Myocardial protection during bypass and arrest. A possible hazard with lactate-containing infusates

Severe myocardial tissue damage may results from the use of prolonged ischemic arrest during cardiac surgery. A number of experimental and clinical studies have been reported in which various protective agents have been infused into the coronary vessels before the onset of ischemia in an attempt to reduce or delay this damage. Although these agents are undoubtedly able to protect the ischemic myocardium, their efficacy may be considerably reduced or enhanced by the composition of the medium in which these agents are dissolved. In experiments with a rat heart model of bypass and ischemic arrest, we found that lactate-based media are detrimental to optimal tissue protection.     

Effects of lidocaine, phenytoin and quinidine on the ischemic canine myocardium

The effects of therapeutic concentrations of lidocaine, quinidine and phenytoin on the electrograms and excitability of ischemic canine myocardium were investigated. The threshold stimulation current was determined as the minimum current necessary to drive the ventricles at 300 msec intervals. Administration of the drugs did not change the threshold stimulation current of the control myocardium, but lidocaine (P less than 0.002), quinidine (P less than 0.01) and phenytoin (P less than 0.05) all markedly increased the threshold stimulation current of the ischemic tissue. The effects on the electrograms were small but consistent with current electrophysiological knowledge. This selective depression of the electrical activity of the ischemic tissue may form an important mechanism of action of these antiarrhythmic agents. However, this same effect may under certain conditions precipitate serious arrhythmias.     

Glycoprotein IIb/IIIa receptor antagonists in the management of cardiovascular diseases

Recent studies of the effects of glycoprotein (GP) IIb/IIIa receptor antagonists on the clinical outcomes of patients with cardiovascular diseases are reviewed. The GP IIb/IIIa receptor antagonists studied include abciximab (a murine monoclonal antibody); eptifibatide (a synthetic peptide); and tirofiban, lamifiban, xemilofiban, sibrafiban, and lefradafiban (synthetic nonpeptides). A majority of clinical trials of GP IIb/IIIa receptor antagonists have been performed in patients with unstable angina or acute myocardial infarction and in patients undergoing percutaneous coronary interventions in whom an intracoronary thrombus may lead to ischemic complications. There is abundant evidence that GP IIb/IIIa receptor antagonists reduce the risk of death, acute myocardial infarction, and urgent revascularization procedures in high- and low-risk patients undergoing percutaneous coronary interventions. Abciximab remains the most studied of these agents in interventional settings. Data are accumulating on synthetic peptide and nonpeptide GP IIb/IIIa receptor antagonists that also demonstrate lower rates of death and ischemic complications in the treatment of acute coronary syndromes. In patients who have had a successful response to intravenous GP IIb/IIIa receptor antagonists, oral agents may represent an option for secondary prevention. Additional studies are required in order to determine further uses for these agents. A growing body of evidence supports the role of GP IIb/IIIa receptor antagonists in invasive and pharmacologic treatment approaches to acute coronary syndromes.     

Local immunoglobulin G antibodies in the stomach may contribute to immunity against Helicobacter infection in mice

The central nervous system consumes 20% of the cardiac output for normal function. The neurons are very sensitive to the effects of ischemia. Cessation of cerebral blood flow results in severe damage to neurons and other brain structures. This is secondary to a combination of energy loss, excessive excitation promoting intracellular calcium (Ca2+) buildup, relative lack of inhibitory responses, generation of oxygen free radicals (especially during the reperfusion period) and several other destructive cascades. Medications that antagonize the effects of glutamate at post-synaptic receptors are either ineffective or have serious side-effects. Ca2+ entry blockers have shown disappointing results in clinical trials in patients with acute cerebral infarction. Data with protective effects of oxygen free radical scavengers in the post-ischemic period have shown conflicting results. There is recent interest with the use of agents that increase cerebral inhibitory responses after an ischemic insult. Such agents are effective when used before, during or up to 4 hours after the ischemic insult. Many such medications have few side-effects and are in clinical use for other indications. This review will summarize inhibitory mechanisms that may be important in cerebral ischemia, and provide experimental evidence for their potential efficacy.     

