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Objective: To examine the effects of an intensive lifestyle intervention (ILI) on cardiovascular disease (CVD), the Action for Health in Diabetes (Look AHEAD) trial randomized 5,145 participants with type 2 diabetes and overweight/obesity to a ILI or diabetes support and education. Although the primary outcome did not differ between the groups, there was suggestive evidence of heterogeneity for prespecified baseline CVD history subgroups (interaction P = 0.063). Event rates were higher in the ILI group among those with a CVD history (hazard ratio 1.13 [95% CI: 0.90-1.41]) and lower among those without CVD (hazard ratio 0.86 [95% CI: 0.72-1.02]).Methods: This study conducted post hoc analyses of the rates of the primary composite outcome and components, adjudicated cardiovascular death, nonfatal myocardial infarction (MI), stroke, and hospitalization for angina, as well as three secondary composite cardiovascular outcomes.Results: Interaction P values for the primary and two secondary composites were similar (0.060-0.064). Of components, the interaction was significant for nonfatal MI (P = 0.035). This interaction was not due to confounding by baseline variables, different intervention responses for weight loss and physical fitness, or hypoglycemic events. In those with a CVD history, statin use was high and similar by group. In those without a CVD history, low-density lipoprotein cholesterol levels were higher (P = 0.003) and statin use was lower (P ≤ 0.001) in the ILI group.Conclusions: Intervention response heterogeneity was significant for nonfatal MI. Response heterogeneity may need consideration in a CVD-outcome trial design. [ABSTRACT FROM AUTHOR]

It is unclear whether metabolic syndrome (MetS) is associated with atrial fibrillation (AF) in an older population with greater cardiovascular risk, including those with chronic kidney disease. The authors investigated the association between MetS and AF in participants in SPRINT (Systolic Blood Pressure Intervention Trial). MetS was defined based on the Modified Third National Cholesterol Education Program. The baseline prevalence rate for MetS was 55%, while 8.2% of the participants had AF. In multivariate regression analyses, AF was not associated with presence of MetS in either chronic kidney disease or non-chronic kidney disease subgroups. Age, race, history of cardiovascular diseases, decreased triglycerides, decreased pulse pressure, and albuminuria remained significantly associated with AF risk. In contrast to the general population, MetS was not associated with AF in the older population with increased cardiovascular risk studied in SPRINT. [ABSTRACT FROM AUTHOR]

Arterial health may influence muscle function in older adults. Study purpose was to determine whether arterial elasticity is related to strength, central and peripheral fatigue, fatigue at rest, and treadmill endurance. Subjects were 91 healthy women aged >60. Treadmill endurance and maximal oxygen uptake (VO2 max) were measured. Peripheral and central fatigue for the knee extensors were evaluated using two isometric fatigue tests (one voluntary and one adding electrical stimulation). Arterial elasticity was determined using radial artery pulse wave analysis. Linear multiple regression was used in statistical analysis. Large artery elasticity was associated with central fatigue (ρ < 0.01) and treadmill endurance (ρ < 0.02) after adjusting for VO2 max and knee extension strength. Subjective fatigue at rest was related to large artery elasticity after adjusting for ethnic origin (<0.02). Strength was significantly related to small artery elasticity after adjusting for ethnic origin, leg lean tissue, age, and blood pressure. Arterial elasticity is independently related to strength and fatigue in older women, especially in the central nervous system where arterial elasticity is independently related to perceptions of fatigue at rest and central fatigue. These results suggest that arterial health may be involved with the ability of the central nervous system to activate muscle in older women. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether combined (aerobic and anaerobic) training decreases blood pressure (BP) and improves vascular properties. Seventy-nine postmenopausal women were randomly assigned to 3 groups that trained at different frequencies. Maximum oxygen uptake, body composition, BP, and arterial elasticity were evaluated prior to training and after 16 weeks of training. There was a significant time effect (decrease) for resting systolic BP (SBP) and rate pressure product. Exercise SBP, diastolic BP (DBP), heart rate, and RPP also decreased. Changes in total vascular impedance were related to SBP and changes in systemic vascular resistance were related to changes in DBP independent of body composition changes. Our findings suggest that combined training reduces SBP and improves vascular properties and that combined training 1 d/wk decreases BP similar to more frequent combined training. Training-induced changes in arterial resistance and impedance may be involved in inducing changes in BP. J Clin Hypertens (Greenwich). 2012;00:00-00 ©2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The new drug application database submitted to the US Food and Drug Administration for drug approval (phases I-III or phases 1-3) is limited both in scope and size. Although randomized controlled trials, the hallmark of phase III trials, are the gold standard for the drug-approval process, they invariably have a number of limitations, including relatively small sample sizes, selective populations, short follow-up, the use of intermediate (surrogate) endpoints (almost always), and limited generalizability. The challenges of monitoring drugs once approved are also numerous. After approval by the Food and Drug Administration, marketed drugs undergo continued scrutiny, and this scrutiny is increasing because of problems that have surfaced with some drugs after their approval. Postmarketing research includes a variety of study designs and the use of registries and self-reporting of drug side effects. Along with this has come great confusion about what postmarketing research is and what a phase IV study is. Among the important strengths of phase IV research are the exposure of a broader range of patients to the drug under study, resulting in more "real-world" information about the drug's safety and efficacy, and consideration of a broader range of clinical endpoints. As a result, phase IV or postmarketing research, has become an integral part of the drug evaluation process for a wide range of agents. The authors discuss the different types of study designs that are common under the phase IV terminology and provide some examples. They also discuss the use of registries and self-reporting of adverse events using the Med Watch System. [ABSTRACT FROM AUTHOR]

