Extent Of Myocardial Ischemic Injury Research Articles

Limitation of Infarct Size and the Open Artery Hypothesis: A Conversation With Eugene Braunwald, MD.

Eugene Braunwald received an MD from the New York University School of Medicine. He completed an internal medicine residency at Johns Hopkins Hospital and cardiology fellowships at Mount Sinai Hospital, Columbia University, and the National Heart Institute. He served as chief of cardiology and subsequently clinical director of the institute. From 1968 to 1972, he was the founding chair of medicine at the University of California, San Diego. From 1972 to 1996, he served as chair of medicine at the Brigham and Women’s Hospital. In 1975, he was elected to the National Academy of Sciences. He is now the Distinguished Hersey Professor of Medicine at Harvard Medical School and a senior investigator of the TIMI Study Group, which he founded in 1984. Dr Braunwald replies: I became aware of the importance of AMI in 1951 during an elective in cardiology during my senior year at the New York University School of Medicine. At the time, AMI was by far the most common cause of death in adults in the United States. Of the patients who survived to be admitted to hospitals (no one knew how many AMI patients failed to reach hospital emergency departments), about one third died before discharge, either suddenly, presumably from an arrhythmia, or secondary to pump failure. Of the patients who were discharged alive, about one quarter died within a year, most frequently as a consequence of heart failure or recurrent MI. Pathologists had taught that AMI was usually associated with coronary thrombosis. Indeed, during my cardiology elective, Herrick’s classic article describing AMI was required reading. Its title, “Clinical Features of Sudden Obstruction of the Coronary Arteries,” showed how these 2 conditions (coronary occlusion and AMI) were intertwined.1 My direct involvement in the care of several patients who did not survive the acute event left …

Early evolution from ischemia to myocardial necrosis.

The presence, age, and extent of myocardial ischemic injury can be determined with some precision using pathologic techniques. Electron microscopic studies can detect very early ischemic injury, only minutes old, even before irreversible injury (i.e., necrosis) is present; however, because of the small amount of tissue sampled, ultrastructural studies are not very useful for quantifying the size of the ischemic zone. Histologic studies can detect irreversible injury only hours old, and because large samples can be studied, the necrotic zone can be measured quite efficiently. In addition, the age of the infarct can be determined. The knowledge gleaned from such morphologic studies continues to contribute to the development of new diagnostic tests and therapies for patients with ischemic heart disease.

Osmotic shock: modulation of contractile function, pHi, and ischemic damage in perfused guinea pig heart.

To determine the contribution of changes in extracellular osmolarity to ischemic injury, isolated guinea pig hearts were perfused with hyposmotic (220 mosM) or hyperosmotic (380 mosM) buffer. 31P NMR spectroscopy was used to follow changes in intracellular pH (pHi) and energetics. Hyposmotic buffer decreased myocardial developed pressure by 30 +/- 2% and pHi by 0.02 +/- 0.01 unit, whereas hyperosmotic buffer increased myocardial developed pressure by 34 +/- 1% and pHi by 0.14 +/- 0.01 unit. All hearts recovered to control values on restoration of isosmotic (300 mosM) buffer. The hyperosmolar-induced intracellular alkalosis and developed pressure increase were not prevented by inhibition of Na+/H+ exchange with use of 1 microM HOE-642 but were abolished with use of bicarbonate-free buffers. After 20 min of total global ischemia, hearts perfused with hyposmotic buffer showed significantly greater recoveries of developed pressure, phosphocreatine, and ATP than control hearts, but hearts perfused with hyperosmotic buffer did not recover after ischemia. In conclusion, buffer osmolarities between 220 and 380 mosM alter myocardial pHi and developed pressure but are not deleterious during perfusion. However, buffer osmolarity significantly alters the extent of myocardial ischemic injury.

