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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
cardiovascular system




TNF-a
IL-6
MMP
IL-10
 RAAS
 Sympathetic
nervous
system
activity
 Cardiorenal
syndrome
Reduction
(apoptosis,
fibrosis,
remodeling)
Pourdjabbar A, 2013
Beveridge LA, 2013
Soukoulis V, 2009
Lee JH, 2011
Micronutrient
Function
CoQ10
Carrier 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 - B6
Carbohydrate energy metabolism; beta-oxidation of lipids;
red blood cells production
Taurine
Antioxidant and important endogenous regulator of
intracellular 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
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
Baseline
8 weeks
P Value
Q-ter® + creatine
8.4 ± 7.4
7.7 ± 8.1
0.44
Placebo
9.1 ± 5.6
8.2 ± 6.3
0.09
Q-ter® + creatine
6.5 ± 5.1
5.1 ± 6.5
<0.01
Placebo
6.8 ± 6.4
5.9 ± 5.6
0.21
Q-ter® + creatine
7.8 ± 7.0
7.5 ± 7.3
0.78
Placebo
10.0 ± 8.6
9.0 ± 9.9
0.18
SIP total score
SIP physical score
SIP psychosocial score
Q-ter®: Coenzyme Q10 terclatrate; SIP: Sickness Impact Profile
Fumagalli S,
Clin Cardiol 2011
The effects of Q-ter® & Creatine on Peak VO2
p = 0.003
4
+ 3.6
p < 0.05
16
3
+ 7.5%
+ 10.4%
7.5%
14.4
14
+ 1.8
13.4
2
13.2
12.8
1
12
D Peak VO2 (mL/min/Kg)
Peak VO2 (mL/min/Kg)
18
+ 0.1
0
p = 0.108
baseline
Q-ter® + creatine
Placebo
0
8 weeks
Q-ter® + Creatine (320 / 340 mg) vs Placebo
Adjusted 8-week difference – confounder:
Peripheral Artery Disease
Fumagalli S,
Clin Cardiol 2011
Cumulative Proportion Surviving
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 CoQ10
requires selenium in the
form of the selenoprotein
TrxR1, which contains the
unique amino acid
selenocysteine (SeC) in its
active site
Multivariate
HR (95%CI):
Selenium + CoQ10
N=13/221 (5.9%)
Placebo
N=28/222 (12.6%)
0.46 (0.24-0.90), p=0.02
Time (days)
Follow-up (median): 1891 days
Alehagen U, 2013
D EF
Study
Pooled Mean Net Change (95% CI)
(I2 = 67.5%; p<0.001)
-10
0
Favors Placebo
Mean Net Change (95% CI)
+3.67%
(1.60, 5.74)
10
20
30
Favors CoQ10
Studies – N=13 (1985-2005)
Patients – N=395; Age: 50-68 years
EF: 22-46%; NYHA Class: II-III
CoQ10 dose: 60-300 mg
Fotino AD, 2013
The effects of Q-ter® & Creatine on Total Work Capacity
+ 784
3500
800
p = 0.46
3000
+ 10.4%
2500
400
2322
+ 212
2118
2000
2125
2013
0
1500
- 360
p = 0.06
0
baseline
Q-ter® + creatine
Placebo
D Total Work Capacity (Kg•m)
Total Work Capacity (Kg•m)
p = 0.04
-400
8 weeks
Q-ter® + creatine (320 / 340 mg) vs Placebo
Adjusted 8-week difference – confounder:
Diabetes
Fumagalli S,
Clin Cardiol 2011
Changes of Coenzyme Q10 Concentrations in Serum by Statins
in Human Studies
D Coenzyme Q10 concentration (%)
L L L P P P P S S S S S S S S S S S S A A A A A
40 40 80 40 20 40 40 80 20 20 40 20 20 20 20 05 20 20 20 10 20 80 40 10
0
-10
-7.7
-12.4
-20
-30
-18.8
-21.3
-19.4
-19.7
-22
-25.2
-25.5
-27.3
-27.7
-31.2
-28.8
-33.1
-40
-30.7
-32
-33.1
-39.6
-42.9
-45.8
-50
-51.2
-60
L = Lovastatin; P = Pravastatin;
S = Simvastatin; A = Atorvastatin
-50
5, 10, 20, 40, 80 = Highest dose (mg)
-48.5
-50.8
Mabuchi H,
Curr Drug Ther 2007
Ischemic HF (N=1191)
Age: 73 years; EF: 29%
[Plasma Coenzyme Q10 (mg/mL)]
