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Objective: To examine an intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) on 4-year change in fitness and physical activity (PA), and to examine the effect of change in fitness and PA, adjusting for potential confounders, on glycemic control in the Look AHEAD Trial.Research Design and Methods: Subjects were overweight/obese adults with type 2 diabetes mellitus (T2DM) with available fitness data at 4 years (n = 3,942).This clinical trial randomized subjects to DSE or ILI. DSE subjects received standard care plus information related to diet, PA, and social support three times per year. ILI subjects received weekly intervention contact for 6 months, which was reduced over the 4-year period, and were prescribed diet and PA. Measures included weight, fitness, PA, and HbA1c.Results: The difference in percent fitness change between ILI and DSE at 4 years was significant after adjustment for baseline fitness and change in weight (3.70 vs. 0.94%; P < 0.01). At 4 years, PA increased by 348 (1,562) kcal/week in ILI vs. 105 (1,309) kcal/week in DSE (P < 0.01). Fitness change at 4 years was inversely related to change in HbA1c after adjustment for clinical site, treatment, baseline HbA1c, prescribed diabetes medication, baseline fitness, and weight change (P < 0.01). Change in PA was not related to change in HbA1c.Conclusions: A 4-year ILI increased fitness and PA in overweight/obese individuals with T2DM. Change in fitness was associated with improvements in glycemic control, which provides support for interventions to improve fitness in adults with T2DM. [ABSTRACT FROM AUTHOR]

Abstract: Background: Smoking is associated with increased postprandial hypertriglyceridemia (PPT). Inflammation and insulin resistance are potential “drivers” for this phenomenon. We tested whether inflammatory patterns and/or insulin resistance explain the effect of smoking on PPT. Methods and results: Men and women in the NHLBI Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) study (n =1036, age 49±16y) were included. Each participant was asked to suspend use of lipid-lowering drugs for 3 weeks and was given a high-fat milkshake (83% fat and 700kcal/m2). Triglyceride concentrations at 0, 3.5 and 6h after the fat load were measured. Inflammatory markers were measured at baseline. Principal component analysis was used to derive inflammatory patterns from individual inflammatory markers (hsCRP, IL2 soluble receptor-α, IL6, TNF-α and MCP1). Insulin resistance (IR) was estimated using the HOMA equation. Repeated measures-ANOVA was used for analyses. Two inflammatory patterns, namely CRP-IL6 pattern and MCP1-TNF-α pattern, were derived. We found significant main (smoking and time) and interaction (smoking×time) effects (P <0.01) for triglycerides. The multivariate-adjusted triglyceride (mg/dL) concentrations (mean±S.E.M.) for never, past and current smokers were 127.38±1.04, 119.82±1.05 and 134.92±1.08 at 0h; 229.42±1.04, 238.39±1.05 and 293.94±1.08 at 3.5h; and 194.63±1.04, 208.38±1.05 and 248.27±1.08 at 6h after the fat load, respectively. Smoking remained significant after adjusting for HOMA-IR and/or inflammatory patterns which showed independent associations with PPT (P <0.05). Conclusions: These data confirm impaired metabolism of fat among smokers and suggest that mechanisms other than inflammation or insulin resistance may explain the observed hypertriglyceridemia among smokers. [Copyright &y& Elsevier]

Background: Adherence to study medications is crucial to evaluating treatment effects in clinical trials. To assess whether in the SPRINT trial, adherence and cardiovascular outcomes are associated regardless of intervention assignment., Methods: This study included 9,361 participants aged ≥50 years, recruited from 102 clinics. Participants were randomized to a Standard Treatment Group (targeted systolic blood pressure [SBP] <140 mm Hg) or an Intensive Treatment Group (targeted SBP <120 mm Hg) and followed for incident cardiovascular events until the study was halted early for benefit. The 8-item Morisky Medication Adherence Scale (MMAS-8) was administered at baseline, and at the 12- and 48-month (or close out) visit., Results: Adjusting for covariates, there was no association between the baseline 8-item MMAS-8 and the likelihood of the primary composite endpoint, any of the secondary endpoints, or blood pressure (BP) control. Low adherence was associated with a higher body mass index, SBP, diastolic BP, and Patient Health Questionnaire, and high adherence was associated with a higher Montreal Cognitive Assessment. There was no difference in the MMAS-8 over time by treatment arm assignment. For the primary outcome (a composite of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes), baseline odds ratios (95% confidence intervals) for the Low vs. Medium and vs. High; and, for Medium vs. High MMAS-8 were 1.02 (0.82-1.28), 1.07 (0.85-1.34), and 1.05 (0.88-1.250)., Conclusions: In SPRINT, medication adherence as measured using the MMAS-8 was not associated with outcomes or BP control., (© The Author(s) 2021. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.)

