Does Vitamin D Provide Added Benefit to Antihypertensive Therapy in Reducing Left Ventricular Hypertrophy Determined by Cardiac Magnetic Resonance?

Abstract

BACKGROUND

Left ventricular hypertrophy (LVH) and vitamin D deficiency have been linked to hypertension (HTN) and cardiovascular disease, particularly in African Americans (AAs). Our objective was to determine if the addition of vitamin D to antihypertensive therapy would lead to greater regression of LV mass index (LVMI) as determined by cardiac magnetic resonance (CMR) after 1 year in vitamin D deficient AA patients with uncontrolled HTN and LVH.

METHODS

This study was a randomized, double-blind, placebo-controlled, single-center study. AA patients with HTN (systolic blood pressure [BP] >160 mm Hg), increased LVMI, and vitamin D deficiency (<20 ng/ml) were randomized. All patients received antihypertensive therapy combined with biweekly 50,000 IU vitamin D3 (vitamin D group, n = 55) or placebo (placebo group, n = 58).

RESULTS

At 1 year, there were no statistical differences between the vitamin D and placebo groups in LVMI (−14.1 ± 14.6 vs. −16.9 ± 13.1 g/m²; P = 0.34) or systolic BP (−25.6 ± 32.1 vs. −25.7 ± 25.6 mm Hg; P = 0.99) reduction, respectively. Serum vitamin D levels increased significantly in the vitamin D group compared with placebo (12.7 ± 2.0 vs. 1.8 ± 8.2 ng/ml; P < 0.001).

CONCLUSIONS

In this high-risk cohort of AAs we did not find an association between vitamin D supplementation and differential regression of LVMI or reduction in systolic BP. However, our study suffered from a small sample size with low statistical power precluding a definitive conclusion on the therapeutic benefit of vitamin D in such patients.

CLINICAL TRIALS REGISTRATION

Trial Number NCT01360476. Full trial protocol is available from corresponding author.

Graphical Abstract

Graphical Abstract.

Hypertension (HTN) is the single most important contributor to racial differences in cardiovascular disease (CVD), explaining close to 50% of the excess risk that exists within the African American (AA) community.¹ AAs experience higher disease prevalence² and, especially in males, poorer overall blood pressure (BP) control than their Caucasian and Hispanic counterparts.³ As a result, AAs are at increased risk for adverse BP-related consequences, especially left ventricular hypertrophy (LVH) and other structural or functional manifestations of subclinical hypertensive heart disease (SHHD).^4,5 This disparity is most accentuated in urban cohorts.^6,7

While primary prevention of HTN is the ideal, secondary prevention of pressure-related complications such as LVH and SHHD can be achieved through use of BP lowering therapies.⁸ Regression of LVH and SHHD correlates with a lower likelihood of cardiovascular morbidity and mortality.^9,10 The magnitude of BP reduction is a major determinant of such benefit¹¹ with regression of LVH beginning as early as 6 months after initiation of antihypertensive therapy.¹²

Although largely inconclusive, vitamin D deficiency has been linked to incident CVD¹³ and the development of HTN,¹⁴ particularly at increasing distances from the equator.¹⁵ Low vitamin D levels in AAs may account for excess cardiovascular risk.¹⁶ Vitamin D deficiency is common among AAs and is at least partially attributed to melanin interference with ultraviolet B radiation, differences in dietary intake (<95 IU/d vs. the recommended daily intake 600–800 IU/d), and latitude.¹⁷ Although a recent meta-analysis suggested vitamin D supplementation does not lower BP in the general population,¹⁸ a study in AA supplemented with vitamin D did show a significant dose-dependent reduction in systolic BP.¹⁹ Given the potential added therapeutic benefit of vitamin D in AAs with respect to CVD prevention, we sought to investigate the effect of vitamin D supplementation in combination with antihypertensive BP control on LVH regression using cardiac magnetic resonance (CMR) imaging, the most precise method to measure left ventricular mass (LVM),²⁰ in a high-risk AA population with uncontrolled HTN, LVH, and vitamin D deficiency.

METHODS

Study design

This study was a randomized, double-blind, placebo-controlled study. The primary outcome measure was the change in LVM index (LVMI) at 1-year postintervention. Secondary outcome measures were serial changes in systolic and diastolic BP and serum vitamin D levels. The protocol was approved by the institutional review board at Wayne State University and written informed consent was obtained from each participant.

Study setting

Participants were recruited from the emergency department (ED) at Detroit Receiving Hospital (Detroit, MI). Enrolled participants with known HTN and poorly controlled BP that fulfilled inclusion and exclusion criteria and were found to be deficient in vitamin D (25-OH D) were recruited (primary screening); those who consented underwent subsequent CMR (secondary screening). Participants identified with LVH on CMR were randomized to receive antihypertensive therapy with placebo or antihypertensive therapy with supplemental vitamin D (50,000 IU vitamin D3) every other week for 52 weeks with BP goals (<130/80 mm Hg).