New strategies for intraoperative myocardial protection

In the past, most strategies for intraoperative myocardial protection were developed in models using nondiseased adult hearts from various animal species. In the clinical setting, however, myocardial status in cardiac patients may be quite different and there is a need to adapt our current protective strategies to the actual pathophysiological status of the heart. In the immature heart as well as in the senescent heart, current protective techniques have been shown to be deficient and further research is required. New insights have been gained into the pathophysiological processes underlying chronic ischemic left ventricular dysfunction in the "hibernating" myocardium. It has been shown that viability in these hearts is associated with subcellular alterations related to dedifferentiation of the myocytes. This finding explains the delayed recovery in function of these hearts after revascularization and the need for intraoperative protective strategies focusing on the prevention of stunning in the nonhibernating segments. Tepid continuous retrograde blood cardioplegia is suggested as the optimal technique. Unraveling the mechanisms of preconditioning in the heart and understanding endogenous myocardial protection may provide clues for novel cardioprotective techniques. Adenosine itself may be used as an adjunct to cardioplegia, and treatment with adenosine regulating agents or nucleoside transport inhibitors shows promising results. Like adenosine, other hyperpolarizing agents (potassium-channel openers) are suggested for arrest of the heart instead of the depolarizing agents commonly used in cardioplegia. Finally, the role of Na(+)-H+ exchange in the development of ischemic and postischemic injury has become more clear. By the use of a new selective Na(+)-H+ exchange inhibitor, postischemic contracture can be dramatically reduced and contractility improved. This opens prospective approaches in emergency coronary bypass surgery for evolving myocardial infarction.     

Children''s spiritual response: validation of the nursing diagnosis spiritual distress

A variety of new radiopharmaceutical agents have been introduced to probe myocardial function in vivo. This review will introduce these new techniques which have recently been available in Japan. Tc-99m perfusion imaging agents provide excellent myocardial perfusion images which may enhance diagnostic accuracy in the study of coronary artery disease. In addition, greater photon flux from the tracer permits simultaneous assessment of regional perfusion and function with use of first-pass angiography or ECG-gated acquisition. Positron emission tomography enables metabolic assessment in vivo. Preserved FDG uptake indicates ischemic but viable myocardium which is likely to improve regional dysfunction after revascularization. In addition, FDG-PET seems to be valuable for selecting a high risk subgroup. Recently I-123 BMIPP, a branched fatty acid analog, has been clinically available in Japan. Less uptake of BMIPP than thallium is often observed in the ischemic myocardium. Such perfusion metabolic mismatch which seems to be similarly observed in FDG-PET is identified in the stunned or hibernating myocardium with regional dysfunction. Both of them are likely to recover afterwards. Severe ischemia is identified as reduced BMIPP uptake at rest, suggesting its role as an ischemic memory imaging. I-123 MIBG uptake in the myocardium reflects adrenergic neuronal function in vivo. In the study of coronary artery disease, neuronal denervation is often observed around the infarcted myocardium and post ischemic region as well. More importantly, reduced MIBG uptake in these patients can identify high risk for ventricular arrhythmias and assess severity of congestive heart failure. These new techniques will provide insights into new pathological states in the ischemic heart disease and enable to select optimal treatment in these patients.     

The acute coronary ischemic syndromes--the central role of thrombosis

The postulate that thrombotic coronary occlusion was the underlying pathophysiologic event in the acute coronary ischemic syndromes was developed over the years 1912-60. This concept prompted the development of anticoagulant and thrombolytic therapies and the use of acetylsalicylic acid in such patients. A central role for coronary thrombus came to be questioned in the 1970s and the use of anticoagulants dramatically decreased and thrombolytic therapy was little used. Coronary angiographic studies among patients during the early hours of evolving myocardial infarction re-established the etiologic role of coronary thrombosis in the acute coronary ischemic syndromes, and were supplemented by careful autopsy studies. The concepts of meta-analysis lead to more accurate interpretations of earlier randomized, controlled trials of anticoagulant, antiplatelet and thrombolytic therapies. Large clinical trials have provided confirmatory evidence and have established the benefits of antiplatelet and thrombolytic agents in the acute ischemic syndromes. The benefit of long term anticoagulation following myocardial infarction has been demonstrated, although the benefit during the acute in-hospital phase of myocardial infarction is still uncertain. Currently, clinical trials are evaluating new antithrombins, antiplatelet agents, and thrombolytic agents and regimens among patients with unstable angina, acute myocardial infarction, and undergoing angioplasty for complex coronary lesions.     