Background: Patients with stage 1 systolic hypertension have increased risk of cardiovascular disease (CVD) events., Methods: Using Cox models, we assess the effect of targeting an intensive SBP goal of less than 120 mmHg compared with standard SBP goal of less than 140 mmHg on the risk of CVD events in adults with stage 1 systolic hypertension with diabetes mellitus enrolled in Action to Control Cardiovascular Risk in Diabetes Blood Pressure trial (ACCORD BP) (n = 1901) and without diabetes mellitus enrolled in Systolic Blood Pressure Intervention Trial (SPRINT) (n = 3484) that used identical SBP goal interventions., Outcomes: In ACCORD BP, the primary composite CVD outcome was the first occurrence of myocardial infarction, stroke, or CVD mortality. In SPRINT, the primary composite CVD outcome was the first occurrence of myocardial infarction, other acute coronary syndrome, stroke, heart failure, or CVD mortality., Results: In SPRINT, targeting an intensive SBP goal significantly reduced the risk of the primary CVD outcome [hazard ratio 0.75 (95% confidence interval, 0.58-0.98); events 1.78 vs. 2.37%/year]. In ACCORD BP, the relationships of SBP goal with the primary CVD outcome was modified by the glycemia goal intervention (interaction P = 0.039). In the standard glycemia subgroup (A1c target 7-7.9%), intensive SBP goal significantly reduced the risk of the primary CVD outcome [hazard ratio 0.61 (0.40-0.94); events 1.63 vs. 2.56%/year]. In the intensive glycemia subgroup (A1c target <6%), the risk of the primary CVD outcome was not significantly different between groups [hazard ratio 1.20 (0.76-1.89); events 1.91 vs. 1.60%/year]., Conclusion: Targeting an intensive SBP goal significantly reduced the risk of CVD events in patients with stage 1 systolic hypertension without diabetes and with diabetes on standard glycemia goal.

The functional implications of serum tumor necrosis factor-alpha (TNF-α), a marker of oxidative stress, on hemodynamic parameters at rest and during physical exertion are unclear. The aims of this investigation were to examine the independent associations of TNF-α on myocardial oxygen demand at rest and during submaximal exercise, while also evaluating the association of TNF-α on exercise tolerance. Forty, postmenopausal women, provided blood samples and completed a modified-Balke protocol to measure maximal oxygen uptake (VO 2max ). Large artery compliance was measured by pulse contour analyses while rate-pressure product (RPP), an index of myocardial oxygen demand, was measured at rest and during two submaximal workloads (i.e., ≈55% and ≈75% VO 2max ). RPP was calculated by dividing the product of heart rate and systolic blood pressure (via auscultation) by 100. Exercise tolerance corresponded with the cessation of the graded exercise test. During higher-intensity exertion, ≈75% VO 2max , multiple linear regression revealed a positive association ( r = 0.43; p = 0.015) between TNF-α and RPP while adjusting for maximal heart rate, VO 2max , large artery compliance, and percent body fat. Path analyses revealed a significant indirect effect of large artery compliance on exercise tolerance through TNF-α, β = 0.13, CI [0.03, 0.35], indicating greater levels of TNF-α associated with poorer exercise tolerance. These data suggest TNF-α independently associates with myocardial oxygen demand during physical exertion, thus highlighting the utility of higher-intensity efforts to expose important phenomena not apparent at rest. TNF-α also appears to be indirectly associated with the link between large artery compliance and exercise tolerance.