Selection of participants

Inclusion criteria

We screened for age-eligible, self-identified AAs who resided in the Detroit metropolitan area and presented to the ED with known HTN (defined by self-reported history of antihypertensive medication use or documented diagnosis in a previous ED, clinic or inpatient electronic medical record report) and a triage systolic BP ≥160 mm Hg. Inclusion criteria were self-reported AA race, repeat SBP ≥160 mm Hg within 1 hour of ED arrival, age 30–74 years, and asymptomatic state (class I, as defined by the Goldman Specific Activity Scale).²¹

Exclusion criteria

Exclusion criteria were dyspnea or chest pain as a primary or secondary chief complaint; hospital admission; estimated glomerular filtration rate ≤60 ml/min; liver enzyme elevations >1.5× normal, serum calcium >10.5 mg/dl; acute or chronic alcohol or cocaine intoxication/use; acute or decompensated psychiatric disorder; pregnant or plan to become pregnant; allergy or hypersensitivity to gadolinium contrast; severe claustrophobia; planned move >50 miles within 9 months; or history of heart failure, coronary artery disease, myocardial infarction, cardiomyopathy, valvular heart disease, renal failure, cerebrovascular disease, hepatitis, nephrolithiasis, hypercalcemia, primary hyperparathyroidism, sarcoidosis or other granulomatous disease, cancer (other than skin), or human immunodeficiency virus.

Study procedures

After the initial screening process, written consent and demographic and medical/social histories were obtained and blood was sent for analysis of 25-hydroxy vitamin D (25-OH D), calcium, and liver enzymes (ALT and AST) (primary screening). Vitamin D deficient participants (25-OH D <20 ng/ml) with normal calcium, liver enzymes, and renal function returned within 1 week for subsequent CMR (secondary screening). CMR imaging was performed with image analysis by Argus function (Siemens Healthineers). All images were interpreted by a single blinded, independent, board-certified radiologist with fellowship training in CMR interpretation. LVH was defined as LVMI >89 g/m² for men and >73 g/m² for women, in accordance with published standards.²² As a measure of quality assurance, a second interpretation was performed for a subgroup (n = 98) by an outside reading center (Northwestern University) and interobserver correlations were calculated to be 0.89 and 0.71 for LVM and LVMI, respectively.

Participants with LVH on CMR continued in the study with 1:1 randomization (week 0) to receive antihypertensive therapy with placebo (placebo group) or with supplemental vitamin D3 (vitamin D group). Society for Hypertension in Blacks²³ guidelines were used for all participants to guide antihypertensive therapies with a goal BP of <130/80 mm Hg and was harmonized with BP medications being taken at study onset; therapeutic intensity scores were calculated as a means of standardizing dosing regimens.²⁴ When BP remained >130/80 mm Hg at study follow-up visits (see below), medications were titrated or modified as needed.

A single randomization schedule was generated to assign participants to 2 groups using block sizes of 2, 4, and 6. Participants in the vitamin D group were administered 50,000 IU of cholecalciferol (vitamin D3) by mouth every 2 weeks for 52 weeks. This regimen was selected based on previous recommendations²⁵ and is equivalent to 3,571 IU/d. Medications were packaged in the research pharmacy and then unlabeled drug packets were dispensed to participants. Patients and study personnel were blinded throughout the study. All costs associated with the medications were covered by the study.

Study timeline and data collection

From October 2011 through November 2014, a total of 354 participants were screened (primary screening) and met the inclusion criteria, of which 155 participants were eligible for secondary screening using CMR. Participants were assigned to placebo (58) or to the vitamin D (55) groups (Figure 1).

Figure 1.

Study flow diagram and retention. Abbreviations: CMR, cardiac magnetic resonance; ED, emergency department; eGFR, estimated glomerular filtration rate; LVH, left ventricular hypertrophy.

Follow-up visits were scheduled for 2-, 8-, 16-, 28-, 40-, and 52-week postrandomization. BP assessments were performed by a clinic oscillatory cuff measurement obtained using the average of 5 seated BP readings with an appropriately sized cuff using the BpTru measurement device. At weeks 16 and 52, repeated CMRs were obtained as well as serum chemistries. All laboratory analysis was done by DMC laboratories (Detroit, MI). All data were entered into an OnCore (Forte Research) database.

Power analysis and sample size calculation

Power analysis was performed to determine the appropriate sample size for each treatment group in order to detect a mean difference in LVMI between baseline and 1 year using the 2-sample t-test method. With at least 80% power and a 5% significance level (2-tailed alpha), 96 total subjects (48 per group) were needed to detect a 7 g/m² difference in LVMI from baseline to 1 year between treatment groups assuming a sample SD of 12 g/m². The estimated effect size is based on projections of an additional 10% reduction in LVMI²⁶ above that which is expected to occur with antihypertensive therapy alone.²² Based on a 25-OH D deficiency prevalence of 75%, LVH prevalence of 60%, and a dropout rate of 20%, a minimum of 267 participants would need to be screened.

Statistical analysis

First, descriptive statistics were calculated and the differences in variables of interests at baseline (week 0) between treatment groups were examined using the chi-square test for categorical variables and the independent-sample t-test for continuous variables. Second, the means of outcomes from baseline to 16 weeks and to 52 weeks were examined using the independent-sample t-test and the post hoc for repeated measures ANOVA method was employed to examine the changes within a group. Third, generalized linear models were performed to examine the effect of intervention on changes of LVMI and LVM after controlling for baseline covariates (age, gender, body mass index, smoking, serum vitamin D, and serum creatinine) that were selected based on their clinical importance (determined a priori) and differences between treatment groups identified at baseline (Table 1). A sensitivity analysis was conducted deleting 11 cases who had vitamin D supplements at baseline in placebo group. All analyses were conducted using intention-to-treat (ITT) methods. SPSS (version 28.0) and R (version 3.7) were used for data analysis.

Table 1.

