Synthetic high density lipoproteins for the treatment of myocardial ischemia/reperfusion injury

Synthetic high density lipoproteins (sHDL) are discoidal lipoprotein particles made of an apolipoprotein and a phospholipid, which mimic most, if not all, of the atheroprotective properties of plasma HDL, including stimulation of reverse cholesterol transport (RCT), prevention of endothelial dysfunction, and inhibition of lipid oxidation. sHDL are currently under development as a novel treatment for atherosclerotic cardiovascular disease. A number of preclinical studies have demonstrated the ability of single or multiple injections of sHDL to induce the regression of atherosclerotic plaques and prevent arterial restenosis. In the first phase II trial in patients with acute coronary syndromes, a short-term treatment with sHDL containing the disulfide-linked dimer of the apolipoprotein A-IMilano variant (A-IM/A-IM) caused a remarkable reduction of atheroma volume. sHDL also display a direct cardioprotective activity in ex vivo and in vivo models of myocardial ischemia/reperfusion (I/R) injury, and may become a useful adjunctive therapy to improve clinical outcomes in patients with acute coronary syndromes or undergoing coronary procedures.     

Differences in betablocking drugs in cardiovascular therapy

Clinically significant differences between various beta-adrenoceptor blocking drugs exist. Patients with ischaemic heart disease and exertional angina pectoris benefit from all types of beta-blockers. Drugs with intrinsic sympathomimetic action (ISA) given intravenously may be safer in some patients with acute myocardial infarction than those drugs without ISA. In cardiac patients at rest they may have a vasodilator action and cause less myocardial depression than beta-blockers without ISA. When, however, the cardiac sympathetic tone is high pindolol and other beta-blockers with ISA act as any other beta-blockers, producing haemodynamic impairment. Studies have shown that beta-blockers with ISA confer less benefit in secondary prevention after myocardial infarction and they are not suitable for the treatment of obstructive cardiomyopathy. Non-selective beta-blockers may be advantageous in hypokalaemic arrhythmias. Beta 1-blockers may be preferred for patients with bronchoconstriction, diabetes, peripheral vascular disease and, theoretically to some extent in theory also in patients with hypertension. The extent and nature of side effects may also influence the selection of the most suitable beta-blocker in cardiovascular therapy.     

Trace elements in serum from Pakistani patients with acute and chronic ischemic heart disease and hypertension

We examined sera from 159 patients with ischemic heart disease and hypertension and from 50 apparently healthy control subjects for content of trace elements, cholesterol, triglyceride, and enzymes. Concentrations of copper, cobalt, cholesterol, and triglyceride were increased in all patients, but calcium was decreased in patients with hypertension, acute myocardial ischemia, and acute myocardial infarction. Also accompanying acute myocardial infarction were decreased concentrations of zinc and iron but increases in nickel, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase. Magnesium concentration was lower in patients with acute myocardial ischemia. In acute myocardial infarction, the concentrations of copper, zinc, and iron were higher after 21-30 h (as compared with the values at 0-10 h), by which time concentrations of calcium, magnesium, cobalt, and alanine aminotransferase had decreased. The variation in concentration of trace elements in serum from cases of ischemic heart disease and hypertension corresponds to the severity of the disorder.     

