Adam D. Gepner

A Prospective Randomized Controlled Trial of the Effects of Vitamin D Supplementation on Cardiovascular Disease Risk

Vitamin D (VitD) supplementation has been advocated for cardiovascular risk reduction; however, supporting data are sparse. The objective of this study was to determine whether VitD supplementation reduces cardiovascular risk. Subjects in this prospective, randomized, double-blind, placebo-controlled trial of post-menopausal women with serum 25-hydroxyvitamin D concentrations >10 and <60 ng/mL were randomized to Vitamin D3 2500 IU or placebo, daily for 4 months. Primary endpoints were changes in brachial artery flow-mediated vasodilation (FMD), carotid-femoral pulse wave velocity (PWV), and aortic augmentation index (AIx). The 114 subjects were mean (standard deviation) 63.9 (3.0) years old with a 25-hydroxyvitamin D level of 31.3 (10.6) ng/mL. Low VitD (<30 ng/mL) was present in 47% and was associated with higher body-mass index, systolic blood pressure, glucose, CRP, and lower FMD (all p<0.05). After 4 months, 25-hydroxyvitamin D levels increased by 15.7 (9.3) ng/mL on vitamin D3 vs. −0.2 (6.1) ng/mL on placebo (p<0.001). There were no significant differences between groups in changes in FMD (0.3 [3.4] vs. 0.3 [2.6] %, p = 0.77), PWV (0.00 [1.06] vs. 0.05 [0.92] m/s, p = 0.65), AIx (2.7 [6.3] vs. 0.9 [5.6] %, p = 0.10), or CRP (0.3 [1.9] vs. 0.3 [4.2] mg/L, p = 0.97). Multivariable models showed no significant interactions between treatment group and low VitD status (<30 ng/mL) for changes in FMD (p = 0.65), PWV (p = 0.93), AIx (p = 0.97), or CRP (p = 0.26).In conclusion, VitD supplementation did not improve endothelial function, arterial stiffness, or inflammation. These observations do not support use of VitD supplementation to reduce cardiovascular disease risk. Trial Registration ClinicalTrials.gov NCT00690417 Trial Registration ClinicalTrials.gov NCT01049048

Effect of Vitamin D Supplementation on Blood Pressure: A Systematic Review and Meta-analysis Incorporating Individual Patient Data

IMPORTANCE Low levels of vitamin D are associated with elevated blood pressure (BP) and future cardiovascular events. Whether vitamin D supplementation reduces BP and which patient characteristics predict a response remain unclear. OBJECTIVE To systematically review whether supplementation with vitamin D or its analogues reduce BP. DATA SOURCES We searched MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.com augmented by a hand search of references from the included articles and previous reviews. Google was searched for gray literature (ie, material not published in recognized scientific journals). No language restrictions were applied. The search period spanned January 1, 1966, through March 31, 2014. STUDY SELECTION We included randomized placebo-controlled clinical trials that used vitamin D supplementation for a minimum of 4 weeks for any indication and reported BP data. Studies were included if they used active or inactive forms of vitamin D or vitamin D analogues. Cointerventions were permitted if identical in all treatment arms. DATA EXTRACTION AND SYNTHESIS We extracted data on baseline demographics, 25-hydroxyvitamin D levels, systolic and diastolic BP (SBP and DBP), and change in BP from baseline to the final follow-up. Individual patient data on age, sex, medication use, diabetes mellitus, baseline and follow-up BP, and 25-hydroxyvitamin D levels were requested from the authors of the included studies. For trial-level data, between-group differences in BP change were combined in a random-effects model. For individual patient data, between-group differences in BP at the final follow up, adjusted for baseline BP, were calculated before combining in a random-effects model. MAIN OUTCOMES AND MEASURES Difference in SBP and DBP measured in an office setting. RESULTS We included 46 trials (4541 participants) in the trial-level meta-analysis. Individual patient data were obtained for 27 trials (3092 participants). At the trial level, no effect of vitamin D supplementation was seen on SBP (effect size, 0.0 [95% CI, -0.8 to 0.8] mm Hg; P=.97; I2=21%) or DBP (effect size, -0.1 [95% CI, -0.6 to 0.5] mm Hg; P=.84; I2=20%). Similar results were found analyzing individual patient data for SBP (effect size, -0.5 [95% CI, -1.3 to 0.4] mm Hg; P=.27; I2=0%) and DBP (effect size, 0.2 [95% CI, -0.3 to 0.7] mm Hg; P=.38; I2=0%). Subgroup analysis did not reveal any baseline factor predictive of a better response to therapy. CONCLUSIONS AND RELEVANCE Vitamin D supplementation is ineffective as an agent for lowering BP and thus should not be used as an antihypertensive agent.

