Response to Letter Regarding Article, “Trimetazidine, a Metabolic Modulator, Has Cardiac and Extracardiac Benefits in Idiopathic Dilated Cardiomyopathy”
We thank Dr Scheuer for his interest and kind comments on our recent article.1 Dr Scheuer draws attention to the increase in left ventricular (LV) mass seen in the trimetazidine group but not in the control group. He suggests mechanisms related to apoptosis or alternatively to the inhibition of AMP-kinase activity could explain the unexpected finding.
We agree with Dr Scheuer that the increase in LV mass seen in the trimetazidine group after such a short period is unexpected. We have no obvious mechanistic explanation. Hemodynamic factors are unlikely to cause these changes because blood pressure, heart rate, and stroke volumes remained unchanged. With regard to possible effects of trimetazidine on apoptosis, if we postulate that the untreated LV is in approximate balance between myocyte regeneration and apoptosis, then decreased apoptosis in the trimetazidine group would increase LV mass. The AMP-kinase hypothesis is intriguing but does not explain why in our study the LV mass increased and the ejection fraction rose, whereas in the study by Zhang et al the knockout of this enzyme not only increased LV mass but decreased the LV ejection fraction.2
The method used to evaluate LV mass in this study was the standard echocardiography technique, and all the measurements were performed by the same very experienced echo specialist. However, the results on LV mass should be interpreted cautiously because (1) previous larger studies on trimetazidine in heart failure patients have not revealed similar findings (even after a longer period of therapy), (2) measurements of LV mass were not the primary end point of the study, and (3) we have to take into account that evaluation of LV mass by echocardiography is generally not highly accurate even at the best of times.
Despite these limitations, we believe that reporting these results was important because they create further hypotheses that should be tested. For example, relative to the decrease in LV wall stress, the larger LV in the trimetazidine-treated group did more work (as judged by the increased LV ejection fraction) with less wall stress, so that a superior mechanical situation seems to have evolved. Further larger studies focusing on the effect of trimetazidine on LV mass are needed to confirm the finding and to investigate the potential mechanisms and especially the clinical consequences of these changes in the long term.
Tuunanen H, Engblom E, Naum A, Nagren K, Scheinin M, Hesse B, Juhani Airaksinen KE, Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J. Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy. Circulation. 2008; 118: 1250–1258.
Zhang P, Hu X, Xu X, Fassett J, Zhu G, Viollet B, Xu W, Wiczer B, Bernlohr DA, Bache RJ, Chen Y. AMP activated protein kinase-alpha2 deficiency exacerbates pressure-overload-induced left ventricular hypertrophy and dysfunction in mice. Hypertension. 2008; 52: 918–924.