Download Role of micronutrients.

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