Nutrizione e metabolismo: due facce dello stesso problema

1. Nutrizione e metabolismo: due facce dello stesso problema Nutrition and metabolism: two sides of the same problem Stefano Fumagalli – SOD Cardiologia e Medicina Geriatrica, AOU Careggi e Università di Firenze

2. Potential biological pathways for effects of vitamin D on the cardiovascular system • RAAS • Sympatheticnervoussystemactivity • Cardiorenalsyndrome • TNF-a • IL-6 • MMP • IL-10 • (apoptosis, fibrosis, remodeling) Reduction Beveridge LA, 2013 Pourdjabbar A, 2013

3. Soukoulis V, 2009 Lee JH, 2011

4. Q-ter® + Creatine - N=35 Age: 72 y; EF: 30%; NYHA II: 89% Placebo -N=32; Age: 71 y; EF: 31%; NYHA II: 94% The effects of Q-ter®& Creatine (320 / 340 mg) on Health Related Quality of Life Q-ter®: Coenzyme Q10terclatrate; SIP: Sickness Impact Profile Fumagalli S, ClinCardiol2011

5. Q-ter® + creatine Placebo The effects of Q-ter® & Creatineon Peak VO2 p = 0.003 4 18 18 + 3.6 p < 0.05 3 16 16 + 7.5% + 7.5% + 10.4% 14.4 2 DPeak VO2 (mL/min/Kg) Peak VO2 (mL/min/Kg) 14 14 + 1.8 13.4 13.2 12.8 1 12 12 + 0.1 p = 0.108 p = 0.108 0 0 0 baseline baseline 8 weeks 8 weeks Q-ter® + Creatine (320 / 340 mg) vs Placebo Adjusted 8-week difference – confounder: Peripheral Artery Disease Fumagalli S, ClinCardiol2011

6. Cardiovascular mortality among individuals on Selenium + CoQ10 versus individuals on placebo (a KM analysis of a rural elderly population) Selenium + CoQ10(200 mg / 200 mg)N=221; Age: 78 years Placebo N=222; Age: 78 years Regeneration of CoQ10requiresselenium in the form of the selenoprotein TrxR1, which contains the unique amino acid selenocysteine(SeC) in its active site Selenium + CoQ10 N=13/221 (5.9%) Cumulative Proportion Surviving Placebo N=28/222 (12.6%) MultivariateHR(95%CI): 0.46 (0.24-0.90), p=0.02 Time (days) Follow-up (median): 1891 days Alehagen U, 2013

7. D EF Study Mean Net Change (95% CI) Pooled Mean Net Change (95% CI) (I2 = 67.5%; p<0.001) Studies – N=13 (1985-2005) Patients – N=395; Age: 50-68 years EF: 22-46%; NYHA Class: II-III CoQ10 dose: 60-300 mg +3.67% (1.60, 5.74) -10 0 10 20 30 Favors Placebo Favors CoQ10 Fotino AD, 2013

8. Q-ter® + creatine Placebo The effects of Q-ter® & Creatineon Total Work Capacity p = 0.04 + 784 3500 3500 800 p = 0.46 3000 3000 + 10.4% 400 2322 2500 2500 + 212 D Total Work Capacity (Kg•m) Total Work Capacity (Kg•m) 2118 2125 2000 2000 2013 0 1500 1500 - 360 p = 0.06 p = 0.06 -400 0 0 baseline baseline 8 weeks 8 weeks Q-ter® + creatine(320 / 340 mg) vsPlacebo Adjusted 8-week difference – confounder: Diabetes Fumagalli S, ClinCardiol2011

9. Changes of Coenzyme Q10 Concentrations in Serum by Statins in Human Studies D Coenzyme Q10 concentration (%) L = Lovastatin; P = Pravastatin; S = Simvastatin; A = Atorvastatin 5, 10, 20, 40, 80 = Highest dose (mg) Mabuchi H, Curr Drug Ther 2007

10. Ischemic HF (N=1191) Age: 73 years; EF: 29% Baseline and 3-Month Follow-up Values for Coenzyme Q10 Tertile 1 – CoQ10: 0.49 mg/mL (N = 400) Tertile 2 – CoQ10: 0.74 mg/mL (N = 387) Tertile 3 – CoQ10: 1.10 mg/mL (N = 404) NMC= -0.25mg/mL P<0.0001 NMC = -0.27mg/mL P<0.0001 NMC = -0.35mg/mL P<0.0001 NMC = Net Median Change [Plasma Coenzyme Q10 (mg/mL)] Placebo 3 m = 3-Month Follow-up Rosuvastatin McMurray JJV, JACC 2010

11. Prognostic Model for Testing Baseline Coenzyme Q10 as Risk Factor for Total Mortality Step 1 Placebo Rosuvastatin McMurray JJV, JACC 2010