Animal models of perinatal asphyxia: contributions, contradictions, clinical relevance

Animal models have contributed immensely to our understanding of hypoxic ischemic encephalopathy in the newborn. A number of animal models have been used, including both primate and subprimate species. Although the Rhesus monkey model has a dramatically similar pathological distribution of brain injury when compared with the human, other pathologic processes secondary to asphyxia may be more appropriately assessed in other species. The maxim that because primates are closer on the phylogenetic tree to humans than are subprimates all observations in the primate are applicable to the human is simply not true. Understanding of the neurochemical consequences of asphyxia in the past decade have arisen from experiments primarily in the neonatal rat. We have come to understand that not only is the hypoxic event of major significance, but that, once reperfused, reoxygenation causes further injury. Free-radical generation following reperfusion may be massive and may further contribute to cell membrane injury. These observations have lead to rational theoretic approaches to the treatment of hypoxic ischemic brain injury. On the other hand, previously used treatments such as osmotic agents and glucocorticoids would appear to be not only inefficacious but hazardous in the treatment of hypoxic ischemic brain injury. The role of nitric oxide (NO) in the pathogenesis of brain injury is yet uncertain, but there is little doubt that it plays a significant role. Although survival of the immature animal subjected to hypoxic environment is longer than in the mature animal, the central nervous system of the immature animal is more sensitive to glutamate and N-Methyl-D-aspartate (NMDA) receptor-mediated injury.     

Antiarrhythmic versus antifibrillatory actions: inference from experimental studies

Pathophysiology of the coronary circulation is a major contributor to altering the myocardial substrate, rendering the heart susceptible to the onset of arrhythmias associated with sudden cardiac death. Antiarrhythmic drug therapy for the prevention of sudden cardiac death has been provided primarily on the basis of trial and error and in some instances based on ill-suited preclinical evaluations. The findings of the Cardiac Arrhythmia Suppression Trial (CAST) requires a reexamination of the manner in which antiarrhythmic drugs are developed before entering into clinical testing. The major deficiency in this area of experimental investigation has been the lack of animal models that would permit preclinical studies to identify potentially useful or deleterious therapeutic agents. Further, CAST has emphasized the need to distinguish between pharmacologic interventions that suppresses nonlethal disturbances of cardiac rhythm as opposed to those agents capable of preventing lethal ventricular tachycardia or ventricular fibrillation. Preclinical models for the testing of antifibrillatory agents must consider the fact that the superimposition of transient ischemic events on an underlying pathophysiologic substrate makes the heart susceptible to lethal arrhythmias. Proarrhythmic events, not observed in the normal heart, may become manifest only when the myocardial substrate has been altered. We describe a model of sudden cardiac death that may more closely simulate the clinical state in humans who are at risk. The experimental results show a good correlation with clinical data regarding agents known to reduce the incidence of lethal arrhythmias as well as those showing proarrhythmic actions.     

Effects of renal cytoprotective agents on erythrocyte membrane stability

To elucidate potential mechanisms of ischemic renal injury, investigators often use drugs that interfere with specific pathological pathways and study their protective efficacy in in vitro models of ischemia, such as isolated renal proximal tubules subjected to hypoxia. However, the protective effects of certain drugs may depend on non-specific membrane-stabilizing properties. We have studied the effects of several drugs on membrane integrity using osmotic lysis of erythrocytes as a model system. Freshly isolated rabbit erythrocytes were subjected to a hypotonic shock, and the protective effects of various calcium channel blockers, phospholipase inhibitors, free fatty acids, the NO-synthase inhibitor L-NAME, the amino acid glycine and its receptor-analogue strychnine, and two chloride channel blockers were examined. Most agents protected erythrocytes against hypotonic hemolysis when added to the medium in the same concentration range as used in suspensions of hypoxic proximal tubules. Only the protective agents that proposedly act via a blockade of chloride influx (glycine, strychnine and the chloride channel blockers), did not attenuate hypotonic hemolysis. The erythrocyte hemolysis assay may provide an easy and rapid method to screen for non-specific membrane-stabilizing effects of potentially cytoprotective agents.     

