Out-of-hospital administration of intravenous glucose-insulin-potassium in patients with suspected acute coronary syndromes: the IMMEDIATE randomized controlled trial.

Context: Laboratory studies suggest that in the setting of cardiac ischemia, immediate intravenous glucose-insulin-potassium (GIK) reduces ischemia-related arrhythmias and myocardial injury. Clinical trials have not consistently shown these benefits, possibly due to delayed administration.

Objective: To test out-of hospital emergency medical service (EMS) administration of GIK in the first hours of suspected acute coronary syndromes (ACS).

Study design for the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care (IMMEDIATE) Trial: A double-blind randomized controlled trial of intravenous glucose, insulin, and potassium for acute coronary syndromes in emergency medical services.

Background: Experimental studies suggest that metabolic myocardial support by intravenous (IV) glucose, insulin, and potassium (GIK) reduces ischemia-induced arrhythmias, cardiac arrest, mortality, progression from unstable angina pectoris to acute myocardial infarction (AMI), and myocardial infarction size. However, trials of hospital administration of IV GIK to patients with ST-elevation myocardial infarction (STEMI) have generally not shown favorable effects possibly because of the GIK intervention taking place many hours after ischemic symptom onset. A trial of GIK used in the very first hours of ischemia has been needed, consistent with the timing of benefit seen in experimental studies.

Diastolic dysfunction after coronary artery bypass grafting--the effect of glucose-insulin-potassium infusion.

Background: Glucose-insulin-potassium (GIK) infusion improves clinical outcome after coronary artery bypass surgery (CABG). The mechanism of benefit is unclear, but GIK limits ischemia and reperfusion injury. This study was designed to assess whether the clinical benefit of perioperative GIK infusion is mediated through reduction in the severity of diastolic dysfunction that occurs after CABG.

Unveiling gender differences in demand ischemia: a study in a rat model of genetic hypertension.

Objective: Female gender is associated with reduced tolerance against acute ischemic events and a higher degree of left ventricular hypertrophy under chronic pressure overload. We tested whether female and male rats with left ventricular hypertrophy present the same susceptibility to demand ischemia.

Methods: Hearts from hypertrophied female and male salt-resistant and salt-sensitive Dahl rats (n=8 per group) underwent 30min of demand ischemia induced by rapid pacing (7Hz) and an 85% reduction of basal coronary blood flow, followed by 30min of reperfusion on an isovolumic red cell perfused Langendorff model.

A challenge to the metabolic approach to myocardial ischaemia.

The negative results of glucose-insulin-potassium (GIK) in the very large CREATE-ECLA trial that studied 20,201 patients with ST-elevation acute myocardial infarction (AMI), are disappointing and warrant thorough evaluation. We attempt to put the new data into perspective and uncover the serious flaws in the trial design, otherwise the whole metabolic concept will be disparaged. The crucial issue, developed from basic science data, is that GIK should be initiated very early, before, or at the time of reperfusion.

Biphasic temporal pattern in exercise capacity after myocardial infarction in the rat: relationship to left ventricular remodeling.

After myocardial infarction (MI), there is progressive left ventricular (LV) remodeling and impaired exercise capacity. We tested the hypothesis that LV remodeling results in structural and functional changes that determine exercise impairment post-MI. Rats underwent coronary artery ligation (n = 12) or sham (n = 11) surgery followed by serial exercise tests and echocardiography for 16 wk post-MI.

Human amyloidogenic light chains directly impair cardiomyocyte function through an increase in cellular oxidant stress.

Primary amyloidosis is a systemic disorder characterized by the clonal production and tissue deposition of immunoglobulin light chain (LC) proteins. Congestive heart failure remains the greatest cause of death in primary amyloidosis, due to the development of a rapidly progressive amyloid cardiomyopathy. Amyloid cardiomyopathy is largely unresponsive to current heart failure therapies, and is associated with a median survival of less than 6 months and a 5-year survival of less than 10%.

Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.

Background: This study sought to determine whether tight glycemic control with a modified glucose-insulin-potassium (GIK) solution in diabetic coronary artery bypass graft (CABG) patients would improve perioperative outcomes.

Methods And Results: One hundred forty-one diabetic patients undergoing CABG were prospectively randomized to tight glycemic control (serum glucose, 125 to 200 mg/dL) with GIK or standard therapy (serum glucose <250 mg/dL) using intermittent subcutaneous insulin beginning before anesthesia and continuing for 12 hours after surgery. GIK patients had lower serum glucose levels (138+/-4 versus 260+/-6 mg/dL; P<0.

Increased myocardial dysfunction after ischemia-reperfusion in mice lacking glucose-6-phosphate dehydrogenase.

Background: Free radical injury contributes to cardiac dysfunction during ischemia-reperfusion. Detoxification of free radicals requires maintenance of reduced glutathione (GSH) by NADPH. The principal mechanism responsible for generating NADPH and maintaining GSH during periods of myocardial ischemia-reperfusion remains unknown.

Effects of AT1 receptor block begun late in life on normal cardiac aging in rats.

The goal of this study was to determine how short-term (12 weeks) angiotensin type I (AT1) block begun late in life affects aspects of myocardial biology and physiologic function altered by normal aging. Exercise capacity, myocardial morphology, histopathology, and coronary vascular function (degree of coronary vasodilation in response to adenosine) were evaluated in 53 Fischer 344 rats. Adult (6 months of age) and old (21 months of age) rats were studied after 12 weeks of either control drinking water, a low dose of candesartan that did not significantly lower blood pressure (1 mg/kg/d), or a high dose of candesartan (10 mg/kg/d).

