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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. Potential biological pathways for effects of vitamin D on the

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slide1

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

slide2

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

slide3

Soukoulis V, 2009

Lee JH, 2011

slide4

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

slide5

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

slide6

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

slide7

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

slide8

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

slide9

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

slide10

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

slide11

Prognostic Model for Testing Baseline Coenzyme Q10 as Risk Factor for Total Mortality

Step 1

Placebo

Rosuvastatin

McMurray JJV, JACC 2010

slide12

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

slide13

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

slide14

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

slide15

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

slide16

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

slide17

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

slide18

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

slide19

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

slide20

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

slide21

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