Characteristics of participants at baseline (week 0)

Variables at baseline	Total	Placebo	Vitamin D	Mean difference	95% CI		P †
	Mean ± SD	Mean ± SD	Mean ± SD		Lower	Upper
Total, N (%)	113	58 (51.3%)	55 (48.7%)	—	—	—	—
Biological characteristics
Age (years)	45.4 ± 7.6	44.6 ± 7.2	46.2 ± 8.0	1.7	−4.5	1.2	0.252
BMI (kg/m2)	34.2 ± 7.8	33.2 ± 35.4	35.4 ± 7.9	2.1	−5.0	0.8	0.160
Female, n (%)	61 (54.0%)	24 (41.4%)	37 (67.3%)	—	—	—	0.008
Risk behaviors						—
Ever cigarette smokers, n (%)	71 (62.8%)	33 (56.9%)	38 (69.1%)	—	—	—	0.180
Ever alcohol users, n (%)	51 (46.4%)	24 (43.6%)	27 (49.1%)	—	—	—	0.566
Chronic condition
Diabetes, n (%)	12 (10.6%)	5 (8.6%)	7 (12.7%)	—	—		0.479
HTN history (in years)	10.3 ± 8.4	10.5 ± 8.6	10.2 ± 8.3	0.2	−3.1	3.6	0.887
Supplements
Dietary vitamin D intake (units)	88.4 ± 118.2	94.6 ± 134.2	81.8 ± 99.3	12.8	−31.4	57.0	0.568
Dietary calcium intake (mg)	568.9 ± 499.2	609.6 ± 575.2	526.1 ± 405.1	83.5	−102.8	269.9	0.376
Supplemental vitamin D, n (%)	19 (16.8%)	11 (19.0%)	8 (14.5%)	—	—	—	0.530
Supplemental calcium, n (%)	34 (30.1%)	22 (37.9%)	12 (21.8%)	—	—	—	0.062
Health outcomes
Heart rate (bpm)	85.9 ± 15.5	86.3 ± 15.6	85.4 ± 15.1	0.9	−4.9	6.7	0.759
SBP (mm Hg)	160 ± 25.7	160 ± 24.2	161 ± 27.5	0.8	−10.4	8.8	0.869
DBP (mm Hg)	102 ± 14.7	103 ± 14.0	100 ± 15.4	3.4	−2.1	8.9	0.218
Serum vitamin D (ng/ml)	11.0 ± 3.8	11.4 ± 4.0	10.6 ± 3.6	0.8	−0.6	2.3	0.240
Serum calcium (mg/dl)	9.1 ± 0.4	9.1 ± 0.4	9.0 ± 0.3	0.1	−0.0	0.2	0.175
Serum creatinine (mg/dl)	1.0 ± 0.3	1.0 ± 0.3	0.9 ± 0.3	0.2	0.1	0.3	<0.001
Serum potassium (mmol/l)	4.1 ± 0.5	4.0 ± 0.5	4.2 ± 0.6	0.2	−0.4	0.0	0.111
Serum glucose NF (mg/dl)	109.6 ± 71.2	113.2 ± 75.4	105.7 ± 67.0	7.5	−19.2	34.1	0.579
eGFR (ml/min/1.73 m2)	92.1 ± 19.9	88.7 ± 18.6	95.8 ± 20.8	7.1	−14.5	0.2	0.057
Plasma PTH (pg/ml)	61.7 ± 29.5	60.6 ± 32.7	62.9 ± 26.0	2.3	−13.3	8.8	0.685
Aldosterone (ng/dl)	6.7 ± 6.0	7.5 ± 6.6	5.9 ± 5.4	1.6	−0.6	3.9	0.157
Plasma renin (ng/ml/h)	2.6 ± 7.5	1.9 ± 3.4	3.4 ± 10.1	1.5	−4.4	1.3	0.294
Aldosterone/renin ratio	35.6 ± 232.2	57.1 ± 323.5	12.8 ± 19.1	44.3	−42.3	130.9	0.313
Urine albumin/Cr ratio	66.1 ± 160.4	65.9 ± 161.6	66.3 ± 160.7	0.4	−63.5	62.6	0.989
BUN (mg/dl)	13.6 ± 4.2	13.9 ± 4.4	13.3 ± 4.0	0.6	−0.9	2.2	0.433
CMR measures outcome
LVMI (g/m2)	97.2 ± 15.8	99.3 ± 16.7	95.0 ± 14.6	4.3	−1.5	10.2	0.145
LVM (g)	199.6 ± 44.2	204.1 ± 49.2	194.8 ± 38.1	9.3	−7.2	25.8	0.265
Anterior wall thickness (mm)	13.3 ± 3.0	13.0 ± 3.1	13.5 ± 2.9	0.5	−1.6	0.6	0.342
Septal wall thickness (mm)	12.4 ± 3.3	12.1 ± 3.8	12.7 ± 2.8	0.6	−1.8	0.7	0.384
Posterior wall thickness (mm)	12.4 ± 3.1	12.4 ± 3.3	12.4 ± 2.8	0.1	−1.2	1.1	0.889

Bold text represents values that are statistically significant with P < 0.05.

Note: Original dataset. Abbreviations: BMI, body mass index; BUN, blood urea nitrogen; CI, confidence interval; CMR, cardiac magnetic resonance; Cr, creatinine; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HTN, hypertension; LVM, left ventricular mass; LVMI, left ventricular mass index; NF, nonfasting; PTH, parathyroid hormone; SBP, systolic blood pressure.

^†Independent-sample t-test for continuous variables and chi-square test for categorical variables at baseline.

