-inferior to CEA in patients at high-risk for CEA. The outcome of CAS compared to low-risk CEA is less clear. METHODS: Retrospective analysis of 96 consecutive patients who underwent CAS (N = 31) or CEA (N = 65). The cumulative 30-day, six-month, and one-year incidence of ipsilateral transient ischemic attack (TIA) or stroke, restenosis or reocclusion, need for target vessel revascularization, non-fatal myocardial infarction (MI), and death were compared. RESULTS: All patients in the CAS group were at high risk for CEA. Among the CEA group, 50 (76.9%) were at high risk and the remaining 15 (23.1%) were considered to be at low risk. The cumulative incidence of adverse outcomes with CAS and CEA, respectively, at 30 days (3.2% vs 9.2%, P = ns), six months (3.2 vs 18.5%, P = 0.047), and one year (9.7% vs 18.5%, P = ns) favored CAS. This difference was primarily due to adverse events in the high-risk CEA patients. There was no significant difference in outcome between the CAS and low-risk CEA groups. The independent significant predictors for adverse outcomes within six months were the group (P = 0.047) and number of risk factors (P = 0.01). Interestingly, the use of angiotensin-converting enzyme inhibitors (ACE-I) predicted adverse outcomes within one year (P = 0.01). CONCLUSION: CAS may be superior to high-risk CEA with better six-month outcomes. The outcomes with CAS were not significantly different compared to low-risk CEA, suggesting that CAS may be non-inferior to low-risk CEA.

Effects of yoga on inflammation and exercise capacity in patients with chronic heart failure.

BACKGROUND: Despite recent advances in pharmacologic and device therapy, morbidity and mortality from heart failure (HF) remain high. Yoga combines physical and breathing exercises that may benefit patients with HF. We hypothesized that an 8-week regimen of yoga in addition to standard medical therapy would improve exercise capacity, inflammatory markers, and quality of life (QoL) in patients with HF. METHODS AND RESULTS: New York Heart Association Class I-III HF patients were randomized to yoga treatment (YT) or standard medical therapy (MT). Measurements included a graded exercise test (GXT) to V O(2Peak) and the following serum biomarkers: interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and extracellular superoxide dismutase (EC-SOD). The Minnesota Living with Heart Failure Questionnaire (MLHFQ) was administered to assess changes in QoL. A total of 19 patients were enrolled after the initial screening. Of the 19 patients, 9 were randomized to YT and 10 to MT. Patients had a mean EF of 25%. GXT time and V O(2Peak) were significantly improved in the YT versus MT groups (+18% in the YT and -7.5% in MT; P = .03 vs. control and +17 in YT and -7.1 in MT; P = .02, respectively). There were statistically significant reductions in serum levels of IL-6 and hsCRP and an increase in EC-SOD in the YT group (all P < .005 vs. MT). MLHFQ scores improved by 25.7% in the YT group and by 2.9% in the MT group. CONCLUSIONS: Yoga improved exercise tolerance and positively affected levels of inflammatory markers in patients with HF, and there was also a trend toward improvements in QoL.

Mechanisms of benefit of angiotensin receptor blockers in coronary atherosclerosis.

There is mounting evidence that dysfunction of the renin angiotensin system is a vital contributor to the development of atherosclerosis. Nonetheless, the efficacy of angiotensin receptor blockers on clinical outcomes in patients with coronary atherosclerosis has been limited. This review will examine the potential mechanisms by which angiotensin receptor blockers potentially affect several key steps in the atherosclerotic process: endothelial function, inflammation, and thrombosis. Despite the mounting evidence for these agents on multiple processes in the development of atherosclerosis, their clinical utility in patients with coronary artery disease remains unclear.

Investigations of statins in heart failure: inflammatory biomarkers and hormones.

The primary role of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is to treat dyslipidemia. The clinical benefits with statin therapy have been demonstrated in the primary and secondary prevention of atherosclerotic vascular diseases. More recently, it has been observed that pleiotropic effects of statins (which may or may not be associated with lipid lowering) have been described as treatment of various cardiovascular disease processes and in noncardiac disease processes. This article evaluates the potential mechanisms for these effects in the management of heart failure and postulates their clinical and beneficial use.

Targeting multiple dyslipidemias with fixed combinations--focus on extended release niacin and simvastatin.

