Clinical studies have suggested that the diabetic heart is more sensitive to ischemic injury than the non-diabetic heart. However, results from a number of experimental studies using animal models of diabetes reported no change, increased or decreased sensitivity to ischemia. The purpose of this review is to discuss the possible explanations for this apparent discrepancy. Analysis of the conflicting literature on this subject reveals a pattern which suggests that the disparity of experimental findings stems from differences in the duration and severity of the diabetic state, the ischemic flow rate and whether fatty acids are provided as an exogenous substrate. It appears that short-term or mild diabetes is associated with decreased sensitivity to zero-flow ischemic injury. However, as the duration or severity of diabetes increases, this beneficial effect disappears. The diabetic heart also appears to be more vulnerable to injury during low-flow ischemia and when elevated fatty acids are present.

It is apparent from the foregoing discussion that carnitine plays an essential role in human intermediary metabolism. The question of a dietary requirement for carnitine, particularly for the human infant, is of significant theoretical and practical interest. Aberrant carnitine metabolism resulting from abnormal genetic or acquired conditions may have serious consequences for the affected individual. At present many of the treatment modalities for carnitine deficiency are empirical. Further clarification of the mechanisms by which carnitine depletion is manifest in these conditions is essential for designing treatment programs. Moreover, therapeutic use of carnitine in several human diseases not involving carnitine deficiency per se has been indicated. Before such treatment becomes generally accepted, we must determine precisely the role of this amino acid in the biochemical and physiological events that participate in the pathogenesis of each disease.

The metabolism of endogenous triacylglycerols (TG) was studied in perfused working hearts of control and 12-day-old streptozotocin-treated diabetic rats. TG synthesis was assessed by the incorporation of exogenous [9,10(-3)H]palmitate. TG lipolysis was assessed by the following two methods: 1) measurement of the decrease in [14C]TG after prior in vivo isotopic prelabeling with [1-14C]palmitate and 2) calculation of the change in TG content as TG synthesis minus TG lipolysis. Control and diabetic hearts were perfused with buffer containing substrate concentrations characteristic of the in vivo state [normal: 9 mM glucose, 0.5 mM free fatty acid (FFA); diabetic: 27 mM glucose, 1.2 mM FFA]. Diabetic hearts were also perfused under normal substrate conditions. In diabetic hearts perfused under diabetic conditions elevated TG levels were maintained, lipolysis was reduced or unchanged (depending on the method of determination), and synthesis was enhanced. Oxidation of TG fatty acids (TGFA) was not impaired. Control hearts showed net lipolysis coupled with lower rates of exogenous FFA uptake and TG synthesis. In diabetic hearts perfused under normal substrate conditions lipolysis and TGFA oxidation were markedly enhanced. Thus we suggest that the basis of TG accumulation seen in the diabetic heart is due to both inhibition of lipolysis and enhancement of synthesis resulting from high levels of exogenous FFA and glucose.

The effects of L-propionylcarnitine on the recovery of cardiac contractile performance after global ischaemia and reperfusion were studied in isolated perfused rat hearts. The addition of either 5.5 or 11 mmol X litre-1 L-propionylcarnitine significantly improved the recovery of cardiac output, left ventricular pressure, and dP/dt after 90 min of ischaemia and 15 min of reperfusion. Myocardial adenosine triphosphate and creatine phosphate concentrations were significantly higher in the L-propionylcarnitine treated hearts than in controls, but the concentrations of long chain acyl carnitine and coenzyme A were unaffected. The protecting effects of L-propionylcarnitine were compared with those of L-carnitine and L-acetylcarnitine. A 11 mmol X litre-1 dose of L-propionylcarnitine and L-acetylcarnitine significantly improved the recovery of cardiac output after 90 min of ischaemia and 15 min of reperfusion, but L-carnitine did not. L-Propionylcarnitine was the most protective agent. The effects of these derivatives on L-3H-carnitine transport and 14C-palmitate oxidation were also measured. All of these derivatives competitively inhibited L-3H-carnitine transport in isolated cardiac myocytes, but L-propionylcarnitine was the most potent. Carnitine and L-propionylcarnitine stimulated palmitate oxidation in the homogenate, whereas L-acetylcarnitine inhibited it. In myocytes only L-propionylcarnitine affected palmitate oxidation. These data show that L-propionylcarnitine protects the ischaemic myocardium. Its protection is greater than that for L-carnitine or L-acetylcarnitine, and the difference in effectiveness may relate to the rate of transport into the cells and the effects on fatty acid utilisation.

No abstract