RESULTS

The average age of randomized participants was 45 ± 7.6 years with most covariates similar between treatment groups except that there were more females in the vitamin D group (67% vs. 41%; P < 0.01) (Table 1). Although the absolute differences were small, participants in the vitamin D group had a statistically lower serum creatinine (0.9 vs. 1.0 mg/d; P < 0.01) that equated to a marginally higher eGFR (88.7 vs. 95.8 ml/min/1.73 m²). Vitamin D at baseline was 11.0 ± 3.8 ng/ml and serum calcium 9.1 ± 0.4 mg/dl (Table 1).

At primary screening, mean BP was 193 ± 20/110 ± 15 mm Hg but decreased to 160 ± 26/101 ± 15 mm Hg at secondary screening (Figure 2a); this was statistically significant (P < 0.001) for both systolic and diastolic BPs. The mean BP was similar in the treatment and placebo groups at baseline: 161 ± 28/100 ± 15 vs. 160 ± 24/103 ± 14 mm Hg, respectively (Table 2; Figure 2a). At 52 weeks, BP statistically trended downwards in both groups to 136 ± 20/90 ± 11 and 134 ± 17/90 ± 12 mm Hg (P < 0.001) (Table 2) without any statistically significant differences in BP between the treatment groups.

Figure 2.

Effect of vitamin D supplementation and standardized, evidence-based antihypertensive therapy with goal systolic blood pressure <130 mm Hg on (a) systolic and diastolic BPs over 1 year and (b) antihypertensive therapeutic intensity (a metric of antihypertensive treatment that is derived from the number of antihypertensive medications and percentage of maximal efficacious dose).²⁴ Data are shown as mean ± SD. Note: Circle symbols represent placebo and square symbols represent vitamin D treatment groups. Asterisk (*) represents cardiac magnetic resonance (CMR) date. Abbreviations: BP, blood pressure; ED, emergency department.

Table 2.

Serum vitamin D, blood pressure, and cardiac measurements at baseline (week 0), week 16, and week 52 for placebo and vitamin D supplemented treatment groups

Outcomes/cardiac measurement					Changes from weeks 0 to 16				Changes from weeks 0 to 52
	Placebo	Vitamin D	Diff	P ‡	Placebo	Vitamin D	Diff	P ‡	Placebo	Vitamin D	Diff	P ‡
	Mean ± SD	Mean ± SD			Mean ± SD	Mean ± SD			Mean ± SD	Mean ± SD
Serum vitamin D (ng/ml)					2.29 ± 6.83	16.47 ± 10.84	−14.18	<0.001	1.79 ± 8.20	14.52 ± 11.29	−12.73	<0.001
Week 0	11.40 ± 3.96	10.55 ± 3.59	0.84	0.240
Week 16	13.97 ± 5.84	26.88 ± 11.40	−12.90	<0.001
Week 52	13.43 ± 8.29	25.20 ± 11.26	−11.77	<0.001
SBP (mm Hg)					−20.85 ± 25.16	−27.6 ± 31.72	6.41	0.263	−25.72 ± 25.64	−25.63 ± 32.07	−0.09	0.988
Week 0 (1)	160 ± 24.15	161 ± 27.51	2.19	0.572
Week 16 (2)	138 ± 17.13	133 ± 20.20	4.64	0.217
Week 52 (3)	134 ± 17.17	136 ± 19.98	−1.91	0.622
Post hoc†	1–2*** 1–3***	1–2*** 1–3***
DBP (mm Hg)					−11.20 ± 15.08	−10.85 ± 18.29	0.36	0.915	−13.48 ± 13.46	−9.63 ± 16.53	−3.85	0.219
Week 0 (1)	103 ± 13.96	100 ± 15.44	3.73	0.198
Week 16 (2)	91 ± 10.96	88 ± 12.69	3.33	0.162
Week 52 (3)	90 ± 12.33	90 ± 11.40	−0.02	0.995
Post hoc†	1–2*** 1–3***	1–2*** 1–3***
LVMI (g/m2)					−11.25 ± 10.31	−12.36 ± 14.47	1.11	0.670	−16.88 ± 13.12	−14.12 ± 14.62	−2.76	0.342
Week 0 (1)	99.32 ± 16.71	94.99 ± 14.59	4.34	0.145
Week 16 (2)	87.61 ± 13.75	83.36 ± 13.44	4.25	0.139
Week 52 (3)	83.57 ± 15.21	82.04 ± 10.46	1.53	0.581
Post hoc†	1–2*** 1–3*** 2–3**	1–2*** 1–3***
LVM (g)					−21.36 ± 20.48	−25.30 ± 26.84	3.94	0.428	−32.52 ± 27.29	−28.50 ± 30.41	−4.02	0.506
Week 0 (1)	204.13 ± 49.23	194.82 ± 38.12	9.31	0.265
Week 16 (2)	178.93 ± 40.74	170.83 ± 33.79	8.10	0.306
Week 52 (3)	175.86 ± 49.08	170.07 ± 24.77	5.79	0.486
Post hoc†	1–2*** 1–3*** 2–3*	1–2*** 1–3***
Anterior wall thickness (mm)					−0.75 ± 3.34	−1.12 ± 2.24	0.37	0.538	−0.86 ± 2.86	−1.13 ± 2.78	0.26	0.658
Week 0	13.00 ± 3.06	13.53 ± 2.87	−0.53	0.342
Week 16	11.91 ± 2.97	12.44 ± 2.83	−0.53	0.388
Week 52	12.10 ± 2.83	12.61 ± 2.66	−0.50	0.384
Septal wall thickness (mm)					−0.02 ± 4.05	−1.29 ± 3.61	1.26	0.120	−1.16 ± 3.39	−1.63 ± 3.49	0.47	0.514
Week 0	12.12 ± 3.79	12.67 ± 2.79	−0.55	0.384
Week 16	11.62 ± 3.10	11.33 ± 2.79	0.29	0.640
Week 52	10.96 ± 2.50	11.04 ± 2.49	−0.08	0.886
Posterior wall thickness (mm)					−0.09 ± 3.12	−1.17 ± 3.13	1.09	0.099	−0.03 ± 3.89	−1.34 ± 3.60	1.31	0.098
Week 0	12.35 ± 3.32	12.43 ± 2.79	−0.08	0.889
Week 16	12.15 ± 2.57	11.29 ± 2.88	0.86	0.134
Week 52	11.93 ± 2.74	11.26 ± 2.65	0.67	0.236

