John D. Sluyter

Effect of Monthly High-Dose Vitamin D Supplementation on Cardiovascular Disease in the Vitamin D Assessment Study : A Randomized Clinical Trial

Importance Cohort studies have reported increased incidence of cardiovascular disease (CVD) among individuals with low vitamin D status. To date, randomized clinical trials of vitamin D supplementation have not found an effect, possibly because of using too low a dose of vitamin D. Objective To examine whether monthly high-dose vitamin D supplementation prevents CVD in the general population. Design, Setting, and Participants The Vitamin D Assessment Study is a randomized, double-blind, placebo-controlled trial that recruited participants mostly from family practices in Auckland, New Zealand, from April 5, 2011, through November 6, 2012, with follow-up until July 2015. Participants were community-resident adults aged 50 to 84 years. Of 47 905 adults invited from family practices and 163 from community groups, 5110 participants were randomized to receive vitamin D3 (n = 2558) or placebo (n = 2552). Two participants retracted consent, and all others (n = 5108) were included in the primary analysis. Interventions Oral vitamin D3 in an initial dose of 200 000 IU, followed a month later by monthly doses of 100 000 IU, or placebo for a median of 3.3 years (range, 2.5-4.2 years). Main Outcomes and Measures The primary outcome was the number of participants with incident CVD and death, including a prespecified subgroup analysis in participants with vitamin D deficiency (baseline deseasonalized 25-hydroxyvitamin D [25(OH)D] levels <20 ng/mL). Secondary outcomes were myocardial infarction, angina, heart failure, hypertension, arrhythmias, arteriosclerosis, stroke, and venous thrombosis. Results Of the 5108 participants included in the analysis, the mean (SD) age was 65.9 (8.3) years, 2969 (58.1%) were male, and 4253 (83.3%) were of European or other ethnicity, with the remainder being Polynesian or South Asian. Mean (SD) baseline deseasonalized 25(OH)D concentration was 26.5 (9.0) ng/mL, with 1270 participants (24.9%) being vitamin D deficient. In a random sample of 438 participants, the mean follow-up 25(OH)D level was greater than 20 ng/mL higher in the vitamin D group than in the placebo group. The primary outcome of CVD occurred in 303 participants (11.8%) in the vitamin D group and 293 participants (11.5%) in the placebo group, yielding an adjusted hazard ratio of 1.02 (95% CI, 0.87-1.20). Similar results were seen for participants with baseline vitamin D deficiency and for secondary outcomes. Conclusions and Relevance Monthly high-dose vitamin D supplementation does not prevent CVD. This result does not support the use of monthly vitamin D supplementation for this purpose. The effects of daily or weekly dosing require further study. Trial Registration clinicaltrials.gov Identifier: ACTRN12611000402943

Prediction of fatness by standing 8-electrode bioimpedance: a multiethnic adolescent population.

The objective of this study was to validate an 8‐electrode bioimpedance analysis (BIA8) device (BC‐418; Tanita, Tokyo, Japan) for use in populations of European, Maori, Pacific Island, and Asian adolescents. Healthy adolescents (215 M, 216 F; 129 Pacific Island, 120 Asian, 91 Maori, and 91 European; age range 12–19 years) were recruited by purposive sampling of high schools in Auckland, New Zealand. Weight, height, sitting height, leg length, waist circumference, and whole‐body impedance were measured. Fat mass (FM) and fat‐free mass (FFM) derived from the BIA8 manufacturers equations were compared with measurements by dual‐energy X‐ray absorptiometry (DXA). DXA‐measured FFM was used as the reference to develop prediction equations based on impedance. A double cross‐validation technique was applied. BIA8 underestimated FM by 2.06 kg (P < 0.0001) and percent body fat (%BF) by 2.84% (P < 0.0001), on average. However, BIA8 tended to overestimate FM and %BF in lean and underestimate FM and %BF in fat individuals. Sex‐specific equations developed showed acceptable accuracy on cross‐validation. In the total sample, the best prediction equations were, for boys: FFM (kg) = 0.607 height (cm)2/impedance (Ω) + 1.542 age (y) + 0.220 height (cm) + 0.096 weight (kg) + 1.836 ethnicity (0 = European or Asian, 1 = Maori or Pacific) − 47.547, R2 = 0.93, standard error of estimate (SEE) = 3.09 kg; and, for girls: FFM (kg) = 0.531 height (cm)2/impedance (Ω) + 0.182 height (cm) + 0.096 weight (kg) + 1.562 ethnicity (0 = non‐Pacific, 1 = Pacific) − 15.782, R2 = 0.91, SEE = 2.19 kg. In conclusion, equations for fatness estimation using BIA8 developed for our sample perform better than reliance on the manufacturers estimates. The relationship between BIA and body composition in adolescents is ethnicity dependent.

