Abstract
Background
Vitamin D supplementation leads to regression of left ventricular (LV) hypertrophy and improves LV function in animal models. However, limited data exist from prospective human studies. We examined whether vitamin D supplementation improved cardiac structure and function in midlife/older individuals in a large randomized trial.
Methods and Results
The VITAL (Vitamin D and OmegA‐3 Trial) was a nationwide double‐blind, placebo‐controlled randomized trial that tested the effects of vitamin D3 (2000 IU/d) and n−3 fatty acids (1 g/d) on cardiovascular and cancer risk in 25 871 individuals aged ≥50 years. We conducted a substudy of VITAL in which participants underwent echocardiography at baseline and 2 years. Images were interpreted by a blinded investigator at a central core laboratory. The primary end point was change in LV mass. Among 1054 Greater Boston–area participants attending in‐clinic visits, we enrolled 1025 into this study. Seventy‐nine percent returned for follow‐up and had analyzable echocardiograms at both visits. At baseline, the median age was 64 years (interquartile range, 60–69 years), 52% were men, and 43% had hypertension. After 2 years, the change in LV mass did not significantly differ between the vitamin D and placebo arms (median +1.4 g versus +2.6 g, respectively; P=0.32). Changes in systolic and diastolic LV function also did not differ significantly between arms. There were no significant changes in cardiac structure and function between the n−3 fatty acids and placebo arms.
Conclusions
Among adults aged ≥50 years, neither vitamin D3 nor n−3 fatty acids supplementation had significant effects on cardiac structure and function after 2 years.
Registration
URL: https://clinicaltrials.gov/; Unique identifiers: NCT01169259 (VITAL) and NCT01630213 (VITAL‐Echo)
Keywords: cardiac structure and function, echocardiography, n−3 fatty acids, randomized controlled trial, vitamin D
Subject Categories: Pharmacology, Primary Prevention
Nonstandard Abbreviations and Acronyms
- TAPSE
tricuspid annular plane systolic excursion
- VITAL
Vitamin D and Omega‐3 Trial
- VITAL‐Echo
Vitamin D and Omega‐3 Trial‐Cardiac Structure and Function
Clinical Perspective.
What Is New?
Among adults aged ≥50 years without history of cardiovascular disease, neither vitamin D3 nor n−3 fatty acids supplementation had significant effects on cardiac structure and function after 2 years.
What Are the Clinical Implications?
Routine vitamin D3 or n−3 fatty acid supplementation may not be indicated for the sole purpose of preventing adverse cardiac remodeling in this population.
Vitamin D (25‐hydroxyvitamin D) deficiency is highly prevalent worldwide and in the United States. 1 , 2 Experimental evidence from animal models indicates that activated vitamin D (1,25‐dihydroxyvitamin D) exerts direct antihypertrophic effects on the heart, which leads to regression of left ventricular (LV) hypertrophy (LVH) and improvement in systolic and diastolic LV function. 3 , 4 However, data on the effects of vitamin D on cardiac structure in humans are limited. Larger trials examining this question have not been performed.
The VITAL‐Echo (Vitamin D and Omega‐3 Trial‐Cardiac Structure and Function) was an ancillary study to VITAL (Vitamin D and Omega‐3 Trial) and examined whether vitamin D compared with placebo in midlife/older adults (1) reduces LV mass and (2) improves LV systolic and diastolic function. Thus, we aimed to examine whether vitamin D supplementation improved cardiac structure and function in a large randomized trial.
