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