Randomized controlled trials remain the gold standard study design and yield the highest level of scientific credence. However, recognition of the limitations of the randomized controlled trial is important. This review highlights 10 potentially problematic areas one should carefully assess when performing or reading an article reporting the results of a randomized controlled trial, problematic areasthat can affect the outcome of the trial and therefore mislead the reader. These areas include ethical issues, eligibility criteria, masking (blinding), randomization, analyticmethods, the selection of subjects for the interventional and comparison groups, selection of end points, and the interpretation of the results. Each of these is discussed,and examples of published articles are used to highlight the main points. [ABSTRACT FROM PUBLISHER]

Drugs and diseases have differential effects on functional and structural components of large-conduit arteries and smaller vessels. The objective of this study was to demonstrate functional and structural effects of doxazosin (DOX) on largevessel and small-vessel arterial elasticity in hypertension (HTN). This was an open-label, single-blind, active-therapy study. Patients with stage 1 to 2 HTN were administered DOX 2 mg/day for 3 months and 4 mg/day for 1 month, if indicated, followed by 2-week washout period. Arterial elasticity was measured noninvasively at baseline, at 3 months and 4 months of treatment, and 2 weeks following DOX withdrawal. Although the observed effects were not statistically significant, large-vessel elasticity (C1) increased in a dose-related manner and returned to baseline 2 weeks after drug withdrawal. There was a trend toward an increase in small-vessel elasticity in a dose-related manner. However, 2 weeks after drug withdrawal, C2 (distal elasticity) had not returned to baseline and was statistically significantly different from baseline (p = 0.032). It was concluded that large-artery compliance increased in a dose-related manner. Almost all benefit was lost within 2 weeks of discontinuation, suggesting the DOX effect was functional. Small-artery compliance improved in a dose-related manner but only partially returned to baseline after DOX withdrawal, suggesting changes in artery structure by DOX. [ABSTRACT FROM PUBLISHER]

L- and T-type voltage-dependent transmembrane calcium channels are important for normal functioning of the cardiovascular system. T-type channels are a heterogeneous group, and have physiologic and pathophysiologic relevance in a number of organ systems, including the heart and central nervous system. They appear to be involved in the control of blood pressure in patients with essential hypertension and in protection from ischemic damage. Alterations of both L- and T-type calcium channels are involved in the development of hypertension. Pharmacologic modulation of T-type calcium channels appears to reduce membrane calcium flux and ameliorate hypertension. During early ischemic damage, T-type calcium channels appear to remain functional whereas L-type channels are already inactivated. T-type calcium channels also appear to be involved in the development of supraventricular arrhythmias, some forms of arrhythmias in cardiomyopathy, and cardiac hypertrophy. The heterogeneity of T-type calcium channels should make it possible to target drugs to specific subgroups of T-type calcium channels. A new class of calcium antagonist, the benzimidazolyl-substituted tetraline derivatives, has been shown to block both L- and T-type calcium channels. The first member of this class approved for clinical use is mibefradil. Clinical studies have demonstrated the efficacy of mibefradil in lowering blood pressure and as an antianginal and antiischemic agent. At clinically recommended doses, mibefradil has a heart rate lowering effect without a negative inotropic effect, and a favorable side effect profile. Because it is metabolized by the cytochrome P450 pathway, it should be used cautiously with other agents similarly metabolized. [ABSTRACT FROM AUTHOR]