Methods
Study Design and Participants
The parent trial, VITAL, was a double‐blind, placebo‐controlled randomized controlled trial that tested the effects of vitamin D3 and n−3 fatty acids supplementation on the prevention of incident cardiovascular disease and cancer. 5 VITAL enrolled 25 871 participants nationwide (men aged ≥50 and women aged ≥55 years) who were randomized between November 2011 and March 2014 to receive vitamin D3 (2000 IU/d of cholecalciferol) and n−3 fatty acids (1 g/d of Omacor, containing 840 mg of eicosapentaenoic acid [460 mg]+docosahexaenoic acid [380 mg]) or matching placebos in a 2×2 factorial design. Participants were randomized by a computer‐generated process within sex, race, and 5‐year age groups in blocks of 8. Participants were excluded from the parent trial if they met any of the following criteria: history of cancer (except for nonmelanoma skin cancer) or cardiovascular disease; additional vitamin D3 intake >800 IU/d; use of fish oil supplements; history of kidney failure, hypercalcemia, or cirrhosis; history of any other serious condition that would preclude participation. Pharmavite LLC of Northridge, California (vitamin D) and Pronova BioPharma of Lysaker, Norway and BASF of Ludwigshafen, Germany (Omacor fish oil) donated the study agents, matching placebos, and packaging in the form of calendar packs. Quest Diagnostics (San Juan Capistrano, CA) measured serum 25‐hydroxyvitamin D and plasma omega‐3 index at no cost to the study.
The rationale for the doses chosen for vitamin D3 and n−3 fatty acids is described in a previously published design article. 6 Briefly, the vitamin D3 dose was based on extrapolation of data from prior observational studies suggesting that 2000 IU/d would be required to reach a serum level of 36 ng/mL in the active vitamin D group. 7 , 8 , 9 This threshold has been associated with reduced risks of colorectal cancer, falls, fractures, and physical functioning. 7 The dose of n−3 fatty acids (1 g/d) was selected based on guidelines from the American Heart Association and data from a large secondary prevention trial that showed benefit in cardiovascular death. 10 , 11
All participants provided written informed consent, and approvals for the parent VITAL and this study were obtained from the institutional review board of Brigham and Women's Hospital.
For the VITAL‐Echo study, we recruited participants from VITAL who lived in the Greater Boston area (within 45 miles of Boston, MA), were participating in the in‐clinic component of the study, and were willing to undergo echocardiography (at baseline and at 2 years). Participants who had a pacemaker, prosthetic valve(s), surgical wires, or other devices that could alter the echocardiographic image findings were excluded. VITAL‐Echo participants were randomized equally into the treatment groups of vitamin D versus placebo and n−3 fatty acids versus placebo in a 2×2 factorial design. Study flow is described in Figure 1. The data, methods used in the analysis, and materials used to conduct the research will be made available to any researcher for purposes of reproducing the results or replicating the procedure.
Figure 1. Flow of participants in VITAL‐Echo (Vitamin D and Omega‐3 Trial‐Cardiac Structure and Function).
VITAL indicates Vitamin D and Omega‐3 Trial.
Echocardiography
After enrollment, participants underwent transthoracic echocardiography at baseline (prerandomization) and after approximately 2 years performed by technicians blinded to treatment allocation. Echocardiography was performed using a commercially available system (Vivid‐i; GE Healthcare, Waukesha, WI) with a 1.9‐ to 3.8‐mHz phased‐array transducer. Two‐dimensional Doppler and color tissue Doppler imaging were performed from standard parasternal and apical transducer positions. All data were stored digitally, and offline data analyses were performed using EchoPac version 6.5 (GE Healthcare).
All echocardiograms were read by a primary reader (M.H.P.) blinded to treatment allocation at the echocardiography core laboratory at Massachusetts General Hospital, Boston, Massachusetts. Measurements were performed according to guidelines from the American Society of Echocardiography. 12 All echocardiographic measurements were performed by 1 author (M.H.P.). For quality control, M.H.P. performed paired LV mass measurements on 18 participants 1 month apart. The LV mass was calculated from the LV end‐diastolic dimension, the interventricular septal wall thickness, and the posterior wall thickness. Intraclass correlation coefficient was 0.95 (95% CI, 0.88–0.98), which indicates excellent intrarater reliability. LV mass was calculated from 2‐dimensional LV linear dimensions and indexed to body surface area (LV mass index). LVH was defined by LV mass index ≥115 g/m2 in men and ≥95 g/m2 in women. Relative wall thickness was calculated from posterior wall thickness and LV end‐diastolic dimension. LV volumes were measured using apical 4‐chamber and 2‐chamber views and calculated by the modified Simpson method. These LV volumes were used to derive biplane LV ejection fraction. Pulsed‐wave Doppler was used to measure early transmitral velocity (E wave) from the apical 4‐chamber view. Peak LV relaxation velocity (e') was measured from septal and lateral mitral annulus. Speckle tracking was used to measure global longitudinal strain.
