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First clinical trial with etomoxir in patients with chronic congestive heart failure
S Schmidt-Schweda1, C Holubarsch
1Medizinische Universitätsklinik, University of Freiburg, Department of Cardiology & Angiology, Hugstetter Strasse 55, 79106 Freiburg, Germany.
Insights
Etomoxir treatment improved cardiac function in chronic heart failure patients by enhancing stroke volume and left ventricular ejection fraction. This carnitine palmitoyltransferase inhibitor showed no adverse effects in this pilot study.
Area of Science:
- Cardiology
- Pharmacology
Background:
- Heart failure involves impaired calcium handling and altered contractile proteins.
- Carnitine palmitoyltransferase inhibition with etomoxir may modulate key cardiac proteins.
Purpose of the Study:
- To investigate the long-term effects of oral etomoxir on cardiac function in patients with chronic heart failure.
Main Methods:
- 10 patients with NYHA class II-III heart failure received 80 mg etomoxir daily for 3 months.
- Echocardiography assessed left ventricular ejection fraction.
- Pulmonary artery catheterization and thermodilution measured central hemodynamics at rest and during exercise.
Main Results:
- All patients showed clinical improvement with no reported side effects or deaths.
- Exercise cardiac output increased significantly (p<0.01) due to enhanced stroke volume.
- Left ventricular ejection fraction significantly improved from 21.5% to 27.0% (p<0.01).
Conclusions:
- Etomoxir treatment appears beneficial for patients with chronic heart failure, improving cardiac function and clinical status.
- The drug demonstrated no acute inotropic or vasodilatory effects.
- Further placebo-controlled studies are warranted to confirm these findings.
Abstract:
In the failing human myocardium, both impaired calcium homoeostasis and alterations in the levels of contractile proteins have been observed, which may be responsible for reduced contractility as well as diastolic dysfunction. In addition, levels of a key protein in calcium cycling, i.e. the sarcoplasmic reticulum Ca(2+)-ATPase, and of the alpha-myosin heavy chain have been shown to be enhanced by treatment with etomoxir, a carnitine palmitoyltransferase inhibitor, in normal and pressure-overloaded rat myocardium. We therefore studied, for the first time, the influence of long-term oral application of etomoxir on cardiac function in patients with chronic heart failure. A dose of 80 mg of etomoxir was given once daily to 10 patients suffering from heart failure (NYHA functional class II-III; mean age 55+/-4 years; one patient with ischaemic heart disease and nine patients with dilated idiopathic cardiomyopathy; all male), in addition to standard therapy. The left ventricular ejection fraction was measured echocardiographically before and after a 3-month period of treatment. Central haemodynamics at rest and exercise (supine position bicycle) were defined by means of a pulmonary artery catheter and thermodilution. All 10 patients improved clinically; no patient had to stop taking the study medication because of side effects; and no patient died during the 3-month period. Maximum cardiac output during exercise increased from 9.72+/-1.25 l/min before to 13.44+/-1.50 l/min after treatment (P<0.01); this increase was mainly due to an increased stroke volume [84+/-7 ml before and 109+/-9 ml after treatment (P<0.01)]. Resting heart rate was slightly reduced (not statistically significant). During exercise, for any given heart rate, stroke volume was significantly enhanced (P<0.05). The left ventricular ejection fraction increased significantly from 21.5+/-2.6% to 27.0+/-2.3% (P<0.01). In acute studies, etomoxir showed neither a positive inotropic effect nor vasodilatory properties. Thus, although the results of this small pilot study are not placebo-controlled, all patients seem to have benefitted from etomoxir treatment. Etomoxir, which has no acute inotropic or vasodilatory properties and is thought to increase gene expression of the sarcoplasmic reticulum Ca(2+)-ATPase and the alpha-myosin heavy chain, improved clinical status, central haemodynamics at rest and during exercise, and left ventricular ejection fraction.