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Acute Heart Failure: A New Paradigm Role of Micronutrients Professor John GF Cleland University of Hull Kingston-upon-Hull United Kingdom Conflict of Interest: I have received funding from NUMICO, a manufacturer of neutriceuticals Survival After Discharge for Patients Admitted with Heart Failure 0.00 0.50 0.25 0.50 0.75 0.75 1.00 1.00 National Audit England & Wales 2008-2009 0% 25% In-patient mortality Age <75 years – 5% Age >75 years – 16% 50% 25 0 90 180 270 Survival time (days post-discharge) Age 55-64 yrs Age 75-84 yrs Age 65-74 yrs Age >=85 yrs 360 What are Micronutrients? • Nutrients needed in small quantities (<~100µg/day) • Minerals: – Boron, Cobalt, Chloride, Chromium, Copper, Fluoride, Iodine, Iron, [Magnesium], Manganese, Molybdenum, Selenium, Zinc • Vitamins: – A, B1-12, Choline, C, D, E & K, – Carotenoids, Flavonoids & Lycopenes • Essential amino acids – Isoleucine, Leucine, (Arginine), Lysine, Methionine, [LCarnitine], (Cysteine), Phenylalanine, Threonine, (Glutamine), Tryptophan, (Glycine), Valine, (Proline), • Organic Acids and Carbohydrates – Acetic, Citric, Lactic, Malic Acids, Creatine, Taurine, Inositol • Co-enzyme Q10 • Essential Fatty Acids (Vitamin F) – ά-linolenic (Ω-3), Linoleic (Ω-6), PUFA, Lauric (saturated), and Palmitoleic (monosaturated), Arachidonic Acid Role of Micronutrients • Pathophysiology of Deficiency – Consequence of heart failure – Cause of heart failure • Therapy – Prevention – Physiological restoration – Pharmacological (supra-physiological) – Sniper (Silver-Bullet) – Shotgun – Blunderbuss Reasons for Micronutrient Deficiency in Heart Failure • Reduced Intake – Poor Diet • Quantity • Quality – Reduced absorption – Sunlight • Reduced Assimilation/Conversion – Statins block synthesis of endogenous Q10 – Aspirin may impair mitochondrial respiratory chain and conversion of arachidonic acid to vasodilator prostaglandins • Increased Wastage – Gut – Urine • Diuretics Micronutrients • Vasodilatation • Enhanced Energy Substrate • Improved Energy Utlilisation • Myocardial „Protection‟ • Reduction in Arrhythmias ↓IL-2, γIFN and TNF-α, ↑IL-4 and IL-10 production, ↓transplant rejection 7-Dehydrocholesterol 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 Calcium absorption, renin angiotensin suppression Parathyroid hormone (PTH) The pleiotropic effects of vitamin D and their potential importance in heart failure Inhibition of PTH release Calcium absorption Inhibited if dietary calcium sufficient PTH Calcium absorption Calcium loading, oxidative stress peripheral blood mononuclear cell activation Sir John Hunter The „Father‟ of Modern Scientific Medicine “But why think, why not try the experiment?” Conclusion of a letter to Edward Jenner (leading to the discovery of vaccination for smallpox) 2nd August 1775 Wet Beri-Beri • Discovery of Thiamine – Takaki Kanehiro 1884 – Japanese Naval Cadets – 1890-1930: Christiaan Eijkman, Sir Frederick Hopkins, Casimir Funk • Pathophyiology – Vasodilation – High output heart failure – Peripheral oedema • Treatment – Intravenous replacement • Only available preparation in UK is Pabrinex - 250mg of thiamine & Vitamin C, Nicotinamide, Pyridoxine and Riboflavin. – Improvement with hours – But vasoconstriction in the presence of primary cardiac disorder can lead to paradoxical exacerbation • Thiamine deficiency in 33% of those admitted with worsening CHF (v 12% in controls (p =0.007). • Thiamine deficiency was related to – Urine thiamine loss – Lack of thiamine supplements Thiamine for the treatment of acute decompensated heart failure. Smithline HA. Am J Emerg Med 2007;25:124–6 CORONA (Rosuvastatin v Placebo in Chronic Heart Failure with Reduced LVEF) Outcome According to Tertiles of Plasma Co-enzyme Q10 Lowest Chronic Supplementation in Chronic HF • Co-enzyme Q10 – Morisco et al 1993 – 642 patients followed for one year – HF Hospitalisation (n = 73 v 118, P < 0.001). Chronic Supplementation in Chronic HF L-Carnitine & Propionyl-L-Carnitine • CEDIM Trial – 2,330 patients post-MI (stopped due to low event rate) – HR = 0.61, 95% CI 0.37–0.98, p = 0.041 – Improved LV remodelling • Ferrari EHJ 1999 Circulation. 1994;89: 660-666 RCTs of Chronic Supplementation in Chronic HF • • • • • • • • Creatine Arginine D-Ribose Iron Vitamin C Folic Acid PUFA Multi-nutrient What would A Study of Micronutrients in AHFS Look Like? • Haemodynamics? • Symptoms? – speed or completeness of resolution) • Short-term prognosis? • Starting point of a long-term outcome trial? • Interventions – Increase availability and utilisation of carbohydrates rather than fatty acids • Prevent cellular acidosis – – – – Improve mitochondrial function & ATP production Improve calcium handling Off-load the failing heart Reduce arrhythmias