Ischemic/reperfused myocardium can express recombinant protein following direct DNA or retroviral injection.

A non-contracting scar following myocardial infarction can adversely affect ventricular topography and hemodynamic function. Gene transfer has the potential to prevent or alter such pathophysiological processes. Normal myocardium is a proven target for delivery of DNA or viral vectors but the potential for gene therapy in ischemic myocardium has not been evaluated.

Transmural channels can protect ischemic tissue. Assessment of long-term myocardial response to laser- and needle-made channels.

Background: We previously found that transmural laser channels failed to acutely increase myocardial blood flow. Nevertheless, this method is being used to treat patients with coronary artery disease who are unable to undergo angioplasty or bypass graft surgery and in cases in which previous surgery has failed. To reconcile the lack of an acute increase in blood flow with beneficial effects claimed in patients, our hypothesis was that the channel-making process might, over time, stimulate a protective effect, possibly by the growth of new vessels linking channels to the existing circulation.

Does ischemic preconditioning trigger translocation of protein kinase C in the canine model?

Background: Brief episodes of ischemia protect or "precondition" the heart and reduce the size of infarcts caused by subsequent sustained coronary artery occlusion, yet the mechanisms responsible for this cardioprotection remain unresolved. We tested the theory that translocation of protein kinase C (PKC) to the myocyte membranes, initiated in response to brief preconditioning ischemia and manifest during the initial minutes of the sustained occlusion, mediates this phenomenon by attempting to (1) blunt the cardioprotective effects of preconditioning by administration of the PKC inhibitors H-7 and polymyxin B, (2) visualize by fluorescence staining and confocal microscopy changes in the amount or location of PKC, and (3) quantify by incorporation of 32P into PKC-specific peptide changes in the subcellular distribution of PKC in preconditioned versus control hearts.

Methods And Results: In the first three limbs of this study, anesthetized open-chest dogs underwent four 5-minute episodes of preconditioning ischemia or a comparable control period before 1 hour of sustained occlusion and 4 to 5 hours of reperfusion.

Echocardiographic and cardiac Doppler assessment of mice.

Recent studies have suggested that intermediate-frequency M-Mode transthoracic echocardiographic imaging is a promising method for evaluating the left ventricle in transgenic mice. However, there is a paucity of data regarding two-dimensional (2-D) echocardiography and cardiac Doppler echocardiography in this model. Therefore we studied 15 mice (body weights 38 to 65 gm) with an ultrasound system equipped with a 9 MHz transducer.

Effect of two perfluorocarbon emulsions on reperfusion injury after coronary artery occlusion in rabbits.

Because of their high oxygen-carrying capability and small particle size, it has been suggested that perfluorochemical emulsions may be useful to reduce reperfusion injury after coronary artery occlusion and reperfusion. We tested the ability of Fluosol and a more concentrated perfluorochemical emulsion (perflubron) to decrease infarct size in anesthetized rabbits undergoing 30 min of coronary occlusion and 4 h of reperfusion. All rabbits were ventilated with 100% oxygen.

Transient pre-ischemic acidosis protects the isolated rabbit heart subjected to 30 minutes, but not 60 minutes, of global ischemia.

Adenosine released during brief episodes of ischemia, due to the breakdown of ATP, is thought to be an endogenous mediator of ischemic preconditioning. In this study we sought to determine whether protons, also released from ATP during ischemia, may protect the heart from sustained ischemic insult. Experiments were performed in isolated Langendorff-perfused rabbit hearts.

Effect of amlodipine on left ventricular mass in the Amlodipine Cardiovascular Community Trial.

As part of the Amlodipine Cardiovascular Community Trial (ACCT), which was a large multicenter study designed to assess the effects of the calcium channel blocker amlodipine besylate (Norvasc) as monotherapy for treatment of mild to moderate hypertension, we sought to determine the effects of amlodipine on regression of left ventricular (LV) hypertrophy (LVH). The study began with a 2-week placebo run-in period (baseline), before which antihypertensive drugs had been discontinued. Amlodipine was then administered at 5-10 mg/day during a 4-week titration/efficacy period.

Low-dose i.v. acetylcholine acts as a "preconditioning-mimetic" in the canine model.

Brief episodes of ischemia paradoxically protect or "precondition" the heart and reduce infarct size caused by a subsequent, more sustained, coronary artery occlusion, perhaps by stimulation of adenosine receptors coupled to muscarinic receptors via the inhibitory G protein. However, brief ischemia is not a desirable form of therapy. Using the anesthetized canine model, we therefore sought to determine if small intravenous (i.

Clinical aspects of preconditioning and implications for the cardiac surgeon.

Ischemic preconditioning is one of the most powerful means to reduce myocardial ischemic cell death in the experimental laboratory. Data are now emerging suggesting that ischemic preconditioning also can occur in the human heart. Studies performed on human myocardial biopsies, angioplasty studies, clinical studies assessing acute tolerance to angina, and some studies evaluating the effect of angina prior to myocardial infarction, lend support to the concept that the human heart can be preconditioned.

