Effects of Vitamin D Supplementation on Cardiovascular and Glycemic Biomarkers.

Background Experimental and observational studies have suggested a link between vitamin D and cardiovascular and metabolic disease, but this has not been confirmed in randomized controlled trials. We sought to determine whether vitamin D supplementation reduces biomarkers of insulin resistance, inflammation, neurohormonal activation, and lipids. Methods and Results This was a prespecified, secondary analysis of the DAYLIGHT (Vitamin D Therapy in Individuals at High Risk of Hypertension) randomized controlled trial. We measured circulating homeostatic model assessment of insulin resistance, hs-CRP (high-sensitivity C-reactive protein), N-terminal pro-B-type natriuretic peptide, renin, aldosterone, and lipids at baseline and at 6 months in 289 individuals with low vitamin D status (25-hydroxyvitamin-D [25-OH-D] ≤25 ng/mL) receiving low-dose (400 IU/d) versus high-dose (4000 IU/d) vitamin D3 for 6 months. A meta-analysis of randomized controlled trials reporting biomarker changes after vitamin D supplementation was then performed. Levels of 25-OH-D increased in the high-dose relative to the low-dose vitamin D group (+15.5 versus +4.6 ng/mL, P<0.001). Changes in biomarkers of glycemia, inflammation, and neurohormonal activation did not differ by dose. Lipids did not differ between groups, other than triglycerides, which increased in the high-dose compared with the low-dose group (+11.3 versus -6.2 mg/dL, P<0.001). The meta-analysis showed potential modest decreases in homeostatic model assessment of insulin resistance and hs-CRP, but no changes in low-density lipoprotein, after vitamin D supplementation compared with control groups. Conclusions In the DAYLIGHT randomized controlled trial, high-dose vitamin D supplementation did not improve biomarkers of glycemia, inflammation, neurohormonal activation, or lipids. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01240512.

Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association.

Resistant hypertension (RH) is defined as above-goal elevated blood pressure (BP) in a patient despite the concurrent use of 3 antihypertensive drug classes, commonly including a long-acting calcium channel blocker, a blocker of the renin-angiotensin system (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic. The antihypertensive drugs should be administered at maximum or maximally tolerated daily doses. RH also includes patients whose BP achieves target values on ≥4 antihypertensive medications. The diagnosis of RH requires assurance of antihypertensive medication adherence and exclusion of the "white-coat effect" (office BP above goal but out-of-office BP at or below target). The importance of RH is underscored by the associated risk of adverse outcomes compared with non-RH. This article is an updated American Heart Association scientific statement on the detection, evaluation, and management of RH. Once antihypertensive medication adherence is confirmed and out-of-office BP recordings exclude a white-coat effect, evaluation includes identification of contributing lifestyle issues, detection of drugs interfering with antihypertensive medication effectiveness, screening for secondary hypertension, and assessment of target organ damage. Management of RH includes maximization of lifestyle interventions, use of long-acting thiazide-like diuretics (chlorthalidone or indapamide), addition of a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and, if BP remains elevated, stepwise addition of antihypertensive drugs with complementary mechanisms of action to lower BP. If BP remains uncontrolled, referral to a hypertension specialist is advised.

Vitamin D Supplementation Modulates T Cell-Mediated Immunity in Humans: Results from a Randomized Control Trial.

CONTEXT: Although studies have linked vitamin D deficiency with immune-mediated diseases, data demonstrating a direct effect on T-cell function are sparse. OBJECTIVE: Our objective was to determine whether oral vitamin D3 influences T-cell activation in humans with vitamin D deficiency. DESIGN: This was a single-center ancillary study within Vitamin D Therapy in Individuals at High Risk of Hypertension, a double-blind, multicenter, randomized controlled trial. SETTING: This study was undertaken in a single academic medical center. PARTICIPANTS: Adults with vitamin D deficiency and untreated pre- or early stage I hypertension were included. INTERVENTION: In Vitamin D Therapy in Individuals at High Risk of Hypertension, participants were randomized to either low- (400 IU daily) or high- (4000 IU daily) dose oral vitamin D3 for 6 months. In this ancillary study of 38 patients, we measured CD4+ T-cell activation estimated by intracellular ATP release after stimulation of whole blood with plant lectin phytohemagglutinin collected at baseline (pretreatment) and 2-month follow-up. MAIN OUTCOME MEASURE: Determining whether ATP level changes were significantly different between treatment groups was the main outcome measure. RESULTS: Treatment with 4000 IU of vitamin D3 decreased intracellular CD4+ ATP release by 95.5 ng/ml (interquartile range, -219.5 to 105.8). In contrast, 400 IU of vitamin D3 decreased intracellular CD4+ ATP release by 0.5 ng/ml (interquartile range, -69.2 to 148.5). In a proportional odds model, high-dose vitamin D3 was more likely than low-dose vitamin D3 to decrease CD4+ ATP release (odds ratio, 3.43; 95% confidence interval, 1.06-1.11). CONCLUSIONS: In this ancillary study of a randomized controlled trial, we found that high-dose vitamin D3 significantly reduced CD4+ T-cell activation compared to low-dose vitamin D3, providing human evidence that vitamin D can influence cell-mediated immunity.

