Effects of Vitamin D on Cardiac Function in Patients With Chronic HF The VINDICATE

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Patients suffering from cardiovascular disease are frequently deficient in the steroid hormone vitamin D, and vitamin D deficiency has been shown to be associated with the development of chronic HF in a number of studies (6)(7)(8)(9)(10). Approximately 90% of chronic HF patients have hypovitaminosis D (11), even in sunny climates (12). The agent has a range of pleiotropic effects that in the setting of chronic HF may impact on disease severity (13,14), but despite this, clinical trials examining vitamin D supplementation in chronic HF patients have to date been inconclusive (15,16). The supplement and dose were chosen based upon guidelines for studies of vitamin D supplementation (17). These guidelines suggest that studies should: 1) aim to replace physiological requirements, supplementing between 75 and 250 mg/day; 2) last at least 9 months; 3) supplement with vitamin D 3 (not D 2 ); 4) assay supplements for potency; 5) include a regular serum measurement of 25(OH)D 3 levels; and 6) aim to achieve serum levels in patients on active therapy between 100 and 160 nmol/l (40 ng/ml to 64 ng/ml).
Also, on the basis of recent data demonstrating the adverse effect of hyperparathyroidism in chronic HF OUTCOME VARIABLES. The pre-specified primary endpoint in VINDICATE was the difference in change in 6-min walk test distance (6MWT) (baseline to 12 months) between the 2 groups. Key pre-specified secondary endpoints included cardiac structure and function, and safety endpoints of serum calcium concentration, renal function, and vitamin D levels. Hypervitaminosis D was defined as 25(OH)D 3 >200 nmol/l (80 ng/ml), and hypercalcemia as >2.6 nmol/l (10.4 mg/dl). STUDY PROCEDURES. At baseline each patient performed a 6MWT according to standard criteria (20).
Each patient also underwent echocardiography and blood sampling for serum calcium, serum creatinine, vitamin D, and PTH levels. Patients were also invited to undergo cardiac magnetic resonance (CMR) imaging to measure LV volumes. Subsequent visits took place at 3, 6, 9, and 12 months and blood draws were repeated at each visit for safety data.   (24). We assumed, based upon our preliminary data from a pilot study (19), that there would be a change between the 2 groups at 12 months of 30 m. The SD of change in 6MWT was estimated from these data; the upper limit of the 80% confidence interval (CI) (estimated using bootstrapping) was used in these calculations to allow for the small sample size in the proof of concept. This determined that 210 patients were required to have 90% power to show a difference in change in 6MWT of 28 m or more with 5% significance (SD ¼ 62). We aimed to recruit 230 patients (115 per group) to allow for w10% dropout.
STATISTICAL ANALYSIS. Differences in baseline variables between allocations were tested using Student t tests (continuous data) or the chi-square test An agreed operating procedure for any subject who developed a serum vitamin D concentration >200 nmol/l (80 ng/ml) involved reducing the dose of treatment from 2 to 1 tablets per day to maintain patient blinding.

RESULTS
We enrolled 229 patients into VINDICATE. Six patients were found to be ineligible at the baseline visit, leaving 223 patients randomized to treatment.  Table 1. There were no important clinical differences at baseline between patients completing the study and those who dropped out. The 2 groups of completing participants were balanced for baseline clinical variables ( Table 1).  Figure 3).
There was a dose-response relationship between the increase in vitamin D levels and the increase in LVEF  There was no effect of vitamin D supplementation  Values are n (%) or mean AE SD. Conversion factors: vitamin D nmol/l $ 0.4 ¼ ng/ml; creatinine mmol/l $ 0.11 ¼ mg/dl; calcium mmol/l $ 4 ¼ mg/dl; parathyroid hormone pmol/l $ 9.4 ¼ pg/ml.
ACEi ¼ angiotensin-converting enzyme inhibitor; ARB ¼ aldosterone receptor blocker; BMI ¼ body mass index; BP ¼ blood pressure; CRT ¼ cardiac resynchronization therapy; ICD ¼ implantable cardioverter defibrillator; LVEDD ¼ left ventricular end-diastolic diameter; LVEDV ¼ left ventricular end-diastolic volume; LVEF ¼ left ventricular ejection fraction; LVESD ¼ left ventricular end-systolic diameter; LVESV ¼ left ventricular endsystolic volume; NYHA ¼ New York Heart Association functional class; VINDICATE ¼ VitamIN D treatIng patients with Chronic heArT failurE.   Hence, vitamin D deficiency could contribute to a more rapid progression to HF following myocardial damage due to more aggressive adverse remodeling (40).
However, adverse remodeling is also the result of persistent neurohormonal activation, particularly that of the renin angiotensin aldosterone system (RAAS) which strongly contributes to deteriorating cardiac function, cardiomyocyte loss, and interstitial fibrosis (41). Inhibition of the RAAS leads to attenuated or reverse LV remodeling in patients with HF (42).
STUDY LIMITATIONS. VINDICATE was performed at a single center. However, the study was based upon results from a randomized, placebo-controlled pilot study in 53 patients using the same dose for 12 months that also showed a favorable effect of vitamin D on cardiac structure and function (19