Background: N-terminal pro B-type peptide (NT-proBNP) has been associated with risk of myocardial infarction (MI), but less is known about the relationship between NT-proBNP and very small non ST-elevation MI, also known as microsize MI. These events are now routinely detectable with modern troponin assays and are emerging as a large proportion of all MI. Here, we sought to compare the association of NT-proBNP with risk of incident typical MI and microsize MI in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study., Methods: The REGARDS Study is a national cohort of 30,239 US community-dwelling black and white adults aged ≥ 45 years recruited from 2003 to 2007. Expert-adjudicated outcomes included incident typical MI (definite/probable MI with peak troponin ≥ 0.5 μg/L), incident microsize MI (definite/probable MI with peak troponin < 0.5 μg/L), and incident fatal CHD. Using a case-cohort design, we estimated the hazard ratio of the outcomes as a function of baseline NT-proBNP. Competing risk analyses tested whether the associations of NT-proBNP differed between the risk of incident microsize MI and incident typical MI as well as if the association of NT-proBNP differed between incident non-fatal microsize MI and incident non-fatal typical MI, while accounting for incident fatal coronary heart disease (CHD) as well as heart failure (HF)., Results: Over a median of 5 years of follow-up, there were 315 typical MI, 139 microsize MI, and 195 incident fatal CHD. NT-proBNP was independently and strongly associated with all CHD endpoints, with significantly greater risk observed for incident microsize MI, even after removing individuals with suspected HF prior to or coincident with their incident CHD event., Conclusion: NT-proBNP is associated with all MIs, but is a more powerful risk factor for microsize than typical MI.

Orthostatic changes in systolic blood pressure (SBP) impact cardiovascular outcomes. In this study, we aimed to determine the pattern of orthostatic systolic pressure changes in participants enrolled in the SBP Intervention Trial (SPRINT) at their baseline visit before randomization and sought to understand clinical factors predictive of these changes. Of the 9323 participants enrolled in SPRINT, 8662 had complete data for these analyses. The SBP after 1 minute of standing was subtracted from the mean value of the three preceding seated SBP values. At the baseline visit, medical history, medications, anthropometric measures, and standard laboratory testing were undertaken. The mean age of SPRINT participants was 68 years, two-thirds were male, with 30% black, 11% Hispanic, and 55% Caucasian. The spectrum of SBP changes on standing demonstrated that increases in SBP were as common as declines, and about 5% of participants had an increase, and 5% had a decrease of >20 mm Hg in SBP upon standing. Female sex, taller height, more advanced kidney disease, current smoking, and several drug classes were associated with larger declines in BP upon standing, while black race, higher blood levels of glucose and sodium, and heavier weight were associated with more positive values of the change in BP upon standing. Our cross-sectional results show a significant spectrum of orthostatic SBP changes, reflecting known (eg, age) and less well-known (eg, kidney function) relationships that may be important considerations in determining the optimal target blood pressure in long-term outcomes of older hypertensive patients., (Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Background: The association between lipid levels and stroke rates is less than lipid levels and coronary heart disease (CHD)., Objective: To assess if there are geographic, racial, and ethnic differences in total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglyceride levels with incident stroke., Methods: From the REasons for Geographic And Racial Differences in Stroke (REGARDS) study we evaluated baseline levels of LDL-C, HCL-C, TC, Non-HDL-C (Total-HDL-C) and triglycerides in participants free of prevalent stroke at baseline. Cox Proportional-Hazard models were the main analytical tool used to examine the association between incident stroke and lipids. For each adjusted lipid measure (LDL-C, HDL-C, triglycerides, TC, and non-HDL-C) we calculated a series of incremental models., Results: The analysis cohort was 23,867 participants with a mean follow-up time of 7.5±2.9years, and 1031 centrally adjudicated strokes (874 ischemic and 77 hemorrhagic strokes). HDL-C baseline level was associated with an overall unadjusted 13% risk reduction (HR 0.87, 95% confidence interval [CI]: 0.81-0.93; p<0.05; 14% for ischemic and 16% for hemorrhagic strokes), and TC with an 8% (HR 0.92, 95%CI: 0.87-0.99; p<0.05) risk reduction of all strokes. When the results were fully adjusted a significant association was observed only for LDL-C and non-HDL-C and ischemic stroke. There were no significant differences in these associations when adjusted for age, race, age∗race, gender, education, region, or income., Conclusion: In a disease free population, LDL-C and non-HDL-C baseline levels are significantly associated with the risk of ischemic stroke., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Studies of prognosis following acute myocardial infarction (AMI) conventionally examine the first recurrent coronary heart disease (CHD) event which may not adequately characterize the full burden of CHD hospitalizations. We therefore examined the cumulative number of CHD rehospitalizations following AMI among older adults in the United States., Methods: We conducted a retrospective cohort study of 78,085 Medicare beneficiaries aged ≥66 years without recent CHD history who were hospitalized for AMI in 2000-2010. Counts of CHD rehospitalizations over a maximum of 10 years of follow-up were calculated. Characteristics were assessed through claims and enrollment information and associations with CHD rehospitalizations were evaluated using Poisson models., Results: Over 25 % of beneficiaries were aged ≥85 years, 55 % were women, and 89 % were white. Comorbidities were common, including diabetes (22.9 %), hypertension (46.7 %), heart failure (10.3 %), and chronic obstructive pulmonary disease (19.2 %). Following AMI, 16,078 beneficiaries (20.6 %) were hospitalized for CHD a total of 23,132 times. Among those who experienced at least one CHD rehospitalization, 35.9 % had ≥2 CHD rehospitalizations (n = 5773, 7.4 % of all beneficiaries with AMI) in the ensuing decade. Associations of demographics, comorbidities, and index hospitalization characteristics with rates of first and total CHD rehospitalizations were largely similar. Age ≥85 years versus 66-69 years was more strongly associated with first (rate ratio [RR] 1.43) than total (RR 1.35) CHD rehospitalization (p < 0.05), as was male versus female sex (RR 1.13 and 1.07)., Conclusions: Emphasizing the first recurrent CHD rehospitalization underestimates the burden of disease experienced among older adults with AMI.

