Increased ischemic injury but decreased hypoxic injury in hypertrophied rat hearts.

Abstract

The purpose of this study was to compare the degree of ischemic and hypoxic injury in normal versus hypertrophied rat hearts to investigate basic mechanisms responsible for irreversible myocardial ischemic injury. Hearts from rats with bands placed on the aortic arch at 23 days of age (BAND) and sham-operated rats (SHAM, 8 weeks postoperative) were isolated, perfused with Krebs buffer, and had a left ventricular balloon to measure developed pressure. Hearts were made globally ischemic until they developed peak ischemic contracture and were reperfused for 30 minutes. Additional hearts were perfused for 15 minutes with glucose-free hypoxic buffer followed by 20 minutes of oxygenated perfusion. There was an 87% increase in heart weight of BAND compared with SHAM (p less than 0.01). During ischemia, lactate levels increased faster in BAND compared with SHAM, ischemic contracture occurred earlier in BAND than in SHAM despite no difference in ATP levels, and postischemic recovery of left ventricular pressure was less in BAND (26.8 +/- 5.6% of control left ventricular pressure, mean +/- SEM) compared with SHAM (40 +/- 4.6%, p less than 0.05). During hypoxic perfusion, lactate release was greater in BAND than in SHAM (48.8 +/- 1.2 versus 26.6 +/- 0.97 mumols/g, p less than 0.01), and with reoxygenation, lactate dehydrogenase release was less in BAND than in SHAM (13.2 +/- 0.7 versus 19.5 +/- 0.2 IU/g, p less than 0.01). After hypoxia and reoxygenation, left ventricular pressure recovery was greater in BAND than in SHAM (93 +/- 8.4% versus 66 +/- 5.3%, p less than 0.01). Thus, this study suggests that hypertrophied hearts have a greater potential for glycolytic metabolism, resulting in an increased rate of by-product accumulation during ischemia, which may be responsible for the increased susceptibility of hypertrophied hearts to ischemic injury.

Overexpression of TRPC3 increases apoptosis but not necrosis in response to ischemia-reperfusion in adult mouse cardiomyocytes

“…However, hypertrophic agonists such as angiotensin and phenylephrine, which have been shown to stimulate CCE, are also known to induce apoptosis. Furthermore, cardiac hypertrophy, which increases TRPC1 expression levels in the normal intact adult heart (30), is also associated with decreased tolerance to ischemic injury (1).…”

Inhibition of Glycogen Synthase Kinase-3β Improves Tolerance to Ischemia in Hypertrophied Hearts

“…Inhibition of GSK-3β by lithium or the specific inhibitor IMI as cardioplegic additives results in significantly improved recovery of systolic and diastolic function after reperfusion concomitant with increased glycolysis during ischemia and early reperfusion, as indicated by increased lactate production. Alterations in energy metabolism have been implicated as contributing to worse recovery of contractile function in hypertrophied myocardium after ischemia [5]. During ischemia, anaerobic glycolysis is the primary source for ATP production as lack of oxygen and accumulation of nicotinamide adenine dinucleotide phosphate in the mitochondria rapidly inhibit oxidative phosphorylation.…”

“…However, during myocardial ischemia, hypertrophied hearts exhibit accelerated loss of high-energy nucleotides, earlier onset of ischemic contracture, and accelerated calcium overload during early reperfusion [4]. A number of morphologic, metabolic, and physiologic changes in the hypertrophied heart contribute to increased susceptibility to ischemic injury [5]. As we and others have previously shown, in hypertrophied myocardium, insulin-stimulated glucose transport and uptake rate is reduced, and this impairment likely contributes to decreased tolerance to ischemia [1,6,7].…”

Trimetazidine Normalizes Postischemic Function of Hypertrophied Rat Hearts

“…Left ventricular dysfunction after ischemia is greater in hearts hypertrophied in response to pressure overload than in nonhypertrophied hearts (Anderson et al, 1990;Wambolt et al, 2000). During the hypertrophic response to pressure overload, changes occur in the myocytes, vasculature, and interstitium of the heart (Frohlich et al, 1992;Swynghedauw, 1999), many of which may be responsible for the detrimental effects of hypertrophy on the outcome after ischemia.…”

“…During the hypertrophic response to pressure overload, changes occur in the myocytes, vasculature, and interstitium of the heart (Frohlich et al, 1992;Swynghedauw, 1999), many of which may be responsible for the detrimental effects of hypertrophy on the outcome after ischemia. Alteration in myocardial energy metabolism, particularly glucose metabolism, is one of the changes in myocytes thought to contribute to the increased susceptibility of hypertrophied hearts to dysfunction following ischemia and reperfusion (Anderson et al, 1990;Wambolt et al, 2000;Sambandam et al, 2002).…”