Nutrizione e metabolismo: due facce dello stesso problemaNutrition and metabolism: two sides of the same problemStefano Fumagalli – SOD Cardiologia e Medicina Geriatrica, AOU Careggi e Università di Firenze

Potential biological pathways for effects of vitamin D on thecardiovascular system

RAAS Sympathetic

nervous system activity

Cardiorenal syndrome TNF-a

IL-6 MMP IL-10 (apoptosis, fibrosis, remodeling)

Reduction

Beveridge LA, 2013Pourdjabbar A, 2013

Micronutrient Function

CoQ10Carrier for electrons … essential role in ATP formation. CoQ10 also functions as an antioxidant

L-Carnitine Fatty acid transport into the mitochondria; it improves glycolysis, glucose oxidation coupling and Krebs cycle

Thiamine (B1) Carbohydrate metabolism. Thiamine deficiency results in ATP production and cellular acidosis

Riboflavin - B2,Pyridoxine - B6Carbohydrate energy metabolism; beta-oxidation of lipids; red blood cells production

Taurine Antioxidant and important endogenous regulator ofintracellular calcium homeostasis

Creatine Energy metabolism regulator in all muscles. Mitochondrial energy of ATP is transferred to phosphocreatine

Magnesium & Potassium Deficiencies primarily related to arrhythmias

Zinc, Selenium Antioxidants

Soukoulis V, 2009 Lee JH, 2011

Baseline 8 weeks P Value

SIP total score

Q-ter® + creatine 8.4 ± 7.4 7.7 ± 8.1 0.44

Placebo 9.1 ± 5.6 8.2 ± 6.3 0.09

SIP physical score

Q-ter® + creatine 6.5 ± 5.1 5.1 ± 6.5 <0.01

Placebo 6.8 ± 6.4 5.9 ± 5.6 0.21

SIP psychosocial score

Q-ter® + creatine 7.8 ± 7.0 7.5 ± 7.3 0.78

Placebo 10.0 ± 8.6 9.0 ± 9.9 0.18

Q-ter®: Coenzyme Q10 terclatrate; SIP: Sickness Impact Profile

The effects of Q-ter® & Creatine (320 / 340 mg) on Health Related Quality of Life

Fumagalli S,Clin Cardiol 2011

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 on Peak VO2

Q-ter® + creatine

+ 10.4%

Placebo

8 weeksbaseline

+ 7.5%

0

12

14

16

18

p = 0.108

8 weeksbaseline

+ 7.5%

0

12

14

16

18

p = 0.108

1

2

3

4

0

+ 3.6

+ 0.1

Pea

k V

O2

(mL/

min

/Kg)

D P

eak

VO

2 (m

L/m

in/K

g)

p < 0.05

+ 1.8

12.8

13.4

13.2

14.4

p = 0.003

Q-ter® + Creatine (320 / 340 mg) vs PlaceboAdjusted 8-week difference – confounder: Peripheral Artery Disease

Fumagalli S,Clin Cardiol 2011

Cu

mu

lati

ve P

rop

ort

ion

Su

rviv

ing

Time (days)

Selenium + CoQ10

N=13/221 (5.9%)

PlaceboN=28/222 (12.6%)

Multivariate HR (95%CI): 0.46 (0.24-0.90), p=0.02

Selenium + CoQ10 (200 mg / 200

mg) N=221; Age: 78 years

PlaceboN=222; Age: 78 years

Follow-up (median): 1891 days

Cardiovascular mortality among individuals on Selenium + CoQ10 versus individuals on placebo (a KM analysis of a rural elderly population)

Alehagen U, 2013

Regeneration of CoQ10 requires selenium in the form of the selenoprotein TrxR1, which contains the unique amino acid selenocysteine (SeC) in its active site

Study Mean Net Change (95% CI)

-10 300 10 20Favors Placebo Favors CoQ10

Pooled Mean Net Change (95% CI)(I2 = 67.5%; p<0.001)

+3.67%(1.60, 5.74)

D EF

Studies – N=13 (1985-2005)Patients – N=395; Age: 50-68 yearsEF: 22-46%; NYHA Class: II-IIICoQ10 dose: 60-300 mg

Fotino AD, 2013

baseline 8 weeks0

1500

2000

2500

3000

3500

p = 0.06

baseline 8 weeks0

1500

2000

2500

3000

3500

p = 0.04

p = 0.06

Tota

l W

ork

Cap

acit

y (K

g•m

)

Q-ter® + creatine

Placebo

Q-ter® + creatine (320 / 340 mg) vs PlaceboAdjusted 8-week difference – confounder: Diabetes

0

400

800

-400

+ 784

- 360 D T

ota

l W

ork

Cap

acit

y (K

g•m

)

p = 0.46

+ 212

2013

2118

2125

2322

+ 10.4%

The effects of Q-ter® & Creatine on Total Work Capacity

Fumagalli S,Clin Cardiol 2011

L 40

L 40

L 80

P 40

P 20

P 40

P 40

S 80

S 20

S 20

S 40

S 20

S 20

S 20

S 20

S 05

S 20

S 20

S 20

A 10

A 20

A 80

A 40

A 10

-60

-50

-40

-30

-20

-10

0

-18.8-21.3

-28.8

-33.1

-51.2

-19.7

-45.8

-39.6

-50

-27.7-25.2

-31.2

-27.3-25.5

-19.4

-30.7

-22

-32

-12.4

-7.7

-48.5-50.8

-33.1

-42.9

D C

oenz

yme

Q10

con

cent

ratio

n (%

)

