Trimetazidine and l‑carnitine prevent heart aging and cardiac metabolic impairment in rats via regulating cardiac metabolic substrates.

BACKGROUND: This study aimed to investigate the effects of trimetazidine and l‑carnitine on heart aging and cardiac metabolism in the natural aging rats and explore the possible mechanism regarding the regulation of cardiac metabolic substrates.

METHODS: A total of 28 young (2-month-old) and 28 aged (14-month-old) male Sprague-Dawley rats were randomly allocated to the following groups: young control (YC, n = 8), young trimetazidine (YT, n = 10), young l‑carnitine (YL, n = 10), aging control (AC, n = 8), aging trimetazidine (AT, n = 10), and aging l‑carnitine (AL, n = 10). All rats were intragastrically treated with saline, trimetazidine, or l‑carnitine for 4 weeks. Blood sample parameters (MDA, SOD, Glu, TG, TC, LDL-c, HDL-c, AST, ALT, ALP, BUN, Cr, LDH), Echocardiographic paramerters, ATP levels of cardiac apex, cardiac pathology (HE staining and mitochondrial ultrastructures), and cardiac metabolism-related parameters (glucose transporter type-4[GLUT-4], carnitine palmitoyl transferase‑1[CPT-1]) were analyzed in each group.

RESULTS: The left ventricular ejection fractions were normal in most groups, with a higher value observed in the AT group than in the AC group. The AC group showed decreased ATP levels of cardiac apex compared with the YC group. But both trimetazidine and l‑carnitine attenuated the aging-induced decrease in ATP levels of cardiac apex. The AC group also showed increased myocardial fiber fragmentations and dissolutions, and interstitial proliferation compared with the YC group. However both trimetazidine and l‑carnitine protected against the aging-induced pathological changes in myocardium. Furthermore, both trimetazidine and l‑carnitine prevented mitochondria of cardiomyocytes from aging-induced injury. Both the AT and AL groups had significantly fewer focal cavitations and higher mitochondrial matrix electron densities than the AC group. GLUT-4 and CPT-1 protein levels were significantly lower while GLUT-4/CPT-1 ratios were higher in aging rats than YC rats. The AT and AL groups had significantly higher GLUT-4 and CPT-1 levels than the AC group, with more significant changes observed in the AT group.

CONCLUSIONS: Trimetazidine and l‑carnitine may partially improve the age-related changes of rat myocardial metabolisms and heart function via regulating cardiac metabolic substrates, with trimetazidine being superior. Interestingly, they may also reduce cardiac energy generation and impair mitochondrial structures in young rats. These findings suggest that age should be taken as an independent factor during the use of metabolic modulatory drugs in the patients with cardiovascular diseases because it may completely change the effects of drugs.