The latest issue of JACC (2016;67:2593-603) reports a randomized study that assesses the efficacy and safety of high dose vitamin D (D) in patients with chronic systolic heart failure (HF) accompanied with deficiency in vitamin D. 229 patients of HF and low D (< 20 ng/ml) were provided 100 mcg or 4000 units of 25(OH) vitamin D3 (cholecalciferol) supplementation. The primary endpoint was 6 minute walking distance and secondary endpoints were change in left ventricle ejection fraction (LVEF) at one year. Safety measures of renal function and serum calcium concentration were measured every 3 months.
The 6-minute walking distance did not improve after 1 year of high dose D but there was significant increase in LVEF by 6.07% (p<0.0001) and decrease in LV end diastolic diameter (-2.49 mm: p=0.002) and LV systolic diameter by 2.09 mm (p=0.043). The researchers concluded that 1 year of high dose vitamin D3 supplements despite not improving 6 minute walking distance, did improve LV function significantly.
The mean age of patients enrolled in this study (VINDICATE) was 69 years and almost 80% were males. Ischemic heart disease accounted for 58% of HF patients, while non-ischemic cardiomyopathy was the cause in 37% of patients, and the remaining 5 % of patients suffered from valvular disease. All patients were on optimal medical therapy consisting of beta- blocker, ACE inhibitor, aldosterone antagonist and a diuretic. Interestingly more patients were with a device (ICD or CRT) in the placebo group than the treated group (33% vs. 26%). Mean LVF at base line was 26% while 6-minute walking distance was 293 meters, and almost 45% of patients were complicated by atrial fibrillation.
At 12 months post randomization the placebo group had a D level of 9.8 ng/ml while the treated group had achieved a D level of 46 ng/ml confirming the effectiveness of vitamin D supplementation. It took on an average 3 months for normalization of vitamin D levels in the treated group. No patient displayed any evidence of hypervitaminosis D.
The VINDICATRE trial demonstrates that 4000 IU of vitamin D3 given for 12 months is safe well tolerated and crucially improved LV function, albeit without increasing 6-minute walking distance. It has been reported earlier that patients with chronic HF are frequently deficient in vitamin D, and that low vitamin D are at increased risk of HF, and also are associated with worse outcomes in patients with chronic HF.
How does vitamin D correct LV remodeling? Vitamin D deficiency may interfere with calcium transport at cellular level and hence contribute to cardiomyocyte dysfunction. Probably low vitamin D levels may lead to cardiac inflammation, interstitial fibrosis and cardiomyocyte hypertrophy. Moreover vitamin D also acts as a counter to the adverse effects of the renin angiotensin aldosterone system (RAAS). Vitamin D deficiency increases RAAS activity while vitamin D supplementation seems to reduce renin synthesis and plasma renin activity.
Several observational studies have shown an increased risk of incidental HF and mortality in people with deficient vitamin D. The VIDICATE trial, a randomized double blind, placebo controlled trial of vitamin D supplementation in patients with chronic HF and hypovitaminosis of vitamin D has demonstrated that 1 year of vitamin D3 supplementation had a favorable effect on LVEF (measured by echocardiography), with a 3% to 8% improvement in the treated arm. It is to be noted that an 8% increase in LVEF by vitamin D supplementation in patients with chronic HF matches improvement in LVEF with much more complex interventions such as biventricular pacing (CRT). Each 5% increase in LVEF from baseline in the MADIT-CRT was associated with a 28% to 50% in the risk of heart failure hospitalization or death.
The VINDICATE trial is however a small trial involving only a little more than 160 patients with a high incidence of dropouts. Nearly 90 % of patients were Caucasians and there is no mention of Indians included in the study. But it is essential that given the low cost of vitamin D more randomized studies be conducted to determine whether the efficacy on LV functions can be replicated and moreover translated into clinical benefits. There are millions of patients around the globe that could be helped. Low vitamin D it must be noted is quite common in Indian patients.