Implementation of legislative requirements for emergency medical services in prepaid group practice organizations

This study was based on the concept that intracellular accumulation of calcium plays a role in mediating ischemic myocardial injury and that inhibition of entry of calcium into cells may have a salutary effect on the ischemic heart. Nifedipine, a potent vasodilator and inhibitor of transmembrane calcium flux, was infused into the aortic root of 6 dogs (5 microgram/kg/hr) during 2 hours of myocardial ischemia while on cardiopulmonary bypass. Seven control animals received normal saline at the same flow rate and temperature (20 degrees C). The results showed that none of the 7 control animals were able to maintain adequate aortic pressure or cardiac output after 30 to 60 minutes of normothermic reperfusion. All had marked left ventricular failure and were unresponsive to large doses of inotropic agents. In contrast, the 6 dogs treated with nifedipine were weaned from bypass either without difficulty or requiring small doses of calcium chloride and norepinephrine. Light microscopy demonstrated more marked ischemic damage in the control group than in the group of drug-treated dogs. We conclude that the concept of inhibition of transmembrane calcium flux offers a new and potent method for myocardial preservation during ischemia.     

Retinal and optic nerve head ischemic disorders and atherosclerosis: role of serotonin

Ischemic disorders of the retina and optic nerve head (OPH) constitute a common cause of visual loss in the middle-aged and elderly population. These disorders have a high association with atherosclerosis. This review has considered the various aspects of atherosclerosis and its role, as well as that of serotonin, in the development of ischemic disorders of the retina and ONH. It is known that when platelets aggregate on an atheromatous plaque, serotonin is one of the agents released. Studies in experimental atherosclerotic monkeys have shown that, although serotonin has no effect on ocular vasculature in normal monkeys, in atherosclerotic monkeys it produces vasopasm of the central retinal artery (CRA) and/or posterior ciliary artery (PCA) in various combinations but not vasopasm of the arterioles in the retina; vasospasm of the CRA and/or PCA(s) can consequently cause transient, complete occlusion or impaired blood flow in these arteries. It is postulated that in some atherosclerotic individuals this mechanism may play an important role in the development of ischemic disorders of the retina and ONH, including amaurosis fugax, (CRA) occlusion and anterior ischemic optic neuropathy, and possibly also glaucomatous optic neuropathy, particularly in normal tension glaucoma. Studies have also shown that dietary treatment of atherosclerosis abolishes or markedly improves the serotonin induced vasoconstriction within a few months. All these considerations may have important implications for our understanding of the pathogenesis and management of these blinding disorders.     

A review of vasomotor responses of arterioles on the surface of the mouse brain: the necessary prelude to studies using genetically manipulated mice

OBJECTIVE: To review the published data concerning the vasomotor responses of arterioles on the surface of the mouse brain. This information is essential to the planning of studies using genetically manipulated mice to investigate the control of cerebral vascular resistance. RESULTS: Cerebral vasomotor responses of mice have been reported using a wide variety of vasoactive agents. The responses are usually like those of other laboratory animals. Some agents are capable of eliciting opposing dilating and constricting responses. The initial tone of the arteriole is one of several factors that can determine the direction of the response elicited by such agents. Endothelium-dependent dilators and constrictors have been described. There are a variety of endothelium-derived relaxing factors (EDRFs). Only one of these is synthesized by nitric oxide synthase (NOS). Antisense data suggests that both the endothelial and the neuronal isoforms of NOS may exist in the endothelial cells of these vessels. Several diseases can be modeled in mice and cerebrovascular responses studied. Studies of genetically modified mice suggest that the endothelial form of NOS contributes to microvascular events, which limit ischemic damage to brain parenchyma. However, during and following ischemia there may be loss of this NOS or inability to mobilize a storage form of the EDRF, which it produces. CONCLUSIONS: Data available from studies of mice provide a good basis for planning further studies, examining cerebrovascular control mechanisms in health and disease, by workers now using genetically modified mice. The latter represent a powerful and increasingly popular tool for this purpose.     

