Therapeutic strategies to protect the ischemic myocardium have been studied extensively. Reperfusion is the definitive treatment for acute coronary syndromes, especially acute myocardial infarction; however, reperfusion has the potential to exacerbate lethal tissue injury, a process termed "reperfusion injury." Ischemia/reperfusion injury may lead to myocardial infarction, cardiac arrhythmias, and contractile dysfunction. Ischemic preconditioning of myocardium is a well described adaptive response in which brief exposure to ischemia/reperfusion before sustained ischemia markedly enhances the ability of the heart to withstand a subsequent ischemic insult. Additionally, the application of brief repetitive episodes of ischemia/reperfusion at the immediate onset of reperfusion, which has been termed "postconditioning," reduces the extent of reperfusion injury. Ischemic pre- and postconditioning share some but not all parts of the proposed signal transduction cascade, including the activation of survival protein kinase pathways. Most experimental studies on cardioprotection have been undertaken in animal models, in which ischemia/reperfusion is imposed in the absence of other disease processes. However, ischemic heart disease in humans is a complex disorder caused by or associated with known cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, insulin resistance, atherosclerosis, and heart failure; additionally, aging is an important modifying condition. In these diseases and aging, the pathological processes are associated with fundamental molecular alterations that can potentially affect the development of ischemia/reperfusion injury per se and responses to cardioprotective interventions. Among many other possible mechanisms, for example, in hyperlipidemia and diabetes, the pathological increase in reactive oxygen and nitrogen species and the use of the ATP-sensitive potassium channel inhibitor insulin secretagogue antidiabetic drugs and, in aging, the reduced expression of connexin-43 and signal transducer and activator of transcription 3 may disrupt major cytoprotective signaling pathways thereby significantly interfering with the cardioprotective effect of pre- and postconditioning. The aim of this review is to show the potential for developing cardioprotective drugs on the basis of endogenous cardioprotection by pre- and postconditioning (i.e., drug applied as trigger or to activate signaling pathways associated with endogenous cardioprotection) and to review the evidence that comorbidities and aging accompanying coronary disease modify responses to ischemia/reperfusion and the cardioprotection conferred by preconditioning and postconditioning. We emphasize the critical need for more detailed and mechanistic preclinical studies that examine car-dioprotection specifically in relation to complicating disease states. These are now essential to maximize the likelihood of successful development of rational approaches to therapeutic protection for the majority of patients with ischemic heart disease who are aged and/or have modifying comorbid conditions.

Interaction of Cardiovascular Risk Factors with Myocardial Ischemia/Reperfusion Injury, Preconditioning, and Postconditioning

Experimental work during the past 15 years has demonstrated that endothelial cells in the heart play an obligatory role in regulating and maintaining cardiac function, in particular, at the endocardium and in the myocardial capillaries where endothelial cells directly interact with adjacent cardiomyocytes. The emerging field of targeted gene manipulation has led to the contention that cardiac endothelial-cardiomyocytal interaction is a prerequisite for normal cardiac development and growth. Some of the molecular mechanisms and cellular signals governing this interaction, such as neuregulin, vascular endothelial growth factor, and angiopoietin, continue to maintain phenotype and survival of cardiomyocytes in the adult heart. Cardiac endothelial cells, like vascular endothelial cells, also express and release a variety of auto- and paracrine agents, such as nitric oxide, endothelin, prostaglandin I(2), and angiotensin II, which directly influence cardiac metabolism, growth, contractile performance, and rhythmicity of the adult heart. The synthesis, secretion, and, most importantly, the activities of these endothelium-derived substances in the heart are closely linked, interrelated, and interactive. It may therefore be simplistic to try and define their properties independently from one another. Moreover, in relation specifically to the endocardial endothelium, an active transendothelial physicochemical gradient for various ions, or blood-heart barrier, has been demonstrated. Linkage of this blood-heart barrier to the various other endothelium-mediated signaling pathways or to the putative vascular endothelium-derived hyperpolarizing factors remains to be determined. At the early stages of cardiac failure, all major cardiovascular risk factors may cause cardiac endothelial activation as an adaptive response often followed by cardiac endothelial dysfunction. Because of the interdependency of all endothelial signaling pathways, activation or disturbance of any will necessarily affect the others leading to a disturbance of their normal balance, leading to further progression of cardiac failure.

