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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Echocardiography. Author manuscript; available in PMC 2017 May 1.
Published in final edited form as:
PMCID: PMC4916967
NIHMSID: NIHMS793443

Vitamin D Attenuates Left Atrial Volume Changes in African American Males with Obesity and Prediabetes

Satish Jacob Chacko, M.D.,* Sunil Pauwaa, M.D., Elena Barengolts, M.D.,§ Irina Ciubotaru, M.D., Ph.D.,§ and Mayank M. Kansal, M.D.*

Abstract

Vitamin D deficiency is common among African Americans in the United States and is associated with increased cardiovascular disease risk. In this study, prediabetic African American males who were found to be vitamin D–deficient were randomized to vitamin D supplementation and assessed for changes in left atrial (LA) volume. Prediabetic African American males who were vitamin D–deficient (25(OH)D: 5.0–29 ng/mL) were randomized to high-dose ergocalciferol or placebo. Echocardiography was performed at baseline and at 1 year. Ejection fraction (EF), septal and posterior wall thickness, LA area, LA length, LA volume, E, A, septal and lateral e′ and a′, deceleration time, and isovolumetric relaxation time were collected. Eighty-one of 158 (51%) subjects received vitamin D2. Baseline characteristics were similar among both groups. In the placebo group, left atrial volume significantly increased on follow-up (LA volume increased 6.3 mL, P = 0.0025). Compared with placebo group, the treatment group with ergocalciferol had attenuated increases in left atrial volume (LA volume increased 2.6 mL, P = 0.29). Changes in left atrial volume persisted when indexed to body surface area. There was no significant difference in other diastolic parameters and blood pressure between groups. In conclusion, vitamin D–deficient prediabetic African American males who were treated with high-dose vitamin D2 were found to have attenuated increases in left atrial volume compared with controls over 12-month follow-up.

Keywords: vitamin D, left atrium, diabetes, supplementation

Left atrial enlargement is well known to be a strong prognostic factor in cardiovascular outcomes. Left atrial volume increases as a result of either pressure or volume overload. The increase in left atrial size as a response to increased filling pressures has been documented on invasive studies,1 while chronic volume overload states also result in chamber enlargement. Increased left atrial volume is a marker of diastolic dysfunction, and these patients have been shown to have higher rates of cardiovascular events, including atrial fibrillation, stroke, heart failure, hypertension, and all-cause mortality.2 In patients with type 2 diabetes mellitus, left atrial dysfunction has been found to be significantly greater than controls.3

While vitamin D deficiency is typically thought to involve the musculoskeletal system, there has been significant evidence linking it with adverse cardiovascular events.4 In the Framingham Offspring Study, individuals with vitamin D deficiency (25(OH)D3 < 37.5 nmol/L) had a hazard ratio of 1.62 for development of cardiovascular disease compared with those with normal levels.5 Vitamin D–deficient individuals have been found to have over a twofold increased risk of MI, even after adjustment for common risk factors.6 Patients with low 25-hydroxy vitamin D levels have a higher risk of sudden cardiac death, heart failure, cardiovascular mortality, and all-cause mortality.7 Patients with newly diagnosed type 2 diabetes have been found to have lower levels of 25-hydroxy vitamin D as compared to healthy controls,8, 9 and low 25(OH)D is a risk factor for hyperglycemia.10 Diabetes has long been known to be a significant risk factor for cardiovascular disease, but the effect of vitamin D supplementationon cardiovascular parameters has not been studied in this population. In this study, prediabetic African American males who were found to be vitamin D–deficient were randomized to vitamin D supplementation and assessed for changes in left atrial area and volume.

Methods

This study was ancillary to a vitamin D supplementation study conducted in veterans between 2011 and 2013. Vitamin D Intervention in Veteran Administration (DIVA Study) has been described elsewhere.11 Briefly, DIVA was a double-blind placebo-controlled randomized clinical trial conducted to test the effect of supplementation with high doses of vitamin D for 12 months on oral glucose insulin sensitivity in African American males with obesity and prediabetes. Secondary outcomes included changes in left atrial area and volume. The study was approved by the University of Illinois Institutional Review Board and by the Jesse Brown VA Medical Center (JBVAMC) Research and Development Committee. The study was registered at clinicaltrials.gov (NCT01375660).