Study End Points
The primary end point was the change in LV mass over 2 years, which was compared between the vitamin D group and the placebo group. Secondary end points were the change in LV systolic and diastolic function, change in LV systolic function assessed by left ventricular ejection fraction and global longitudinal strain, and change in LV diastolic function assessed by the E wave, E‐wave deceleration time, e', E/e' ratio, and left atrial volume. The effect of n−3 fatty acids supplementation on these measurements were evaluated as well, thereby taking advantage of the factorial design of the parent trial.
Sample Size
A sample size of 1000 participants provided 88% power to detect a difference in the change in LV mass of at least 7.5 mg, with a 2‐sided α=0.05 and allowing for 20% dropout before the follow‐up echocardiogram. The minimum detectable difference excluded differences in LV mass change that would be considered clinically relevant. A more detailed analysis plan is included in Data S1 and Table S1.
Statistical Analysis
Baseline characteristics of participants randomized to active treatment versus placebo are displayed in Table 1. Similarly, baseline cardiac structure and function of participants randomized to active treatment versus placebo are displayed in Table 2. Testing for significance in baseline differences was not performed per guidelines. 13 Primary analyses compared the changes in cardiac structure and function parameters from baseline with follow‐up between participants to active treatment and placebo using the Wilcoxon‐Mann‐Whitney test. Trend plots (mean±SE) of echocardiographic parameters are presented to visualize vitamin D's effects. To estimate the effect size and 95% CI on changes in cardiac structure and function, we performed a 2‐sample t test. Analyses were performed in a 2×2 factorial trial design consistent with the main VITAL. 5 Given that some participants did not attend the follow‐up visit, we performed analyses comparing participants who returned for follow‐up and those who did not by using the Wilcoxon test and Pearson test where appropriate.
Table 1.
Baseline Characteristics of Patients Enrolled in Vitamin D and Omega‐3 Trial‐Cardiac Structure and Function at the Time of Randomization, Stratified by Treatment Groups
| Baseline characteristics | Combined, N=1025 | Vitamin D, N=509 | Placebo, N=516 |
|---|---|---|---|
| Age, y | 64.4 [60.3, 68.7] | 64.3 [60.3, 68.4] | 64.5 [60.3, 69.1] |
| Men | 522 (51%) | 258 (51%) | 264 (51%) |
| Race | |||
| Non‐Hispanic White | 849 (85%) | 420 (84%) | 429 (85%) |
| Black | 86 (9%) | 41 (8%) | 45 (9%) |
| Hispanic | 29 (3%) | 12 (2%) | 17 (3%) |
| Asian/Pacific | 16 (2%) | 11 (2%) | 5 (1%) |
| American Indian/Alaska Native | 5 (1%) | 2 (0%) | 3 (1%) |
| Other or unknown | 19 (2%) | 14 (3%) | 5 (1%) |
| BMI, kg/m2 | 26.3 [23.9, 29.6] | 26.3 [23.9, 29.2] | 26.3 [23.8, 30.0] |
| Systolic BP, mm Hg | |||
| <110 | 73 (9%) | 34 (9%) | 39 (10%) |
| 110–119 | 222 (28%) | 117 (30%) | 105 (26%) |
| 120–129 | 293 (37%) | 136 (35%) | 157 (39%) |
| 130–139 | 166 (21%) | 83 (21%) | 83 (20%) |
| 140–149 | 40 (5%) | 20 (5%) | 20 (5%) |
| 150–159 | 5 (1%) | 4 (1%) | 1 (0%) |
| 160–169 | 1 (0%) | 0 (0%) | 1 (0%) |
| 170–179 | 1 (0%) | 0 (0%) | 1 (0%) |
| Hypertension | 449 (44%) | 215 (42%) | 234 (46%) |
| n−3 fatty acids | 510 (50%) | 254 (50%) | 256 (50%) |
| 25(OH) D level, ng/mL | 28.0 [22.0, 34.0] | 27.0 [22.0, 34.0] | 29.0 [22.0, 34.0] |
Values represent median [25th, 75th percentiles] or n (%). BMI indicates body mass index; and BP, blood pressure.