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Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity

Administration of nitric oxide (NO), NO donors or drugs that enhance NO release (statins, calcium antagonists, ACE-inhibitors, dexamethasone) prior to ischemia protects the myocardium against ischemia/reperfusion injury. While this exogenous administration of NO prior to ischemia can initiate a preconditioning-like phenomenon, endogenous NO-synthase (NOS)-derived NO is not involved in triggering or mediating the early phase of ischemic preconditioning's protection, but does play a pivotal role for initiating and mediating the delayed phase of ischemic preconditioning's protection. The present review now summarizes the importance of endogenous and exogenous NO when given at the time of reperfusion for vascular and myocardial function and morphological outcome following ischemia/reperfusion. Given the inconsistency of the published data, potential confounding factors that might affect experimental results on the role of NO in myocardial ischemia/reperfusion were identified, such as (1) the lack of characterization of the involved NOS isoforms in myocardial ischemia/reperfusion injury in different animal species, (2) the lack of direct measurements of myocardial NO concentration and/or NOS activity to assure sufficient NOS inhibition, (3) the lack of consideration of nonenzymatic NO production as a potential source of NO, and (4) the absence of plasma or blood components in in vitro studies influencing NO delivery and metabolism. Future research on the importance of NO in ischemia/reperfusion injury will have to focus more precisely on the identification and standardization of potential confounding experimental factors that influence synthesis, transport, and interaction of NO with various targets in blood and tissue.

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Nitric oxide in myocardial ischemia/reperfusion injury.

Since diabetic cardiomyopathy was first reported four decades ago, substantial information on its pathogenesis and clinical features has accumulated. In the heart, diabetes enhances fatty acid metabolism, suppresses glucose oxidation, and modifies intracellular signaling, leading to impairments in multiple steps of excitation–contraction coupling, inefficient energy production, and increased susceptibility to ischemia/reperfusion injury. Loss of normal microvessels and remodeling of the extracellular matrix are also involved in contractile dysfunction of diabetic hearts. Use of sensitive echocardiographic techniques (tissue Doppler imaging and strain rate imaging) and magnetic resonance spectroscopy enables detection of diabetic cardiomyopathy at an early stage, and a combination of the modalities allows differentiation of this type of cardiomyopathy from other organic heart diseases. Circumstantial evidence to date indicates that diabetic cardiomyopathy is a common but frequently unrecognized pathological process in asymptomatic diabetic patients. However, a strategy for prevention or treatment of diabetic cardiomyopathy to improve its prognosis has not yet been established. Here, we review both basic and clinical studies on diabetic cardiomyopathy and summarize problems remaining to be solved for improving management of this type of cardiomyopathy.

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Diabetic cardiomyopathy: pathophysiology and clinical features.

Heart diseases due to myocardial ischemia, such as myocardial infarction or ischemic heart failure, are major causes of death in developed countries, and their number is unfortunately still growing

Pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures

BACKGROUND: Isoflurane exerts cardioprotective effects that mimic the ischemic preconditioning phenomenon. Generation of free radicals is implicated in ischemic preconditioning. The authors investigated whether isoflurane-induced preconditioning may involve release of free radicals. METHODS: Sixty-one alpha-chloralose-anesthetized rabbits were instrumented for measurement of left ventricular (LV) pressure (tip-manometer), cardiac output (ultrasonic flowprobe), and myocardial infarct size (triphenyltetrazolium staining). All rabbits were subjected to 30 min of occlusion of a major coronary artery and 2 h of subsequent reperfusion. Rabbits of all six groups underwent a treatment period consisting of either no intervention for 35 min (control group, n = 11) or 15 min of isoflurane inhalation (1 minimum alveolar concentration end-tidal concentration) followed by a 10-min washout period (isoflurane group, n = 12). Four additional groups received the radical scavenger N-(2-mercaptoproprionyl)glycine (MPG; 1 mg. kg-1.min-1) or Mn(III)tetrakis(4-benzoic acid)porphyrine chloride (MnTBAP; 100 microg.kg-1.min-1) during the treatment period with (isoflurane + MPG; n = 11; isoflurane + MnTBAP, n = 9) or without isoflurane inhalation (MPG, n = 11; MnTBAP, n = 7). RESULTS: Hemodynamic baseline values were not significantly different between groups (LV pressure, 97 +/- 17 mmHg [mean +/- SD]; cardiac output, 228 +/- 61 ml/min). During coronary artery occlusion, LV pressure was reduced to 91 +/- 17% of baseline and cardiac output to 94 +/- 21%. After 2 h of reperfusion, recovery of LV pressure and cardiac output was not significantly different between groups (LV pressure, 83 +/- 20%; cardiac output, 86 +/- 23% of baseline). Infarct size was reduced from 49 +/- 17% of the area at risk in controls to 29 +/- 19% in the isoflurane group (P = 0.04). MPG and MnTBAP themselves had no effect on infarct size (MPG, 50 +/- 14%; MnTBAP, 56 +/- 15%), but both abolished the preconditioning effect of isoflurane (isoflurane + MPG, 50 +/- 24%, P = 0.02; isoflurane + MnTBAP, 55 +/- 10%, P = 0.001). CONCLUSION: Isoflurane-induced preconditioning depends on the release of free radicals

Isoflurane preconditions myocardium against infarction via release of free radicals.