Arterial compliance, defined as a change in dimension in response to a given change in stress, is becoming an increasingly important clinical parameter. Related concepts, such as distensibility, elasticity, and stiffness, and more traditional concepts such as resistance, afterload, and impedance need to be differentiated from compliance, although they are frequently (inappropriately) used interchangably. Many studies cannot differentiate between compliance changes due to a drug's effect on blood pressure and those due to a drug's effect on vessel wall integrity. This differentiation is important because a more physiologic therapy, one that benefits pulsatile and nonpulsatile flow, should be of greater clinical benefit than a therapy that only lowers blood pressure. A number of methods have been used to estimate compliance, but to date there is no generally agreed-on best method. There also are no longitudinal studies that relate abnormal compliance and drug effects to outcome. Nonetheless, patients at risk from a variety of disease states, such as hypertension, diabetes mellitus, and hypercholesterolemia, may benefit from earlier recognition of abnormal compliance. Earlier recognition may lead to interventions that would reduce their risk. This review includes a discussion of compliance and related estimates of blood vessel function and attempts to summarize the data currently available regarding the effects of cardioactive drugs on arterial compliance. [ABSTRACT FROM AUTHOR]

A double-blind, randomized, placebo-controlled study was conducted to test the peak and trough antianginal and antiischemic monotherapy efficacy and safety of a new extended-release formulation of nisoldipine (nisoldipine Coat Core [Bayer Corporation], 20 mg, 40 mg, and 60 mg once daily compared to placebo). Study patients had a history of chronic, stable angina pectoris, exercise-induced angina in association with ST segment depression, and exercise test reproducibility. Of the 483 patients enrolled in the study, results were valid for safety analysis for 312 and for efficacy analysis for 284. There was a statistically significant improvement in total exercise time at both peak and trough for patients taking 20 mg and 60 mg of nisoldipine compared with patients taking placebo, but the group taking 60 mg was not better than the group taking 20 mg (33.9 and 33.7 seconds, respectively, at trough). The results were similar for the secondary endpoints (time to onset of angina and time to 1 mm ST segment depression). No correlation was evident between plasma nisoldipine levels and total exercise duration. Headache and peripheral edema were the most frequently reported adverse events and were dose related. There were no discontinuations due to adverse events in patients randomized to the 20-mg nisoldipine group. No deaths occurred while patients were receiving active nisoldipine therapy. Therapy with this extended-release formulation of nisoldipine is an effective once-daily treatment for chronic stable angina pectoris. It represents one of the few dihydropyridine calcium channel antagonists that has shown efficacy when administered as monotherapy to patients with angina. [ABSTRACT FROM AUTHOR]

Benazepril hydrochloride (CGS 14824A) is an orally active, nonsulfhydryl compound that is transformed in vivo to a long-acting inhibitor of angiotensin-converting enzyme (ACE). Previous studies have shown benazepril to lower blood pressure in hypertensive patients and to confer acute hemodynamic benefits in patients with congestive heart failure (CHF). In the current multicenter investigation, 16 patients with chronic CHF due to left ventricular systolic dysfunction (ejection fraction < 0.40 at rest) whose symptoms corresponded to New York Heart Association classes II to IV were given open-label benazepril once daily in ascending doses of 2 to 20 mg and followed biweekly for 12 weeks. Evaluation of the 15 subjects who completed the trial showed a progressive increase in treadmill exercise duration (from 7.65 ± 3.64 [ SD] minutes at baseline to 9.74 ± 3.66 minutes at 12 weeks, P < .001); augmentation of the mean left ventricular ejection fraction (from 0.266 ± 0.133 at baseline to 0.292 ± 0.136 at 12 weeks, P < .025); relief of exertional dyspnea in 7 of the 15 patients (P < .02); and improvement in global symptomatic status in 10 of the patients (P < .01). These responses were accompanied by a reduction in serum ACE activity of 75% (from 27.2 ± 10.5 IU/L at baseline to 6.7 ± 1.9 IU/L at 12 weeks, P < .001), which was independent of dose and duration of treatment. The magnitude of ACE inhibition did not correlate with changes in the efficacy variables. Aside from two instances of symptomatic hypotension (one of which was complicated by volume depletion), the drug was well tolerated. Long-term therapy with benazepril for patients with CHF shows promise. A large-scale, double-blind trial of benazepril in this population is currently in progress. [ABSTRACT FROM AUTHOR]

