Short-term vitamin D3 supplementation lowers plasma renin activity in patients with stable chronic heart failure:
An open-label, blinded end point, randomized prospective trial (VitD-CHF trial)
Nicolas F. Schroten, MD; Willem P.T. Ruifrok, MD, PhD; Lennaert Kleijn, MD; Martin M. Dokter, BASc
Herman H. Silljé, PhD; Hiddo J. Lambers Heerspink, PhD; Stephan J.L. Bakker, MD, PhD
Ido P. Kema, PhD; Wiek H. van Gilst, PhD; Dirk J. van Veldhuisen, MD, PhD
Hans L. Hillege, MD, PhD; Rudolf A. de Boer, MD, PhD r.a.de.boer at umcg.nl
Received 30 December 2012; accepted 2 May 2013. published online 27 June 2013.
Background: Many chronic heart failure (CHF) patients have low vitamin D (VitD) and high plasma renin activity (PRA), which are both associated with poor prognosis.
Vitamin D may inhibit renin transcription and lower PRA.
We investigated whether vitamin D3 (VitD3) supplementation lowers PRA in CHF patients.
Methods and Results: We conducted a single-center, open-label, blinded end point trial in 101 stable CHF patients with reduced left ventricular ejection fraction. Patients were randomized to 6 weeks of 2,000 IU oral VitD3 daily or control. At baseline, mean age was 64 ± 10 years, 93% male, left ventricular ejection fraction 35% ± 8%, and 56% had VitD deficiency. The geometric mean (95% CI) of 25-hydroxyvitamin D3 increased from 48 nmol/L (43-54) at baseline to 80 nmol/L (75-87) after 6 weeks in the VitD3 treatment group and decreased from 47 nmol/L (42-53) to 44 nmol/L (39-49) in the control group (P < .001).
The primary outcome PRA decreased
- from 6.5 ng/mL per hour (3.8-11.2)
- to 5.2 ng/mL per hour (2.9-9.5)
in the VitD3 treatment group and increased from 4.9 ng/mL per hour (2.9-8.5) to 7.3 ng/mL per hour (4.5-11.8) in the control group (P = .002). This was paralleled by a larger decrease in plasma renin concentration in the VitD3 treatment group compared to control (P = .020).
No significant changes were observed in secondary outcome parameters, including N-terminal pro–B-type natriuretic peptide natriuretic peptide and fibrosis markers.
Conclusions: Most CHF patients had VitD deficiency and high PRA levels. Six weeks of supplementation with 2,000 IU VitD3 increased 25-hydroxyvitamin D3 levels and decreased PRA and plasma renin concentration.
- Gotsman I, Shauer A, Zwas DR, et al. Vitamin D deficiency is a predictor of reduced survival in patients with heart failure; vitamin D supplementation improves outcome. Eur J Heart Fail. 2012;14:357–366
- Liu L, Chen M, Hankins SR, et al. Serum 25-hydroxyvitamin D concentration and mortality from heart failure and cardiovascular disease, and premature mortality from all-cause in United States adults. Am J Cardiol. 2012;110:834–839; Full-Text PDF (344 KB)
- Meems LM, van der Harst P, van Gilst WH, et al. Vitamin d biology in heart failure: molecular mechanisms and systematic review. Curr Drug Targets. 2011;12:29–41
- Resnick LM, Muller FB, Laragh JH. Calcium-regulating hormones in essential hypertension. Relation to plasma renin activity and sodium metabolism. Ann Intern Med. 1986;105:649–654
- Park CW, Oh YS, Shin YS, et al. Intravenous calcitriol regresses myocardial hypertrophy in hemodialysis patients with secondary hyperparathyroidism. Am J Kidney Dis. 1999;33:73–81
- Full-Text PDF (57 KB)
- Kimura Y, Kawamura M, Owada M, et al. Effectiveness of 1,25-dihydroxyvitamin D supplementation on blood pressure reduction in a pseudohypoparathyroidism patient with high renin activity. Intern Med. 1999;38:31–35
- Li YC. Vitamin D, regulation of the renin-angiotensin system. J Cell Biochem. 2003;88:327–331
- Sigmund CD. Regulation of renin expression and blood pressure by vitamin D(3). J Clin Invest. 2002;110:155–156
- Kuipers I, van der Harst P, Navis G, et al. Nuclear hormone receptors as regulators of the renin-angiotensin-aldosterone system. Hypertension. 2008;51:1442–1448
- Fryer RM, Rakestraw PA, Nakane M, et al. Differential inhibition of renin mRNA expression by paricalcitol and calcitriol in C57/BL6 mice. Nephron Physiol. 2007;106:p76–p81