Computer model analysis of the relationship of ST-segment and ST-segment/heart rate slope response to the constituents of the ischemic injury source

The objective of the study was to investigate a proposed linear relationship between the extent of myocardial ischemic injury and the ST-segment/heart rate (ST/HR) slope by computer simulation of the injury sources arising in exercise electrocardiographic (ECG) tests. The extent and location of the ischemic injury were simulated for both single- and multivessel coronary artery disease by use of an accurate source-volume conductor model which assumes a linear relationship between heart rate and extent of ischemia. The results indicated that in some cases the ST/HR slope in leads II, aVF, and especially V 5 may be related to the extent of ischemia. However, the simulations demonstrated that neither the ST-segment deviation nor the ST/HR slope was directly proportional to either the area of the ischemic boundary or the number of vessels occluded. Furthermore, in multivessel coronary artery disease, the temporal and spatial diversity of the generated multiple injury sources distorted the presumed linearity between ST-segment deviation and heart rate. It was concluded that the ST/HR slope and ST-segment deviation of the 12-lead ECG are not able to indicate extent of ischemic injury or number of vessels occluded.

31P-MRS study of bio-energy recovering phenomenon

The ATP and creatine phosphate (PCr) contents in isolated guinea-pig hearts were determined by 31P-MRS measurement at 80.75 MHz using the Langendorff technique. Reperfusion of post-ischemic hearts with adenosine for 180 minutes increased ATP to 117.4% and decreased PCr to 59.8% of the preischemic value. Reperfusion without adenosine did not increase ATP and did not decrease PCr. The depressed cardiac function due to ischemia was remarkably improved in post-ischemic hearts by the increase in ATP due to adenosine. We found that the loss of ATP due to ischemia is not necessarily proportional to the extent of myocardial ischemic injury.

Influence of left ventricular dimensions on endocardial and epicardial QRS amplitude and ST-segment elevations during acute myocardial ischemia.

The influence of acute myocardial ischemia and changes in ventricular dimensions on endocardial and epicardial electrograms were evaluated in 17 anesthetized open-chest dogs before and after left ventricular volume expansion and before and after coronary artery ligation. In eight dogs, regional myocardial blood flow was determined by the labeled microsphere technique. Endocardial QRS (endo-QRS) amplitude in ischemic and nonischemic zones, and epicardial QRS (epi-QRS) in nonischemic zones maintained a negative linear relation with left ventricular end-diastolic dimension before and after coronary artery ligation, although acute ischemia decreased endo-QRS independently. Epi-QRS amplitude in the ischemic zone decreased after coronary artery ligation but changed inconsistently during volume expansion. Ischemia-induced epicardial ST-segment elevation decreased during volume expansion and was associated with improved epicardial blood flow. Changes in epi-QRS in ischemic zones, however, were not related to epicardial blood flow during volume expansion. These findings indicate the potential problems of using changes in QRS amplitude for determining the extent of myocardial ischemic injury.

Influence of left ventricular dimensions on endocardial and epicardial qrs amplitude and st segment elevations during acute myocardial ischemia

The influence of acute myocardial ischemia and changes in ventricular dimensions on endocardial and epicardial electrograms were evaluated in 17 anesthetized open-chest dogs before and after left ventricular volume expansion and before and after coronary artery ligation. In eight dogs, regional myocardial blood flow was determined by the labeled microsphere technique. Endocardial QRS (endo-QRS) amplitude in ischemic and nonischemic zones, and epicardial QRS (epi-QRS) in nonischemic zones maintained a negative linear relation with left ventricular end-diastolic dimension before and after coronary artery ligation, although acute ischemia decreased endo-QRS independently. Epi-QRS amplitude in the ischemic zone decreased after coronary artery ligation but changed inconsistently during volume expansion. Ischemia-induced epicardial ST-segment elevation decreased during volume expansion and was associated with improved epicardial blood flow. Changes in epi-QRS in ischemic zones, however, were not related to epicardial blood flow during volume expansion. These findings indicate the potential problems of using changes in QRS amplitude for determining the extent of myocardial ischemic injury.