Bold text represents values that are statistically significant with P < 0.05.

Note: Original dataset. Abbreviations: DBP, diastolic blood pressure; Diff, mean difference; LVM, left ventricular mass; LVMI, left ventricular mass index; SBP, systolic blood pressure.

^† Post hoc for repeated measures ANOVA (*P < 0.05, **P < 0.01, ***P < 0.001).

^‡Independent-Sample t-test 2-sided P value.

The use of antihypertensive medications was monitored and titrated over the study with a target SBP of <130 mm Hg. At randomization, 38% of participants were taking antihypertensive medications which increased to 97% after randomization. The total number of antihypertensive medications in the treatment groups increased over the course of the study to 2.4 medications and were similar between groups (P = 0.49), with an overall therapeutic intensity score of 1.43 ± 0.56 in the placebo group and 1.38 ± 0.69 in the vitamin D group (Figure 2b; Supplementary Table S1 online). Details of the antihypertensive medications used in each study group are shown in Supplementary Table S2 online. No study related adverse events were encountered throughout the trial period in either treatment group.

In bivariate analysis, several factors did appear to be significantly associated with LVMI regression (Table 3). Patients who were smokers (P = 0.017), euglycemic (P = 0.008), nondiabetic participants (P = 0.033) had statistical improvement in LMVI with supplemental vitamin D (Table 3). Similarly, patients with elevated parathyroid hormone (PTH) levels (>65; P = 0.038), lower aldosterone/renin ratios (<25; P = 0.019)), and low urine albumin/creatinine ratios (<30; P = 0.014) appeared to show an improvement in LVMI favoring the vitamin D group. Within each treatment group, repeated ANOVA analysis illustrates statistically significant regression in LVMI and LVM at both weeks 16 and 52 (P < 0.01) (Table 2).

Table 3.

Association analysis of LVMI changes over time between vitamin D group and placebo group.