The role of prophylactic fasciotomy and medical treatment in limb ischemia and revascularization

Multiple studies have demonstrated that muscle poorly tolerates ischemia. When the ischemic state is unduly prolonged, the successfully replanted or revascularized limb undergoes deleterious biochemical reactions that cascade to vessel intimal damage, increased vessel permeability, and lowering of pH. The resultant tissue edema leads to increasing compartment pressures, which not only impede the recovery of function, but also can lead to irreversible muscle necrosis, increased risk of infection, and sepsis if not reversed in a timely fashion. The development of compartment syndrome jeopardizes not only the injured limb, but life itself secondary to the biochemical toxins produced by the ischemic extremity. A thorough understanding of the biochemistry of ischemia and reperfusion provides insight into the role of fasciotomy in the replanted or revascularized extremity. The scientific basis for fasciotomy in the revascularized or replanted limb is discussed as well as the potential "protective" role of pharmacologic agents in ischemic and reperfusion injury.     

Induction of increased cardiac tolerance against damage--a new therapeutic principle?

In animal experiments, brief periods of myocardial ischemia have shown to improve cardiac tolerance against a subsequent ischemic exposure. We argue that ischemic preconditioning may be only one example of a general protective biological adaption to harmful stimuli. We refer to several studies indicating that ischemic preconditioning may occur in patients, e.g. during episodes of angina pectoris, or during percutaneous transluminal coronary angioplasty or cardiac surgery. The phenomenon has also been demonstrated in cultured human myocytes after anoxic periods. In the future, therefore, it may be possible to use suitable drugs to induce higher ischemic tolerance in patients with cardiac disorders. It may also be possible to induce protection against other harmful stimuli. Extensive research is necessary, however, to reveal the underlying mechanisms and choose the most suitable procedures.     

Contrast-enhanced transcranial color-coded duplex sonography in ischemic cerebrovascular disease

BACKGROUND AND PURPOSE: Echo contrast agents have been shown to provide conclusive examinations in most patients with insufficient ultrasound penetration through the temporal bone. We investigated the diagnostic value of contrast-enhanced (CE) transcranial color-coded duplex sonography (TCCD) in patients with ischemic cerebrovascular disease and insufficient temporal windows and evaluated TCCD criteria that predict whether CE-TCCD studies may become conclusive. METHODS: Thirty-three patients presenting with ischemic strokes (n = 21) and transient ischemic attacks (n = 12) were investigated. Extracranial color duplex imaging showed normal findings in 24 patients, eight > or = 70% stenoses and one occlusion of the carotid arteries in 8 patients, and severe occlusive disease of both vertebral arteries in 1 patient. Seven carotid stenoses and vertebral artery obstructions were confirmed by angiography. The galactose/palmitic acid-based echo contrast agent was injected intravenously as bolus of 200, 300, or 400 mg/mL in a dosage of 10, 5, and 5 mL, respectively. RESULTS: Thirty-two of the 33 patients were completely examined because 1 patient who felt pain at the injection site declined further investigations. Twenty-one (66%) of 32 CE studies were conclusive and showed cross-flow through three anterior and two posterior communicating arteries, but no stenoses and occlusions. Precontrast identification of any cerebral artery provided an overall accuracy of 97% in predicting a conclusive CE investigation. Precontrast TCCD identified no arterial Doppler signals in patients with inconclusive CE studies. CONCLUSIONS: CE-TCCD provided conclusive examinations in two thirds of patients with ischemic cerebrovascular disease and ultrasound-refractory temporal windows. Precontrast detection of any cerebral artery reliably predicted a conclusive CE investigation.     

Whither paediatric dentistry?

