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 ↓ IL-2, γ IFN and TNF- α , ↑ IL-4 and Promyelocyte to IL-10 production, monocyte Improved cardiac ↓ transplant differentiation contractility, ↑ LVEF rejection Circulating vitamin D 3 Pancreatic islet cell insulin release 25-hydroxylase Increased muscle -ve strength and reduced fall 25 (OH) vitamin D 3 frequency Vitamin D receptor 1-hydroxylase Vasodilatation -ve 1, 25 (OH)2 vitamin D 3 Calcium absorption, renin angiotensin suppression Parathyroid hormone (PTH) The pleiotropic effects Inhibition of PTH PTH release of vitamin D and their Calcium absorption potential importance in Calcium heart failure Inhibited if absorption dietary Calcium loading, calcium oxidative stress sufficient peripheral blood mononuclear cell activation Witte, Byrom, JACC HF 2014
VINDICATE Medical Research Council - Developmental Clinical Studies: VINDICATE: V itam IN D treating pat I ents with Chronic he A r T failur E Methods Popula'on Interven'on Oral 100µg 25-OH vitamin D 3 or non-calcium Inclusion criteria: placebo for 1 year 25-(OH) Vitamin D <50nmol/L (<20ng/mL) Provided by Cultech Ltd, Port Talbot, Wales, UK Stable CHF due to leF ventricular systolic Primary outcome dysfunc'on (LVEF ≤ 45%) Op'mal stable medical therapy (3 months) Change in 6-minute walk distance (baseline – 12 Ongoing symptoms (> NHYA class I) months) Secondary outcomes Exclusion criteria: Cogni've dysfunc'on Change in cardiac func'on (BL-12 months) Significant renal dysfunc'on (eGFR <30) Change in neurohormones, inflammatory markers Sarcoidosis, untreated tuberculosis Sample size Severe airways disease (FEV1 <50% Aim for 210 pa'ents to complete predicted) (expected difference of 30m between the CHF due to untreated valvular heart groups at 12 m (80% power, two sided) disease, anaemia or thyrotoxicosis Registered on ClinicalTrials.gov as NCT01619891
VINDICATE Medical Research Council - Developmental Clinical Studies: VINDICATE: V itam IN D treating pat I ents with Chronic he A r T failur E Pa'ent disposi'on Witte et al JACC 2016
VINDICATE Medical Research Council - Developmental Clinical Studies: VINDICATE: V itam IN D treating pat I ents with Chronic he A r T failur E Pa'ent characteris'cs Total (n=163) Placebo (n=83) Vitamin D (n=80) Male sex (n)[%] 129 [79.1] 62 [74.7] 67 [83.8] Age 68.7 (13.10) 69.0 (13.78) 68.5 (12.45) Caucasian (n)[%] 146 [90] 74 [89] 72 [90] AeEology (n)[%] Ischaemic heart disease 94 [57.7] 50 [60.2] 44 [55.0] Non-ischaemic CDM 61 [37.4] 29 [34.9) 32 [40.0) Valvular heart disease 8 [4.9] 4 [4.8] 4 [5.0] Diabetes mellitus (n)[%] 37 [22.7] 20 [24.1] 17 [21.3] BMI (Kg/m 2 ) 30.0 (11.41) 30.3 (14.36) 29.8 (7.26) NYHA II (n)[%] 145 [89] 71 [85.5] 74 [92.5] Beta blockers (n)[%] 155 [95.1] 79 [95.2] 76 [95.0] ACEi/ARB (n)[%] 150 [92.0] 76 [91.6] 74 [92.5] Furosemide dose (mg/day) 61.4 (46.38) 64.4 (52.07) 58.6 (41.00) Digoxin (n)[%] 29 [18.0] 15 [18.3] 14 [17.7] Spironolactone (n)[%] 83 [51.2] 41 [50.0] 42 [52.5] Device (ICD or CRT) (n)[%] 48 [29.5] 27 [32.5] 21 [26.3] Atrial fibrillaEon (n)[%] 68 [45.0] 33 [42.9] 35 [47.3] Baseline heart rate 70.5 (13.10) 72.7 (14.72) 68.2 (10.86) Systolic BP (mmHg) 120.3 (20.81) 122.9 (22.44) 117.6 (18.74) Diastolic BP (mmHg) 71.2 (13.21) 72.8 (14.96) 70.0 (10.99) Witte et al JACC 2016
VINDICATE Medical Research Council - Developmental Clinical Studies: VINDICATE: V itam IN D treating pat I ents with Chronic he A r T failur E Baseline outcome variables Total (n=163) Placebo (n=83) Vitamin D (n=80) 6 Minute walk test 292.9 (120.35) 283.7 (116.84) 302.2 (123.81) LVEF (%) 26.1 (10.68) 26.5 (10.62) 25.6 (10.80) LVEDD (mm) 57.8 (7.58) 58.0 (6.49) 57.6 (8.62) LVESD (mm) 50.3 (8.50) 50.7 (7.58) 49.8 (9.42) LVEDV (mls) 163.0 (66.60) 164.1 (60.07) 161.8 (73.58) LVESV (mls) 115.4 (59.39) 119.4 (53.30) 111.0 (63.58) 25(OH) Vitamin D (nmol/L) 37.3 (22.56) 36.4 (20.24) 38.2 (24.81) Parathyroid hormone (pmol/L) 11.4 (8.09) 11.7 (7.50) 11.0 (8.75) CreaEnine (μmol/L) 96 (29.3) 94.4 (29.42) 96.6 (29.26) 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
VINDICATE Medical Research Council - Developmental Clinical Studies: VINDICATE: V itam IN D treating pat I ents with Chronic he A r T failur E Safety measures • Vitamin D levels normalise rapidly • No adverse effects aFer 12 months on calcium or renal func'on • PTH levels normalised in most (ANCOVA between groups p<0.0001) Witte et al JACC 2016
VINDICATE Medical Research Council - Developmental Clinical Studies: VINDICATE: V itam IN D treating pat I ents with Chronic he A r T failur E 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: Reduc'on in dimensions Reduc'on in volumes Improvement in LV ejec'on frac'on Ancova Endpoint Difference in mean change p-value Six minute walk distance (m) -24.11 [-65.81, 17.60] 0.255 LVEF (%) 6.07 [3.20, 8.94] <0.001 LVEDD (mm) -2.49 [-4.09, -0.90] 0.002 LVESD (mm) -2.09 [-4.11, -0.06] 0.043 LVEDV (mls) -13.11 [-25.63, -0.60] 0.040 LVESV (mls) -12.65 [-24.76, -0.54] 0.041 Witte et al JACC 2016
VINDICATE Medical Research Council - Developmental Clinical Studies: VINDICATE: V itam IN D treating pat I ents with Chronic he A r T failur E Conclusions – Vitamin D levels are low in most heart failure pa'ents – One year of high-dose vitamin D3 supplementa'on 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
Acknowledgements and collaborators Collaborators: Mark T Kearney, Julian H Barth, Sue Paviq, 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 Founda'on Bri'sh Medical Associa'on
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