Variables at baseline	Placebo	Vitamin D	Mean difference	95% CI		P †
	Mean ± SD	Mean ± SD		Lower	Upper
Group	90.70 ± 16.73	87.49 ± 14.33	3.20	−0.38	6.78	0.079
Age
<45 years	93.29 ± 19.55	87.06 ± 16.42	6.23	−0.20	12.67	0.058
≥45 years	88.17 ± 13.06	87.77 ± 12.97	0.40	−3.59	4.40	0.842
BMI
BMI <30	90.38 ± 13.57	87.75 ± 13.87	2.63	−3.40	8.67	0.388
BMI ≥30	90.60 ± 18.09	87.42 ± 14.54	3.18	−1.29	7.65	0.162
Gender
Female	83.42 ± 13.88	85.07 ± 13.74	1.65	−6.07	2.78	0.464
Male	95.75 ± 16.74	92.19 ± 14.43	3.57	−2.06	9.19	0.213
Ever cigarette smoke
No	88.33 ± 15.04	89.08 ± 14.17	0.75	−6.30	4.81	0.790
Yes	92.43 ± 17.74	86.70 ± 14.42	5.73	1.04	10.42	0.017
Ever alcohol use
No	91.28 ± 18.42	88.26 ± 12.36	3.03	−1.96	8.01	0.232
Yes	89.87 ± 14.94	86.63 ± 16.35	3.25	−2.17	8.66	0.238
Diabetes
No	91.17 ± 17.20	86.91 ± 14.72	4.26	0.35	8.18	0.033
Yes	84.99 ± 7.63	91.04 ± 11.38	6.05	−13.63	1.53	0.114
HTN history
<10 years	89.47 ± 15.27	85.62 ± 14.85	3.85	−1.08	8.78	0.125
≥10 years	92.65 ± 15.90	89.10 ± 13.68	3.55	−1.94	9.04	0.203
Dietary vitamin D supplement
<Mean	90.59 ± 16.56	87.57 ± 15.13	3.02	−1.16	7.21	0.155
≥Mean	91.05 ± 17.54	87.28 ± 11.91	3.77	−3.31	10.85	0.291
Dietary calcium
<Mean	90.91 ± 17.19	87.51 ± 16.02	3.41	−1.32	8.13	0.157
≥Mean	90.28 ± 15.95	87.47 ± 10.76	2.80	−2.55	8.15	0.301
Supplemental vitamin D
No	90.77 ± 17.48	88.00 ± 14.81	2.77	−1.29	6.83	0.180
Yes	90.38 ± 13.34	84.25 ± 10.51	6.13	−1.15	13.41	0.097
Supplemental calcium
No	92.02 ± 18.36	88.46 ± 14.78	3.56	−1.00	8.11	0.125
Yes	88.58 ± 13.60	84.07 ± 12.23	4.52	−1.27	10.30	0.124
Serum calcium
<9 mg/dl	89.90 ± 17.71	88.30 ± 15.67	1.60	−4.55	7.74	0.607
≥9 mg/dl	91.16 ± 16.21	86.92 ± 13.36	4.24	−0.176	8.67	0.060
Serum creatinine
<2 mg/dl	90.70 ± 16.73	87.49 ± 14.33	3.20	−0.38	6.78	0.079
≥2 mg/dl	—	—	—	—	—	—
Serum potassium
≤6 mmol/l	90.70 ± 16.73	87.61 ± 14.48	3.08	−0.54	6.71	0.095
>6 mmol/l	—	—	—	—	—	—
Serum glucose
≤99 mg/dl	91.72 ± 17.60	85.19 ± 13.44	6.53	1.74	11.32	0.008
> 99 mg/dl	89.23 ± 15.41	90.43 ± 14.99	1.20	−6.56	4.16	0.658
eGFR
<60 ml/min/1.73 m2	—	—	—	—	—	—
≥60 ml/min/1.73 m2	90.70 ± 16.73	87.49 ± 14.33	3.20	−0.38	6.78	0.079
PTH
<65 pg/ml	89.30 ± 14.03	88.38 ± 14.42	0.92	−3.26	5.11	0.664
≥65 pg/ml	93.12 ± 20.50	86.27 ± 14.24	6.85	0.38	13.33	0.038
Aldosterone
<15 ng/dl	89.75 ± 15.41	86.98 ± 13.97	2.77	−0.76	6.30	0.124
≥15 ng/dl	99.60 ± 26.46	94.24 ± 17.99	5.36	−14.70	25.43	0.585
Plasma renin
<1 ng/ml/h	91.55 ± 16.12	87.63 ± 14.69	3.92	−0.64	8.48	0.092
≥1 ng/ml/h	90.42 ± 17.71	87.34 ± 13.93	3.08	−3.07	9.23	0.323
ARR
<25	90.52 ± 17.77	85.75 ± 13.13	4.77	0.81	8.73	0.019
≥25	91.60 ± 10.19	95.61 ± 17.02	4.01	−11.87	3.85	0.310
uACR
<30	92.45 ± 16.22	87.05 ± 13.65	5.40	1.10	9.70	0.014
≥30	85.88 ± 19.21	89.09 ± 15.34	3.20	−11.26	4.86	0.431
BUN
≤20 mg/dl	89.25 ± 15.43	87.30 ± 14.50	1.95	−1.64	5.54	0.285
>20 mg/dl	105.32 ± 22.37	90.34 ± 6.95	14.98	−1.12	31.08	0.067

Bold text represents values that are statistically significant with P < 0.05.

Note: Long data format. Abbreviations: ARR, aldosterone/renin ratio; BMI, body mass index; BUN, blood urea nitrogen; CI, confidence interval; Cr, creatinine; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HTN, hypertension; LVM, left ventricular mass; LVMI, left ventricular mass index; PTH, parathyroid hormone; SBP, systolic blood pressure; uACR, urine albumin/creatinine ratio.

^†Independent-sample t-test 2-sided P value.

After controlling for covariates, a generalized linear model indicated that there were no differences in CMR-determined LVMI and LVM between groups at 52 weeks after initiation of supplemental vitamin D however baseline gender, body mass index, serum vitamin D, and serum creatinine did affect LVMI and/or LVM (Table 4). The serum vitamin D levels were significantly different between the 2 treatment groups (P < 0.01) at 52 weeks. A subset sensitivity analysis performed without the placebo subjects who took supplemental vitamin D demonstrated no differences from the whole sample (Table 4).

Table 4.

Generalized linear model for the effect of intervention on regression of LVMI, LVM, and serum vitamin