Table 2.
Baseline Cardiac Structure and Function of Participants at the Time of Randomization Who Returned for Follow‐Up Visit, Stratified by Vitamin D Versus Placebo
| Structure and function | Vitamin D, N=395 | Placebo, N=411 |
|---|---|---|
| Structure | ||
| Interventricular septum, cm | 1.10 [0.97, 1.20] | 1.10 [0.99, 1.20] |
| Posterior wall thickness, cm | 0.97 [0.89, 1.10] | 0.96 [0.87, 1.10] |
| Relative wall thickness | 0.44 [0.39, 0.49] | 0.44 [0.39, 0.50] |
| LV end‐diastolic diameter, cm | 4.40 [4.10, 4.70] | 4.30 [4.00, 4.70] |
| LV mass, g | 177 [142, 213] | 177 [142, 218] |
| LV mass index, g/m2 | 92 [78, 108] | 92 [78, 109] |
| LV hypertrophy | 116 (29%) | 124 (30%) |
| Systolic function | ||
| LV ejection fraction, % | 64.8 [61.8 67.8] | 64.5 [61.8, 68.0] |
| Global longitudinal strain, % | −19.0 [−21.4, −17.2] | −19.4 [−21.3, −17.6] |
| Global circumferential strain, % | −17.5 [−20.8, −14.9] | −17.7 [−21.1, −15.0] |
| TAPSE, cm | 24.7 [22.1, 27.0] | 24.7 [22.1, 27.4] |
| Diastolic function | ||
| E wave, m/s | 0.73 [0.64, 0.82] | 0.72 [0.63, 0.84] |
| E‐wave deceleration time, ms | 212 [185, 242] | 210 [185, 246] |
| E‐A ratio | 1.06 [0.86, 1.23] | 1.04 [0.85, 1.24] |
| Septal e′, m/s | 0.07 [0.06, 0.09] | 0.07 [0.06, 0.08] |
| Septal E/e′ ratio | 9.7 [8.1, 11.8] | 10.0 [8.5, 11.7] |
| Left atrial volume, mL | 51 [40, 64] | 49 [36, 62] |
Values are median [25th, 75th percentiles] or n (%). A wave atrial filling velocity; e′ indicates tissue Doppler imaging e′ wave; E wave early filling velocity; LV, left ventricular; and TAPSE, tricuspid annular plane systolic excursion.
In addition, we performed multivariable ordinal regression models (ie, treating continuous echocardiographic outcomes as ordinal variables), to assess the association between randomization to vitamin D and changes in echocardiographic variables. Ordinal regression makes no assumptions about the distribution of outcomes and thus avoids the need for data transformation and is robust to outliers. 14 Specifically, ordinal regression models were conducted with the echocardiographic parameter at year 2 as the dependent variable and the vitamin D group as the main predictor, adjusting for age, sex, race, history of hypertension, randomization to omega‐3s, follow‐up time, body mass index, and baseline value of the echocardiographic parameter. Covariates were prespecified based on evidence from prior studies identifying variables that contribute to intraindividual variation in echocardiographic measurements. 15 The effects of the baseline value of the echocardiographic and continuous covariates were assumed to be smooth but not linear by using restricted cubic spline functions with 3 knots. We fitted a series of models up to 5 knots. Based on lowest possible Akaike information criterion, models with 3 knots were selected.
In exploratory analyses, we examined whether vitamin D's effects differed by baseline LVH and randomization to n−3 fatty acids. Multiplicative interaction terms (ie, vitamin D group*LVH and vitamin D group* n−3 fatty acids) were used to test for effect modification of baseline LVH and n−3 fatty acids on the association of vitamin D with echocardiographic measures. We also performed analyses in which we stratified the association between changes in cardiac structure/function and vitamin D by baseline LVH status and fish oil randomization. All statistical analyses were performed using R version 3.3.1 (R Foundation for Statistical Computing). Two‐tailed P values <0.05 were considered significant.