Background: Statins reduce the risk of coronary heart disease (CHD) in individuals with a history of CHD or risk equivalents. A 10-year CHD risk >20% is considered a risk equivalent but is frequently not detected. Statin use and low-density lipoprotein cholesterol (LDL-C) control were examined among participants with CHD or risk equivalents in the nationwide Reasons for Geographic and Racial Differences in Stroke study (n = 8812)., Methods: Participants were categorized into 4 mutually exclusive groups: (1) history of CHD (n = 4025); (2) no history of CHD but with a history of stroke and/or abdominal aortic aneurysm (AAA) (n = 946); (3) no history of CHD or stroke/AAA but with diabetes mellitus (n = 3134); or (4) no history of the conditions in (1) through (3) but with 10-year Framingham CHD risk score (FRS) >20% calculated using the third Adult Treatment Panel point scoring system (n = 707)., Results: Statins were used by 58.4% of those in the CHD group and 41.7%, 40.4% and 20.1% of those in the stroke/AAA, diabetes mellitus and FRS >20% groups, respectively. Among those taking statins, 65.1% had LDL-C <100 mg/dL, with no difference between the CHD, stroke/AAA, or diabetes mellitus groups. However, compared with those in the CHD group, LDL-C <100 mg/dL was less common among participants in the FRS >20% group (multivariable adjusted prevalence ratio: 0.72; 95% confidence interval: 0.62-0.85). Results were similar using the 2013 American College of Cardiology/American Heart Association cholesterol treatment guideline., Conclusions: These data suggest that many people with high CHD risk, especially those with an FRS >20%, do not receive guideline-concordant lipid-lowering therapy and do not achieve an LDL-C <100 mg/dL.

Background/objective: Aspirin for primary prophylaxis is controversial. This study evaluated associations between prophylactic aspirin use and incident acute coronary heart disease (CHD) events., Methods and Results: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study was accessed for aspirin use examining black and white hazards for incident CHD, for men and women, each adjusting incrementally for sampling, sociodemographics, and CHD risk factors. Stratified models examined risks across strata of the Framingham risk score, and all-cause mortality. 23,949 participants (mean 64 yo), had 503 incident events over a 3.5 year follow-up. Prophylactic aspirin use was not associated with incident acute CHD, HR 1.05 (95% CI 0.86, 1.29). Modeling had little impact on the HR (1.09 {95% CI 0.89, 1.33) nor did the addition of risk factors (HR 1.00 {95% CI 0.81, 1.23). Aspirin use was not associated with incident CHD for any Framingham risk level. Findings were similar when including all aspirin users (not just those taking aspirin prophylactically), and when examining associations with all-cause mortality. There was no excess hospitalized bleeding in the aspirin users., Conclusion: Aspirin was not associated with lower risk for incident acute CHD overall, or within race, gender, or Framingham Risk Score.