Effects of smoking and smoking cessation on lipids and lipoproteins: Outcomes from a randomized clinical trial

BACKGROUND the effects of smoking and smoking cessation on lipoproteins have not been studied in a large contemporary group of smokers. This study was designed to determine the effects of smoking cessation on lipoproteins. METHODS this was a 1-year, prospective, double-blind, randomized, placebo-controlled clinical trial of the effects of 5 smoking cessation pharmacotherapies. Fasting nuclear magnetic resonance spectroscopy lipoprotein profiles were obtained before and 1 year after the target smoking cessation date. The effects of smoking cessation and predictors of changes in lipoproteins after 1 year were identified by multivariable regression. RESULTS the 1,504 current smokers were (mean [SD]) 45.4 (11.3) years old and smoked 21.4 (8.9) cigarettes per day at baseline. Of the 923 adult smokers who returned at 1 year, 334 (36.2%) had quit smoking. Despite gaining more weight (4.6 kg [5.7] vs 0.7 kg [5.1], P < .001], abstainers had increases in high-density lipoprotein cholesterol (HDL-C) (2.4 [8.3] vs 0.1 [8.8] mg/dL, P < .001), total HDL (1.0 [4.6] vs -0.3 micromol/L [5.0], P < .001), and large HDL (0.6 [2.2] vs 0.1 [2.1] micromol/L, P = .003) particles compared with continuing smokers. Significant changes in low-density lipoprotein (LDL) cholesterol and particles were not observed. After adjustment, abstinence from smoking (P < .001) was independently associated with increases in HDL-C and total HDL particles. These effects were stronger in women. CONCLUSIONS despite weight gain, smoking cessation improved HDL-C, total HDL, and large HDL particles, especially in women. Smoking cessation did not affect LDL or LDL size. Increases in HDL may mediate part of the reduced cardiovascular disease risk observed after smoking cessation.

Comparison of Coronary Artery Calcium Presence, Carotid Plaque Presence, and Carotid Intima-Media Thickness for Cardiovascular Disease Prediction in the Multi-Ethnic Study of Atherosclerosis

Background—Presence of coronary artery calcium (CAC), carotid plaque, and increased carotid intima-media thickness (IMT) may indicate elevated cardiovascular disease (CVD) risk; however, no large studies have compared them directly. This study compares predictive uses of CAC presence, carotid artery plaque presence, and high IMT for incident CVD events. Methods and Results—Participants were from the Multi-Ethnic Study of Atherosclerosis (MESA). Predictive values of carotid plaque, IMT, and CAC presence were compared using Cox proportional hazards models, c-statistics, and net reclassification indices. The 6779 participants were mean (SD) 62.2 (10.2) years old; 49.9% had CAC, and 46.7% had carotid plaque. The mean left and right IMT were 0.754 (0.210) mm and 0.751 (0.187) mm, respectively. After 9.5 years (mean), 538 CVD events, 388 coronary heart disease (CHD) events, and 196 stroke/transient ischemic attacks were observed. CAC presence was a stronger predictor of incident CVD and CHD than carotid ultrasound measures. Mean IMT ≥75th percentile (for age, sex, and race) alone did not predict events. Compared with traditional risk factors, c-statistics for CVD (c=0.756) and CHD (c=0.752) increased the most by the addition of CAC presence (CVD, 0.776; CHD, 0.784; P<0.001) followed by carotid plaque presence (CVD, c=0.760; CHD, c=0.757; P<0.05). Compared with risk factors (c=0.782), carotid plaque presence (c=0.787; P=0.045) but not CAC (c=0.785; P=0.438) improved prediction of stroke/transient ischemic attacks. Conclusions—In adults without CVD, CAC presence improves prediction of CVD and CHD more than carotid plaque presence or high IMT. CAC and carotid ultrasound parameters performed similarly for stroke/transient ischemic attack event prediction.