Effect of Monthly, High‐Dose, Long‐Term Vitamin D Supplementation on Central Blood Pressure Parameters: A Randomized Controlled Trial Substudy

Background The effects of monthly, high‐dose, long‐term (≥1‐year) vitamin D supplementation on central blood pressure (BP) parameters are unknown. Methods and Results A total of 517 adults (58% male, aged 50–84 years) were recruited into a double‐blinded, placebo‐controlled trial substudy and randomized to receive, for 1.1 years (median; range: 0.9–1.5 years), either (1) vitamin D3 200 000 IU (initial dose) followed 1 month later by monthly 100 000‐IU doses (n=256) or (2) placebo monthly (n=261). At baseline (n=517) and follow‐up (n=380), suprasystolic oscillometry was undertaken, yielding aortic BP waveforms and hemodynamic parameters. Mean deseasonalized 25‐hydroxyvitamin D increased from 66 nmol/L (SD: 24) at baseline to 122 nmol/L (SD: 42) at follow‐up in the vitamin D group, with no change in the placebo group. Despite small, nonsignificant changes in hemodynamic parameters in the total sample (primary outcome), we observed consistently favorable changes among the 150 participants with vitamin D deficiency (<50 nmol/L) at baseline. In this subgroup, mean changes in the vitamin D group (n=71) versus placebo group (n=79) were −5.3 mm Hg (95% confidence interval [CI], −11.8 to 1.3) for brachial systolic BP (P=0.11), −2.8 mm Hg (95% CI, −6.2 to 0.7) for brachial diastolic BP (P=0.12), −7.5 mm Hg (95% CI, −14.4 to −0.6) for aortic systolic BP (P=0.03), −5.7 mm Hg (95% CI, −10.8 to −0.6) for augmentation index (P=0.03), −0.3 m/s (95% CI, −0.6 to −0.1) for pulse wave velocity (P=0.02), −8.6 mm Hg (95% CI, −15.4 to −1.9) for peak reservoir pressure (P=0.01), and −3.6 mm Hg (95% CI, −6.3 to −0.8) for backward pressure amplitude (P=0.01). Conclusions Monthly, high‐dose, 1‐year vitamin D supplementation lowered central BP parameters among adults with vitamin D deficiency but not in the total sample. Clinical Trial Registration URL: http://www.anzctr.org.au. Unique identifier: ACTRN12611000402943.

Dietary intakes of Pacific, Māori, Asian and European adolescents: the Auckland High School Heart Survey

Objective: To compare dietary intakes of European, Māori, Pacific Island and Asian adolescents living in Auckland.

Body mass index and percent body fat in a New Zealand multi-ethnic adolescent population

Abstract Objective. Previous studies show that body mass index (BMI) does not fully explain differences in percent body fat (%BF) between ethnic groups and few studies have investigated this in adolescents. We sought to compare %BF for a given BMI between adolescents from four ethnic groups and to explain ethnic differences in this relationship. Methods. Weight, height and waist circumference were measured in 202 boys and 197 girls (age range 12-19 years; 129 Pacific Island, 91 European, 90 Maori and 89 Asian Indian). Fat mass, appendicular skeletal muscle mass (ASMM), leg length, bone mineral content (BMC), and fat distribution measures were derived from dual-energy X-ray absorptiometry. Results. For the same BMI and age, compared with European boys, %BF in Maori, Pacific Island and Asian Indian boys was 2.8% lower (P=0.017), 5.2% lower (P<0.0001), and 3.5% higher (P=0.0025), respectively. Compared with European girls, %BF, adjusted for BMI, for Maori, Pacific Island and Asian Indian girls was 1.9% lower (P=0.024), 4.1% lower (P<0.0001) and 3.6% higher (P<0.0001), respectively. Adjustment for ASMM, BMC and fat distribution variables, in particular, significantly reduced the differences between ethnic groups. In boys, readily measured variables, conicity index and waist circumference/height, had notable effects on ethnic differences in %BF. Conclusions. Our results show that BMI is not an equivalent measure of %BF between adolescent Europeans, Maori, Pacific Islanders and Asian Indians. Differences in muscularity, bone mass, relative leg length, fat distribution and body shape contribute to this disparity.