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 = -0.25 mg/mL
P<0.0001
NMC = -0.27 mg/mL
P<0.0001
NMC = -0.35 mg/mL
P<0.0001
1.2
1.11 1.1
NMC = Net Median Change
0.93
0.8
0.73 0.75
0.7
0.58
0.53
0.48 0.49
0.4
0.46
0.35
0
Placebo
B
Rosuvastatin
3m
B
3m
B
3m
3 m = 3-Month Follow-up
McMurray JJV, JACC 2010
Prognostic Model for Testing Baseline Coenzyme Q10 as Risk
Factor for Total Mortality
Step 1
Placebo
Rosuvastatin
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
McMurray JJV, JACC 2010
Change in FMD with Placebo and CoQ10 (mean ± SEM)
Statin Tx patients - N=23
Age: 68 years; HbA1c: 6.9%;
LDL Cholesterol <100 mg/dL
8
P = 0.04
4
Change in % FMD
Change in FMD (%)
6
2
0
-2
-4
-6
Base: 2.2 ± 0.6 %
12 W: 2.1 ± 0.7 %
Base: 2.2 ± 0.7 %
12 W: 3.2 ± 0.5 %
-8
Placebo
Placebo
FMD: brachial artery Flow-Mediated
Dilatation (<5.5% as a marker of
endothelial dysfunction)
CoQ
Coenzyme
Q10
10
Base: Baseline, Pretreatment
12 W: 12 weeks, Treatment end
Hamilton SJ,
Diabetes Care 2009
Systemic lipid
peroxidation
(8)
(8)
(10)
(12)
Myocardium superoxide
generation
(10)
(9)
(8)
(8)
(10)
(12)
(10)
(9)
P<0.05
P<0.001
P<0.05 vs
db/+
Ramipril
P<0.001
P<0.05 vs
db/db
Untreated
MDA: Malondialdeyde
RLU: Relative Light Unit
CoQ10, Ramipril: 10-week Treatment
P<0.05 vs
db/db
Untreated
6-week old NON Diabetic (db/+) mice
6-week old Diabetic (db/db) mice
Huynh K,
Diabetologia 2012
P<0.001
P<0.05
vs db/db
Untreated
P<0.05
vs db/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
The Electron Transport Chain & the Electron Carrier Function of Q10
Cytosol
Mytochondrial outermembrane
Intermembrane space
Mytochondrial
innermembrane
Matrix
Coenzyme Q10
COMPLEX:
I
II
Substrates:
Malate,
glutamate,
pyruvate
Succinate
III
IV
V
Asc + TMPD
Asc: Ascorbate
TMPD: Tetramethyl-p-phenylenediamine
Larsen S, 2013
Larsen S, 2013
O2 flux (pmol/mg/s)
p<0.05
Maximal ex vivo
OXPHOS capacity
I
Controls (Tx: none)
N=9; Age: 45 years; BMI: 27 Kg/m2;
Cholesterol: 4.3 nmol/L; HbA1c: 5.2%
II
I+II
COMPLEX
COMPLEX IV O2 flux (pmol/mg/s)
Mitochondrial oxidative phosphorylation (OXPHOS) Capacity for
Complexes I, II, I + II, and IV
IV
Patients – Hypercholesterolemia (Tx:
simvastatin). N=10; Age: 45 years; BMI: 27
Kg/m2; Cholesterol: 4.8 nmol/L; HbA1c: 5.7%
*: p<0.05
Glucose AUC ((nmol/L)/min)
Glucose concentration (nmol/L)
Plasma Glucose Concentrations During the 120-min OGTT
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
1 nmol/L: 18 mg/dL
OGTT Time (min)
Controls (Tx: none)
N=9; Age: 45 years; BMI: 27 Kg/m2;
Cholesterol: 4.3 nmol/L; HbA1c: 5.2%
Glucose AUC
Patients – Hypercholesterolemia
(Tx: simvastatin)
N=10; Age: 45 years; BMI: 27 Kg/m2;
Cholesterol: 4.8 nmol/L; HbA1c: 5.7%
AUC: Area Under the Curve
Cholesterol
1 nmol/L: 39 mg/dL
Larsen S, 2013
• 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
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 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
D NYHA
Class
Study
Pooled Mean Net Change
(95% CI)
(I2 = 80.5%; p=NS)
-1.06
Favors CoQ10
Mean Net Change (95% CI)
-0.30
(-0.66, 0.06)
0
1.06
Favors Placebo
Fotino AD, 2013
P<0.05
P<0.05
P<0.05
vs db/db
Untreated
vs db/db
Untreated
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