Results
Baseline Characteristics
We enrolled 1025 of the 1054 participants undergoing in‐clinic assessments. At baseline, participants enrolled in VITAL‐Echo had a median age of 64 years; 51% were men, and 85% were non‐Hispanic White. Median baseline 25‐hydroxyvitamin D level was 28.0 ng/mL (22.0–34.0 ng/mL). Baseline characteristics of the intention‐to‐treat population are described in Table 1. Seventy‐nine percent returned for follow‐up and had analyzable echocardiograms at both visits (395 in treatment, 411 in placebo). Baseline characteristics of participants who returned for follow‐up visit are described in Table S2. We performed additional analyses comparing participants who returned for follow‐up with those who did not (Table S3). We found that there were no significant differences other than a small difference in body mass index (26.0 kg/m2 [23.7–29.2] versus 27.0 kg/m2 [24.6–30.4]).
Table 2 shows measurements of cardiac structure and function at baseline, according to vitamin D randomization status. Participants in both groups had normal median interventricular septum diameter, LV end‐diastolic diameter, and LV mass. The median relative wall thickness of 0.44 was slightly above the upper limit of normal as defined by the American Society of Echocardiography (0.42), whereas 30% of the participants had LVH at baseline. 7 Participants also had normal median LV ejection fraction, global longitudinal strain, septal e', and left atrial volume.
Changes in LV Structure and Function
The median interval between the 2 echocardiograms was 734 days (interquartile range, 728–747). The change in LV mass did not significantly differ between the vitamin D and placebo arms (median +1.4 versus +2.6 g, respectively; P=0.32) (Table 3, Figure 2). Similarly, there were no significant differences between the groups with regard to changes in interventricular septal thickness, posterior wall thickness, and relative wall thickness. There was a smaller increase in LV end‐diastolic diameter in participants randomized to vitamin D compared with placebo (median, 0.0 versus +0.10 cm; P=0.035). Of note, 25‐hydroxyvitamin D level was also measured at this time, with median level of 39.0 ng/mL (34.0–45.0) in the vitamin D group versus 29.0 ng/mL (22.0–34.0) in the placebo group.
Table 3.
Changes in Cardiac Structure and Function Between Baseline and Follow‐Up (Vitamin D Versus Placebo)
| Structure and function | Vitamin D, N=395 | Placebo, N=411 | P value* | Mean difference on changes (95% CI) |
|---|---|---|---|---|
| Structure | ||||
| Interventricular septum, cm | 0.00 [−0.11, 0.10] | 0.00 [−0.14, 0.10] | 0.57 | 0.00 (−0.02 to 0.03) |
| Posterior wall thickness, cm | 0.00 [−0.10, 0.10] | 0.00 [−0.10, 0.10] | 0.79 | 0.00 (−0.02 to 0.03) |
| Relative wall thickness | −0.00 [−0.06, 0.05] | −0.01 [−0.07, 0.05] | 0.19 | 0.01 (−0.00 to 0.02) |
| LV end‐diastolic diameter, cm | 0.00 [−0.20, 0.30] | 0.10 [−0.20, 0.30] | 0.035 | −0.06 (−0.12 to −0.01) |
| LV mass, g | 1.4 [−22.8, 24.2] | 2.6 [−18.0, 28.7] | 0.32 | −4.0 (−10.2 to 2.2) |
| LV mass index, g/m2 | 0.7 [−11.4, 13.5] | 1.5 [−9.8, 14.3] | 0.32 | −2.1 (−5.3 to 1.2) |
| Systolic function | ||||
| LV ejection fraction, % | 2.1 [−2.4, 6.3] | 2.0 [−2.7, 5.5] | 0.40 | 0.5 (−0.4 to 1.4) |
| Global longitudinal strain, % | −1.2 [−3.5, 1.1] | −1.3 [−3.7, 0.7] | 0.50 | 0.2 (−0.4 to 0.7) |