The Turnover of Cholesterol in Human Atherosclerotic Arteries

The equilibration of cholesterol between plasma and atherosclerotic arteries was studied in 13 patients with obstructive atherosclerosis 2-96 days after the intravenous and/or oral administration of isotopic cholesterol. Arterial specimens were obtained in 12 patients during surgery for arterial reconstruction and in a 13th patient at autopsy. Equilibration was calculated as the specific radioactivity of cholesterol in the arterial tissue relative to that in the plasma (percent).In specimens obtained 2-4 days after pulse labeling, the specific activity of cholesterol in atheroma ranged from 0.3 to 4.5% of that in the plasma. By 17-27 days, the relative specific activity ranged from 6 to 20% in different arteries. In contrast, cholesterol of skeletal muscle had a relative specific activity of 96% by 22 days. By 61-96 days, atheroma cholesterol in the abdominal aorta, common iliac, and femoral arteries had equilibrated to 55, 30, and 26%, respectively. In the patient who died at 96 days, the cholesterol in the coronary arteries had a mean equilibration of 66%, similar to the values for the abdominal (66%) and thoracic (57%) aortas. The route of administration of the isotope did not influence the equilibration.Within the atheromatous plaque, the superficial layers equilibrated better than the deeper layers (75% vs. 22%). The free cholesterol in the atheroma equilibrated to a significantly higher extent than did esterified cholesterol (59% vs. 38%). There was a fourfold higher specific activity of cholesterol in the media than in the corresponding intima (916 vs. 230 dpm/mg).The estimated minimal influx rates of plasma cholesterol into the atheromatous intima ranged from 0.065 to 0.274 mg of cholesterol/g dry tissue per day for different arteries. The approximated turnover times of atheroma cholesterol ranged from 442 days for the abdominal aorta and the coronary arteries to 580 days for the common iliac and 821 and 934 days, respectively, for the femoral and the carotid arteries.These data indicate a definite, though slow, exchange of cholesterol between the plasma and severely atherosclerotic human arteries. Within the atheroma, there are multiple pools of cholesterol, each turning over differently and more slowly than the cholesterol of most other tissues, such as the skeletal muscle. The estimates of influx rate and turnover time of atheroma cholesterol suggest the possibility that this cholesterol is mobilizable, an indication of potential regression of atheromatous lesions in man.     

Cardiovascular complications of cocaine abuse.

Cocaine abuse may lead to serious cardiac complications, including myocardial ischemia and infarction, myocarditis, cardiomyopathy and arrhythmias. With concomitant use of alcohol and cocaine, cocaethylene is produced by hepatic transformation. Cocaethylene is now thought to be primarily responsible for the deaths that occur among cocaine abusers. Treatment of cardiovascular complications focuses on cocaine-induced ischemia, hypertension and arrhythmias. The use of thrombolytic agents in myocardial infarction remains controversial. Concurrent detoxification with bromocriptine and norepinephrine is recommended.     

Cholesterol embolism: the great masquerader.

Embolization of cholesterol crystals from ulcerated atheromatous lesions can produce distinct syndromes that mimic more common disease processes. Cholesterol emboli can present as renal failure, hypertension, spells of numbness, abdominal pain, and myocardial infarction, or as a multisystem disease that closely approximates the presentation, clinical course, and even biopsy picture of polymyositis or periarteritis nodosa. A review of this problem with particular attention to the clinical presentations should help in the early diagnosis and treatment of cholesterol emboli and avoid unnecessary and inappropriate therapies.     

Acute myocardial infarction as a complication of clonidine withdrawal

Abrupt withdrawal from clonidine therapy is a well-known cause of hyperadrenergic symptoms, but reports of acute myocardial infarction are extremely rare. We present the case of an 86-year-old woman who developed severe hypertension and a myocardial infarction 36 h after terminating her therapy of clonidine, 0.4 mg/day. Symptoms quickly responded to the administration of labetolol and diazepam. Subsequent cardiac catheterization showed no evidence of coronary occlusion, suggesting that excessive myocardial oxygen demand was responsible for the infarction.     

Cross-sectional survey of beta-blockers use in primary and secondary care for patients with arterial disease

Beta-blockers reduce mortality in ischaemic heart disease and, when given perioperatively, in vascular surgery. We investigated the use of and attitudes towards beta-blockers by British vascular surgeons and primary care physicians (GPs). We performed a cross-sectional postal survey by questionnaire sent to 367 GPs and 397 members of the Vascular Surgical Society. Specific questions related to beta-blockers use and indications. Two hundred and thirty-four GPs, 95 full-time vascular surgeons (VS) and 137 general surgeons (GS) with a vascular interest responded. Thirty-eight percent of VS and 16% of GS often or always used perioperative beta-blockade (p<0.001). Common indications were ischaemic heart disease (39.2%), hypertension (30.6%), arrhythmia (16.3%) and myocardial protection (6.9%). Sixty-eight percent of VS and 42% of GS would prescribe beta-blockers to patients with occlusive arterial disease (p < 0.001). Common indications were ischaemic heart disease (39.6%), hypertension (29.2%) and arrhythmia (13.3%). Of those who would not prescribe beta-blockers in occlusive arterial disease, 65% felt that beta-blockers were contraindicated in this condition. GPs widely regarded occlusive arterial disease as a contraindication to beta-blockade. Beta-blockers are underused by GPs and GS especially, perhaps because of a perceived risk of side effects in patients with occlusive arterial disease. Further evidence is needed on the effect of beta-blockade on quality of life of patients with arterial disease.     