Background: Studies have shown that aspirin used for secondary prevention significantly reduces cardiovascular and stroke risk. The data for aspirin and primary prevention of cardiovascular disease, and in particular stroke, are less clear, especially among blacks., Objective: To evaluate prophylactic aspirin use and incident stroke in a large cohort of black and white participants., Methods: The Reasons for Geographic and Racial Differences in Stroke study is a national, population-based, longitudinal study of 30,239 African Americans and whites, older than 45 years. Participants with stroke at baseline were excluded, reducing the cohort to 27,219. Proportional hazard models were used to estimate the association of incident stroke with prophylactic aspirin use, adjusted for confounding factors. Separate analyses were performed for subjects who self-reported baseline aspirin use for primary prevention of vascular disease compared with those using aspirin use for other indications., Results: In all, 10,177 participants taking prophylactic aspirin were followed for a mean of 4.6 years. Univariate analysis showed an increased stroke risk for prophylactic aspirin use (hazard ratio [HR]: 1.37; 95% confidence interval: 1.16-1.62), but the association was attenuated (HR: 1.06; 95% CI: .86-1.32) with multivariable adjustment, adjusting for demographic factors (age, race, sex, and region), socioeconomic factors (income and education), perceived general health, cardiovascular disease (CVD) risk factors (hypertension, diabetes, dyslipidemia, cigarette smoking, and alcohol use), and finally the Framingham Stroke Risk Score (in a separate model). No racial, sex, or regional differences in the association were demonstrated., Conclusions: In this observational study, prophylactic aspirin use was not associated with risk of first stroke, and there were no sex, race, or regional differences., (Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

The morning blood pressure surge (MBPS) has been shown to be an independent predictor of cardiovascular events. There is insufficient evidence on the effect of nebivolol, a vasodilating β1-receptor blocker, on the MBPS when given in the morning or the evening. This is a prospective, randomized, double-blind, crossover study designed to test morning vs. evening dosing of nebivolol in nondiabetic, hypertensive patients. Patients received nebivolol 5 mg/day (force-titrated to 10 mg/day after 1 week) in the morning or evening and corresponding placebos. Patients underwent ambulatory BP monitoring at baseline and after each treatment phase. Forty-two patients were randomized, of whom 38 completed both study periods. Both morning and evening dosed nebivolol significantly lowered daytime, nighttime, and 24-hour BP after 3 weeks of treatment. Evening (but not morning) dosing significantly reduced prewaking systolic BP from baseline (8.64 ± 26.46 mm Hg, P = .048). Nebivolol given in the morning or the evening significantly reduces 24-hour BP parameters. Evening dosed nebivolol may confer some advantage over morning dosing in reducing prewaking systolic BP., (© 2012 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Background: High pulse pressure (PP) is associated with cardiovascular events, but subclinical abnormalities in cardiac structure and function in relation to high pulse pressure are not well described., Methods and Results: 2225 hypertensive and 1380 non-hypertensive participants with adequate echocardiographic left ventricular measurements were evaluated. Non-hypertensives in the highest PP tertile (compared to the lower tertiles) were older (44 years vs. 40 years, p<0.009), had higher systolic pressure [(SBP) 136 mmHg vs. 108 mmHg] and lower diastolic pressure [(DBP) 54 vs. 71 mmHg (p=.0001)], greater BMI (27 vs. 25 kg/m2, p<.001) and more diabetes (4% vs. 2.25%, p<.001). In the hypertensive group, subjects in the highest PP tertile were older (52 vs 42 years), had higher SBP (157 vs. 116 mmHg) but lower DBP (65 vs. 83 mmHg). In the non-hypertensive group, higher PP (>60 mmHG) was associated with a higher frequency of echocardiographic structural and functional abnormalities, specifically, greater posterior and relative wall thickness, longer isovolumic relaxation time, and concentric left ventricular (LV) hypertrophy., Conclusion: In a population-based sample of hypertensive and non-hypertensive participants, higher PP was associated with subclinical abnormalities of cardiac structure and function, which exist even in the absence of hypertension and/or the use of antihypertensive treatment.

