First clinical trial with etomoxir in patients with chronic congestive heart failure

In the failing human myocardium, both impaired calcium homoeostasis and alt erations in the levels of contractile proteins have been observed, which ma y be responsible for reduced contractility as well as diastolic dysfunction . In addition, levels of a key protein in calcium cycling, i.e. the sarcopl asmic reticulum Ca2+-ATPase, and of the alpha-myosin heavy chain have been shown to be enhanced by treatment with etomoxir, a carnitine palmitoyltrans ferase inhibitor, in normal and pressure-overloaded rat myocardium. We ther efore studied, for the first time, the influence of long-term oral applicat ion 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 idi opathic cardiomyopathy; all male), in addition to standard therapy. The lef t ventricular ejection fraction was measured echocardiographically before a nd after a 3-month period of treatment. Central haemodynamics at rest and e xercise (supine position bicycle) were defined by means of a pulmonary arte ry catheter and thermodilution. All 10 patients improved clinically; no pat ient had to stop taking the study medication because of side effects; and n o patient died during the 3-month period. Maximum cardiac output during exe rcise increased from 9.72 +/- 1.25 I/min before to 13.44 +/- 1.50 I/min aft er treatment (P < 0.01); this increase was mainly due to an increased strok e volume [84 +/- 7 mi before and 109 +/- 9 mi after treatment (P < 0.01)]. Resting heart rate was slightly reduced (not statistically significant). Du ring exercise, for any given heart rate, stroke volume was significantly en hanced (P < 0.05). The left ventricular ejection fraction increased signifi cantly from 21.5 +/- 2.6% to 27.0 +/- 2.3% (P < 0.01). In acute studies, et omoxir showed neither a positive inotropic effect nor vasodilatory properti es. Thus, although the results of this small Pilot study are not placebo-co ntrolled, all patients seem to have benefitted from etomoxir treatment. Eto moxir, which has no acute inotropic or vasodilatory properties and is thoug ht to increase gene expression of the sarcoplasmic reticulum Ca2+-ATPase an d the alpha-myosin heavy chain, improved clinical status, central haemodyna mics at rest and during exercise, and left ventricular ejection fraction.