脉管康复片心脑血管作用的实验研究

目的：观察脉管康复片对实验动物心脑血管的药理效应。方法：应用脉管康复片分别对实验动物模型进行实验研究。与华佗再遭丸相对照。观察脉譬康复片对大鼠心肌坏死的保护作用、对麻醉大鼠缺血再灌注心律失常和脯质过氧化物的保护作用、对丝裂霉素细胞中毒性心肌损伤的保护作用、对大鼠琐动脉血检形成的抑制作用和对家兔血脂及动脉粥样斑块形成的影响。蛄果：实验蛄果证明．脉管康复片具以下作用：（1）明显增加冠状动脉血流量，能明显地缩小心肌梗死范围，保护弄丙肾上腺与所致大鼠心肌坏死的作用。（2）保持心肌细胞氧化和抗氧化平衡，阻断脂质过氧化连锁反应．降低细胞内Ca”超负荷，减少CK-MB肆从心肌蛔胞中涡出。（3）对心肌起微蛄构损伤。特别是肌原歼堆及细胞质损伤有明显的保护作用。（4）对大鼠颈动脉血栓有抑制作用。有促进表皮蛔胞合成井释放PGl4，而不影响TXA2生物合成的歼溶作用。（5）能明显抑制家鬼血清肛回醇升高作用，对动脉粥样斑形成有抑制和消除作用．抗高脂血癌，不增加主动脉、肝脏及肾上腺蛆织内的脂质含量。姑论：脉管康复片对·0脑血管具有良好的保护作用。可作为心脑血管痰病治疗的一线药物应用。     

Modified Lipoproteins,Cytokines and Macrovascul Disease in Non-insulin-dependent Diabetes Mellitus

The processes of glycation and oxidation play a significant role in the acceleration of atherosclerosis in diabetes mellitus. Glycation is thought not only to increase the susceptibility of low-density lipoprotein (LDL) to oxidation but also to enhance the propensity of vessel wall structural proteins to bind extravasated plasma proteins, including LDL, and thus to contribute to a more marked oxidative modification of LDL. Glycated and oxidized lipoproteins induce cholesteryl ester accumulation in human macrophages and may promote platelet and endothelial cell dysfunction. Furthermore, these modified lipoproteins have the ability to trigger an autoimmune response that leads to the formation of autoantibodies and subsequently to the formation of immune complexes containing LDL. Both the modified lipoproteins and the immune complexes formed with autoantibodies reactive with modified lipoproteins may be responsible for several alternative and not mutually exclusive pathways leading to foam cell formation, macrophage activation and endothelial cell damage and may thus be of potential significance in initiating and/or contributing to the acceleration of the development of atherosclerosis. In this review we discuss how modified LDL affects lipoprotein metabolism, how immune complexes containing LDL induce the transformation of macrophages into foam cells and promote macrophage activation leading to the release of cytokines and thus initiating a sequence of events leading to endothelial cell damage and to the recruitment and activation of leucocytes. We also summarize our work showing that macrophage activation by LDL containing immune complexes leads to a paradoxical increase in LDL-receptor expression thus further impairing cholesterol homeostasis and enhancing the development of atheromatous lesions.     

Effects of cardiovascular therapy on risk of the development of ischemia and myocardial infarction in the postoperative period in cancer patients with ischemic heart diseases]

Analysis of 636 surgical interventions for malignant tumors in 576 chronic coronary patients showed that beta-blockers decreased the relative risk of ischemia and myocardial infarction during the postoperative period. Calcium antagonists verapamil and dihydropyridines also essentially decreased the probability of myocardial infarction and less so of myocardial ischemia. Antiischemic effect of nitrates was insignificant, and they increased the risk of myocardial infarction. Antioxidants did not prevent ischemia but significantly decreased the risk of infarction. Therapy with non-fractionated heparin involved the risk of ischemia and myocardial infarction. The causes of low cardioprotective effects of nitrates and heparin can be explained by the discontinuation syndrome, which increases the risk of exacerbation of coronary disease during the postoperative period.     

Prevention of ventricular fibrillation, acute myocardial infarction (myocardial necrosis), heart failure, and mortality by bretylium: is ischemic heart disease primarily adrenergic cardiovascular disease?