| Global circumferential strain, % | −1.3 [−4.6, 1.7] | −1.4 [−4.6, 2.4] | 0.75 | −0.2 (−1.0 to 0.6) |
| TAPSE, cm | 0.4 [−2.7, 3.3] | 0.6 [−2.8, 3.2] | 0.82 | 0.2 (−0.5 to 0.9) |
| Diastolic function | ||||
| E wave, m/s | 0.00 [−0.08, 0.10] | 0.00 [−0.09, 0.10] | 0.82 | 0.00 (−0.02 to 0.02) |
| E‐wave deceleration time, ms | 4.4 [−31.5, 41.5] | 0.7 [−36.08, 38.7] | 0.37 | 3.96 (−5.38 to 13.29) |
| E‐A ratio | 0.03 [−0.13, 0.18] | 0.01 [−0.16, 0.18] | 0.16 | 0.02 (−0.08 to 0.13) |
| Septal e′, m/s | 0.00 [−0.01, 0.01] | 0.00 [−0.01, 0.01] | 0.80 | −0.00 (−0.01 to 0.00) |
| Septal E/e′ ratio | −0.19 [−1.75, 1.46] | −0.35 [−1.83, 1.60] | 0.86 | −0.06 (−0.47 to 0.35) |
| Left atrial volume, mL | −4.2 [−20.4, 10.6] | −3.6 [−18.6, 14.3] | 0.25 | −2.4 (−5.9 to 1.2) |
Values are median [25th, 75th percentiles] unless otherwise indicated. e′ indicates tissue Doppler imaging e′ wave; E wave, early transmitral velocity; LV, left ventricular; and TAPSE, tricuspid annular plane systolic excursion.
*Wilcoxon test was performed.
Figure 2. Changes in cardiac structure and function, stratified by treatment assignment.
Bars represent mean±SE. e' indicates tissue Doppler imaging e' wave; and LV, left ventricular.
There were no significant differences in changes in any of the LV measurements in those randomized to n−3 fatty acids versus the corresponding placebo (Table 4). In ordinal regression models, randomization to vitamin D was not associated with any of the echocardiographic end points at follow‐up after adjustment for age, sex, race, history of hypertension, randomization to omega‐3s, follow‐up time, body mass index, and baseline value. Furthermore, there were no significant statistical interactions between baseline LVH status or randomized n−3 fatty acid assignment and randomization to vitamin D in the ordinal regression models. In the analysis in which we stratified the association between changes in cardiac structure/function and vitamin D by baseline LVH status and fish oil randomization, there were 2 statistically borderline significant associations, and neither favored vitamin D supplementation (Table S4).
Table 4.
Changes in Cardiac Structure and Function at 2 Years (n−3 Fatty Acids Versus Placebo)
| Structure and function | N−3 fatty acids, N=397 | Placebo, N=409 | P value* | Mean difference on changes (95% CI) |
|---|---|---|---|---|
| Structure | ||||
| Interventricular septum, cm | 0.00 [−0.13, 0.10] | 0.00 [−0.12, 0.10] | 0.73 | 0.00 (−0.02 to 0.03) |
| Posterior wall thickness, cm | 0.00 [−0.10, 0.10] | 0.00 [−0.10, 0.10] | 0.50 | 0.01 (−0.02 to 0.03) |
| Relative wall thickness | −0.01 [−0.06, 0.05] | −0.00 [−0.06, 0.05] | 0.97 | −0.00 (−0.02 to 0.01) |
| LV end‐diastolic diameter, cm | 0.10 [−0.20, 0.30] | 0.00 [−0.20, 0.30] | 0.12 | 0.03 (−0.03 to 0.09) |
| LV mass, g | 5.2 [−18.0, 27.5] | −2.2 [−22.4, 23.3] | 0.10 | 2.7 (−3.5 to 8.9) |
| LV mass index, g/m2 | 2.7 [−10.0, 14.2] | −1.2 [−11.9, 12.2] | 0.09 | 1.1 (−2.2 to 4.3) |
| Systolic function | ||||
| LV ejection fraction, % | 2.0 [−2.4, 5.8] | 2.2 [−2.7, 6.2] | 0.67 | −0.1 (−1.0 to 0.7) |
| Global longitudinal strain, % | −1.29 [−3.76, 0.74] | −1.18 [−3.41, 0.97] | 0.35 | −0.10 (−0.64 to 0.44) |
| Global circumferential strain, % | −1.7 [−4.9, 2.1] | −1.1 [−4.5, 2.1] | 0.23 | −0.5 (−1.3 to 0.3) |