Predictors of Carotid Thickness and Plaque Progression During a Decade: The Multi-Ethnic Study of Atherosclerosis

Background and Purpose— Carotid artery intima-media thickness (IMT) and plaque are noninvasive markers of subclinical arterial injury that predict incident cardiovascular disease. We evaluated predictors of longitudinal changes in IMT and new plaque during a decade in a longitudinal multiethnic cohort. Methods— Carotid IMT and plaque were evaluated in Multi-Ethnic Study of Atherosclerosis (MESA) participants at exams 1 and 5, a mean (standard deviation) of 9.4 (0.5) years later. Far wall carotid IMT was measured in both common and internal carotid arteries. A plaque score was calculated from all carotid segments. Mixed-effects longitudinal and multivariate regression models evaluated associations of baseline risk factors and time-updated medication use with IMT progression and plaque formation. Results— The 3441 MESA participants were aged 60.3 (9.4) years (53% women; 26% blacks, 22% Hispanic, 13% Chinese); 1620 (47%) had carotid plaque. Mean common carotid artery IMT progression was 11.8 (12.8) &mgr;m/year, and 1923 (56%) subjects developed new plaque. IMT progressed more slowly in Chinese (&bgr;=−2.89; P=0.001) and Hispanic participants (&bgr;=−1.81; P=0.02), and with higher baseline high-density lipoprotein cholesterol (per 5 mg/dL; &bgr;=−0.22; P=0.03), antihypertensive use (&bgr;=−2.06; P=0.0004), and time on antihypertensive medications (years; &bgr;=−0.29; P<0.0001). Traditional risk factors were associated with new plaque formation, with strong associations for cigarette use (odds ratio, 2.31; P<0.0001) and protection by black ethnicity (odds ratio, 0.68; P<0.0001). Conclusions— In a large, multiethnic cohort with a decade of follow-up, ethnicity was a strong, independent predictor of carotid IMT and plaque progression. Antihypertensive medication use was associated with less subclinical disease progression.

25-Hydroxyvitamin D and Parathyroid Hormone Are Not Associated With Carotid Intima-Media Thickness or Plaque in the Multi-Ethnic Study of Atherosclerosis

Objective—Observational evidence supports independent associations of 25-hydroxyvitamin D (25-OHD) and parathyroid hormone (PTH) with cardiovascular risk. A plausible hypothesis for these associations is accelerated development of atherosclerosis. Approach and Results—We evaluated cross-sectional and longitudinal associations of 25-OHD and PTH with carotid intima-media thickness (IMT) and carotid plaques among 3251 participants free of cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. 25-OHD and PTH were measured at baseline by mass spectrometry and immunoassay, respectively. All subjects underwent a carotid ultrasound examination at baseline and 9.4 years later (median, range 8–11.1 years). Multivariable linear and logistic regressions were used to test associations of 25-OHD and PTH with the extent and progression of IMT and the prevalence and incidence of carotid plaque. Mean (SD) 25-OHD and PTH were 25.8 ng/mL (10.6) and 44.2 pg/mL (20.2), respectively. No independent associations were found between 25-OHD or PTH and IMT at baseline (increment of 1.9 &mgr;m [95% confidence interval, −5.1 to 8.9] per 10 ng/mL lower 25-OHD; increment of 0.8 &mgr;m [95% confidence interval, −3.2 to 4.8] per 10 pg/mL higher PTH) or progression of IMT (increment of 2.6 &mgr;m [95% confidence interval, −2.5 to 7.8] per 10 ng/mL lower 25-OHD, increment of 1.6 &;m [95% confidence interval, −1.9 to 5.2] per 10 pg/mL higher PTH). No associations were found with the baseline prevalence of carotid plaque or the incidence of new plaques during the study period. We did not observe any interaction by race or ethnicity (White, Chinese, Black, and Hispanic). Conclusions—The consistent lack of association of vitamin D and PTH with carotid IMT and plaque suggests that these hormones may influence cardiovascular risk through pathways not reflected by carotid atherosclerosis.