Some consider the measurements of arterial elasticity and flow-mediated dilation to be an indirect "biomarker" of endothelial dysfunction. As such, we describe the various uses of these techniques in the evaluation of the natural history of vascular disease. These measures are potential markers of disease, as abnormalities reflect changes in the integrity of vascular structure but occur prior to the manifestation of symptomatic cardiovascular events. In this review, the natural history of arterial elasticity is discussed, and the effects of aging and inflammation are reviewed. The role that arterial elasticity and flow-mediated dilation have in predicting future cardiovascular disease, and the effects of pharmacologic agents on these measures, is also reviewed.

Hypertension is a common disorder associated with increased cardiovascular morbidity and mortality. Unfortunately, in the US only about one-third of those who are aware of their hypertensive status have their blood pressure adequately controlled. One reason for this is the variable and unpredictable response individuals have to pharmacologic treatment. Clinicians often resort to "trial-and-error" to match patients with effective drug treatment. Hypertension pharmacogenetics seeks to find genetic predictors of drug response. To date, more than forty studies have investigated associations between genetic polymorphisms and response to antihypertensive drugs. Angiotensin-converting enzyme inhibitors and beta blockers have been most frequently studied, followed by angiotensin II blockers, diuretics, adrenergic alpha-agonists, and calcium channel blockers. Renin-angiotensin-aldosterone system genes have been the most widely studied, with the angiotensin-converting enzyme I/D variant being typed in about one-half of all hypertension pharmacogenetic studies. In total, 160 possible gene polymorphism-drug interactions have been explored, with about one-quarter of these showing that genes predict drug response. However, disparate and conflicting findings have been the rule rather than the exception, and the discovery of clinically relevant antihypertensive drug-response genes remains elusive. While there is a growing enthusiasm that pharmacogenetics of hypertension is important, the translation of pharmacogenetic findings to clinical practice in the future will depend on additional studies to enhance our pharmacogenetics knowledge base, the availability of pharmacogenetic screening tests that are affordable and easy to implement in clinical practice, a cohort of clinicians who are trained to interpret genetic test results, and health care systems that pay for them. Caution regarding the future of hypertension pharmacogenetics is warranted.

Hypertension is associated with increased cardio- and cerebrovascular morbidity and mortality; antihypertensive drugs have been shown to reduce the risk of adverse cardio- and cerebrovascular events. These events tend to be more common during the morning hours, a time when both normo- and hypertensives show a circadian peak in blood pressure (BP). Although clinicians have a number of safe and well-tolerated antihypertensive agents in various classes and formulations at their disposal, few are designed to specifically attenuate the morning BP surge while maintaining 24-h efficacy. A novel, once-daily, long-acting formulation of diltiazem HCl (DTZ-LA) has been developed with chronodynamics in harmony with diurnal BP variation. DTZ-LA effectively reduces BP in a dose-dependent fashion over a 24-h dosing interval in patients with moderate-to-severe essential hypertension. When compared with a morning dose, the evening dose is associated with significant and clinically meaningful greater reductions in BP during the morning hours, when adverse cardiovascular events tend to cluster. Evening-dosed DTZ-LA was more effective than morning-dosed amlodipine in reducing morning diastolic BP in African-Americans. Evening-dosed DTZ-LA was also more effective than evening-dosed ramipril in reducing morning BP. Evening dosing of DTZ-LA significantly increased exercise tolerance in patients with angina pectoris over the 24-h interval. DTZ-LA is associated with adverse effects consistent with other diltiazem formulations, and overall is safe and well tolerated, even when titrated to doses of 540 mg/day.