| TAPSE, cm | 0.78 [−2.44, 3.55] | 0.40 [−2.88, 3.15] | 0.45 | 0.21 (−0.47 to 0.89) |
| Diastolic function | ||||
| E wave, m/s | 0.00 [−0.09, 0.09] | 0.01 [−0.09, 0.11] | 0.56 | −0.01 (−0.03 to 0.01) |
| E‐wave deceleration time, msec | 6.4 [−35.4, 41.8] | 1.7 [−32.6, 38.6] | 0.62 | 2.8 (−6.6 to 12.2) |
| E‐A ratio | 0.01 [−0.14, 0.18] | 0.02 [−0.14, 0.18] | 0.96 | 0.03 (−0.08 to 0.14) |
| Septal e′, m/s | 0.001 [−0.009, 0.013] | 0.004 [−0.008, 0.013] | 0.24 | 0.00 (−0.01 to 0.01) |
| Septal E/e′ ratio | −0.27 [−1.70, 1.47] | −0.27 [−1.92, 1.49] | 0.75 | −0.02 (−0.43 to 0.39) |
| Left atrial volume, mL | −5.0 [−19.1, 13.2] | −3.4 [−19.1, 12.0] | 0.84 | 0.1 (−3.5 to 3.7) |
Values are median [25th, 75th percentiles] unless otherwise indicated. e′ indicates tissue Doppler imaging e′ wave; E wave, early transmitral velocity; LV, left ventricular; and TAPSE, tricuspid annular plane systolic excursion.
*Wilcoxon test was performed.
Strain and Tissue Doppler Imaging Results
Table 3 also shows the results of the strain and tissue Doppler imaging analyses. There were no significant differences in changes in LV systolic or diastolic function using these methods between the vitamin D and placebo arms. Similarly, no significant differences were observed between participants randomized to n−3 fatty acids or placebo (Table 4). The ordinal regression results indicated no association between randomization to vitamin D and the strain and tissue Doppler findings on follow up.
Discussion
In this large ancillary study of a randomized controlled trial, supplementation with vitamin D3 or n−3 fatty acids did not lead to significant changes in cardiac structure, systolic function, or diastolic function over a 2‐year period. There effects were not modified by baseline LVH or vitamin D status. Our findings do not support a role for vitamin D3 or n−3 fatty acids supplementation for the prevention of LVH or other abnormalities in cardiac structure and function among adults aged ≥50 years.
Whereas vitamin D supplementation has long been used to treat bone‐related disorders, the expression of vitamin D receptors in cardiovascular tissue, including cardiomyocytes and endothelium, 1 , 16 has led to robust interest in its potential role in modulating cardiac structure and function. Moreover, multiple observational studies and meta‐analyses have shown associations between low serum levels of vitamin D and increased risks of cardiovascular disease. 17 , 18 , 19 The bioactive metabolite 1,25(OH)2 vitamin D3 is a nuclear hormone receptor ligand that has been shown to cause antihypertrophic activity in multiple experimental models. 20 For instance, studies in rats suggest that activated vitamin D attenuates endothelin‐stimulated cardiomyocyte hypertrophy. 21 , 22 Moreover, vitamin D's inhibitory effect on renin leads to reduced activation of the renin‐angiotensin system, a central neurohormonal mediator of cardiac remodeling. 23 , 24 Vitamin D supplementation with paricalcitol in Dahl salt‐sensitive rats fed a high‐salt diet and 1,25(OH)2D3 in 1α‐hydroxylase knockout mice have shown regression of LVH and improvement in systolic and diastolic function. 3 , 4 However, these animal studies tested activated forms of vitamin D and not the agent tested in VITAL.