Subjects were recruited from JBVAMC in Chicago, and eligible participants were randomized to placebo or vitamin D groups. They had follow-up every 3 months and the final assessment after 12 months of treatment. The subjects provided written informed consent prior to participation.

Inclusion Criteria

The main inclusion criteria were as follows: African American male veterans, age 35–85 years, BMI 28–39 kg/m2, fasting glucose 95–125 mg/dL and/or A1c 5.7–6.4%, and 25(OH)D 5.0–29 ng/mL. Participants who were diagnosed with diabetes during screening or intervention were allowed in the study if they did not need to take antidiabetic medications and A1c remained <7%.

The main exclusion criteria were diabetes and any medical conditions that would be expected to interfere with the study or increase risk to the subject, such as kidney stones, hypercalcemia, hyperparathyroidism, sarcoidosis, and chronic kidney disease (CKD) beyond stage 3a (eGFR < 45 mLs/min/1.73 m2).

A total of 2067 subjects were prescreened, 205 randomized, and 173 (84%) came for the final visit. Of these 173 subjects, 158 (91%) had successful baseline and exit echocardiograms and were analyzed for the present study.

Vitamin D

All subjects received cholecalciferol (D3) 400 IU as multiple vitamins and in addition either weekly ergocalciferol (D2) 50 000 IU (Pliva Co., Zagreb, Croatia) or placebo. Out of n = 158 subjects included in the present ancillary study, n = 77 received weekly placebo and n = 81 received vitamin D2 50 000 IU. Serum vitamin 25(OH)D was measured at baseline and 12 months.

Outcomes

The main outcome of interest involved the change in left atrial dimensions, specifically left atrial area, length, and volume. Other parameters measured were left ventricular ejection fraction, septal and posterior wall thickness, and markers of LV diastolic function (early [E] and late [A] mitral inflow wave velocities, early [E′] and late [A′] mitral annular relaxation velocity, isovolumetric relaxation time [IVRT], and E-wave deceleration time). Biplane Simpson’s method was used to calculate left atrial volume from apical four- and two-chamber views at end-systole. All parameters were measured by a single sonographer in accordance with the American Society of Echocardiography guidelines.12, 13

Statistical Analysis

The sample size for the study was calculated according to general recommendations and previously published study.14 Before statistical analysis, normal distribution and homogeneity of the variances were tested. Baseline characteristics were compared with independent t-tests. The mean circulating 25(OH) vit D was across five measurements: baseline and follow-up at 3, 6, 9, and 12 months. Values were represented as means and standard deviations (SD). The significance was determined at P < 0.05 (two tailed). Statistical analysis was conducted using IBM SPSS 21 (Armonk, NY, USA).

Results

Baseline Characteristics

Baseline characteristics were similar between groups (Table I). All subjects were African American males and had equivalent hemoglobin A1c, BMI, and blood pressure values. Average age of those in the therapy arm was 58.1 ± 7.3 years, while those in the placebo arm were 59.6 ± 8.5 years. There was also similar prevalence of major cardiovascular risk factors including hypertension, hyperlipidemia, peripheral vascular disease, obstructive sleep apnea, and tobacco use.

TABLE I
Baseline Characteristics

Baseline echocardiographic measurements were similar between the two groups (Table II). Both groups had a normal ejection fraction. Left atrial volume indexed to body surface area (LaVi) was mildly abnormal, and left atrial diameter was moderately abnormal. Wall thickness was similar between the two groups. Isovolumetric relaxation time (IVRT) and deceleration time (DT) were prolonged, and both septal and lateral early diastolic mitral annular velocity (septal E′ and lateral E′) were decreased, suggesting abnormal diastolic function.

