Post on 05-May-2019
Giuseppe M.C. Rosano, MD, PhD
Cardiovascular and Cell Sciences Research Institute,
St George's University of London
Dept of Medical Sciences
IRCCS San Raffaele - Roma
Metabolic approach to heart failure
Normal
Asymptomatic LV
Dysfunction
Compensated CHF
Decompensated CHF
Refractory CHF
Evolution of Clinical Stages
No symptoms
Normal exercise
Normal LV fxn
No symptoms
Normal exercise
Abnormal LV fxn
Symptoms not controlled
with treatment
Ischemic Heart Failure
Symptoms
Exercise
Abnormal LV fxn
No symptoms
Exercise
Abnormal LV fxn
Ischemic Events
Progression of CAD
Chronic Hypoperfusion
Myocardial Metabolism at Rest
Boucher F.R. J Cardiovasc Pharmacol. 1994; 24:45–49
Glucose
40%
Free fatty acids
60%
Glycolysis
ATP
Acetyl CoA
ATP (contractile work)
O2
Cytosol
Mitochondria
ATP/O2 = 6.3 ATP/O2 = 5.6
Carbohydrate
oxidation
Piruvate
ß-oxidation
Fatty acyl CoA
Myocardial Metabolism During Increased
Demands
Boucher F.R. J Cardiovasc Pharmacol. 1994; 24:45–49
Glucose
70% Free fatty acids
30%
Glycolysis
ATP
Acetyl CoA
ATP (contractile work)
O2
Cytosol
Mitochondria
ATP/O2 = 6.3 ATP/O2 = 5.6
Carbohydrate
oxidation
Piruvate
ß-oxidation
Fatty acyl CoA
Acetyl CoA
Glucose
Pyruvate
Glycolysis
Pyruvate Dehydrogenase
Fatty Acids
ß-Oxidation Spiral
Acetyl CoA
Contractile
Function
Electron
Transport
Chain
ADP ATP
Glycolysis
Glucose
Oxidation
Fatty
Acid
Oxidation
Lactate
O2 H2O
ATP
ADP
Hyperinsulinemia
Diabetes
Kreb’s
Cycle
Glucose
Uptake
FFA
Uptake
Acetyl CoA
Glucose
Pyruvate
Glycolysis
Pyruvate Dehydrogenase
Fatty Acids
ß-Oxidation Spiral
Acetyl CoA
Contractile
Function
Electron
Transport
Chain
ADP ATP
Glycolysis
Glucose
Oxidation
Fatty
Acid
Oxidation
Lactate
O2 H2O
ATP
ADP
Ischemia
Kreb’s
Cycle
Impaired capacity for glucose uptake and glycolysis
Decrease in carbohydrate oxidation
Increased FFA oxidation
Metabolic changes in Diabetes, Ischemia,
LV dysfunction
Glucose Free fatty acids
Glycolysis
Acetyl CoA
ATP (contractile work)
O2
Cytosol
Mitochondria
Carbohydrate
oxidation
Piruvate
ß-oxidation
Fatty acyl CoA
H+ H+
Ca2+ Ca2+
Cell acidosis Lactate
Membrane damage
Metabolic Changes in Chronic
Ischemia and Diabetes Leading to HF
ATP Production
Ca Sarcoplasmic Uptake Ca availability for
acto-myosin interaction
Diastolic HF Systolic HF
Hypertension Ischemia Chronic hypoperfusion
ATP Reserve
Subclinical impairment
of diastole
Subclinical impairment
of systole
Herrero P et al JACC 2006, 47 (3)
Increased myocardial FFA metabolism in diabetics
Myocardium
Extraction
Glucose FFA
Utilization
ND
DM
0.12
0.10
0.08
0.06
0.04
0.02
0.00
0.12
0.10
0.08
0.06
0.04
0.02
0.00
ND
DM
700
500
400
300
200
100
0
600
ND DM
0.40
0.30
0.20
0.10
0.00
0.50
ND
DM
400
300
200
100
0
Extraction Utilization (nmol/g/min) (nmol/g/min)
Plasma
70.0
60.0
50.0
40.0
30.0
20.0
10.0
0.0
ND DM
Insulin
(µU/ml)
8.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
7.0
ND DM
Glucose
(µmol/mL)
1.2
1.0
0.8
0.6
0.4
0.2
0.0
ND DM
Lactate
(µmol/mL)
FFA
(µmol/mL)
ND DM
1.0
0.7
0.5
0.4
0.3
0.2
0.1
0.0
0.8
0.9
0.6
J Am Coll Cardiol 2003; 42:328-35
