Reductions in mitochondrial O₂consumption and preservation of high-energy phosphate levels after simulated ischemia in chronic hibernating myocardium

Abstract

Reductions in mitochondrial O 2 consumption and preservation of high-energy phosphate levels after simulated ischemia in chronic hibernating myocardium. Am J Physiol Heart Circ Physiol 297: H223-H232, 2009. First published April 24, 2009 doi:10.1152/ajpheart.00992.2008.-We performed the present study to determine whether hibernating myocardium is chronically protected from ischemia. Myocardial tissue was rapidly excised from hibernating left anterior descending coronary regions (systolic wall thickening ϭ 2.8 Ϯ 0.2 vs. 5.4 Ϯ 0.3 mm in remote myocardium), and high-energy phosphates were quantified by HPLC during simulated ischemia in vitro (37°C). At baseline, ATP (20.1 Ϯ 1.0 vs. 26.7 Ϯ 2.1 mol/g dry wt, P Ͻ 0.05), ADP (8.1 Ϯ 0.4 vs. 10.3 Ϯ 0.8 mol/g, P Ͻ 0.05), and total adenine nucleotides (31.2 Ϯ 1.3 vs. 40.1 Ϯ 2.9 mol/g, P Ͻ 0.05) were depressed compared with normal myocardium, whereas total creatine, creatine phosphate, and ATP-to-ADP ratios were unchanged. During simulated ischemia, there was a marked attenuation of ATP depletion (5.6 Ϯ 0.9 vs. 13.7 Ϯ 1.7 mol/g at 20 min in control, P Ͻ 0.05) and mitochondrial respiration [145 Ϯ 13 vs. 187 Ϯ 11 ng atoms O 2 ⅐ mg protein Ϫ1 ⅐ min Ϫ1 in control (state 3), P Ͻ 0.05], whereas lactate accumulation was unaffected. These in vitro changes were accompanied by protection of the hibernating heart from acute stunning during demand-induced ischemia. Thus, despite contractile dysfunction at rest, hibernating myocardium is ischemia tolerant, with reduced mitochondrial respiration and slowing of ATP depletion during simulated ischemia, which may maintain myocyte viability. energy metabolism; mitochondrial respiration; stunned myocardium ALTHOUGH REVERSIBLE MYOCARDIAL dysynergy can arise from a number of specific pathophysiological states, chronic hibernating myocardium is unique, in that it is characterized by regional contractile dysfunction and reduced resting flow in the absence of infarction (4, 18). In chronic hibernating myocardium, regional O 2 consumption is reduced at rest, as well as during increases in myocardial O 2 demand, yet evidence of acute myocardial ischemia is absent (11), which contrasts with findings in short-term hibernating myocardium (45,46). This appears to be partially related to a downregulation in many of the enzymes involved in oxidative metabolism and electron transport (39). Thus this regional dissociation between O 2 consumption and external workload protects the heart during submaximal increases in demand and attenuates apoptosisinduced myocyte loss in the chronic state.Collectively, these findings raise the possibility that hibernating myocardium may be chronically protected against ischemia. In support of this notion, Ausma et al.(1) demonstrated increased tolerance to ischemia in myocytes from hibernating myocardium. Similarly, Milei et al. (34) demonstrated a reduction in ischemia-reperfusion injury during cardiopulmonary bypass in hibernating myocardium compared with segments with normal systolic function. Unfortunately, these previo...

Long-term preservation of myocardial energetic in chronic hibernating myocardium

“…One of the reasons for this discrepancy could be the increased fibrosis (30%) in the hibernating myocardial specimens in the study of Elsasser et al (7). In a porcine model of chronic hibernating myocardium, Hu et al (17) report normal baseline total creatine, PCr, and ATP/ADP in biopsy specimens from hibernating myocardium 3 mo after the placement of the ameroid occluder. These authors did observe a global reduction of absolute ATP, ADP, and total adenine nucleotide levels in the hibernating myocardium, but despite these reductions, the overall energetic state as determined by the ATP/ADP and cardioplegia levels was preserved (17).…”

“…In a porcine model of chronic hibernating myocardium, Hu et al (17) report normal baseline total creatine, PCr, and ATP/ADP in biopsy specimens from hibernating myocardium 3 mo after the placement of the ameroid occluder. These authors did observe a global reduction of absolute ATP, ADP, and total adenine nucleotide levels in the hibernating myocardium, but despite these reductions, the overall energetic state as determined by the ATP/ADP and cardioplegia levels was preserved (17). Our group has the unique opportunity to study the myocardial energetic in vivo with NMR spectroscopy as opposed to measuring the levels of high-energy phosphate in vitro in biopsy specimens.…”

“…In chronic heart failure or acute myocardial ischemia, the myocardial energetic state is decreased, which is reflected by a decrease in PCr/ATP (41,43). Baseline high-energy phosphate levels have been previously studied in animal models of hibernating myocardium and human hibernating myocardium with differing results (7,17,24,36). Elsasser et al (7) studied 16 patients with coronary artery disease and LV dysfunction who had documented hibernating myocardium detected by thallium-201 scintigraphy, radionuclide ventriculography, and low-dose dobutamine echocardiography.…”

“…It is possible that intrinsic changes in the mitochondria that reduce oxidant damage within hibernating myocardium preserve energy at high work states. Hu et al (17) have shown that hibernating myocardium have a significant reduction in mitochondrial function in vitro as reflected by a significant reduction in the respiratory control ratio mainly because of a decrease in state 3 respiration. This was also shown by Mc Falls et al (25) who studied isolated mitochondria from hibernating myocardium and demonstrated a decreased respiratory control ratio.…”

“…Chronic hibernating myocardium demonstrates the alteration in metabolism with an increase in glucose uptake and glycogen storage (8,13,23). The energetic state in the hibernating myocardium has been previously studied with diverse results (7,17,24,36).Our laboratory specializes in studying myocardial energetic states in vivo with NMR spectroscopy. Energetic state refers to ⌬G, which is the free energy of ATP hydrolysis (34).…”