Variables at baseline	Model 1: outcome = LVMI			Model 2: outcome = LVM			Model 3: outcome = serum vit D
	B (SE)	95% CI	P	B (SE)	95% CI	P	B (SE)	95% CI	P
Primary analysis
Intervention	−0.04 (1.80)	(−3.57, 3.49)	0.981	3.17 (4.03)	(−4.73, 11.07)	0.432	8.18 (1.11)	(6.00, 10.35)	<0.001
Age	0.12 (0.11)	(−0.10, 0.33)	0.302	0.09 (0.25)	(−0.40, 0.58)	0.714	0.16 (0.07)	(0.03, 0.29)	0.018
Female	7.11 (2.06)	(3.06, 11.15)	<0.001	39.87 (4.62)	(30.81, 48.93)	0.000	−0.64 (1.26)	(−3.12, 1.84)	0.612
BMI	0.13 (0.11)	(−0.09, 0.35)	0.243	2.15 (0.25)	(1.66, 2.64)	0.000	−0.02 (0.07)	(−0.16, 0.11)	0.749
Smoking	−2.19 (1.78)	(−5.69, 1.30)	0.219	−7.38 (3.99)	(−15.20, 0.45)	0.065	1.41 (1.09)	(−0.73, 3.55)	0.195
Serum vitamin D	−0.50 (0.23)	(−0.94, −0.05)	0.028	−1.24 (0.51)	(−2.23, −0.24)	0.015	0.61 (0.14)	(0.34, 0.87)	<0.001
Serum creatinine	12.97 (4.11)	(4.91, 21.03)	0.002	34.63 (9.21)	(16.58, 52.68)	<0.001	2.69 (2.54)	(−2.29, 7.66)	0.290
Sensitivity analysis†
Intervention	0.07 (1.91)	(−3.67, 3.80)	0.971	4.13 (4.23)	(−4.16, 12.41)	0.329	8.63 (1.15)	(6.38, 10.89)	<0.001
Age	0.08 (0.12)	(−0.15, 0.31)	0.498	0.04 (0.26)	(−0.47, 0.55)	0.877	0.15 (0.07)	(0.01, 0.29)	0.031
Female	7.54 (2.24)	(3.15, 11.93)	<0.001	39.10 (4.96)	(29.37, 48.83)	<0.001	−0.30 (1.34)	(−2.94, 2.33)	0.821
BMI	0.14 (0.12)	(−0.10, 0.37)	0.255	2.04 (0.27)	(1.52, 2.57)	<0.001	−0.01 (0.07)	(−0.15, 0.13)	0.889
Smoking	−2.19 (1.90)	(−5.91, 1.54)	0.250	−7.56 (4.22)	(−15.83, 0.70)	0.073	1.42 (1.14)	(−0.81, 3.66)	0.212
Serum vitamin D	−0.49 (0.24)	(−0.97, −0.01)	0.045	−1.17 (0.54)	(−2.23, −0.11)	0.031	0.58 (0.14)	(0.30, 0.86)	<0.001
Serum creatinine	13.56 (4.31)	(5.12, 22.00)	0.002	37.49 (9.55)	(18.77, 56.21)	<0.001	1.92 (2.60)	(−3.18, 7.03)	0.461

Bold text represents values that are statistically significant with P < 0.05.

Note: Analysis performed using long data format. Selected baseline covariates include age, gender, BMI, smoking, serum vitamin D, and serum creatinine. Abbreviations: B, regression coefficient; BMI, body mass index; CI, confidence interval; LVM, left ventricular mass; LVMI, left ventricular mass index; vit D, vitamin D.

^†Sensitivity analysis with a subgroup of the sample with deleting cases (19%) who had the supplemental vitamin D in placebo group at baseline.

A post hoc power analysis was conducted based on the observed SDs and observed mean difference in Table 1. The power was 30% at the 2-sided P value of 0.05 significance level with a group difference on LVMI of 4.3 and SDs of 16.7 and 14.6.

DISCUSSION

Despite increased awareness and susceptibilities across race, the degree of BP control in AAs has remained consistently lower than other races over the past 2 decades.²⁷ Uncontrolled HTN puts patients at increased risk for LVH and HF as well as other CVDs. Vitamin D has been postulated to play a role in the differential risk for HTN and its concomitant complications in AA patients, who are more likely to have vitamin D deficiency due to differences in ultraviolet light absorption, although there have been no studies showing that vitamin D supplementation improves outcomes.^28,29 This study focused on a high-risk, AA patient population with vitamin D deficiency, uncontrolled HTN, and with a high prevalence of SHHD^5,7,30,31 and detected no observed evidence of difference of vitamin D supplementation on LVH as determined by CMR in conjunction with BP control. Importantly, we included a population that stood to benefit most from vitamin D supplementation, with a mean vitamin D level of 11 ng/ml and elevated PTH at the time of randomization, indicating severe deficiency; despite this, we detected no effect on LVMI or BP beyond that achieved from standardized, evidence-based antihypertensive therapy with a universal target SBP <130 mm Hg, suggesting that lack of detected effect was not a result of effect dilution or spectrum bias. Moreover, because we used CMR for LVM evaluation our approach has intrinsic precision²⁰ and, with an inter-rater correlation of 0.89, we are confident that our LVM measurements provide a reliable and accurate depiction of treatment effects. Patient adherence also appeared to be adequate as those randomized to the intervention group saw an increase in serum vitamin D levels to 25.2 ng/ml and a corresponding decrease in PTH levels, indicating that hormonal physiologic effects were achieved,³² though the absolute drop in PTH was less than seen previously.³ Covariate analysis identified a subset of patients in the vitamin D group that showed statistical improvements in LVMI; patients with a smoking history and those that were euglycemic without a history of diabetes. The effects of smoking are known to affect multiple organ systems including contributing to low vitamin D levels³³ and have been found to cause increased LVMI, particularly the posterior wall³⁴; which was shown in the current study to trend downwards but was not statistically significant. Diabetes is well known risk factor for CVD and it has been argued that effects of vitamin D deficiency is an epiphenomenon of insulin resistance,³⁵ however this does not explain current the findings. Nonetheless, these types of covariate analyses are subject to type I errors but may help direct areas for future research.

The overall prevalence of hypovitaminosis D in our sample (90%) mirrors the national average (82%) in AAs³⁶; which is twice that found in the overall population (41%). However, the potential adverse impact of such differences in hypovitaminosis D on CVD remains unclear. Recent studies on vitamin D supplementation have not shown any meaningful benefit on CVD^28,29 while others have shown that vitamin D deficiency has several adverse effects on the CVD and development of HTN³⁷ and may raise BP directly.³⁸ However, these mechanisms are poorly understood. There may be direct activation of the renin–angiotensin–aldosterone system or indirect activity on cardiomyocyte vitamin D receptors leading to upregulation of renin gene expression.³⁹ Elevated PTH levels may also cause interstitial fibrosis, collagen deposition, and cardiomyocyte hypertrophy. Indeed, covariate analysis did reveal that when PTH levels were >65, the vitamin D group had greater regression of LVMI possibly related to the greater physiological deficit in vitamin D. Similarly, low ratios of aldosterone/renin (although the treatment groups are noted to have vastly different baselines) and urine albumin/creatinine ratios resulted in statistically significant reductions in LVMI.