- Bouillon R, Carmeliet G, Verlinden L, et al. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev. 2008;29:726–776
- Schroten NF, Gaillard CA, van Veldhuisen DJ, et al. New roles for renin and prorenin in heart failure and cardiorenal crosstalk. Heart Fail Rev. 2012;17:191–201
- Authors/Task Force Members , McMurray JJ, Adamopoulos S, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33:1787–1847
- Schunkert H, Hense HW, Brockel U, et al. Differential effects of antihypertensive drugs on neurohormonal activation: insights from a population-based sample. J Intern Med. 1998;244:109–119
- Masson S, Solomon S, Angelici L, et al. Elevated plasma renin activity predicts adverse outcome in chronic heart failure, independently of pharmacologic therapy: data from the Valsartan Heart Failure Trial (Val-HeFT). J Card Fail. 2010;16:964–970; Full-Text PDF (350 KB)
- Latini R, Masson S, Anand I, et al. The comparative prognostic value of plasma neurohormones at baseline in patients with heart failure enrolled in Val-HeFT. Eur Heart J. 2004;25:292–299
- Szymanski MK, Damman K, van Veldhuisen DJ, et al. Prognostic value of renin and prorenin in heart failure patients with decreased kidney function. Am Heart J. 2011;162:487–493; Full-Text PDF (168 KB)
- van de Wal RM, Plokker HW, Lok DJ, et al. Determinants of increased angiotensin II levels in severe chronic heart failure patients despite ACE inhibition. Int J Cardiol. 2006;106:367–372; Full-Text PDF (115 KB)
- Nguyen G, Danser AH. Prorenin and (pro)renin receptor: a review of available data from in vitro studies and experimental models in rodents. Exp Physiol. 2008;93:557–563
- Holmer SR, Hengstenberg C, Mayer B, et al. Marked suppression of renin levels by beta-receptor blocker in patients treated with standard heart failure therapy: a potential mechanism of benefit from beta-blockade. J Intern Med. 2001;249:167–172
- Casetta B, Jans I, Billen J, et al. Development of a method for the quantification of 1alpha,25(OH)2-vitamin D3 in serum by liquid chromatography tandem mass spectrometry without derivatization. Eur J Mass Spectrom (Chichester, Eng). 2010;16:81–89
- Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911–1930
- Cranney A, Weiler HA, O'Donnell S, et al. Summary of evidence-based review on vitamin D efficacy and safety in relation to bone health. Am J Clin Nutr. 2008;88:513S–519S
- Schleithoff SS, Zittermann A, Tenderich G, et al. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2006;83:754–759
- Shedeed SA. Vitamin d supplementation in infants with chronic congestive heart failure. Pediatr Cardiol. 2012;33:713–719
- Thadhani R, Appelbaum E, Pritchett Y, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. JAMA. 2012;307:674–684
- Witham MD, Crighton LJ, Gillespie ND, et al. The effects of vitamin D supplementation on physical function and quality of life in older patients with heart failure: a randomized controlled trial. Circ Heart Fail. 2010;3:195–201
- Boxer RS, Kenny AM, Schmotzer BJ, et al. A randomized controlled trial of high-dose vitamin D3 in patients with heart failure. JCHF. 2013;1:84–90
- Elamin MB, Abu Elnour NO, Elamin KB, et al. Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96:1931–1942
- Wang L, Song Y, Manson JE, et al. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes. 2012;5:819–829
- Wood AD, Secombes KR, Thies F, et al. Vitamin D3 supplementation has no effect on conventional cardiovascular risk factors: a parallel-group, double-blind, placebo-controlled RCT. J Clin Endocrinol Metab. 2012;97:3557–3568
- 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. Diabet Med. 2008;25:320–325
- Overview Cardiovascular and vitamin D prevent and TREAT
- Magnesium prevents cardiovascular events – Meta-analysis March 2013
- Vitamin D reduces inflammation (heat shock protein) – Aug 2012
- Search for plasma renin activity in VitaminDWiki 20 items as of June 2013
- All items in Cardiovascular and Vitamin D