It is widely, but mistakenly, believed that ischemic heart disease (IsHD) and its complications are the sole and direct result of reduced coronary blood flow by obstructive coronary artery disease (CAD). However, cardiac angina, acute myocardial infarction (AMI), and sudden cardiac death (SCD) occur in 15%-20% of patients with anatomically unobstructed and grossly normal coronaries. Moreover, severe obstructive coronary disease often occurs without associated pathologic myocardiopathy or prior symptoms, ie, unexpected sudden death, silent myocardial infarction, or the insidious appearance of congestive heart failure (CHF). The fact that catecholamines explosively augment oxidative metabolism much more than cardiac work is generally underappreciated. Thus, adrenergic actions alone are likely to be more prone to cause cardiac ischemia than reduced coronary blood flow per se. The autonomic etiology of IsHD raises contradictions to the traditional concept of anatomically obstructive CAD as the lone cause of cardiac ischemia and AMI. Actually, all the signs and symptoms of IsHD reflect autonomic nervous system imbalance, particularly adrenergic hyperactivity, which may by itself cause ischemia as in rest angina. Adrenergic activity causing ischemia signals cardiac pain to pain centers via sympathetic efferent pathways and tend to induce arrhythmogenic and necrotizing ischemic actions on the cardiovascular system. This may result in ischemia induced metabolic myocardiopathy not unlike that caused by anatomic or spasmogenic coronary obstruction. The clinical study and review presented herein suggest that adrenergic hyperactivity alone without CAD can be a primary cause of IsHD. Thus, adrenergic heart disease (AdHD), or actually adrenergic cardiovascular heart disease (ACVHD), appears to be a distinct entity, most commonly but not necessarily occurring in parallel with CAD. CAD certainly contributes to vulnerability as well as the progression of IsHD. This vicious cycle, which explains the frequent parallel occurrence of arteriosclerosis and IHD, an association that appears to be linked by the same cause, comprises a common vulnerability to deleterious adrenergic actions on the myocardium, lipid metabolism, and vascular system alike, rather than viewing CAD and IsHD as having a putative cause and effect relationship as commonly thought. Adrenergic actions can also cause the abnormal lipid metabolism that is associated with CAD and IsHD by catecholamine-induced metabolic actions on lipid mobilization by activation of phospholipases. This may also be part of toxic catecholamine hypermetabolic actions by enhancing deleterious cholesterol and lipid actions in damaging coronary vessels by plaque formation as well as inducing obstructive coronary spasm and platelet aggregation. This may also cause direct toxic necrosis on the myocardium as well as atherosclerosis in blood vessels. In fact, drugs that inhibit adrenergic actions like propranolol, reserpine, and guanethidine all inhibit arteriosclerosis induced by hypercholesterolemia in experimental animals and prevent carotid vascular disease (associated with stroke) in humans. The concomitant development of myocardiopathy and coronary vascular lesions or coronary and carotid artery intimal medial thickening by catecholamine toxicity is reflected by the frequent primary presentation of patients with catecholamine-secreting pheochromocytoma with cardiovascular disease, ie, hypertension arrhythmias, AMI, SCD, CHF, and vascular disease, which represents a clear example of the primary deleterious impact of catecholamines on the entire cardiovascular system causing adrenergic cardiovascular disease. Thus, like myocardiopathy, CAD and atherosclerosis in general may be the consequences of or a complication of catecholamine actions rather than its putative cause. This report shows how prophylactic bretylium not only prevents arrhythmias but prevents myocardial necrosis, shock, CHF, maintains or restores normal contractility, and lowers mortality in AMI patients by inducing adrenergic blockade.     

Acute myocardial infarction associated with initial cocaine use

We have described a young man who had acute myocardial infarction after his first use of cocaine. This case demonstrates that potentially lethal myocardial infarctions may be associated with such initial "experimentation" with cocaine even in relatively small doses. Cocaine intoxication should be considered in young patients with acute myocardial ischemia or necrosis. We recommend that cocaine metabolites be checked in the urine if a drug history is unreliable in such patients.     