The noninvasive assessment of myocardial viability in patients with coronary artery disease and depressed left ventricular function has proven clinically useful for identifying those patients with ischemic cardiomyopathy who benefit most from coronary revascularization. Thallium-201 (201Tl) imaging at rest has been the radionuclide imaging technique most often utilized for distinguishing viable myocardium from scar. However, new technetium-99m (99mTc) perfusion agents such as 99mTc-sestamibi and 99mTc-tetrofosmin have emerged as alternatives to 201Tl for imaging of regional myocardial perfusion. Whether these new agents, which have better physical properties for imaging with a gamma camera than 201Tl, are valid for use in assessing myocardial viability is still uncertain. Recent clinical studies have demonstrated that these agents, when imaged using quantitative SPECT, can identify patients with myocardial hibernation who exhibit improved regional systolic function following revascularization. Experimental laboratory studies have shown that the uptake of 99mTc-sestamibi and 99mTc-tetrofosmin in ischemic myocardium is only slightly lower than the uptake of 201Tl. These 99mTc-labeled agents remain bound intracellularly in mitochondria of viable myocytes under conditions of myocardial stunning and short-term hibernation, producing severe myocardial asynergy. With respect to determination of viability, the inferior wall region is at times problematic since attenuation of 99mTc-sestamibi and 99mTc-tetrofosmin is greatest in this area. Demonstration of preserved systolic thickening on ECG-gated SPECT images is indicative of viability in the instance of decreased regional 99mTc counts due to attenuation and not scar. Administration of nitrates prior to tracer injection improves the sensitivity for identifying viable myocardial segments using rest imaging with 99mTc-sestamibi or 99mTc-tetrofosmin. Thus, it appears that the new 99mTc perfusion imaging agents can be successfully employed for the determination of myocardial viability in the setting of severe regional dysfunction and chronic coronary artery disease. The greater the myocardial uptake of these agents in the resting state, the greater the probability of improved systolic function after coronary revascularization.     

Secondary prevention of myocardial infarct

Preventive measures are the most powerful measures to treat manifestations of ischemic cardiopathy. Secondary prevention of myocardial infarction involves the following intervention areas: a) Limitation of adverse physiological and emotional consequences of the acute illness; b) Identification of the patients particularly exposed to the risk of new episodes of ischemic cardiopathy or to their consequences, namely reinfarction and sudden death; c) Institution of therapeutic attitudes, surgical or medical, that can prolong life and can oppose functional deterioration and prevent symptoms; d) Institution of measures that can oppose the progression of the initial disease that is, in almost all cases, atherosclerosis. Measures that can oppose the progression of cardiac disease and its consequences after an episode of myocardial infarction, and measures that can oppose the evolution of atherosclerosis are described in this article. The measures that can influence the risk factors after an episode of myocardial infarction are briefly commented: characteristics related to life style and physical exercise; smoking habits; plasmatic lipid levels; high blood pressure; and therapeutic substitution with estrogens after menopause. Pharmacological interventions in secondary prevention of myocardial infarction are described, namely with the following groups of substances: beta-adrenergic blocking agents; platelet active agents; anticoagulants; and angiotensin-converting enzyme inhibitors.     

Elevation of plasma angiotensinogen in rats with experimentally induced nephrosis

Oxidant injury contributes to myocardial stunning, and cardiac ischemic and reperfusion injury. Vitamin E is the major--and perhaps the only--lipid soluble, chain-breaking antioxidant in the heart. Vitamin E and its analogues potentially offer significant advantages for the prevention of ischemic and reperfusion injury. Recent investigations have suggested that modified vitamin E analogues may be more efficacious than vitamin E and may permit myocardial salvage from acute myocardial ischemic injury.     

Use of platelet glycoprotein IIb/IIIa receptor inhibitors in acute coronary syndrome and coronary intervention

New strategies in the treatment of acute coronary syndromes have focused on the potential for blocking platelet aggregation through the use of platelet surface membrane glycoprotein (GP) IIb/IIIa receptor inhibitors. The benefits of GPIIb/IIIa inhibition in preventing ischemic complications of interventional treatment have been well defined in patients with unstable angina. In the future, major therapeutic applications for this class of agents may include the stabilization of patients with unstable angina and potentially as single medical therapy, as several recently completed trials have suggested. This article attempts to review recently published clinical trials regarding the use of GPIIb/IIIa receptor inhibitors, and clarify current problems in the use of this agent and directions for future investigation.