Longitudinal Effects of a Decade of Aging on Carotid Artery Stiffness The Multiethnic Study of Atherosclerosis

Background and Purpose— Arterial stiffening is associated with hypertension, stroke, and cognitive decline; however, the effects of aging and cardiovascular disease risk factors on carotid artery stiffening have not been assessed prospectively in a large multiethnic longitudinal study. Methods— Distensibility coefficient and the Young’s elastic modulus (YEM) of the right common carotid artery were calculated at baseline and after a mean of 9.4 (standard deviation [SD], 0.5) years in 2650 participants. Effects of age and cardiovascular disease risk factors were evaluated by multivariable mixed regression and ANCOVA models. Results— At baseline, participants were 59.9 (SD, 9.4) years old (53% women; 25% black, 22% Hispanic, 14% Chinese). YEM increased from 1581 (SD, 927) to 1749 (SD, 1306) mm Hg (P<0.0001), and distensibility coefficient decreased from 3.1 (SD, 1.3) to 2.7 (SD, 1.1)×10–3 mm Hg−1 (P<0.001), indicating progressive arterial stiffening. YEM increased more among participants who were aged >75 years old at baseline (P<0.0001). In multivariable analyses, older age and less education independently predicted worsening YEM and distensibility coefficient. Stopping antihypertensive medication during the study period predicted more severe worsening of YEM (&bgr;=360.2 mm Hg; P=0.008). Starting antihypertensive medication after examination 1 was predictive of improvements in distensibility coefficient (&bgr;=1.1×10–4 mm Hg–1; P=0.024). Conclusions— Arterial stiffening accelerates with advanced age. Older individuals experience greater increases in YEM than do younger adults, even after considering the effects of traditional risk factors. Treating hypertension may slow the progressive decline in carotid artery distensibility observed with aging and improve cerebrovascular health.

Asthma Predicts Cardiovascular Disease Events The Multi-Ethnic Study of Atherosclerosis