Dyslipidemia is a major risk factor in the initiation and progression of cardiovascular diseases such as atherosclerosis. Several pharmacological agents have been developed over the past 50 years which target various lipid components such as low density lipoprotein (LDL) cholesterol, triglyceride, and high density lipoprotein (HDL) cholesterol. Similar to other risk factors such as hypertension and diabetes mellitus, the management of dyslipidemia can be complicated and may require combination therapy for effective treatment. This review discusses the biochemical mechanisms of action and clinical uses for simvastatin (the most widely available and commercially prescribed statin) and niacin, and the combination of these agents in the management and treatment of dyslipidemia.

The role of quinapril in the presence of a weight loss regimen: endothelial function and markers of obesity in patients with the metabolic syndrome.

Forty-four patients with the metabolic syndrome were placed on a reduced-calorie and reduced-fat regimen to lose weight throughout a 56-week period. The patients were treated in a crossover fashion with placebo and the angiotensin-converting enzyme inhibitor quinapril for 24 weeks each. The study measured endothelial-dependent flow-mediated dilation plus serum obesity markers of adiponectin and leptin. Metabolic parameters improved after 56 weeks. Serum adiponectin level increased by 18% (P<.05 vs baseline) and serum leptin level decreased by 16% with placebo (P<.05 vs baseline). These findings were potentiated further in the quinapril group. In comparison with baseline, flow-mediated dilation was increased by 13% in the placebo group (P=.055 vs baseline) and by 43% in the quinapril group (P<.001 vs baseline and placebo). These findings suggest that weight loss therapy improves endothelial function and markers of obesity. These results are potentiated with quinapril and are independent of changes in metabolic parameters.

Regulation of the renin-angiotensin system in coronary atherosclerosis: a review of the literature.

Activation of the renin-angiotensin system (RAS) is significant in the pathogenesis of cardiovascular disease and specifically coronary atherosclerosis. There is strong evidence that the RAS has effects on the mechanisms of action of atherosclerosis, including fibrinolytic balance, endothelial function, and plaque stability. Pharmacological inhibition of the renin angiotensin system includes angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and renin inhibitors. These agents have clinical benefits in reducing morbidity and mortality in the management of hypertension. In addition, ACE inhibitors and ARBs have shown to be effective in the management of congestive heart failure and acute myocardial infarction. This review article discusses the biochemical and molecular mechanisms involving the RAS in coronary atherosclerosis as well as the effects of RAS inhibition in clinical studies involving coronary atherosclerosis.

Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study.

BACKGROUND: The metabolic syndrome is associated with increased angiotensin II activity, induction of a proinflammatory and oxidative state, and endothelial dysfunction. We evaluated the ability of irbesartan, an angiotensin receptor blocker, and lipoic acid, an antioxidant, to affect endothelial function and inflammation in patients with the metabolic syndrome. METHODS AND RESULTS: We randomized 58 subjects with the metabolic syndrome in a double-blinded manner to irbesartan 150 mg/d (n=14), lipoic acid 300 mg/d (n=15), both irbesartan and lipoic acid (n=15), or matching placebo (n=14) for 4 weeks. Endothelium-dependent and -independent flow-mediated vasodilation was determined under standard conditions. Plasma levels of interleukin-6, plasminogen activator-1, and 8-isoprostane were measured. After 4 weeks of therapy, endothelium-dependent flow-mediated vasodilation of the brachial artery was increased by 67%, 44%, and 75% in the irbesartan, lipoic acid, and irbesartan plus lipoic acid groups, respectively, compared with the placebo group. Treatment with irbesartan and/or lipoic acid was associated with statistically significant reductions in plasma levels of interleukin-6 and plasminogen activator-1. In addition, treatment with irbesartan or irbesartan plus lipoic acid decreased 8-isoprostane levels. No significant changes in blood pressure were noted in any of the study groups. CONCLUSIONS: Administration of irbesartan and/or lipoic acid to patients with the metabolic syndrome improves endothelial function and reduces proinflammatory markers, factors that are implicated in the pathogenesis of atherosclerosis.

Cocaine use in an urban medical population and the development of angiographically significant coronary artery disease.

