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Klaus Witte MD, FRCP, FACC, FESC On behalf of the VINDICATE investigators

Favourable effects of vitamin D on cardiac function in patients with chronic heart failure secondary to left ventricular systolic dysfunction – the results of the MRC-funded VINDICATE Study. Klaus Witte MD, FRCP, FACC, FESC On behalf of the VINDICATE investigators. 7-Dehydrocholesterol.

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Klaus Witte MD, FRCP, FACC, FESC On behalf of the VINDICATE investigators

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  1. Favourable effects of vitamin D on cardiac function in patients with chronic heart failure secondary to left ventricular systolic dysfunction – the results of the MRC-funded VINDICATE Study Klaus Witte MD, FRCP, FACC, FESC On behalf of the VINDICATE investigators

  2. 7-Dehydrocholesterol ↓IL-2, γIFN and TNF-α, ↑IL-4 and IL-10 production, ↓transplant rejection Promyelocyte to monocyte differentiation Improved cardiac contractility, ↑LVEF Circulating vitamin D3 Pancreatic islet cell insulin release 25-hydroxylase Increased muscle strength and reduced fall frequency -ve 25 (OH) vitamin D3 Vitamin D receptor 1-hydroxylase Vasodilatation -ve 1, 25 (OH)2 vitamin D3 Calciumabsorption, renin angiotensin suppression Parathyroid hormone (PTH) The pleiotropic effects of vitamin D and their potential importance in heart failure Inhibition of PTH release PTH Calciumabsorption Calciumabsorption Inhibited if dietary calcium sufficient Calcium loading, oxidative stress peripheral blood mononuclear cell activation Witte, Byrom, JACC HF 2014

  3. Medical Research Council - Developmental Clinical Studies: VINDICATE:VitamIN D treating patIents with Chronic heArT failurE VINDICATE Methods Population Inclusion criteria: 25-(OH) Vitamin D <50nmol/L (<20ng/mL) Stable CHF due to left ventricular systolic dysfunction (LVEF ≤ 45%) Optimal stable medical therapy (3 months) Ongoing symptoms (> NHYA class I) Exclusion criteria: Cognitive dysfunction Significant renal dysfunction (eGFR <30) Sarcoidosis, untreated tuberculosis Severe airways disease (FEV1 <50% predicted) CHF due to untreated valvular heart disease, anaemia or thyrotoxicosis Intervention Oral 100µg 25-OH vitamin D3or non-calcium placebo for 1 year Provided by Cultech Ltd, Port Talbot, Wales, UK Primary outcome Change in 6-minute walk distance (baseline – 12 months) Secondary outcomes Change in cardiac function (BL-12 months) Change in neurohormones, inflammatory markers Sample size Aim for 210 patients to complete (expected difference of 30m between the groups at 12 m (80% power, two sided) Registered on ClinicalTrials.gov as NCT01619891

  4. Medical Research Council - Developmental Clinical Studies: VINDICATE:VitamIN D treating patIents with Chronic heArT failurE VINDICATE Patient disposition Witte et al JACC 2016

  5. Medical Research Council - Developmental Clinical Studies: VINDICATE:VitamIN D treating patIents with Chronic heArT failurE VINDICATE Patient characteristics Witte et al JACC 2016

  6. Medical Research Council - Developmental Clinical Studies: VINDICATE:VitamIN D treating patIents with Chronic heArT failurE VINDICATE Baseline outcome variables Conversion factors: vitamin D nmol/L * 0.4 = ng/mL; creatinine mmol/L * 0.11 = mg/dL; calcium mmol/L * 4 = mg/dL; parathyroid hormone pmol/L * 9.4 = pg/mL. Witte et al JACC 2016

  7. Medical Research Council - Developmental Clinical Studies: VINDICATE:VitamIN D treating patIents with Chronic heArT failurE VINDICATE Safety measures • Vitamin D levels normalise rapidly • No adverse effects after 12 months on calcium or renal function • PTH levels normalised in most (ANCOVA between groups p<0.0001) Witte et al JACC 2016

  8. Medical Research Council - Developmental Clinical Studies: VINDICATE:VitamIN D treating patIents with Chronic heArT failurE VINDICATE Efficacy measures Primary efficacy outcome: No difference in change in 6-minute walk test distance Secondary efficacy outcomes: Evidence of advantageous LV remodelling on echocardiography: Reduction in dimensions Reduction in volumes Improvement in LV ejection fraction Witte et al JACC 2016

  9. Medical Research Council - Developmental Clinical Studies: VINDICATE:VitamIN D treating patIents with Chronic heArT failurE VINDICATE Conclusions • Vitamin D levels are low in most heart failure patients • One year of high-dose vitamin D3 supplementation is safe • One year of high-dose vitamin D3 leads to beneficial cardiac remodelling • Whether vitamin D3 improves outcomes should be the subject of future studies Witte et al JACC 2016

  10. Acknowledgements and collaborators Collaborators: Mark T Kearney, Julian H Barth, Sue Pavitt, David A Cairns, Graham R Law, John Greenwood, Sven Plein Research team: John Gierula, Rowenna Byrom, Maria F Paton, Sally Barnes, Judith E Lowry, Haqeel A Jamil, Hemant Chumun, Lorraine Falk, Andrea Marchant, Lisa Trueman Partners: Cultech, Port Talbot, Wales, UK Funders: Medical Research Council – DPFS grant MR/J00281X/1 Leeds Charitable Foundation British Medical Association

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