Objectives—To identify and characterize an association between persistent asthma and cardiovascular disease (CVD) risk in the Multi-Ethnic Study of Atherosclerosis (MESA). Approach and Results—MESA is a longitudinal prospective study of an ethnically diverse cohort of individuals free of known CVD at its inception. The presence and severity of asthma were assessed in the MESA at examination 1. Persistent asthma was defined as asthmatics using controller medications (inhaled corticosteroids, leukotriene inhibitors, and oral corticosteroids) and intermittent asthma as asthmatics not using controller medications. Participants were followed up for a mean (SD) of 9.1 (2.8) years for development of incident CVD (coronary death, myocardial infarction, angina, stroke, and CVD death). Multivariable Cox regression models were used to assess associations of asthma and CVD. The 6792 participants were 62.2 (SD, 10.2) years old: 47% men (28% black, 22% Hispanic, and 12% Chinese). Persistent asthmatics (n=156), compared with intermittent (n=511) and nonasthmatics (n=6125), respectively, had higher C-reactive protein (1.2 [1.2] versus 0.9 [1.2] versus 0.6 [1.2] mg/L) and fibrinogen (379 [88] versus 356 [80] versus 345 [73] mg/dL) levels. Persistent asthmatics had the lowest unadjusted CVD-free survival rate of 84.1%, 95% confidence interval (78.9%–90.3%) compared with intermittent asthmatics 91.1% (88.5%–93.8%) and nonasthmatics 90.2% (89.4%–91%). Persistent asthmatics had greater risk of CVD events than nonasthmatics (hazard ratio [95% confidence interval], 1.6 [1.01–2.5]; P=0.040]), even after adjustment for age, sex, race, CVD risk factors, and antihypertensive and lipid medication use. Conclusions—In this large multiethnic cohort, persistent asthmatics had a higher CVD event rate than nonasthmatics.Objectives— To identify and characterize an association between persistent asthma and cardiovascular disease (CVD) risk in the Multi-Ethnic Study of Atherosclerosis (MESA). Approach and Results— MESA is a longitudinal prospective study of an ethnically diverse cohort of individuals free of known CVD at its inception. The presence and severity of asthma were assessed in the MESA at examination 1. Persistent asthma was defined as asthmatics using controller medications (inhaled corticosteroids, leukotriene inhibitors, and oral corticosteroids) and intermittent asthma as asthmatics not using controller medications. Participants were followed up for a mean (SD) of 9.1 (2.8) years for development of incident CVD (coronary death, myocardial infarction, angina, stroke, and CVD death). Multivariable Cox regression models were used to assess associations of asthma and CVD. The 6792 participants were 62.2 (SD, 10.2) years old: 47% men (28% black, 22% Hispanic, and 12% Chinese). Persistent asthmatics (n=156), compared with intermittent (n=511) and nonasthmatics (n=6125), respectively, had higher C-reactive protein (1.2 [1.2] versus 0.9 [1.2] versus 0.6 [1.2] mg/L) and fibrinogen (379 [88] versus 356 [80] versus 345 [73] mg/dL) levels. Persistent asthmatics had the lowest unadjusted CVD-free survival rate of 84.1%, 95% confidence interval (78.9%–90.3%) compared with intermittent asthmatics 91.1% (88.5%–93.8%) and nonasthmatics 90.2% (89.4%–91%). Persistent asthmatics had greater risk of CVD events than nonasthmatics (hazard ratio [95% confidence interval], 1.6 [1.01–2.5]; P =0.040]), even after adjustment for age, sex, race, CVD risk factors, and antihypertensive and lipid medication use. Conclusions— In this large multiethnic cohort, persistent asthmatics had a higher CVD event rate than nonasthmatics. # Significance {#article-title-31}