Cocaine is a common drug of abuse in the United States. Although long-term cocaine use has been associated with premature coronary artery disease (CAD), the relationship between cocaine use and the presence of angiographically significant CAD (> or =70%) is not clear. A retrospective analysis of all patients who had undergone cardiac catheterization at an urban medical center over a 1-year period was performed. Five hundred twelve patients were enrolled in the study; 84 (16.4%) had evidence of cocaine use, and 111 (21.7%) were admitted with a myocardial infarction. At the time of cardiac catheterization, 31 (36.9%) cocaine-positive patients had > or =70% stenosis in at least one epicardial vessel, compared with 200 (46.7%) cocaine-negative patients (p = 0.09). Although a trend toward an association was noted on unadjusted analysis, after adjusting for CAD risk factors, cocaine use was not associated with angiographically significant CAD (odds ratio, 0.9; 95% confidence interval, 0.55-1.5; p = 0.7).

Chronic iron administration increases vascular oxidative stress and accelerates arterial thrombosis.

BACKGROUND: Iron overload has been implicated in the pathogenesis of ischemic cardiovascular events. However, the effects of iron excess on vascular function and the thrombotic response to vascular injury are not well understood. METHODS AND RESULTS: We examined the effects of chronic iron dextran administration (15 mg over 6 weeks) on thrombosis, systemic and vascular oxidative stress, and endothelium-dependent vascular reactivity in mice. Thrombus generation after photochemical carotid artery injury was accelerated in iron-loaded mice (mean time to occlusive thrombosis, 20.4+/-8.5 minutes; n=10) compared with control mice (54.5+/-35.5 minutes, n=10, P=0.009). Iron loading had no effect on plasma clotting, vessel wall tissue factor activity, or ADP-induced platelet aggregation. Acute administration of dl-cysteine, a reactive oxygen species scavenger, completely abrogated the effects of iron loading on thrombus formation, suggesting that iron accelerated thrombosis through a pro-oxidant mechanism. Iron loading enhanced both systemic and vascular reactive oxygen species production. Endothelium-dependent vasorelaxation was impaired in iron-loaded mice, indicating reduced NO bioavailability. CONCLUSIONS: Moderate iron loading markedly accelerates thrombus formation after arterial injury, increases vascular oxidative stress, and impairs vasoreactivity. Iron-induced vascular dysfunction may contribute to the increased incidence of ischemic cardiovascular events that have been associated with chronic iron overload.

Quinapril, an ACE inhibitor, reduces markers of oxidative stress in the metabolic syndrome.

OBJECTIVE: Patients with the metabolic syndrome often have abnormal levels of proinflammatory and pro-oxidative mechanisms within their vasculature. We sought to determine whether the ACE inhibitor quinapril regulates markers of oxidative stress in the metabolic syndrome. RESEARCH DESIGN AND METHODS: Forty patients with the metabolic syndrome were randomized in a double-blind manner to either the ACE inhibitor quinapril (20 mg/day) or matching placebo for 4 weeks. Serum markers of vascular oxidative stress were measured. RESULTS: After 4 weeks of therapy, serum 8-isoprostane was reduced by 12% in the quinapril group when compared with placebo (quinapril, 46.7 +/- 1.0; placebo, 52.7 +/- 0.9 pg/ml; P = 0.001). Erythrocyte superoxide dismutase activity increased 35% in the quinapril group when compared with placebo (quinapril, 826.3 +/- 17.1; placebo, 612.3 +/- 6.9 units/g Hb; P < 0.001). In addition, lag time to oxidation of LDL, a marker of oxidative stress, was increased by 48% in the quinapril group when compared with placebo (quinapril 89.2 +/- 9.2 vs. placebo 60.1 +/- 12.3 min; P < 0.001). Therapy with quinapril was well tolerated. CONCLUSIONS: The addition of the ACE inhibitor quinapril reduces markers of vascular oxidative stress and may attenuate the progression of the pathophysiology seen in the metabolic syndrome.

Evidence-based management of acute myocardial infarction in the elderly--current perspectives.