Diastolic Dysfunction Is Associated With Altered Myocardial Metabolism in Asymptomatic Normotensive Patients With Well-Controlled Type 2 Diabetes Mellitus
20 0 -30 ppm
PCr/ATP=1.60
2,3-DPG + Pi PCr ATP Patient
20 0 -30 ppm
PCr/ATP=1.76
Control
2.5
2.0
1.5
1.0
0.5
0
PC
r/A
TP
rat
io
D
M
Control
* p < 0.05 vs. normal
0
3
6
9
12
15
Carbohydrate
Oxidation
Normal Heart
Failure
Patients
*
(µm
ol g
luco
seu
nit
s x
min
-1)
Impaired Carbohydrate Oxidation in Class II-III Heart Failure Patients
From: Paolisso et al, Metabolism 43:174, 1994
0
5
10
15
20
Fatty Acid
Oxidation
Normal Heart
Failure
Patients * p < 0.05 vs. normal
* (µ
mo
l x m
in-1
)
Increased Fatty Acid Oxidation in Class II-III Heart Failure Patients
From: Paolisso et al, Metabolism 43:174, 1994
HEART FAILURE = A KETOSIS-PRONE STATE
Lommi J et al. J Int Med 1997; 242: 231-8
P=0.022
Approaches for the Treatment of Failing
Heart
Contractility
Pre- after-load; heart
rate
Increase in
Oxygen and
energy
consumption
Decrease in
Oxygen and
energy
consumption
Increase in energy production with no
changes on HR and BP
X
Myocardial Free Fatty Acid and Glucose Use After
Carvedilol Treatment in Patients With Congestive
Heart Failure
Wallhaus TR, et al, Circulation 2001
myocardial uptake rates
Pure Heart Rate Reduction and Cardiac
Metabolism
Ceconi C et al. Cardiovascular Research 2009; 84: 72-82
Mode of Action of Metabolic Agents
PDH
Acyl CoA
Acetyl CoA
Free fatty acids
Krebs’ cycle
Glucose
Pyruvate
TMZ
ATP/O2 = 6.3 ATP/O2 = 5.6
-
ß - OX
AA
Parexhelline
Etomoxir
Ranolazine
Metformin – GLP1
Pyruvate
Carnitine palmitoyl
transferase 1 inhibitor
- Niacin
Dichloroacetate
Metformin
Bendavia
Metformin
Eurich DT et al, BMJ 2007;:bmj;bmj.39314.620174.80v1
Metformin reduced ACM or
hopitalisation and did not
increase HF hospitalisation
Metformin in contemporary practice
J Card Fail. 2010 March ; 16(3): 200–206
Advanced HF
Single centre, observational study
Metformin prescription not determined by HF status or prospectively
Modulators of Cardiac Metabolism
Metabolic effect at
farmacological
doses
Anti-
ischemic
effect
Major SE Marketed
Trimetazidine
Parexhelline
Etomoxir
Niacin
Ranolazine
Dichloroacetate
FFA inhibitor
CPI inhibitor
CPI inhibitor
Uptake inhibitor
None
Inhib PDH kinase
++++
+++
----
----
+---
+++
GI
Liver toxicity
LVH,
Lynphoma
QT, Liver
Worldwide
Australia
No
Worldwide
US/EU
No
Trimetazidine and Parhexelline are the only two metabolic agents
with proven anti-ischemic effect
Palmitate
Glucose
Effect of Modulation of FFA Metabolism on Cardiac Function
Gambert S et al Mol and Cell Biochem 2006; 283: 147-152
Cardiac Work
(mm
Hg
• m
l • m
in-1
• 1
0-2)
Ischemia
Perfusion time (min) 0 20 40 60 80 100
0
20
40
60
80
Cardiac Efficiency
(Car
dia
c W
ork
/O2 C
on
sum
pti
on
)
0 20 40 60 80 100 0.0
0.5
1.0
1.5
2.0 Ischemia
Glucose Glucose
+ TMZ
Palmitate Palmitate
+ TMZ
120
100
80
60
40
20
0
LVE
DP
(m
mH
g)
10
8
6
4
2
0
Co
ron
ary
flo
w (
mL
/min
)
Glucose Glucose
+ TMZ
Palmitate Palmitate
+ TMZ
Glucose Glucose
+ TMZ
Palmitate Palmitate
+ TMZ A
sco
rbyl
e fr
ee r
adic
al
rele
ase
(AU
/mL
)
0
16
8
6
4
2
10
12
14
TMZ increases glucose consumption and reduces glycogen content in murine skeletal muscle myotubes.