Background: The efficacy and safety of a once-daily graded-release diltiazem hydrochloride (GRD) formulation dosed at 10 PM in doses of 180, 360, and 420 mg were compared with placebo and with GRD 360 mg dosed once daily at 8 AM in patients (n = 311) with chronic stable angina pectoris., Methods: This was a 3-week multicenter, randomized, double-blind, double-dummy, parallel-group, placebo-controlled trial. Standard Bruce protocol treadmill stress test was performed at baseline and end point between 6 and 8 PM (trough for evening doses) and between 7 and 11 AM (trough for morning doses)., Results: All GRD evening doses showed a significant (P < or = .0201) increase in total duration of exercise at trough and a greater significant increase (P < or = .0002) at peak, compared with placebo. The GRD 360-mg evening dose showed the greatest increase at trough. In contrast, GRD 360-mg morning dose showed an increase in total duration of exercise at trough that was not significantly different (P = .0555) from placebo AM. GRD 360-mg evening dose showed a 4-fold placebo-adjusted improvement compared with GRD 360-mg morning dose between 7 and 11 AM. Significant increases (P < or = .0240) in time to onset of angina were obtained for all evening doses at trough and peak. All GRD doses were well tolerated, and incidence of adverse events for all GRD groups combined was less than that for placebo., Conclusions: Bedtime GRD significantly increases exercise tolerance in patients with angina pectoris over the 24-hour dosing interval. A greater 4-fold placebo-adjusted improvement occurred between 7 and 11 AM compared with the same morning dose, coinciding with the period of increased cardiovascular risk. GRD was safe and well tolerated.

Background: Atherosclerosis begins in the arterial wall, with endothelial dysfunction accompanied by functional and structural changes that influence arterial stiffness. Pulse contour analysis provides an assessment of compliance or elasticity of the large conduit arteries (C(1)) and small microcirculatory arteries (C(2)). In this study, the predictive value of reduced elasticity of these arteries was evaluated by follow-up of subjects who underwent pulse contour analysis at the University of Minnesota., Methods: Questionnaires were sent to 870 subjects who had radial artery pulse wave analysis performed between 1993 and 1999 using a noninvasive sensor, parameter estimating algorithm and modified Windkessel model of the circulation. Responses from 419 subjects >19 years of age reported on any cardiovascular events including death, myocardial infarction, stroke, transient ischemic attacks, angina, or coronary or peripheral vascular interventional procedures., Results: Of the subjects, 168 (41%) reported one or more cardiovascular events. Events were more common in those with elevated blood pressure, elevated cholesterol, diabetes, and family history of events. Age, reduced C(1), and reduced C(2) were univariate predictors of events. After adjusting for age, a 2-unit decrease in C(2) remained a significant predictor (odds ratio 1.50, P <.001), whereas C(1) was no longer predictive., Conclusion: Reduced small artery elasticity, which is a measure of endothelial dysfunction, is significantly associated with cardiovascular events independent of age.

Background: The efficacy and safety of a chronotherapeutic, graded-release diltiazem HCl extended-release (GRD) 120-, 240-, 360- and 540-mg dose administered once-daily at bedtime (10 PM) were evaluated in a 7-week randomized, double-blind comparison to placebo and to GRD 360 mg administered once-daily at 8 AM in 478 patients with moderate-to-severe essential hypertension., Methods: We assessed the change from baseline to end point in trough diastolic blood pressure (DBP) at 6 PM to 10 PM and in mean DBP from 6 AM to 12 noon between GRD 360 mg PM and GRD 360 mg AM, measured by ambulatory BP monitoring (ABPM)., Results: Bedtime doses of GRD showed dose-related mean reductions in trough DBP that were significant for GRD doses of 240 mg and higher. Bedtime GRD 360 mg was associated with a significantly greater reduction in mean DBP between 6 AM and 12 noon compared to morning GRD 360 mg with a least squares mean for treatment difference of -3.3 mm Hg (P =.0004). Similar dose-related and significant reductions in systolic BP (SBP) and heart rate (HR) were obtained. Incidence of adverse events (AEs) for all GRD groups (44.5%) was less than that obtained for the placebo group (49.3%). The 540-mg group showed an incidence of AEs (43.5%) similar to that observed for the 240-mg group (42.6%)., Conclusions: The GRD dose-dependently significantly reduces BP and HR over the 24-h interval after once-daily bedtime dosing. Further greater reductions were obtained between 6 AM and 12 noon, when circadian BP is highest, compared to morning administration of the same dose. The 540-mg GRD was safe, well tolerated, and offers further therapeutic option for patients with severe hypertension who required additional BP control.

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.