Cardiovascular disease accounts for significant morbidity and mortality in the elderly. Despite several, large cardiovascular clinical trials, data to guide therapy in this growing population subset are relatively limited. This review focuses on treatment approaches and recommendations for the management of elderly patients with acute myocardial infarction (MI) obtained from subgroup analyses from major clinical trials.Treatment options for acute MI in the elderly have changed dramatically since the 1990s. Reperfusion therapy by primary percutaneous coronary intervention has superseded the use of thrombolytic therapy for the treatment of acute ST-elevation myocardial infarction (STEMI). Clinical trial data have demonstrated that even transferring patients to facilities that have primary angioplasty capabilities is better than thrombolytic therapy, if the anticipated transfer time is of acceptable duration. Additionally, adjunctive use of the intravenous glycoprotein (GP) receptor antagonist, abciximab, during primary angioplasty affords a reduction in the composite primary end point of death, reinfarction, and target vessel revascularization, with much of the benefit derived from the latter. Thrombolytic therapy, barring any contraindication, must be used when mechanical revascularization is not available; however, the risk for complications in the elderly is higher, especially for those 75 years and older. Studies investigating the use of thrombolytics plus GP receptor antagonists with and without percutaneous coronary intervention show questionable benefit in the elderly.

Effects of eprosartan versus hydrochlorothiazide on markers of vascular oxidation and inflammation and blood pressure (renin-angiotensin system antagonists, oxidation, and inflammation).

Antagonists of the renin-angiotensin system, such as angiotensin type 1 (AT(1)) receptor inhibitors and angiotensin-converting enzyme inhibitors, are becoming increasingly popular agents in treating patients with systemic hypertension and minimizing organ damage. In the present study, we compared the effects of eprosartan, an AT(1) receptor inhibitor, with the diuretic hydrochlorothiazide in a group of newly diagnosed hypertensive patients with multiple risk factors for atherosclerosis. The subjects were monitored and tested at 0 and 4 weeks to determine their individual effects on vascular and inflammatory markers. Although blood pressure reduction was comparable between the 2 agents, there were notable differences in their effects on markers of inflammation and oxidation. We observed a 28% reduction in neutrophil superoxide anion generating capacity, a 34% reduction in soluble monocyte chemotactic protein-1, and a 35% reduction in soluble vascular cell adhesion molecule with eprosartan therapy (all p <0.05 from the start of therapy). In addition, eprosartan showed further benefit in its ability to increase low-density lipoprotein oxidation lag time, suggesting an increased resistance to oxidation and/or modification of low-density lipoprotein. Although hydrochlorothiazide was effective in blood pressure reduction, there were no significant changes in any of the above parameters after 4 weeks of treatment. These findings suggest that eprosartan, an AT(1) receptor inhibitor, effectively reduces systemic blood pressure and, compared with hydrochlorothiazide, suggests additional benefits in the vasculature by inhibiting mechanisms of inflammation and oxidation.

Co-administration of resveratrol and lipoic acid, or their synthetic combination, enhances neuroprotection in a rat model of ischemia/reperfusion.

The present study demonstrates the benefits of combinatorial antioxidant therapy in the treatment of ischemic stroke. Male Sprague-Dawley rats were anaesthetised and the middle cerebral artery (MCA) was occluded for 30 minutes followed by 5.5 hours of reperfusion. Pretreatment with resveratrol 30 minutes prior to MCA occlusion resulted in a significant, dose-dependent decrease in infarct volume (p<0.05) compared to vehicle-treated animals. Neuroprotection was also observed when resveratrol (2 × 10(-3) mg/kg; iv) was administered within 60 minutes following the return of blood flow (reperfusion). Pretreatment with non-neuroprotective doses of resveratrol (2 × 10(-6) mg/kg) and lipoic acid (LA; 0.005 mg/kg) in combination produced significant neuroprotection as well. This neuroprotection was also observed when resveratrol and LA were administered 15 minutes following the onset of MCA occlusion. Subsequently, we synthetically combined resveratrol and LA in both a 1 ∶ 3 (UPEI-200) and 1 ∶ 1 (UPEI-201) ratio, and screened these new chemical entities in both permanent and transient ischemia models. UPEI-200 was ineffective, while UPEI-201 demonstrated significant, dose-dependent neuroprotection. These results demonstrate that combining subthreshold doses of resveratrol and LA prior to ischemia-reperfusion can provide significant neuroprotection likely resulting from concurrent effects on multiple pathways. The additional protection observed in the novel compound UPEI 201 may present opportunities for addressing ischemia-induced damage in patients presenting with transient ischemic episodes.

