Background: Although it has been uncovered decades ago that cardiac diseases including cardiac remodelling after myocardial ischemia and reperfusion (I/R) are accompanied by alterations in substrate metabolism, there are still controversies about the exact nature of the metabolic disturbances. Disease- and time-dependent effects as well as regional differences within the heart might contribute to this lack of clarity. Recently, we and others described that administration of insulin-like growth factor 1 (IGF1) preserves cardiac function after I/R, but it is unknown whether IGF1-treatment also affects cardiac substrate metabolism after I/R.

Methods: Male C57Bl6J mice underwent 45 minutes of LAD-occlusion or sham, respectively. To characterize time-dependency of alterations in substrate metabolism, myocardial tissue was harvested 3, 7, or 28 days after ischemia. In additional animals, IGF1 was administered for three days after ischemia by osmotic pumps to investigate the effect of IGF1 on substrate metabolism. In these experiments, cardiac tissue was harvested at day 3 or day 7 post I/R. Cardiac substrate metabolism was analysed in tissue obtained from the interventricular septum, i.e. remote myocardium, by extracellular flux analysis in vibratome-cut intact cardiac tissue pieces. Oxygen consumption rates (OCR) were measured at baseline and after FCCP-stimulation in palmitate, glucose, and glutamine enriched medium using a Seahorse XFe24 analyser and “islet capture plates”. To determine long-chain fatty acid (LCFA) metabolism, CPT1 was inhibited by etomoxir, and glucose metabolism by inhibition of mitochondrial pyruvate carrier (MPC) with UK5099. Data are mean±SD; n=5-6 animals per group.

Results: At day 3, I/R injury caused an increase in both basal OCR (66±8 vs. 51±8 pmol/min; p=0.02) as well as uncoupled OCR (107±7 vs. 84±12 pmol/min; p=0.01) compared to sham, whilst no effect was observed at day 7 and 28, respectively. CPT1 inhibition by etomoxir caused a larger reduction of uncoupled OCR in I/R compared to sham (62±9 vs. 49±11 pmol/min; p=0.09) at day 3. This increased contribution of long-chain fatty acids (LCFA) to overall metabolism in the I/R group was not found at day 7, and reverted at day 28 (I/R: 37±18, sham: 58±16 pmol/min; p=0.07). Administration of IGF1 increased basal OCR at day 7 by 39% compared to I/R group. With respect to substrate contribution, IGF1 treatment did not influence the effect of MPC inhibition at day 7 compared to I/R (49±19 vs. 47±17 pmol/min; ns). In contrast, IGF1 increased the effect of CPT1 inhibition at day 7 by 80% (64±21 vs. 36±7 pmol/min; p=0.02).  

Conclusions: Acute myocardial infarction affects substrate metabolism in the remote myocardium in a time-dependent manner as seen by an increased LCFA oxidation in the early phase, and reduced LCFA oxidation at day 28, i.e. the chronic phase of cardiac remodelling. IGF1 treatment strongly improves LCFA oxidation at day 7 after I/R, and thereby potentially contributing to the beneficial effect of IGF1 on cardiac remodelling. 

(Funding: DFG SFB1116, A06)