Exercise intolerance during post-MI heart failure in rats: prevention with supplemental dietary propionyl-L-carnitine.

Exercise capacity in patients with several types of cardiovascular disease can be improved with dietary carnitine, or carnitine derivatives. Mechanisms underlying this improvement remain largely unknown in part due to a lack of animal models of cardiac pathology in which carnitine derivatives improve exercise tolerance. Our goal was to evaluate the ability of propionyl-L-carnitine (PLC) to improve exercise tolerance in a rat model of exercise intolerance.

Glucose-6-phosphate dehydrogenase modulates cytosolic redox status and contractile phenotype in adult cardiomyocytes.

Reactive oxygen species (ROS)-mediated cell injury contributes to the pathophysiology of cardiovascular disease and myocardial dysfunction. Protection against ROS requires maintenance of endogenous thiol pools, most importantly, reduced glutathione (GSH), by NADPH. In cardiomyocytes, GSH resides in two separate cellular compartments: the mitochondria and cytosol.

Imaging and diagnostic testing: diastolic dysfunction after coronary artery bypass grafting: a frequent finding of clinical significance not influenced by intravenous calcium.

Background: Diastolic dysfunction is common immediately after coronary artery bypass surgery (CABG). The duration of this phenomenon is unknown. Intravenous calcium is frequently administered during separation from cardiopulmonary bypass (CPB).

Mechanisms underlying ischemic diastolic dysfunction: relation between rigor, calcium homeostasis, and relaxation rate.

Increased diastolic chamber stiffness (upward arrow DCS) during ischemia may result from increased diastolic calcium, rigor, or reduced velocity of relaxation. We tested these potential mechanisms during severe ischemia in isolated red blood cell-perfused isovolumic rabbit hearts. Ischemia (coronary flow reduced 83%) reduced left ventricular (LV) contractility by 70%, which then remained stable.

Influence of gender on the response to hemodynamic overload after myocardial infarction.

After myocardial infarction (MI), the left ventricle (LV) undergoes ventricular remodeling characterized by progressive global dilation, infarct expansion, and compensatory hypertrophy of the noninfarcted myocardium. Little attention has been given to the response of remodeling myocardium to additional hemodynamic overload. Studies have indicated that gender may influence remodeling and the response to both MI and hemodynamic overload.

Infusion of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse hearts.

Background: Primary (AL) amyloidosis is a plasma cell dyscrasia characterized by clonal production of immunoglobulin light chains (LC) resulting in the subsequent systemic deposition of extracellular amyloid fibrils. Cardiac involvement is marked by the hemodynamic pattern of impaired diastolic filling and restrictive cardiomyopathy. Although cardiac death in patients with AL amyloidosis is usually associated with extensive myocardial infiltration, the infiltration alone does not correlated with the degree of heart failure or survival.

Mice lacking inducible nitric oxide synthase have improved left ventricular contractile function and reduced apoptotic cell death late after myocardial infarction.

Nitric oxide produced by inducible nitric oxide synthase (NOS2) has been implicated in the pathophysiology of chronic myocardial remodeling and failure. We tested the role of NOS2 in left ventricular (LV) remodeling early (1 month) and late (4 months) after myocardial infarction (MI) in mice lacking NOS2. MI size measured 7 days, 1 month, and 4 months after MI was the same in NOS2 knockout (KO) and wild-type (WT) mice.

Exercise training attenuates age-associated diastolic dysfunction in rats.

Background: In contrast to systolic function, which is relatively well preserved with advancing age, diastolic function declines steadily after age 30. Our goal was to determine whether changes in diastolic function that occur with aging could be reversed with exercise training. Methods and Results-- Adult (6-month-old) and old (24-month-old) Fischer 344/BNF1 rats were studied after either 12 weeks of treadmill training or normal sedentary cage life.

Left ventricular diastolic dysfunction during demand ischemia: rigor underlies increased stiffness without calcium-mediated tension. Amelioration by glycolytic substrate.

Objectives: The goal of this study was to determine the subcellular mechanism(s) underlying increased left ventricular (LV) diastolic chamber stiffness (DCS) during angina (demand ischemia).

Background: Increased DCS may result from increased diastolic myocyte calcium concentration and/or rigor. Therefore, we assessed the effects of direct alterations of both calcium-activated tension and high-energy phosphates on increased DCS.

Exaggerated left ventricular dilation and reduced collagen deposition after myocardial infarction in mice lacking osteopontin.

Osteopontin (OPN), an extracellular matrix protein, is expressed in the myocardium with hypertrophy and failure. We tested the hypothesis that OPN plays a role in left ventricular (LV) remodeling after myocardial infarction (MI). Accordingly, OPN expression and LV structural and functional remodeling were determined in wild-type (WT) and OPN knockout (KO) mice 4 weeks after MI.

Cell therapy attenuates deleterious ventricular remodeling and improves cardiac performance after myocardial infarction.

Background: Myocardial infarction (MI) promotes deleterious remodeling of the myocardium, resulting in ventricular dilation and pump dysfunction. We examined whether supplementing infarcted myocardium with skeletal myoblasts would (1) result in viable myoblast implants, (2) attenuate deleterious remodeling, and (3) enhance in vivo and ex vivo contractile performance.

Methods And Results: Experimental MI was induced by 1-hour coronary ligation followed by reperfusion in adult male Lewis rats.