TABLE II
Baseline Transthoracic Echocardiogram Measures

Serum Vitamin D Concentration

At 12 months, the mean serum 25(OH) vit D level had increased to 50.5 ± 24.1 ng/mL in the treatment group and to 20.18 ± 9.6 ng/mL in the placebo group (between groups P < 0.001).

Left Atrial Change

Follow-up echocardiographic results are shown in Table III. In the placebo group, left atrial volume significantly increased on follow-up (LA volume increased 6.3 mL, P = 0.0025). Compared with placebo group, the treatment group with ergocalciferol had attenuated increases in left atrial volume (LA volume increased 2.6 mL, P = 0.29). Changes in left atrial volume persisted when indexed to body surface area. Left ventricular ejection fraction and wall thickness did not change significantly in either group, as well as parameters evaluating diastolic function (IVRT, DT, septal E′, lateral E′). Of note, there was no significant difference in blood pressure between groups at 12-month follow-up (P = 0.941). Univariate predictors of left atrial volume change are shown in Table IV, with no variable reaching statistical significance.

TABLE III
Change in Transthoracic Echocardiography Measures from Baseline to 1 year
TABLE IV
Univariate Predictors of Left Atrial Volume Change

Discussion

In this trial, vitamin D–deficient prediabetic African American males who were treated with high-dose vitamin D2 were found to have attenuated increases in left atrial volume compared with controls over 12-month follow-up, despite similar blood pressure control. This is significant because in this high-risk population, abnormal cardiac structure is very prevalent and a marker of worse outcomes.15 While vitamin D supplementation has been studied in various groups, our study is unique in that the population was prediabetic African American males, a cohort that has not been investigated to date. Prediabetics have an increased risk of cardiovascular diseases,16 stemming from early pancreatic β-cell dysfunction and insulin resistance.17 Early intervention has been shown to reduce long-term vascular complications in these patients, 18 and our study suggests that early supplementation in those who are vitamin D–deficient may slow deleterious changes in cardiac structure.

The vitamin D receptor (VDR) is present in numerous tissues, many of which could play a role in the changes seen in our patient population. The VDR is present in endothelium,19 and in diabetics, vitamin D supplementation has been shown to improve endothelial function,20 possibly through improving vascular resistance, reducing inflammation, or by activating vascular endothelial growth factor (VEGF) which in turn increases nitric oxide synthesis in endothelial cells.21 Vitamin D suppresses pro-inflammatory cytokines and causes an increase in IL-10 levels.22 The VDR is also known to inhabit cardiac myocytes.23 In animal models, vitamin D regulated myocyte growth 24 and it has been proposed that the presence of the VDR in sarcolemma may regulate myocyte relaxation.25 Left atrial remodeling may also be affected by vitamin D regulation of extracellular matrix metalloproteinases which would inhibit collagen deposition.26 Possibly most significant is the effect that vitamin D has on inhibiting the renin–aldosterone–angiotensin system (RAAS).27 Atrial wall tension activates RAAS, and subsequent increases in angiotensin II would typically cause fibroblast proliferation and fibrosis formation, but these are attenuated with vitamin D.28 Inhibiting RAAS and PTH also has positive effects on blood pressure regulation, which ultimately impacts left atrial volume.29 It is notable that while increases in left atrial volume were attenuated, Doppler measurements of diastolic function did not significantly change throughout the study. This could possibly be because our sample size was too small to detect a difference in these parameters. However, elsewhere vitamin D levels were also not associated with left ventricular diastolic performance.30

Our study builds on prior work investigating the echocardiographic changes associated with vitamin D. Vitamin D deficiency has been shown to be an independent predictor of left ventricular hypertrophy 31 and in patients with heart failure is associated with left ventricular dilation.32 Even in children, vitamin D deficiency has been associated with increased left ventricular mass and diastolic dysfunction.33 Regarding the left atrium, it has been shown that patients with atrial fibrillation have lower vitamin D levels and larger left atrial diameters than age-matched controls.28 In patients with left ventricular hypertrophy and chronic kidney disease, vitamin D supplementation has been shown to decrease LaVi.27 Our study adds to these findings in a different but similarly at-risk cohort.