An experimental model examining the role of magnesium in the therapy of acute myocardial infarction.

In conclusion, considering the results from our model, magnesium infusion is effective as adjunct therapy to enhance myocardial salvage in the setting of acute myocardial infarction. However, its effectiveness may be limited to a subset of patients whose magnesium therapy can be started early and combined with early reperfusion therapy.

Gender does not influence acute myocardial infarction in adult dogs.

Mechanisms responsible for the well-documented "protection" against myocardial ischemia and infarction in young women and subsequent loss of protection after menopause remain speculative. One possibility is that gender-related variables (such as endogenous hormone levels or regular loss of stored iron) alter the susceptibility of the heart to ischemia: if so, then premenopausal women when compared with men may manifest endogenous protection against acute myocardial ischemic injury. Using the canine model we therefore sought to determine whether gender influences acute myocardial ischemia and infarction.

Basic view on the pathobiology of myocardial ischemia during coronary angioplasty: implications for cardiac protection.

PTCA is not only an effective therapeutic tool but a unique opportunity to study the pathobiology of the human myocardium during ischemia and reperfusion. In addition, it is a good model to assess potential therapeutic interventions. Studies performed during PTCA contributed significantly to the understanding of the metabolic, electrophysiologic, hemodynamic, and coronary perfusion changes in the human heart following coronary occlusion.

Quantitative two-dimensional echocardiographic assessment of regional wall motion during transient ischemia and reperfusion in the rat.

Nonlethal myocardial ischemia produces profound and long-lasting effects on regional ventricular function and metabolism (myocardial stunning) and protects against myocardial infarction from subsequent prolonged ischemia (ischemic preconditioning). Two-dimensional echocardiography (2DE) is an essential tool for quantitative analysis of regional and global left ventricular (LV) function during myocardial ischemia and reperfusion and the study of these phenomena. However, the inability to perform 2DE in the open-chest rat heart has seriously limited the use of this model.

Preconditioning stimuli and inadvertent preconditioning.

There are several factors besides brief episodes of total coronary occlusion which can provide sufficient stress to result in a preconditioning-like effect on the size of a myocardial infarction. Partial coronary artery stenosis, hypoxia, stretch, catecholamines, rapid pacing, and certain pharmacologic therapies may provide preconditioning stimuli. These same factors as well as mechanical complications in which a coronary artery is briefly occluded or stenosed prior to a subsequent coronary occlusion may lead to inadvertent preconditioning and confound the results of experimental cardiology studies.

Do antioxidant vitamins reduce infarct size following acute myocardial ischemia/reperfusion?

There is controversy concerning the ability of antioxidant vitamins to reduce myocardial infarct size. We sought to determine whether a brief prophylactic treatment of vitamin C or vitamin C plus Trolox (a water-soluble form of vitamin E) could reduce myocardial infarct size in an experimental model. We used an anesthetized open-chest rabbit model in which a branch of the circumflex coronary artery was ligated for 30 minutes followed by 4 hours of reperfusion.

Is There a Gender Difference in Infarct Size and Arrhythmias Following Experimental Coronary Occlusion and Reperfusion?

It has been suggested that there may be gender differences in the outcome of myocardial infarction and therapies. However, there is a lack of knowledge regarding the basic science of gender difference in the setting of experimental myocadial infarction. Therefore, we performed a randomized study to determine whether there is a gender-related difference in infarct size as well as arrhythmias in an experimental model of myocardial infarction.

Pathobiology and Clinical Impact of Reperfusion Injury.

Reperfusion injury refers to cellular death or dysfunction caused by restoration of blood flow to previously ischemic tissue. This should be differentiated from the normal reparative processes that follow an ischemic insult. Four types of reperfusion injury have been described in the literature: (1) lethal reperfusion injury, (2) nonlethal reperfusion injury (myocardial stunning), (3) reperfusion arrhythmias, and (4) vascular injury (including the "no-reflow" phenomenon).

Previous angina alters in-hospital outcome in TIMI 4. A clinical correlate to preconditioning?

Background: Ischemic preconditioning has been shown to reduce myocardial infarct size in experimental models, but its role in patients remains unclear. Angina before myocardial infarction reflects brief episodes of ischemia and may be a marker of preconditioning. As part of the Thrombolysis in Myocardial Infarction (TIMI) 4 study, we performed an analysis on the effect of a history of previous angina on in-hospital outcomes for patients with acute myocardial infarction.

Does protein kinase C play a role in ischemic preconditioning in rat hearts?

Protein kinase C (PKC) has been implicated in the cardioprotective effects of ischemic preconditioning in rabbits, but whether it plays a role in rats is unknown. We tested this preconditioning PKC theory by assessing whether the inhibition of PKC with calphostin C, a potent and specific inhibitor of PKC, can block the preconditioning effects in this model. Four groups of rats were studied: 1) control + vehicle, 2) control + calphostin C, 3) preconditioning + vehicle, and 4) preconditioning + calphostin C.