Effect of Monthly, High-Dose, Long-Term Vitamin D on Lung Function: A Randomized Controlled Trial

Although observational studies suggest positive vitamin D-lung function associations, randomized trials are inconsistent. We examined effects of vitamin D supplementation on lung function. We recruited 442 adults (50–84 years, 58% male) into a randomized, double-blinded, placebo-controlled trial. Participants received, for 1.1 years (median; range = 0.9–1.5 years), either (1) vitamin D3 200,000 IU, followed by monthly 100,000 IU doses (n = 226); or (2) placebo monthly (n = 216). At baseline and follow-up, spirometry yielded forced expiratory volume in 1 s (FEV1; primary outcome). Mean (standard deviation) 25-hydroxyvitamin D increased from 61 (24) nmol/L at baseline to 119 (45) nmol/L at follow-up in the vitamin D group, but was unchanged in the placebo group. There were no significant lung function improvements (vitamin D versus placebo) in the total sample, vitamin D-deficient participants or asthma/chronic obstructive pulmonary disease (COPD) participants. However, among ever-smokers (n = 217), the mean (95% confidence interval) FEV1 increase in the vitamin D versus placebo was 57 (4, 109) mL (p = 0.03). FEV1 increases were larger among vitamin D-deficient ever-smokers (n = 54): 122 (8, 236) mL (p = 0.04). FEV1 improvements were largest among ever-smokers with asthma/COPD (n = 60): 160 (53, 268) mL (p = 0.004). Thus, vitamin D supplementation did not improve lung function among everyone, but benefited ever-smokers, especially those with vitamin D deficiency or asthma/COPD.

Arterial waveform parameters in a large, population-based sample of adults: relationships with ethnicity and lifestyle factors.

Little is known about how aortic waveform parameters vary with ethnicity and lifestyle factors. We investigated these issues in a large, population-based sample. We carried out a cross-sectional analysis of 4798 men and women, aged 50–84 years from Auckland, New Zealand. Participants were 3961 European, 321 Pacific, 266 Maori and 250 South Asian people. We assessed modifiable lifestyle factors via questionnaires, and measured body mass index (BMI) and brachial blood pressure (BP). Suprasystolic oscillometry was used to derive aortic pressure, from which several haemodynamic parameters were calculated. Heavy alcohol consumption and BMI were positively related to most waveform parameters. Current smokers had higher levels of aortic augmentation index than non-smokers (difference=3.7%, P<0.0001). Aortic waveform parameters, controlling for demographics, antihypertensives, diabetes and cardiovascular disease (CVD), were higher in non-Europeans than in Europeans. Further adjustment for brachial BP or lifestyle factors (particularly BMI) reduced many differences but several remained. Despite even further adjustment for mean arterial pressure, pulse rate, height and total:high-density lipoprotein cholesterol, compared with Europeans, South Asians had higher levels of all measured aortic waveform parameters (for example, for backward pressure amplitude: β=1.5 mm Hg; P<0.0001), whereas Pacific people had 9% higher loge (excess pressure integral) (P<0.0001). In conclusion, aortic waveform parameters varied with ethnicity in line with the greater prevalence of CVD among non-white populations. Generally, this was true even after accounting for brachial BP, suggesting that waveform parameters may have increased usefulness in capturing ethnic variations in cardiovascular risk. Heavy alcohol consumption, smoking and especially BMI may partially contribute to elevated levels of these parameters.

Different associations between beta-blockers and other antihypertensive medication combinations with brachial blood pressure and aortic waveform parameters

BACKGROUND Comparing the relationships of antihypertensive medications with brachial blood pressure (BP) and aortic waveform parameters may help clinicians to predict the effect on the latter in brachial BP-based antihypertensive therapy. We aimed to make such comparisons with new waveform measures and a wider range of antihypertensive regimens than examined previously. METHODS Cross-sectional analysis of 2933 adults (61% male; aged 50-84years): 1637 on antihypertensive treatment and 1296 untreated hypertensives. Sixteen medicine regimens of up to 4 combinations of drugs from 6 antihypertensive classes were analysed. Aortic systolic BP, augmentation index (AIx), excess pressure integral (EPI), backward pressure amplitude (Pb), reflection index (RI) and pulse wave velocity (PWV) were calculated from aortic pressure waveforms derived from suprasystolic brachial measurement. RESULTS Forest plots of single-drug class comparisons across regimens with the same number of drugs (for between 1- and 3-drug regimens) revealed that AIx, Pb, RI and/or loge(EPI) were higher (maximum difference=5.6%, 2.2mmHg, 0.0192 and 0.13 loge(mmHg⋅s), respectively) with the use of a beta-blocker compared with vasodilators and diuretics, despite no brachial systolic and diastolic BP differences. These differences were reduced (by 34-57%) or eliminated after adjustment for heart rate, and similar effects occurred when controlling for systolic ejection period or diastolic duration. CONCLUSIONS Beta-blocker effects on brachial BP may overestimate effects on aortic waveform parameters. Compared to other antihypertensives, beta-blockers have weaker associations with wave reflection measures and EPI; this is predominantly due to influences on heart rate.

