Carnitine And The Heart: General

• Carnitine is not produced by the heart but …

• The heart is dependent on Carnitineas FFA are the major sources of myocardial energy (80% of oxygen consumption is used to oxide FFA).

• Carnitine from diet or from liver and kidney is actively transported to the heart across the sarcolemma.

Carnitine Deficiency• 1973 Firstly described as cause of

human myopathy.

• There are several forms:

Primary muscular deficiencies.

Primary systemic deficiencies.

Secondary deficiencies.

•PHENOTYPE:Progressive muscular myopathy with lipid accumulation .

PRIMARY MUSCULAR DEFICIENCIES

•CARNITINE LEVEL:Low muscular Carnitine content.

•TREATMENT:Oral L-Carnitine improves muscle bulk, strength and performance.

Rarely unsuccessful likely to be a "Riboflavin-responsive multiple ACYL-COA dehydrogenoses deficiency”.

PRIMARY SYSTEMIC DEFICIENCY

• PHENOTYPE:Recurrent episodes of hepatic encephalopathy, hypotonia, progressive myopathy and / or cardiomyopathy (leading to death) with multi-organ lipid accumulation.

• CARNITINE ASSAY:Low levels in plasma, liver, muscle and heart.

• TREATMENT:Oral L-Carnitine always successful.

SECONDARY DEFICIENCIES

•Genetic organic aciduria.

•Genetic defects of beta oxidation.

•Prolonged haemodialysis.

• Ischaemic heart and peripheral disease.

Secondary Carnitine deficiency causes:• Cytosolic accumulation of ACIL COA.

• Excess ACIL COA further impairs metabolism and function of the ischaemic heart by causing:

Membrane damage arrhythmias.

Inhibition adenin mucleotide translocaseCompartimentalization of ATP in the mitochondria.

Alteration of calcium homeostasis Deterioration of mechanical function.

Depauperation of glutathione Oxidative stress Apoptosis.

EFFECTS OF L-CARNITINE ON POSTISCHEMIC NECROTIC AND APOPTOTIC CARDIOMYOCYTE

DEATH IN ISOLATED RAT HEARTS.

(Cui J et al. In press)

INFA

RC

T SI

ZE (%

) 50

40

30

20

10

25

20

15

10

5

CONTROL

**

24% 17% 44% 30%

L-CARNITINE

APO

PTO

SIS

(%)

Ischaemia Induced Deficiencies In Man• During attack of angina (A-Cs)

• In CAD patients subjected to heart surgery.

• After myocardial infarction.

• In CAD patients subjected to trombolysis(A-Cs).

• In patients heart failure (myocardial biopsy).

• In cardiogenic shock.

Data is scarce. High individual variations. Important area to invest.

Effects of L-Carnitine in CAD patients

•Haemodynamic and metabolic action at rest and during exercise and / or pacing induced ischaemia.

•Large clinical trials in angina and acute myocardial infarction.

Phase IV open label study in 3500 CAD patients treated for 1 year with oral L-Carnitine (2gr daily) :

• No side effects.

• Reduction of concomitant anti-anginal treatment (β blockers, nitrates, CA2+

antagonists).

Fernandez et al JAMA 210, 1985

Effects of L-Carnitine on LV remodelling after acute arterior myocardial infarction CEDIM I (JACC; 26, 1995)• Objectives:

Effects of L-Carnitine (9g / day iv for 5 days followed by oral dose for 12 months) on long term ventricular dilation in 472 patients with AMI

• Methods:High quality two dimensional echo cardiograms with 24 hour of onset of chest pain and at pre-discharge and 3,6,12 months later.

% C

hang

ein

ESV

from

bas

elin

e (a

dmis

sion

)%

Cha

nge

in E

DV

from

bas

elin

e (a

dmis

sion

)CEDIM 1(JACC 1995)

Furthermore:• No significant differences in left

ventricular ejection fraction

• A trend towards a reduction of the combined incidence of death and CHF after discharge:14 (6%) in L-Carnitine group23 (9.6%) in placebo group

• Population:2047 patients with acute anterior infarct .

CEDIM-2

• Randomization:Within 12 hours from symptom.

• Primary end point:CV mortality and HF at six months.

• Secondary end point:Early mortality ( 7 and 30 days).

• Treatment:as in CEDIM-1.

CEDIM-2CONCOMITANT TREATMENT

0%

20%

40%

60%

80%

100%

Trombolisi

ACE-IBeta-bloc.

Eparina

Antiaggr.

PRIMARY END-POINT(mortality and HF)

p= NS

2%

4%

6%

8%

10%

1 2 3 4 5 6

L-CARNITINA

PLACEBO

months

Cumulative Number of deaths

0

20

40

60

80

100

Carnitine 23 27 31 37 42 46 54 58 66 69Placebo 35 44 46 47 50 60 67 69 77 78

3 5 7 10 15 30 60 90 180 365

*

Relative Risk (of death)

0

0,2

0,4

0,6

0,8

1

1,2

1,4

High 1,1 0,98 1,05 1,19 1,25 1,11 1,14 1,17 1,17 1,21

Low 0,38 0,37 0,42 0,5 0,55 0,51 0,55 0,58 0,61 0,63

Close 0,65 0,61 0,66 0,78 0,83 0,75 0,79 0,83 0,84 0,87

3 5 7 10 15 30 60 90 180 365

P = 0.04

CEDIM1

CEDIM2

POOLED

DAY 7

21

,9,8

,7,6

,5,4

,3,2

CONCLUSION:• L-Carnitine treatment is useful in all

primary deficiencies.

• In secondary deficiencies and particularly in ischaemic heart disease it improves cardiac metabolism.

• This results in an improvement of angina symptoms, reduced early mortality after MI and improvement of left ventricular remodelling.

PROPIONYL – L - CARNITINE