The null results of this trial stand in contrast to some but not all smaller studies in humans. Two small studies in patients undergoing hemodialysis showed that vitamin D supplementation was associated with regression of LV mass and improvement in systolic function. 25 , 26 On the other hand, our results are consistent with a larger study that showed lack of benefit of vitamin D supplementation on LV mass index in patients with chronic kidney disease and LVH. 27 It is worth noting that earlier studies on vitamin D supplementation were conducted in chronic kidney disease participants because they have higher prevalence of severe vitamin D deficiency and LVH compared with the general population. 28 , 29 Given the mixed results that were seen in prior studies in patients with chronic kidney disease, it may not be surprising that we were unable to demonstrate significant regression in LV mass in a population that did not have a high prevalence of LVH or vitamin D deficiency at baseline. Nonetheless, this study provides important data addressing a question that has been unanswered to date. We noted a nonsignificant trend toward less increase in LV mass in the vitamin D arm (P=0.32). Even if real, the absolute difference in median change in LV mass index was small (0.8 g/m2) and not likely to be clinically significant.
Strengths of our study include the large sample size for a cardiovascular imaging study, the relatively high rate of retention over >2 years of follow up, high mean rate of medication adherence, 5 and the comprehensive imaging protocol that included measurements in a central core laboratory by a single blinded reader. The consistency of our findings across >15 measures of LV structure and function supports the conclusion that vitamin D or n−3 fatty acid supplementation has no effect on cardiac remodeling. There was a nominally significant difference in the change in LV end‐diastolic diameter between the vitamin D and placebo groups. Nonetheless, this difference was small (~1 mm) and not accompanied by differences in any corresponding measures, suggesting that it was likely attributable to chance. Our findings are consistent with those of another ancillary study of VITAL, VITAL‐HF (Vitamin D and Omega‐3 Trial‐Heart Failure), which concluded that vitamin D or omega‐3 fatty acids supplementation did not significantly reduce the rate of first heart failure hospitalization, a key clinical outcome of adverse LV remodeling. 30 However, the same ancillary study did show that omega‐3 supplementation reduced the rate of recurrent heart failure hospitalizations. Lastly, our study echoes the results from the main VITAL study, which showed that vitamin D supplementation did not result in a lower incidence of overall cardiovascular events. 5
The study has several limitations as well. First, given the follow‐up duration of 2 years, we cannot exclude the possibility that longer periods of vitamin D supplementation could influence cardiac remodeling. The beneficial effects of pharmacologic interventions to prevent or reduce LVH are typically observed in less than a year. 31 , 32 , 33 This is generally less a result of progression of left ventricular mass in the control arm but regression in the treated arm. 34 , 35 , 36 Thus, the fact that no significant changes in cardiac structure were observed over the follow‐up period in the entire sample is consistent with lack of effective treatment in either arm. Second, the trial tested only 1 dose and formulation of vitamin D and omega‐3 fatty acids. However, in the main trial, serum 25‐hydroxyvitamin D levels increased 40% with vitamin D3 supplementation, with a median achieved level of 41.8 ng/mL at 1 year; thus, few patients were deficient following treatment. 5 The improvement in vitamin D status was similar for the participants in the echocardiographic substudy. Third, statistical power to assess effects among subgroups was limited. Fourth, in a sample of 97 participants, the median baseline level of 25‐hydroxyvitamin D was 30.9 ng/mL. 37 Our findings are consistent with the findings from the main VITAL, which had a subgroup (n=15 787) that had their baseline 25‐hydroxyvitamin D levels measured; their serum 25(OH)D baseline level was 30.8±10.0 ng/mL. 5 Thus, we cannot exclude the possibility that cardiac effects of vitamin D supplementation would be more prominent in individuals with more prominent vitamin D insufficiency and deficiency.
In conclusion, among adults aged ≥50 years, neither vitamin D3 nor n−3 fatty acid supplementation had significant effects on cardiac structure and function after 2 years.
Sources of Funding
VITAL was supported by grants U01 CA138962 and R01 CA138962 from the National Cancer Institute, National Heart, Lung, and Blood Institute, Office of Dietary Supplements, National Institute of Neurological Disorders and Stroke, and the National Center for Complementary and Integrative Health. VITAL‐Echo was supported by grant R01 HL112746 from the National Heart, Lung, and Blood Institute. The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the article; or decision to submit the article for publication.
Disclosures
Dr Buring reported that her spouse served on the Scientific Advisory Board of Pharmavite, which provided the vitamin D for the trial. No other disclosures were reported.
Supporting information
Data S1
Table S1–S4
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.121.025008
For Sources of Funding and Disclosures, see page 9.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1
Table S1–S4