Monthly High-Dose Vitamin D Supplementation and Cancer Risk: A Post Hoc Analysis of the Vitamin D Assessment Randomized Clinical Trial

Importance Previous randomized clinical trials have reported inconsistent results on the effect of vitamin D supplementation on cancer incidence. Objective To examine whether high-dose vitamin D supplementation received monthly, without calcium, is associated with a reduction in cancer incidence and cancer mortality in the general population. Design, Setting, and Participants This is a post hoc analysis of data from the Vitamin D Assessment (ViDA) study, a randomized, double-blind, placebo-controlled trial that recruited participants from family practices and community groups in Auckland, New Zealand, from April 5, 2011, through November 6, 2012, with follow-up completed December 31, 2015. Participants were adult community residents aged 50 to 84 years. Of 47 905 adults invited from family practices and 163 from community groups, 5110 participants were randomized to receive vitamin D3 (n = 2558) or placebo (n = 2552). Two participants withdrew consent, and all others (n = 5108) were included in the primary analysis. Data analysis was by intention to treat. Interventions Oral vitamin D3, in an initial bolus dose of 200 000 IU and followed by monthly doses of 100 000 IU, or placebo for a median of 3.3 years (range, 2.5-4.2 years). Main Outcomes and Measures Post hoc primary outcome was the number of all primary invasive and in situ malignant neoplasms (excluding nonmelanoma skin cancers) diagnosed from randomization until the study medication was discontinued on July 31, 2015. Results Of the 5108 participants included in the analysis, the mean (SD) age was 65.9 (8.3) years, 58.1% were male, and 4253 (83.3%) were of European or another race/ethnicity, with the remainder being Polynesian or South Asian. Mean (SD) baseline deseasonalized 25-hydroxyvitamin D concentration was 26.5 (9.0) ng/mL. In a random sample of 438 participants, the mean follow-up 25-hydroxyvitamin D concentration consistently was greater than 20 ng/mL higher in the vitamin D group than in the placebo group. The primary outcome of cancer comprised 328 total cases of cancer (259 invasive and 69 in situ malignant neoplasms) and occurred in 165 of 2558 participants (6.5%) in the vitamin D group and 163 of 2550 (6.4%) in the placebo group, yielding an adjusted hazard ratio of 1.01 (95% CI, 0.81-1.25; P = .95). Conclusions and Relevance High-dose vitamin D supplementation prescribed monthly for up to 4 years without calcium may not prevent cancer. This study suggests that daily or weekly dosing for a longer period may require further study. Trial Registration anzctr.org.au Identifier: ACTRN12611000402943

Pulse rate variability predicts atrial fibrillation and cerebrovascular events in a large, population-based cohort

BACKGROUND Many patients with atrial fibrillation (AF) present with stroke as their first clinical manifestation and since improved AF screening methods are thus required, we investigated whether pulse rate variability parameters predict future AF and cerebrovascular events. METHODS In an observational cohort study of 5000 community-resident adults (58% male; 50-84 years), the beat-to-beat variability of suprasystolic brachial blood pressure waveforms was measured with root mean square of successive differences (RMSSD) and irregularity index (IrrIx). Based on outcome-oriented and previously validated thresholds for detecting AF, RMSSD and IrrIx were dichotomised at 100 ms and 7.7%, respectively. Participants were followed up for 4.6 years (median), accruing 249 AF and 120 cerebrovascular events in the total sample (n = 5000), and 133 AF and 90 cerebrovascular events among those without prior AF diagnosis (n = 4296). RESULTS In multivariable-adjusted analyses, an elevated RMSSD (>100 ms) or IrrIx (>7.7%) was strongly associated with a higher risk of AF (hazard ratios (HRs) = 2.00-2.95) and cerebrovascular events (HRs = 1.91-2.28), even among people without prior AF diagnosis: HRs for AF = 1.70-2.05 and cerebrovascular events = 2.00-2.28. These associations were strongest in the highest RMSSD tertile >100 ms or IrrIx tertile >7.7%: HRs for AF = 2.32-4.47 and cerebrovascular events = 2.43-3.69. Among those without prior AF diagnosis, the highest categorical net reclassification improvement for 5-year cerebrovascular risk was 14% (95% confidence interval: 7-21%). CONCLUSIONS Elevated RMSSD or IrrIx values indicative of the presence of AF predict future AF and cerebrovascular events; more so with increasing pulse irregularity and even among those without prior AF diagnosis.