There are a few limitations to our study. While left atrial size and volume is a marker of worse cardiovascular outcomes, it is just a surrogate for cardiovascular events. Due to our study size, it is difficult to say whether vitamin D supplementation would affect cardiac hospitalizations and mortality in our population. In addition, our inclusion criteria were quite rigorous, and while this provided a very homogenous sample, caution should be made when applying these results to patients outside of this group.

In summary, vitamin D–deficient prediabetic African American males who were treated with high-dose vitamin D2 were found to have attenuated increases in left atrial volume compared with controls over 12-month follow-up. Further studies are warranted to investigate whether vitamin D supplementation in this population has effects on long-term cardiovascular outcomes.

Acknowledgments

This study was supported by a Merit Review grant funded by the Department of Veterans Affairs, Jesse Brown VA Medical Center and in part by NIH grant number UL1RR029879. All authors reviewed and edited the manuscript. The authors thank Brian Glovack, PharmD, and Michael Pacini, PharmD, for maintaining drug inventory and dose adjustments, Bharathi Reddivari for recruiting and following up subjects, and Hajwa Kim for help with statistical analysis. The authors also thank Hiba Mohiuddin, Nathaniel Chertok, Emily Lelchuk, Chizelle Onochie, Hassan Zaidi, Karthik Cherukupally, and Shweta Kurma for recruiting subjects and collecting data.