12. Statin Tx patients - N=23 Age: 68 years; HbA1c: 6.9%; LDL Cholesterol <100 mg/dL Change in FMD with Placebo and CoQ10(mean ± SEM) P = 0.04 Change in FMD (%) Base:2.2 ± 0.6 % 12 W:2.1± 0.7 % Base:2.2 ± 0.7 % 12 W:3.2± 0.5 % Placebo Coenzyme Q10 FMD: brachial artery Flow-Mediated Dilatation (<5.5% as a marker of endothelial dysfunction) Base: Baseline, Pretreatment 12 W: 12 weeks, Treatment end Hamilton SJ, Diabetes Care 2009

13. Systemic lipid peroxidation Myocardium superoxide generation (10) (9) (10) (9) (8) (8) (10) (8) (12) (8) (10) (12) P<0.05 P<0.001 P<0.05 vsdb/+ Ramipril P<0.001 P<0.05vsdb/db Untreated P<0.05vsdb/db Untreated MDA:Malondialdeyde RLU: Relative Light Unit CoQ10, Ramipril: 10-week Treatment 6-week old NON Diabetic (db/+) mice 6-week old Diabetic (db/db) mice Huynh K, Diabetologia 2012

14. P<0.001 P<0.05vsdb/db Untreated P<0.05vsdb/db Untreated 6-week old NON Diabetic (db/+) mice 6-week old Diabetic (db/db) mice CoQ10, Ramipril: 10-week Treatment Huynh K, Diabetologia 2012

15. The Electron Transport Chain & the Electron Carrier Function of Q10 Cytosol Mytochondrial outermembrane Intermembrane space Mytochondrial innermembrane Matrix Coenzyme Q10 COMPLEX: I II III IV V Substrates: Malate, glutamate, pyruvate Succinate Asc + TMPD Asc: Ascorbate TMPD: Tetramethyl-p-phenylenediamine Larsen S, 2013

16. Larsen S, 2013 Mitochondrial oxidative phosphorylation (OXPHOS) Capacity for Complexes I, II, I + II, and IV p<0.05 Maximal ex vivo OXPHOS capacity COMPLEX IV O2 flux (pmol/mg/s) O2 flux (pmol/mg/s) I II I+II IV Controls (Tx: none) N=9; Age: 45 years; BMI: 27 Kg/m2; Cholesterol: 4.3 nmol/L; HbA1c: 5.2% Patients – Hypercholesterolemia (Tx: simvastatin). N=10; Age: 45 years; BMI: 27 Kg/m2; Cholesterol: 4.8 nmol/L; HbA1c: 5.7% COMPLEX

17. Plasma Glucose Concentrations During the 120-min OGTT *: p<0.05 Uncoupling protein 3 (UCP3)has been suggested to protect the mitochondria against an accumulation of nonesterified fatty acids, which, with ceramides and diacylglycerol, in the cytosolic compartment are linked to insulin resistance Glucose concentration (nmol/L) Glucose AUC ((nmol/L)/min) 1 nmol/L: 18 mg/dL Glucose AUC AUC: Area Under the Curve OGTT Time (min) Cholesterol 1 nmol/L: 39 mg/dL Controls (Tx: none) N=9; Age: 45 years; BMI: 27 Kg/m2; Cholesterol: 4.3 nmol/L; HbA1c: 5.2% Patients – Hypercholesterolemia (Tx: simvastatin) N=10; Age: 45 years; BMI: 27 Kg/m2; Cholesterol: 4.8 nmol/L; HbA1c: 5.7% Larsen S, 2013

18. All putative biomarkers should be examined as to whether they are simply associatedwith greater disease severity (“markers”) or, alternatively, play an important mechanistic role in the disease of interest (“mediators”) • Coenzyme Q10 appears to be a marker, and generally only mediators make intuitive sense as targets for intervention 2010

19. 2013 • HF has a multifactorial pathogenesis: peripheral circulatory insufficiency, autonomic imbalance, activation of RAAS, inflammation, oxidative stress, immune system activation, and insulin resistance are intertwined in a complex manner • The resulting metabolic abnormalities can be linked to long-term myocardial dysfunction • These metabolic processes have been shown to affect other organs (i.e. skeletal muscle, leading to fatigue and physical dysfunction) • Metabolic diseases such as anemia, diabetes mellitus, renal dysfunction, and cardiac cachexia greatly influence the prognosisof HF • Therefore, nutrition has recently been considered to be a new therapeutic target for HF Malnutrition, a lack of micronutrients, sodium restriction and fluid management are considered to be critical factors in patients with HF, particularly the elderly or patients with severe HF

20. DNYHA Class Study Mean Net Change (95% CI) -0.30 (-0.66, 0.06) Pooled Mean Net Change (95% CI) (I2 = 80.5%; p=NS) -1.06 0 1.06 Favors CoQ10 Favors Placebo Fotino AD, 2013

21. P<0.05vsdb/db Untreated P<0.05vsdb/db Untreated P<0.05 6-week old NON Diabetic (db/+) mice 6-week old Diabetic (db/db) mice CoQ10, Ramipril: 10-week Treatment The cell survival kinase Akt (Protein Kinase B), a downstream target of the IGF1 receptor–phosphoinositide-3 kinase p110α isoform pathway, is an important mediator of physiological heart growth Huynh K, Diabetologia 2012