Asthma Predicts Cardiovascular Disease Events

Objectives—To identify and characterize an association between persistent asthma and cardiovascular disease (CVD) risk in the Multi-Ethnic Study of Atherosclerosis (MESA). Approach and Results—MESA is a longitudinal prospective study of an ethnically diverse cohort of individuals free of known CVD at its inception. The presence and severity of asthma were assessed in the MESA at examination 1. Persistent asthma was defined as asthmatics using controller medications (inhaled corticosteroids, leukotriene inhibitors, and oral corticosteroids) and intermittent asthma as asthmatics not using controller medications. Participants were followed up for a mean (SD) of 9.1 (2.8) years for development of incident CVD (coronary death, myocardial infarction, angina, stroke, and CVD death). Multivariable Cox regression models were used to assess associations of asthma and CVD. The 6792 participants were 62.2 (SD, 10.2) years old: 47% men (28% black, 22% Hispanic, and 12% Chinese). Persistent asthmatics (n=156), compared with intermittent (n=511) and nonasthmatics (n=6125), respectively, had higher C-reactive protein (1.2 [1.2] versus 0.9 [1.2] versus 0.6 [1.2] mg/L) and fibrinogen (379 [88] versus 356 [80] versus 345 [73] mg/dL) levels. Persistent asthmatics had the lowest unadjusted CVD-free survival rate of 84.1%, 95% confidence interval (78.9%–90.3%) compared with intermittent asthmatics 91.1% (88.5%–93.8%) and nonasthmatics 90.2% (89.4%–91%). Persistent asthmatics had greater risk of CVD events than nonasthmatics (hazard ratio [95% confidence interval], 1.6 [1.01–2.5]; P=0.040]), even after adjustment for age, sex, race, CVD risk factors, and antihypertensive and lipid medication use. Conclusions—In this large multiethnic cohort, persistent asthmatics had a higher CVD event rate than nonasthmatics.Objectives— To identify and characterize an association between persistent asthma and cardiovascular disease (CVD) risk in the Multi-Ethnic Study of Atherosclerosis (MESA). Approach and Results— MESA is a longitudinal prospective study of an ethnically diverse cohort of individuals free of known CVD at its inception. The presence and severity of asthma were assessed in the MESA at examination 1. Persistent asthma was defined as asthmatics using controller medications (inhaled corticosteroids, leukotriene inhibitors, and oral corticosteroids) and intermittent asthma as asthmatics not using controller medications. Participants were followed up for a mean (SD) of 9.1 (2.8) years for development of incident CVD (coronary death, myocardial infarction, angina, stroke, and CVD death). Multivariable Cox regression models were used to assess associations of asthma and CVD. The 6792 participants were 62.2 (SD, 10.2) years old: 47% men (28% black, 22% Hispanic, and 12% Chinese). Persistent asthmatics (n=156), compared with intermittent (n=511) and nonasthmatics (n=6125), respectively, had higher C-reactive protein (1.2 [1.2] versus 0.9 [1.2] versus 0.6 [1.2] mg/L) and fibrinogen (379 [88] versus 356 [80] versus 345 [73] mg/dL) levels. Persistent asthmatics had the lowest unadjusted CVD-free survival rate of 84.1%, 95% confidence interval (78.9%–90.3%) compared with intermittent asthmatics 91.1% (88.5%–93.8%) and nonasthmatics 90.2% (89.4%–91%). Persistent asthmatics had greater risk of CVD events than nonasthmatics (hazard ratio [95% confidence interval], 1.6 [1.01–2.5]; P =0.040]), even after adjustment for age, sex, race, CVD risk factors, and antihypertensive and lipid medication use. Conclusions— In this large multiethnic cohort, persistent asthmatics had a higher CVD event rate than nonasthmatics. # Significance {#article-title-31}

25-Hydroxyvitamin D and Parathyroid Hormone Levels Do Not Predict Changes in Carotid Arterial Stiffness The Multi-Ethnic Study of Atherosclerosis

Objective—To evaluate the impact of vitamin D and parathyroid hormone (PTH) on longitudinal changes in arterial stiffness. Approach and Results—Distensibility coefficient and Young’s elastic modulus of the right common carotid artery were evaluated at baseline and after a mean (SD) of 9.4 (0.5) years in 2580 Multi-Ethnic Study of Atherosclerosis (MESA) participants. Cross-sectional and longitudinal associations were evaluated using multivariable linear regression and analysis of covariance. At baseline, participants were 60.1 (9.4) years old (54% female; 26% black, 20% Hispanic, 14% Chinese). Mean annualized 25(OH)D was <20 ng/dL in 816 participants, and PTH was >65 pg/dL in 285 participants. In cross-sectional analyses, low 25(OH)D (<20 ng/mL) was not associated with stiffer arteries after adjustment for cardiovascular disease risk factors (P>0.4). PTH >65 pg/mL was associated with stiffer arteries after adjustment for cardiovascular disease risk factors, other than systolic blood pressure (distensibility coefficient: &bgr;=−2.4×10−4 mm Hg−1, P=0.003; Young’s elastic modulus: &bgr;=166 mm Hg, P=0.01); however, after adjustment for systolic blood pressure, these associations no longer were statistically significant. Longitudinal arterial stiffening was associated with older age (P<0.0001), higher systolic blood pressure (P<0.008), and use of antihypertensive medications (P<0.006), but not with 25(OH)D or PTH (both P>0.1). Conclusions—Carotid arterial stiffness is not associated with low 25(OH)D concentrations. Cross-sectional associations between arterial stiffness and high PTH were attenuated by systolic blood pressure. After nearly a decade of follow-up, neither baseline PTH nor 25(OH)D concentrations were associated with progression of carotid arterial stiffness.