Changes of Coenzyme Q10 Concentrations in Serum by Statins in Human Studies

L = Lovastatin; P = Pravastatin;S = Simvastatin; A = Atorvastatin

5, 10, 20, 40, 80 = Highest dose (mg)

Mabuchi H,Curr Drug Ther 2007

B 3 m B 3 m B 3 m0

0.4

0.8

1.2

0.48

0.58

0.73 0.7

1.11

0.93

0.49

0.35

0.75

0.46

1.1

0.53

[Pla

sma

Coe

nzym

e Q

10 (m

g/m

L)]

NMC = -0.25 mg/mLP<0.0001

NMC = -0.27 mg/mLP<0.0001

NMC = -0.35 mg/mLP<0.0001

NMC = Net Median Change

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)

3 m = 3-Month Follow-up

Placebo

Rosuvastatin

Baseline and 3-Month Follow-up Values for Coenzyme Q10

McMurray JJV, JACC 2010

Ischemic HF (N=1191)Age: 73 years; EF: 29%

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

McMurray JJV, JACC 2010

HR P Value HR P Value

EF*100 0.96 <0.001 0.96 0.002

NYHA Class 1.99 <0.001 1.37 NS

Age / 10 years 1.57 0.003 1.75 <0.001

BMI, Kg/m2 0.97 NS 0.95 NS

Diabetes 1.34 NS 1.57 0.040

Female sex 0.76 NS 0.49 0.011

Intermittent Claudication 1.21 NS 1.10 NS

HR / 10 b / min 1.05 NS 1.09 NS

CoQ10, mg/mL 0.86 NS 0.55 0.039

Placebo RosuvastatinStep 1

-8

-6

-4

-2

0

2

4

6

8

Ch

an

ge

in %

FM

DC

han

ge

in F

MD

(%

)

Placebo Coenzyme Q10

Base: 2.2 ± 0.6 %12 W: 2.1 ± 0.7 %

Base: 2.2 ± 0.7 %12 W: 3.2 ± 0.5 %

P = 0.04

FMD: brachial artery Flow-Mediated Dilatation (<5.5% as a marker of endothelial dysfunction)

Base: Baseline, Pretreatment12 W: 12 weeks, Treatment end

Change in FMD with Placebo and CoQ10 (mean ± SEM)Statin Tx patients - N=23Age: 68 years; HbA1c: 6.9%;LDL Cholesterol <100 mg/dL

Hamilton SJ,Diabetes Care 2009

Systemic lipid peroxidation

Myocardium superoxide generation

P<0.05P<0.001

P<0.001P<0.05 vs

db/db UntreatedP<0.05 vs

db/db Untreated

P<0.05 vs db/+

Ramipril

MDA: MalondialdeydeRLU: Relative Light UnitCoQ10, Ramipril: 10-week Treatment

6-week old NON Diabetic (db/+) mice6-week old Diabetic (db/db) mice

Huynh K,Diabetologia 2012

(8) (8) (10) (12) (10) (9) (8) (8) (10) (12) (10) (9)

CoQ10, Ramipril: 10-week Treatment

6-week old NON Diabetic (db/+) mice6-week old Diabetic (db/db) mice

P<0.001

P<0.05 vs db/db

UntreatedP<0.05 vs db/db

Untreated

Huynh K,Diabetologia 2012

Cytosol

Mytochondrial outermembrane

Intermembrane space

Mytochondrial innermembrane

Matrix

COMPLEX: I II III IV V

Substrates: Malate, glutamate, pyruvate

Succinate Asc + TMPD

Coenzyme Q10

Asc: AscorbateTMPD: Tetramethyl-p-phenylenediamine

The Electron Transport Chain & the Electron Carrier Function of Q10

Larsen S, 2013

p<0.05

Maximal ex vivo OXPHOS capacity

Mitochondrial oxidative phosphorylation (OXPHOS) Capacity for Complexes I, II, I + II, and IV

Larsen S, 2013

O2

flu

x (p

mo

l/m

g/s

)

COMPLEX

I II I+II IV

CO

MP

LE

X I

V O

2 fl

ux

(pm

ol/

mg

/s)

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%

*: p<0.05

1 nmol/L: 18 mg/dL

AUC: Area Under the Curve

Plasma Glucose Concentrations During the 120-min OGTT

Larsen S, 2013

Glu

cose

co

nce

ntr

atio

n (

nm

ol/

L)

OGTT Time (min)Glucose AUC

Glu

cose

AU

C (

(nm

ol/

L)/

min

)

Controls (Tx: none)N=9; Age: 45 years; BMI: 27 Kg/m2; Cholesterol: 4.3 nmol/L; HbA1c: 5.2%

Cholesterol1 nmol/L: 39 mg/dL

Patients – Hypercholesterolemia (Tx: simvastatin)N=10; Age: 45 years; BMI: 27 Kg/m2; Cholesterol: 4.8 nmol/L; HbA1c: 5.7%

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

• All putative biomarkers should be examined as to whether they are simply associated with 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

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 prognosis of 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

2013

Study Mean Net Change (95% CI)

-1.06 1.060

Favors CoQ10 Favors Placebo

Pooled Mean Net Change (95% CI)(I2 = 80.5%; p=NS)

-0.30(-0.66, 0.06)

D NYHA Class

Fotino AD, 2013

CoQ10, Ramipril: 10-week Treatment

6-week old NON Diabetic (db/+) mice6-week old Diabetic (db/db) mice

P<0.05P<0.05 vs db/db

Untreated

P<0.05 vs db/db

Untreated

Huynh K,Diabetologia 2012

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