Association of differing dietary, metabolic, and clinical risk factors with macrovascular complications of diabetes: a prevalence study of 503 Mexican type II diabetic subjects. I

Macrovascular and microvascular complications of diabetes may be associated with different environmental factors. To investigate this further, a prevalence study of 503 Mexican type II diabetic subjects was carried out while their patterns of nutrition were constrained by government food subsidies. Average daily dietary intakes were 1866 kcal; 46.5% as carbohydrate, 13.7 mmol cholesterol, 8.7 g fiber, and a polyunsaturated/saturated fat ratio of 0.98. With respect to macrovascular disease, 49.3% of patients had evidence of peripheral vascular disease, and 21.6% myocardial ischemia, 6.0% angina, 10.8% EKG evidence of ischemia, 4.8% EKG evidence of myocardial infarction. Only 1.2% (six patients) had a clear history of completed stroke, and all were hypertensive. Six patients had also undergone amputations for diabetic gangrene. Tabulation of the means of clinical characteristics according to presence or absence of myocardial ischemia showed that higher cholesterol, calorie, and fat intake, higher mean blood pressure, higher serum cholesterol, and serum triglyceride levels were found in those with myocardial ischemia. Patients with peripheral vascular disease were more commonly smokers. Stepwise logistic regression revealed significant positive associations between myocardial ischemia and dietary cholesterol, serum cholesterol, and mean blood pressure. In contrast, the presence of peripheral vascular disease was significantly related only to smoking and retinopathy. There were no associations between macrovascular complications and duration of diabetes in the multivariate analysis, and they occurred with equal frequency in men and women. Prospective studies of atherosclerosis in maturity-onset diabetes should assess and seek to modify dietary cholesterol, serum cholesterol, and hypertension.     

Abnormalities in the regulation of sympathetic activity in human hypertension

Various biochemical, pharmacologic, and physiologic techniques were used to evaluate the sympathetic tone and reactivity in labile and sustained hypertension in humans. The results of these studies suggest the existence of an important subgroup of hypertensive patients characterized by increased basal sympathetic tone and reactivity to standing. Such abnormalities could be the result of various dysfunctions, involving the activity of central and peripheral cardiovascular sympathetic fibers, the presynaptic modulation of sympathetic fibers (including the interaction with the parasympathetic system), the inactivation of circulating norepinephrine, and the sensitivity of the efferent cells. The increase in circulating norepinephrine in a group of hypertensive patients seems to reflect a functional increase in the sympathetic tone as shown by the presence of hyperkinetic cardiac functions in hyperadrenergic patients (elevated catecholamine levels), while cardiac functions are normal in normoadrenergic patients (catecholamine levels within normal range). Moreover, the better hypotensive response, combined with normalization of the basal and reactive circulating norepinephrine levels following beta-blockade in hyperadrenergic hypertensive patients, strongly supports the participation of the sympathetic system in the maintenance of hypertension in those patients. The identification and characterization of this subpopulation of patients may be helpful in the development of more rational therapeutic approaches and could eventually permit us to devise better predictors of outcome in hypertension.     

Reduction of infarct size in a rat model of regional myocardial ischemia and reperfusion by the synthetic peptide DAHK

OBJECTIVE: The increased mobilization of iron and copper during ischemia is reported to contribute to postischemic injury. DMI-4983 is a small synthetic peptide, Asp-Ala-His-Lys (DAHK), that mimics the high-affinity copper-binding site of the N-terminus of human albumin. This peptide was reported to inhibit copper-induced formation of reactive oxygen species in vitro, reduce interleukin-8 formation in cultured endothelial cells, and improve left ventricular function after global ischemia and reperfusion in the isolated blood-perfused heart of the rat. The aim of this study was to investigate the effects of DMI-4983 on myocardial infarct size caused by regional ischemia and reperfusion in vivo. DESIGN: Rats were subjected to regional myocardial ischemia (25 mins) followed by reperfusion (2 hrs). Randomized groups received either vehicle or DMI-4983 administered as a 5, 10, or 20 mg/kg intravenous bolus along with a 10 mg/kg/hr continuous infusion starting just before reperfusion and continuing throughout the experiment. Infarct size was determined at the end of the experiment. SETTING: Basic research institute and trauma research laboratory. SUBJECTS: Anesthetized male Wistar rats. MEASUREMENTS AND MAIN RESULTS: The area at risk of infarction and hemodynamic variables were similar in all groups. Rats treated with vehicle resulted in an infarct size of 64% +/- 3% of the area at risk of infarction. Intravenous administration of DMI-4983 reduced infarct size to 52% +/- 3%, 50% +/- 2%, and 45% +/- 3% of the area at risk of infarction for 5, 10, and 20 mg/kg, respectively (p < .05 compared with vehicle for each dosage). CONCLUSIONS: Intravenous DMI-4983 administered before the onset of reperfusion and continuously throughout the reperfusion period caused a significant reduction in tissue necrosis in this in vivo model of regional myocardial ischemia and reperfusion, suggesting that DMI-4983 may represent a novel approach for the treatment of myocardial ischemia and reperfusion injury.     