UPEI-300, a conjugate of lipoic acid and edaravone, mediates neuroprotection in ischemia/reperfusion.

Edaravone, an electron spin trapper with radical scavenging activity, has been shown to be effective in reducing infarct volume in humans following ischemic stroke. However, concerns of edaravone-induced renal toxicity have limited its clinical adoption. Previous work has demonstrated that edaravone produced significant neuroprotection when injected prior to a period of ischemia and/or reperfusion. The current investigation was designed to determine if a newly synthesized co-drug consisting of lipoic acid and edaravone, named UPEI-300, could produce neuroprotection in in vitro and/or an in vivo rodent model of stroke. UPEI-300 produced dose-dependent neuroprotection in vitro and was subsequently tested in vivo. Male rats were anaesthetized and the middle cerebral artery was occluded for 30 min followed by 5.5 h of reperfusion (ischemia/reperfusion; I/R). Pre-administration of UPEI-300 dose-dependently decreased infarct volume. Significant neuroprotection was also observed when UPEI-300 (1.0 mg/kg) was injected during the 30 min period of ischemia as well as up to 60 min following the start of reperfusion. These results indicate that a co-drug consisting of edaravone and lipoic acid is a potent neuroprotectant, and clinically, the use of such a novel co-drug following an ischemic stroke might maintain neuroprotection while potentially decreasing edaravone associated renal toxicity.

Nebivolol monotherapy in younger adults (younger than 55 years) with hypertension: a randomized, placebo-controlled trial.

Nebivolol, a vasodilatory ß1-blocker, may be well suited for the hemodynamics of the younger hypertensive patient. In this 8-week trial, 18- to 54-year-olds with a diastolic blood pressure (DBP) of 95 mm Hg to 109 mm Hg who completed a 4-week placebo-only phase were randomized to receive nebivolol (5 mg/d, titrated to 10-20 mg/d based on achievement of blood pressure <140/90 mm Hg [n=427]) or placebo (n=214). Primary and secondary efficacy parameters were changes in trough seated DBP and systolic blood pressure (SBP), respectively. Safety parameters included adverse events (AEs). The baseline mean age was 45.3 years; SBP/DBP, 154/100 mm Hg; and heart rate, 78 beats per minute. Completion rates were 91.3% (nebivolol) and 88.3% (placebo). At endpoint, there was a significant effect of nebivolol over placebo for DBP (-11.8 mm Hg vs -5.5 mm Hg, P<.001) and SBP (-13.7 mm Hg vs -5.5 mm Hg, P<.001). Total AE rates were 34.7% (nebivolol) and 32.2% (placebo). Nebivolol monotherapy is efficacious and well tolerated in adults younger than 55 years of age with increased DBP.

Changes in biomarkers and 24 hours blood pressure in hypertensive African Americans with the metabolic syndrome: comparison of amlodipine/olmesartan versus hydrochlorothiazide/losartan.

We evaluated the efficacy of amlodipine and olmesartan (A/O; Azor) versus losartan and hydrochlorothiazide (L/H; Hyzaar), on changes in serum and urine biomarkers of inflammation and oxidation, neutrophil reactive oxygen species generation, and changes in systolic blood pressure (BP), diastolic BP, and heart rate as measured with 24 hours ambulatory BP monitoring in a high-risk, hypertensive African-American population with the metabolic syndrome. Sixty-six African-American subjects with Stage 1 and 2 hypertension and characteristics of the metabolic syndrome were treated in open-label, active comparator fashion for 20 weeks. After 14 weeks of therapy, treatment with A/O had a significant effect on reducing the production of reactive oxygen series, plasminogen activator inhibitor-1, F2 isoprostane, myeloperoxidase, and homeostasis model assessment for insulin resistance while L/H treatment only significantly lowered levels of plasminogen activator inhibitor-1 and homeostasis model assessment for insulin resistance. Treatment with A/O showed a trend of a more immediate and sustained systolic and diastolic BP-lowering, as well as night time BP reduction. In addition to a trend toward lower blood pressure, treatment with A/O in comparison with L/H has superior efficacy in reducing reactive oxygen species generation and production of inflammatory and oxidative biomarkers in a hypertensive African-American population with features of the metabolic syndrome.