This is the first reported large clinical trial of the antianginal and acute ischemic effectiveness and safety of dilevalol (the R, R-isomer of labetalol) in patients with chronic stable angina pectoris. This was a multicenter double blind fixed-dose parallel group placebo controlled trial. Patients with chronic stable angina and positive and reproducible exercise tests (±20%) were included. If randomized, patients entered one of four fixed dose groups (twice a day placebo, 100 mgm, 200 mgm and 400 mgm bid for 2 weeks). Exercise testing was performed at 2 hours (peak) and 12 hours (trough) postdosing. This was followed by a 2-week once-a-day dosing regimen in which patients received the same total daily dose as the prior 2 weeks, with the full dose in the morning and a matched placebo in the evening. Exercise testing was performed at 2 hours (peak) and 24 hours (trough) postdosing. Anginal frequency and NTG consumption were significantly reduced, and equally so, by qd and bid regimens. The time of exercise to the onset of angina increased and the proportion of patients terminating exercise because of moderate angina decreased in a dose response fashion for both peak and trough tests and for both qd and bid regimens. There was also a dose related decrease in exercise induced ST segment depression and an increase in time to 1 mm ST depression. In 15 patients, 24-hour ambulatory monitoring also revealed a decrease in episodes of silent ischemia. No significant side effects related to the study drug occurred. Thus, dilevalol was effective in the treatment of angina pectoris since it was well tolerated, favorably improved exercise induced ischemia (both painful and silent ischemia), and reduced anginal frequency and NTG consumption. [ABSTRACT FROM AUTHOR]

This study was designed to evaluate the effects of a new beta-adrenergic blocking agent with beta2 agonist activity (dilevalol, an R-R' isomer of labetalol) on left ventricular hypertrophy regression as seen by M-mode echocardiography. The study design was a 2:1 double blind randomization of dilevalol versus metoprolol. There was an equal blood pressure reduction in the two groups (supine diastolic blood pressure fell from 101 ± 4.5 mm Hg to 87 ± 13.7 mm Hg, P < .001 in the dilevalol group, and 101 ± 4.3 mm Hg to 87 ± 8.6 mm Hg, P < .01, in the metoprolol group). At the end of 2 months, there was an overall 7.5% decrease in left ventricular mass index in the 16 dilevalol treated patients (this was due to a 4.4% decrease in posterior wall thickness, end diastolic dimension increased by only 1%). Of the seven patients with an increased left ventricular mass index, all demonstrated hypertrophy regression (mean 17.14%). In contrast, no significant change in left ventricular mass was seen in the metoprolol treated group. Echocardiography left ventricular mass index and electrocardiographic evidence of left ventricular hypertrophy (using the Sokolow-Lyons criteria and Romhilt-Estes point score) had poor correlation (r = .30 and r = .38, respectively). Resting ejection fraction increased by 5% and velocity of circumferential fiber shortening by 14% in the dilevalol treatment group (not significant), in conclusion, 1) echocardiographic left ventricular hypertrophy regression occurred with dilevalol treatment 2) this left ventricular regression was a result of a decrease in intraventricular septal thickness and posterior wall thickness 3) the poor correlation between echocardiographic increased left ventricular mass and electrocardiographic left ventricular hypertrophy was supported 4) dilevalol and metoprolol had equal antihypertensive effects. [ABSTRACT FROM AUTHOR]

This study addresses the effect of the three major classes of antianginal agents on asymptomatic myocardial ischemia in patients with chronic stable angina pectoris. The authors found that each class (given as monotherapy) resulted in a 50% reduction in asymptomatic ischemia (both in the number of episodes and the ST product). Dual therapy resulted in an overall four fold reduction compared to placebo. Therapy also resulted in a beneficial alteration in the frequency distribution of asymptomatic ischemia. Stratification into three age groups demonstrated an equal prevalence of asymptomatic ischemia in each. All ages had nearly equivalent reductions in asymptomatic ischemia by monotherapy and dual therapy, but the youngest age group seemingly responded better to monotherapy than did the oldest age group. [ABSTRACT FROM AUTHOR]

Background: Perceived stress may increase risk for coronary heart disease (CHD) and death, but few studies have examined these relationships longitudinally. We sought to determine the association of perceived stress with incident CHD and all-cause mortality., Methods and Results: Data were from a prospective study of 24 443 participants without CHD at baseline from the national Reasons for Geographic And Racial Differences in Stroke (REGARDS) study cohort. Outcomes were expert-adjudicated acute CHD and all-cause mortality. Over a mean follow-up of 4.2 (maximum 6.9) years, there were 659 incident CHD events and 1320 deaths. Analyses were stratified by income level because of significant interactions with stress. For individuals with low income, 3529 (35.4%) reported high stress, and for those with high income, 2524 (22.1%) did so. Compared with reporting no stress, those reporting the highest stress had higher risk for incident CHD if they reported low income (sociodemographic-adjusted HR 1.36, 95% CI: 1.04, 1.78) but not high income (sociodemographic-adjusted HR 0.82, 95% CI: 0.57, 1.16); the finding in low income individuals attenuated with adjustment for clinical and behavioral factors (HR 1.29, 95% CI: 0.99, 1.69, P=0.06). After full adjustment, the highest stress category was associated with higher risk for death among those with low income (HR 1.55, 95% CI: 1.31, 1.82) but not high income (HR 1.13, 95% CI: 0.88, 1.46)., Conclusions: High stress was associated with greater risks of CHD and death for individuals with low but not high income.