High-Dose versus Low-Dose Vitamin D Supplementation and Arterial Stiffness among Individuals with Prehypertension and Vitamin D Deficiency.

INTRODUCTION: Vitamin D deficiency is associated with the onset and progression of hypertension and cardiovascular disease (CVD). However, mechanisms underlying vitamin D deficiency-mediated increased risk of CVD remain unknown. We sought to examine the differential effect of high-dose versus low-dose vitamin D supplementation on markers of arterial stiffness among ~40 vitamin D deficient adults with prehypertension. METHODS: Participants were randomized to high-dose (4000 IU/d) versus low-dose (400 IU/d) oral vitamin D3 for 6 months. 24 hr ambulatory blood pressure (BP), carotid-femoral pulse wave velocity, and pulse wave analyses were obtained at baseline and after 6 months of vitamin D supplementation. RESULTS: There were no changes in resting BP or pulse wave velocity over 6 mo regardless of vitamin D dose (all p > 0.202). High-dose vitamin D decreased augmentation index and pressure by 12.3 ± 5.3% (p = 0.047) and 4.0 ± 1.5 mmHg (p = 0.02), respectively. However, these decreases in arterial stiffness were not associated with increases in serum 25-hydroxyvitamin D over 6 mo (p = 0.425). CONCLUSION: High-dose vitamin D supplementation appears to lower surrogate measures of arterial stiffness but not indices of central pulse wave velocity. Clinical Trial Registration. This trial is registered with www.clinicaltrials.gov (Unique Identifier: NCT01240512).

Vitamin D therapy in individuals with prehypertension or hypertension: the DAYLIGHT trial.

BACKGROUND: A large body of epidemiological and experimental evidence suggests that vitamin D deficiency may promote hypertension. This raises the possibility that vitamin D supplementation could be a simple intervention to reduce blood pressure, but data from prospective, randomized trials are limited. METHODS AND RESULTS: A double-blind, randomized, controlled trial was conducted at 4 sites in the United States. We enrolled 534 individuals 18 to 50 years of age with low vitamin D status (25-hydroxyvitamin D levels ≤25 ng/mL) and systolic blood pressure of 120 to 159 mm Hg. Participants were randomized to high-dose (4000 IU/d) versus low-dose (400 IU/d) oral vitamin D3 for 6 months. The primary end point was change in mean 24-hour systolic blood pressure. Secondary end points included change in ambulatory diastolic blood pressure and clinic systolic and diastolic blood pressures. The median age was 38 years, and 62% of participants were men. Forty-six percent of participants were white, and 48% were black. The median 25-hydroxyvitamin D level at baseline was 15.3 ng/mL. Four-hundred fifty-five participants (85%) had at least 1 follow-up blood pressure measurement; 383 participants (72%) completed the full 6-month study. At the end of the study, there was no significant difference in the primary end point (change in mean 24-hour systolic blood pressure, -0.8 versus -1.6 mm Hg in the high-dose and low-dose arms; P=0.71) or in any of the secondary end points. Furthermore, there was no evidence of association between change in 25-hydroxyvitamin D and change in 24-hour systolic blood pressure at 6 months (Spearman correlation coefficient, -0.05, P=0.34). Results were consistent across prespecified subgroups. CONCLUSIONS: Vitamin D supplementation did not reduce blood pressure in individuals with prehypertension or stage I hypertension and vitamin D deficiency. Our findings suggest that the association between vitamin D status and elevated blood pressure noted in observational studies is not causal. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01240512.

A common variant near the KCNJ2 gene is associated with T-peak to T-end interval.

BACKGROUND: T-peak to T-end (TPE) interval on the electrocardiogram is a measure of myocardial dispersion of repolarization and is associated with an increased risk of ventricular arrhythmias. The genetic factors affecting the TPE interval are largely unknown. OBJECTIVE: To identify common genetic variants that affect the duration of the TPE interval in the general population. METHODS: We performed a genome-wide association study on 1870 individuals of Finnish origin participating in the Health 2000 Study. The TPE interval was measured from T-peak to T-wave end in leads II, V(2), and V(5) on resting electrocardiograms, and the mean of these TPE intervals was adjusted for age, sex, and Cornell voltage-duration product. We sought replication for a genome-wide significant result in the 3745 subjects from the Framingham Heart Study. RESULTS: We identified a locus on 17q24 that was associated with the TPE interval. The minor allele of the common variant rs7219669 was associated with a 1.8-ms shortening of the TPE interval (P = 1.1 × 10(-10)). The association was replicated in the Framingham Heart Study (-1.5 ms; P = 1.3 × 10(-4)). The overall effect estimate of rs7219669 in the 2 studies was -1.7 ms (P = 5.7 × 10(-14)). The common variant rs7219669 maps downstream of the KCNJ2 gene, in which rare mutations cause congenital long and short QT syndromes. CONCLUSION: The common variant rs7219669 is associated with the TPE interval and is thus a candidate to modify repolarization-related arrhythmia susceptibility in individuals carrying the major allele of this polymorphism.