Fearraro E et al. Personal communication
Trimetazidine Inhibits Fatty Acid Oxidation and Stimulates Glucose Oxidation
0
675
1350
2025
2700
*
(n
mo
l.g
dry
wt-
1.m
in-1
)
Control TMZ (1 µM)
GLUCOSE OXIDATION
0
110
220
330
440
550 FATTY ACID OXIDATION
*
Control TMZ (1 µM)
(n
mo
l.g
dry
wt-
1.m
in-1
)
Kantor P, et al. Circ Res. 2000;86:580-588
Effect of Trimetazidine on PCr/ATP ratio in patients with CVD
P=0.04
1,00
1,50
2,00
Pc
r/A
TP
ra
tio
placebo TMZ healthy subjects
Fragasso G, et al. Eur Heart J 2006,27: 942-948
Timing of recruitment and definitions
CHF AHF
CHF AHF
Hospitalised
Post-hospitalisation
New category of patients with HF to be included in
Hospitalisation 3 months post hospitalisation
Rosano G et al Cardiovascular Diabetology 2003; 2:16-24
Effect of Trimetazidine on LV Function in Type II
Diabetic Patients with Ischemic Cardiomyopathy
Baseline LVEF <35%
P<0.01 compared with
trimetazidine
-5 -4 -3 -2 -1 0 1 2 3 4 5 6 7
Trimetazidine Placebo
% c
ha
ng
e o
f L
VE
F f
rom
ba
selin
e
P<0.05
*P<0.05
WM
SI
P<0.01
0
0,8
1,6
Trimetazidine Placebo
Baseline 6 months Baseline 6 months P<0.05
LVEDVI
P<0.05
LVESVI
-12 -10
-8
-6 -4 -2 0
2 4
ml/m
2
Placebo
LVEDVI LVESVI
Trimetazidine
Long-term Treatment with Trimetazidine Decreases BNP Levels in HF patients
55 heart failure patients with LV dysfunction (LVEF<40%)
13-month therapy with trimetazidine in addition to conventional treatment
G Fragasso, A Palloshi, P Puccetti, et al. JACC 2006;48:992-998
P=0.05
Baseline 13 months
Trimetazidine Improves NYHA Class
Control Group Trimetazidine Group
0%
20%
40%
60%
80%
100%
NYHA 1
NYHA 2
NYHA 2
NYHA 2
NYHA 2
NYHA 3
NYHA 3 NYHA 3
NYHA 3 NYHA 4 NYHA 4 NYHA 4
Di Napoli P, Taccardi AA, Barsotti A. Heart 2005; 91: 161-165
Baseline 18 mo Baseline 18 mo
*
El-Kady et al. Am J Cardiovasc Drugs. 2005;5(4):271-278
Effects of Long-Term Treatment with
Trimetazidine in 200 ICM Patients
*P<0.0001
Patient Survival 24 Months after acute hospitalisation
%
Effect of Trimetazidine in patients with HFrEF
Di Napoli et al. Circulation 2007; 116:333-334.
Left ventricular ejection fraction (LVEF) for patients with heart failure (HF) receiving trimetazidine (TMZ) or placebo.
Gao D et al. Heart 2011;97:278-286
©2011 by BMJ Publishing Group Ltd and British Cardiovascular Society
Differences for New York Heart Association classification (NYHA) (A) and
exercise duration (B) for patients with heart failure receiving trimetazidine or
placebo.
Gao D et al. Heart 2011;97:278-286
Clinical outcomes of patients with heart failure receiving trimetazidine
or placebo for (A) all-cause mortality and (B) cumulative events.
Gao D et al. Heart 2011;97:278-286
Modulation of carbohydrate metabolism
Inhibition of fatty acid oxidation
Increased AA availability
Improvement of mitocondrial electron transport
Therapeutic stretegies for optimizing
cardiac metabolism
Conclusion
Patients with HF have metabolic disturbances that reduce the ATP
production
The reduced ATP production causes a reduction in contractile reserve
Modulation of cardiac metabolism improves myocardial ischemia, left
ventricular function, muscle strength and prognosis in patients with LVD
secondary to CAD and diabetes mellitus
Optimization of cardiac metabolism should be ideally obtained with
inhibition of FFA oxidation, improvement in insulin sensitivity and fueling
of the Krebs cycle with amino acids
The effect of a comprehensive metabolic approach to HF should be
tested in a RCT
Opie L. Lancet 1999;353:768–769
“The heart is more than a pump. It
is also an organ that needs energy
from metabolism.
A metabolic disease, ischemia, should
ideally be treated by metabolic therapy”
L. Opie