Free oxygen radicals and intracellular calcium homeostasis play important roles in the development of myocardial reperfusion injury. Propofol is a radical scavenger with calcium channel blocking properties. We have investigated the effects of propofol on myocardial reperfusion injury. We used an isolated rat heart model where heart rate, ventricular volume and perfusion pressure were constant. The left anterior descending coronary artery (LAD) was occluded for 30 min and reperfused for 2 h. We studied an untreated control group, an Intralipid group (l μl ml −1 ) and a propofol group (Intralipid I μl ml −1 and propofol l μg ml −1 ) ( n = 12 each). Drugs were infused for 20 min starting 5 min before reperfusion. We measured left ventricular developed pressure (LVDP), coronary flow and infarct size. LAD occlusion reduced mean LVDP from 129 (SEM 4) to 36 (3) mm Hg and mean coronary flow from 12.2 (0.3) to 5.2 (0.2) ml min −1 . During reperfusion, LVDP recovered to 98 (4) mm Hg and coronary flow to 11.9 (0.4) ml min −1 . Haemodynamic variables were similar in all groups. Propofol had no effect on infarct size compared with the Intralipid group (25.0 (3.7) vs 26.9 (3.3)% of the area at risk; P =0.89). Infarct size in the Intralipid group tended to be smaller compared with the control group (34.8 (3.2)%; P =0.19). We conclude that propofol, at a clinically relevant concentration, provided no protective effect against myocardial reperfusion injury in the rat heart in vitro .

Effect of propofol on reperfusion injury after regional ischaemia in the isolated rat heart

Impact of preconditioning protocol on anesthetic-induced cardioprotection in patients having coronary artery bypass surgery

Diabetes mellitus (DM) and the resulting hyperglycaemia may interfere with the cardioprotective effect of ischaemic late preconditioning (LPC). Therefore, we investigated the effect of acute hyperglycaemia (part 1) and the effect of alloxan-induced DM with or without short-term insulin treatment (part 2) on LPC. Rabbits, chronically instrumented with a coronary artery occluder, were subjected to 30 min coronary artery occlusion and 2 h reperfusion (I/R) and infarct size (IS) was assessed. In part 1, four groups were studied. Controls were not treated further. LPC induced by a 5-min period of myocardial ischaemia 24 h before I/R reduced IS from 42±14 (controls) to 22±8% of the area at risk. Hyperglycaemia (600 mg dl−1 by dextrose infusion, H600) before and during the 30 min ischaemia tended to increase IS (57±16%, P=0.14 vs. controls) and blocked cardioprotection by LPC (H600+LPC, 59±19%, P=1.0 vs. H600, P=0.0003 vs. LPC). In part 2, LPC reduced infarct size from 43±13% (control) to 23±10% (P=0.003). In diabetic animals, IS was 39±11%, and cardioprotection by LPC could not be elicited (DM+LPC, 41±16%, P=0.02 vs. LPC). Short-term insulin treatment (I, 90 min before I/R, blood glucose <150 mg dl−1) did not restore the cardioprotective effects of LPC (DM+I, 42±15%; DM+LPC+I, 40±10%, P=0.03 vs. LPC). It is concluded that acute hyperglycaemia and DM block the cardioprotection induced by LPC in rabbits and that the cardioprotection is not restored by short-term insulin treatment.

Effect of acute hyperglycaemia and diabetes mellitus with and without short-term insulin treatment on myocardial ischaemic late preconditioning in the rabbit heart in vivo.

Background In vitro, NO has a biphasic effect on myocardial inotropy. To determine the inotropic effect of NO in vivo, we investigated the activity of glyceryl trinitrate (GTN) and the NO donors S-nitroso-N-acetyl-d,l-penicillamine (SNAP) and sodium-(2)-1-(N,N-diethyl-amino)-diazen-1-ium-1,2-diolat (DEA/NO) in dogs. Methods and Results Eight anesthetized open-chest dogs were instrumented for measurement of left ventricular and aortic pressures (tip manometers) and coronary flow (ultrasonic flow probes). Regional myocardial function was assessed by sonomicrometry as systolic wall thickening (sWT), mean systolic thickening velocity (Vs), and regional myocardial stroke work index (RSW). GTN, SNAP, and DEA/NO were infused into the left anterior descending coronary artery (LAD) to achieve defined coronary plasma concentrations of GTN, SNAP (both 10 to 100 μmol/L), and DEA/NO (2 to 20 μmol/L). All drugs increased LAD flow and myocardial contractile function in the LAD-dependent myocardium within the first 120 s...

D. Ebel

Papers

Isoflurane preconditions myocardium against infarction via release of free radicals.

Effect of propofol on reperfusion injury after regional ischaemia in the isolated rat heart

Impact of preconditioning protocol on anesthetic-induced cardioprotection in patients having coronary artery bypass surgery

Effect of acute hyperglycaemia and diabetes mellitus with and without short-term insulin treatment on myocardial ischaemic late preconditioning in the rabbit heart in vivo.

Inotropic Effects of Glyceryl Trinitrate and Spontaneous NO Donors in the Dog Heart