References

1. Pape LA, Price JM, Alpert JS, et al. Relation of left atrial size to pulmonary capillary wedge pressure in severe mitral regurgitation. Cardiology. 1991;78:297–303. [PubMed]
2. Psaty BM, Manolio TA, Kuller LH, et al. Incidence of and risk factors for atrial fibrillation in older adults. Circulation. 1997;96:2455–2461. [PubMed]
3. Graca B, Ferreira MJ, Donato P, et al. Left atrial dysfunction in type 2 diabetes mellitus: Insights from cardiac MRI. Eur Radiol. 2014;24:2669–2676. [PubMed]
4. Zittermann A, Schleithoff SS, Koerfer R. Putting cardiovascular disease and vitamin D insufficiency into perspective. Br J Nutr. 2005;94:483–492. [PubMed]
5. Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008;117:503–511. [PMC free article] [PubMed]
6. Giovannucci E, Liu Y, Hollis BW, et al. 25-hydroxyvitamin D and risk of myocardial infarction in men: A prospective study. Arch Intern Med. 2008;168:1174–1180. [PMC free article] [PubMed]
7. Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008;168:1340–1349. [PubMed]
8. Laway BA, Kotwal SK, Shah ZA. Pattern of 25 hydroxy vitamin D status in North Indian people with newly detected type 2 diabetes: A prospective case control study. Indian J Endocrinol Metab. 2014;18:726–730. [PMC free article] [PubMed]
9. Barengolts E. Vitamin D role and use in prediabetes. Endocr Pract. 2010;16:476–485. [PubMed]
10. Manickam B, Neagu V, Kukreja SC, et al. Relationship between glycated hemoglobin and circulating 25-hydroxyvitamin D concentration in African American and Caucasian American men. Endocr Pract. 2013;19:73–80. [PMC free article] [PubMed]
11. Barengolts E. Effect of high-dose vitamin D repletion on glycemic control in African American men with prediabetes and hypovitaminosis D. Endocr Pract. 2015;6:604–612. [PMC free article] [PubMed]
12. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: A report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18:1440–1463. [PubMed]
13. Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr. 2009;22:107–133. [PubMed]
14. Nagpal J, Pande JN, Bhartia A. A double-blind, randomized, placebo-controlled trial of the short-term effect of vitamin D3 supplementation on insulin sensitivity in apparently healthy, middle-aged, centrally obese men. Diabetic Med. 2009;26:19–27. [PubMed]
15. Abhayaratna WP, Seward JB, Appleton CP, et al. Left atrial size: Physiologic determinants and clinical applications. J Am Coll Cardiol. 2006;47:2357–2363. [PubMed]
16. Barzilay JI, Spiekerman CF, Wahl PW, et al. Cardiovascular disease in older adults with glucose disorders: Comparison of American Diabetes Association criteria for diabetes mellitus with WHO criteria. Lancet. 1999;354:622–625. [PubMed]
17. Khaw KT, Wareham N, Luben R, et al. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European prospective investigation of cancer and nutrition (EPIC-Norfolk) BMJ. 2001;322:15–18. [PMC free article] [PubMed]
18. Nathan DM, Cleary PA, Backlund JY, et al. Complications Trial/Epidemiology of Diabetes I et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. New Engl J Med. 2005;353:2643–2653. [PMC free article] [PubMed]
19. Merke J, Milde P, Lewicka S, et al. Identification and regulation of 1,25-dihydroxyvitamin D3 receptor activity and biosynthesis of 1,25-dihydroxyvitamin D3. Studies in cultured bovine aortic endothelial cells and human dermal capillaries. J Clin Investig. 1989;83:1903–1915. [PMC free article] [PubMed]
20. Sugden JA, Davies JI, Witham MD, et al. Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels. Diabetic Med. 2008;25:320–325. [PubMed]
21. Ahmad S, Hewett PW, Wang P, et al. Direct evidence for endothelial vascular endothelial growth factor receptor-1 function in nitric oxide-mediated angiogenesis. Circ Res. 2006;99:715–722. [PubMed]
22. Cardus A, Parisi E, Gallego C, et al. 1,25-Dihydroxyvitamin D3 stimulates vascular smooth muscle cell proliferation through a VEGF-mediated pathway. Kidney Int. 2006;69:1377–1384. [PubMed]
23. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81:353–373. [PubMed]
24. Wu J, Garami M, Cheng T, et al. 1,25(OH)2 vitamin D3, and retinoic acid antagonize endothelin-stimulated hypertrophy of neonatal rat cardiac myocytes. J Clin Investig. 1996;97:1577–1588. [PMC free article] [PubMed]
25. Tishkoff DX, Nibbelink KA, Holmberg KH, et al. Functional vitamin D receptor (VDR) in the t-tubules of cardiac myocytes: VDR knockout cardiomyocyte contractility. Endocrinology. 2008;149:558–564. [PubMed]
26. Rahman A, Hershey S, Ahmed S, et al. Heart extracellular matrix gene expression profile in the vitamin D receptor knockout mice. J Steroid Biochem Mol Biol. 2007;103:416–419. [PubMed]
27. Tamez H, Zoccali C, Packham D, et al. Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease. Am Heart J. 2012;164:902–909. e902. [PubMed]
28. Demir M, Uyan U, Melek M. The effects of vitamin D deficiency on atrial fibrillation. Clin Appl Thromb Hemost. 2014;20:98–103. [PubMed]
29. Connell JM, MacKenzie SM, Freel EM, et al. A lifetime of aldosterone excess: Long-term consequences of altered regulation of aldosterone production for cardiovascular function. Endocr Rev. 2008;29:133–154. [PubMed]
30. Pandit A, Mookadam F, Boddu S, et al. Vitamin D levels and left ventricular diastolic function. Open Heart. 2014;1:e000011. [PMC free article] [PubMed]
31. Lai S, Coppola B, Dimko M, et al. Vitamin D deficiency, insulin resistance, and ventricular hypertrophy in the early stages of chronic kidney disease. Ren Fail. 2014;36:58–64. [PubMed]
32. Ameri P, Ronco D, Casu M, et al. High prevalence of vita-min D deficiency and its association with left ventricular dilation: An echocardiography study in elderly patients with chronic heart failure. Nutr Metab Cardiovasc Dis. 2010;20:633–640. [PubMed]
33. Patange AR, Valentini RP, Gothe MP, et al. Vitamin D deficiency is associated with increased left ventricular mass and diastolic dysfunction in children with chronic kidney disease. Pediatr Cardiol. 2013;34:536–542. [PubMed]