Beta-blockers, diuretics and physical fitness as determinants of serum lipids in myocardial infarction patients

Serum lipid levels were followed in myocardial infarction patients for one year after the infarction and related to their drug use and physical performance. Serum triglyceride concentrations were significantly elevated in patients using diuretics or diuretics and beta-blockers together both 3 and 12 months after the infarction when compared to patients not having drugs. The beta-blockers alone did not change triglycerides. No differences were found in total cholesterol concentration between any of the drug groups. The HDL cholesterol levels were significantly lower in all the drug groups 12 months after the infarction in comparison with the group using no drugs, but 3 months after the infarction these differences were not present. Total work in the exercise stress test correlated negatively with serum triglycerides and total cholesterol and positively with HDL/total cholesterol ratio in the group using no drugs 12 months after the infarction. In beta-blocker users, total work correlated negatively with triglyceride and total cholesterol concentrations. In all drug groups no correlation between total work and HDL/total cholesterol ratio could be found. These data suggest that despite differences in the physical working capacity between the groups, the drugs themselves are major determinants of differences in serum lipids.     

Mechanisms of target organ damage caused by hypertension: therapeutic potential

Hypertension is a major risk factor for cardiovascular mortality and morbidity through its effects on target organs like the brain, heart, and kidney. Structural alterations in the microcirculation form a major link between hypertension and target organ damage. In this review, we describe damages related to hypertension in these target organs and the mechanisms involved in the pathogenesis of hypertension-induced cardiovascular diseases such as dementia, cardiac ischemia and remodeling, or nephropathy. We also focus on the therapeutical potential on the basis of such mechanisms. Several antihypertensive agents like diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin II (Ang II) receptor antagonists, beta-blockers, or calcium channel blockers (CCBs) have been shown to reduce effectively hypertension associated cardiovascular events and to improve end organ damage. More recently, aldosterone antagonism has also shown beneficial effects. Part of the favorable effects of these agents is due to blood pressure lowering as such. Other mechanisms such as oxidative stress, inflammation, or endothelial dysfunction have appeared to play a key role in the pathogenesis of target organ damage and therefore represent another important pathway for therapy. In this review, we discuss the different therapeutic approaches aiming at reducing cardiovascular events and damages induced by hypertension.     

Cardiac troponin may be released by ischemia alone,without necrosis

Whilst it is formally stated that cardiac troponin is only released when cardiac myocytes undergo necrosis, there are a number of clinical situations where troponin is present in the circulation, without any apparent cardiac injury. In these cases, troponin half-life in the circulation is usually substantially shorter than that seen when troponin is released following myocardial infarction with frank necrosis.A mechanism has been described in liver, where large cytoplasmic molecules can pass from the intra- to extra-cellular space without cellular necrosis occurring. This occurs by the formation of membranous blebs which bud off from the plasma membrane of the cell. Blebs develop during cellular ischemia. If the ischemia is limited and re-oxygenation occurs, the blebs may be released into the circulation without rupture of the plasma membrane, resulting in a one-off release of cytoplasmic contents including macromolecules.Evidence from cardiac studies is presented supporting the presence of membranous blebs in cardiac myocytes, enabling troponin to be released from cardiac cells due to ischemia alone, without necrosis.     

Mitochondrial function: the heart of myocardial preservation

Over the past several decades, it has become widely recognized that the mitochondria serve an important role in energy production and transfer to myocardial cells. More recently, mitochondria have been shown to play a key role in cell-death pathways by activating mitochondrial permeability transition pore formation and causing the release of several proteins, such as cytochrome c and proapoptotic factors. Although the molecular mechanisms for this process are still under investigation, important mitochondrial adaptations have been identified that can inhibit permeability transition activation and prevent apoptosis and necrosis. Specifically, myocardial preconditioning is an intriguing adaptation by which brief ischemia and reperfusion prime the mitochondria so that a subsequent prolonged period of ischemia is better tolerated. Mitochondrial ATP-dependent potassium channels seem to play a critical role in triggering or mediating this protection. The objective of this review is to outline the role of the mitochondria in supporting myocardial energy under normal and ischemic conditions. It will also provide insight into the mechanisms by which mitochondrial signaling in preconditioning can protect the myocyte during subsequent prolonged ischemic periods.