The importance of inhibiting free fatty acid metabolismin heart failure treatment

The need to improve the management of heart fail-

ure is widely recognised even though we have made

many advances over the last decade (1). Recently two

patients of mine moved rapidly from stable New

York Heart Association class II/III to class IV with

sudden and precipitous haemodynamic collapse. No

implantable defibrillator will rescue this sequence as

it is the left ventricle ‘giving up’ rather than an

arrhythmia causing the demise. I suspect implantable

devices are often used too late in the disease process.

Devices really deal with the consequences of heart

failure whereas the focus should be on modifying

mechanism and thereby aiming to prevent the conse-

quences. A complimentary strategy is the ideal.

The metabolic approach to heart failure I summa-

rised to a degree in my August 2006 editorial (1). In

this edition, Fragasso (2) reviews in more detail the

metabolic approach with the inhibition of free fatty

acid metabolism as the therapeutic target. We know

myocardial energy metabolism may be normal in the

early stages of heart failure, but as the failure pro-

gresses mitochondrial oxidative metabolism is

reduced and glycolysis is increased with downregula-

tion of glucose and fatty acid oxidation. With the

evidence that reducing fatty acid oxidation at the

same time as increasing glucose oxidation can

improve cardiac function and slow the progression

of heart failure has come the concept of metabolic

manipulation with drugs designed to inhibit fatty

acid oxidation and simultaneously promote glucose

oxidation (3).

The most widely studied metabolic agent is trimet-

azidine which inhibits 3-ketoacyl coenzyme A thio-

lase (3-kat) the last enzyme involved in b-oxidation.

Importantly trimetazidine has, as well as good

experimental evidence of efficacy, important subject-

ive and objective evidence of benefit in the heart fail-

ure patient (4). It is effective in addition to current

evidence-based therapies with minimal adverse effects

and no drug interactions. The documented improve-

ment in ejection fraction may be prognostically

important but this is as yet unproven (though one

small study is very encouraging) (5).

Early experimental and clinical data with ranola-

zine identifies similar benefits though there is some

dispute as to whether ranolazine works in a similar

way to trimatazidine (6,7). If accepted as a 3-kat

inhibitor, this reinforces the concept of a new thera-

peutic approach to heart failure. If not, it does not

detract from the impressive data supporting the role

of trimetazidine in the treatment of heart failure of

different causes.

Fragasso’s excellent review sets the benchmark for

the use of a metabolic approach to the treatment of

heart failure. Both Fragasso and myself are in agree-

ment that the ‘time has come to test this huge

potential therapeutic advancement in heart failure

syndromes which still suffer high morbidity and

mortality’. The potential to lengthen life with

improved quality is the optimal medical target giving

heart failure patients new hope for the future.

Disclosures

GJ has received travel and financial support from

Servier (makers of trimetazidine) and CV Therapeu-

tics (makers of ranolazine).

Graham JacksonEditor

References1 Jackson G. Metabolic approach to heart failure – evidence that tri-

metazidine improves symptoms, left ventricular function and poss-

ibly prognosis. Int J Clin Pract 2006; 60: 891–2.

2 Fragasso G. Inhibition of free fatty acids metabolism as a therapeutic

target in patients with heart failure. Int J Clin Pract 2007; 61: 603–10.

3 Lopaschuk GD, Stanley WA, Lopaschuk CC. Metabolic approach in

heart failure: the rationale for metabolic interventions. Heart Metab

2005; 27: 5–10.

4 Vitale C, Wajngaten M, Sposato B et al. Trimetazidine improves left

ventricular function and quality of life in elderly patients with cor-

onary heart disease. Eur Heart J 2004; 25: 1814–21.

5 El-Kady T, El-Sabban K, Gabaly M et al. Effects of trimetazidine on

myocardial perfusion and contractile response of electronically dys-

functional myocardium in ischaemic cardiomyopathy. Am J Cardio-

vasc Drugs 2005; 5: 271–8.

6 Belardinelli L, Shyrock JC, Fraser H. The mechanism of ranolazine

action to reduce ischaemia-induced diastolic dysfunction. Eur Heart

J (Suppl A) 2006; 8: A10–3.

7 Makielski JC, Valdivia CR. Ranolazine and late cardiac sodium cur-

rent – a therapeutic target for angina, arrhythmia and more? Br J

Pharmacol 2006; 148: 4–6 (doi:10.1038/sj.bjp.0706713; published

online 6 March 2006).

doi: 10.1111/j.1742-1241.2007.01332.x

ED ITORIAL

ª 2007 The AuthorsJournal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, April 2007, 61, 4, 535–544 535

the benchmark

for the use of

a metabolic

approach to

the treatment

of heart failure