Given the importance of BP management on LVH, ensuring equipoise in antihypertensive therapy was a critical aspect of this study. Mean primary screening BPs were 192/110 mm Hg and secondary screening BPs were 160/101 mm Hg. This was a substantial drop without any study intervention. After initiation of antihypertensive medications, average BPs for all study participants decreased to 140/92 mm Hg at 2 weeks and then to 135/90 mm Hg at 52 weeks. This study, not unlike the DAYLIGHT trial,^18,40 found that vitamin D supplementation did not significantly reduce BP in the treatment group nor did it reduce the need for antihypertensive medications. Although vitamin D supplementation did not have an effect on LVMI or specific cardiac wall thickness, there was statistically significant improvement in LVH that corresponded to improving BPs as soon as 16 weeks. This phenomenon has been well documented²² but the timeline for regression is poorly defined and our findings add important new information to suggest that significant improvements occur early in the course of treatment.

Study limitations

Our study did have some limitations. It was conducted at a single center and included only AA participants without evidence of renal dysfunction at baseline. Results may not be applicable to other races or ethnicities and may not extend to those with chronic kidney disease. This study had a retention rate of 82% and our post hoc power analysis revealed that our study was grossly underpowered rendering many of our results, including our primary outcome, to be inconclusive. Despite randomization, there were more women in the vitamin D group and since LVH criteria differ by sex, more women in the treatment group may have resulted in less opportunity to observe differences between the groups. Although gender differences between the groups may have led to different physiological responses to vitamin D supplementation, post hoc analysis did not reveal changes to LVMI when sexes were analyzed separately. Nevertheless, future research is needed regarding the effect of vitamin D on LVMI in this high-risk population, particularly smokers, nondiabetics, and those with elevated PTH levels.

Clinical perspectives

In summary, due to a small sample and low statistical power for our observed effect size, we cannot draw any definitive conclusions regarding the potential cardiovascular benefits (or lack thereof) of vitamin D supplementation in this cohort of high-risk vitamin D deficient AA with LVH who were treated with concurrent evidence-based antihypertensive therapy. Regression of LVMI on CMR was strongly associated with BP reduction and as such, regardless of vitamin D status, the goal of treatment for patients with HTN and LVH should be strict BP control.

FUNDING

This work was supported by the National Institutes of Health/National Institute on Minority Health and Health Disparities (NIMHD) (5R01MD005849; Levy).

AUTHORS’ CONTRIBUTIONS

Phillip D. Levy: conceptualization, funding acquisition, investigation, methodology, project administration, resources, supervision, and writing. Michael J. Twiner: project administration, resources, and writing. Aaron M. Brody: conceptualization, investigation, and project administration. Rachelle Dawood: data curation, formal analysis, investigation, and methodology. Brian Reed: data curation, formal analysis, methodology, software, validation, visualization, and writing. LynnMarie Mango: data curation, funding acquisition, project administration, and resources. Laura Gowland: investigation and methodology. Greg Grandits: formal analysis, investigation, methodology, resources, software, validation, and visualization. Kenneth Svendsen: formal analysis, investigation, methodology, resources, software, validation, and visualization. Ewart Mark Haacke: formal analysis, investigation, methodology, resources, software, validation, and visualization. Tao Li: formal analysis, investigation, methodology, resources, software, validation, and visualization. Liying Zhang: statistical analysis and writing. Candace D. McNaughton: project administration and writing. John M. Flack: conceptualization and investigation.

ETHICAL APPROVAL

This study has been approved by institutional review board (IRB) at the Wayne State University and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

DISCLOSURE

The authors declare no conflicts of interest but do have the following funding disclosures: Phillip D. Levy National Heart, Lung, and Blood Institute (R01 HL153607, R01 HL163377, R01 HL146059, R01 HL127215, and T32 HL120822); National Institute on Minority Health and Health Disparities (P50 MD017351); American Heart Association Health Equity Research Network; Michigan Department of Health & Human Services (Centers for Disease Control 1815, 1816, and 1817); Michigan Health Endowment Fund (R-1907-144972); research contracts: Pfizer and Novartis; consulting: Bayer, BMS, Astra Zeneca, UltraSight Medical, Siemens, Ortho Diagnostics, Beckman Coulter, Quidel, and Roche. Candace D. McNaughton: National Heart, Lung, and Blood Institute (K23LH125670 and R21HL140381), VA Office of Rural Health (ORH-10808); research contract: Pfizer. Michael J. Twiner, Aaron M. Brody, Rachelle Dawood, Brian Reed, LynnMarie Mango, Laura Gowland, Greg Grandits, Kenneth Svendsen, Ewart Mark Haacke, Tao Li, Liying Zhang, and John M. Flack: none.

This manuscript was sent to Guest Editor, Hillel W. Cohen, MPH, DrPH for editorial handling and final disposition.

CONSENT FOR PUBLICATION

All authors have read and approved the submission of the manuscript; the manuscript has not been published and is not being considered for publication elsewhere, in whole or in part, in any language, except as an abstract.

DATA AVAILABILITY

Study data are available for sharing upon reasonable request.