The single precordial lead for ST segment monitoring: Comparison with the multiple lead map

ST segment elevation, used as an index of the relative extent of myocardial ischemic injury, was measured using a single precordial lead located at the point of maximum ST elevation. ST changes were followed for two hours after acute coronary occlusion in pigs, and were compared to the sum of ST elevation recorded with an 18 lead precordial map. Some animals were subjected to Reperfusion (n = 12), others to infarct extension (n = 10), while a control group (n = 9) was followed without an ST-modifying intervention. Correlation between ΣST and ST in the single lead was good, with a correlation coefficient of 0.844 at 360 points of comparison. Time to peak ST elevation using the single lead technique was comparable to that using the 18 lead map. Changes in the ST elevation using both techniques were similarly reduced following reperfusion, increased following extension, and followed a similar downslope pattern in the unmodified infarct group. This single lead technique offers the advantage of simplicity of use without sacrifice of accuracy. Its use can facilitate clinical studies of myocardial ischemic injury and its modification.

Effects of increased arterial pressure and positive inotropic agents on the severity of myocardial ischemia in the acutely depressed heart

Recently it has been established that factors that affect myocardial oxygen consumption also influence the magnitude and extent of ischemic injury. In the nonfailing heart when mean arterial pressure was increased, the extent of ischemic injury decreased and, after isoproterenol or digitalis administration, ischemic injury increased. However, agents such as digitalis and catecholamines can have differing effects on myocardial oxygen consumption, depending on the initial contractile state and heart size. Moreover, since many patients with acute myocardial infarction have an associated depression of left ventricular function, the relevance of the earlier findings to the failing heart must be considered. The present study was undertaken to examine the effects of systemic arterial hypertension, digitalis and isoproterenol on the extent of myocardial ischemic injury after acute pharmacologic depression of the dog heart. Following card̄iac depression in 22 experiments, when mean arterial pressure was increased from 110 to 145 mm Hg, mean S-T segment elevation increased from 3.6 to 4.7 mv ( P < 0.05). In 6 acutely depressed left ventricles, ouabain (0.03 mg per body weight kg) resulted in a decrease in mean S-T elevation from 4.2 to 1.5 mv ( P < 0.01), whereas the average left atrial pressure decreased from 25.3 to 11.1 mm Hg. In 3 of 10 studies, administration of isoproterenol in small doses produced a positive inotropic and chronotropic effect on the depressed heart but failed to increase the extent of ischemic injury. These studies indicate that the effects of hemodynamic and pharmacologic interventions can depend on the prior functional status of the left ventricle. Thus, in contrast to findings in the nonfailing heart, in the presence of acute experimental cardiac depression, elevation of systemic arterial blood pressure to above normal levels after coronary occlusion can result in the extension of ischemic injury, whereas digitalis can decrease the extent of myocardial ischemic injury.

Effects of intraaortic balloon counterpulsation on the severity of myocardial ischemic injury following acute coronary occlusion. Counterpulsation and myocardial injury.

The effects of intraaortic balloon counterpulsation (IABC) on the magnitude and severity of myocardial ischemic injury were studied in 19 dogs following acute coronary occlusion and in two patients with cardiogenic shock. In the experimental group, epicardial electrocardiograms were taken from 10-14 sites on the anterior surface of the left ventricle following occlusion of the left anterior descending coronary artery or its apical branch. The average S-T-segment elevation ([see Equation in PDF File]) was used as an index of the magnitude of myocardial ischemic injury. In six dogs, two successive 20-min occlusions were performed, and IABC was started prior to the second occlusion. [see Equation in PDF File] 15 min following occlusion decreased from 3.3 ± 0.9 mv after the control occlusion to 1.4 ± 0.4 mv ( P &lt; 0.01) after the occlusion with IABC. In three dogs in which the occlusion was maintained and IABC initiated 30 min later, [see Equation in PDF File] decreased from 1.2 to 0.6 mv. In six dogs in which IABC was started 3 hours after occlusion, it induced a reduction of [see Equation in PDF File] from 4.2 ± 1.1 to 2.8 ± 1.0 mv ( P &lt; 0.01). In four dogs, ischemic injury was augmented by isoproterenol infusion (0.25 µg/kg/min), and while continuing the infusion IABC was initiated. It reduced [see Equation in PDF File] from 8.0 ± 1.9 to 5.7 ± 1.8 mv ( P &lt; 0.05). Thus, IABC reduced the magnitude and extent of myocardial ischemic injury after experimental coronary occlusion, both when IABC was employed prior to, and 3 hours following, coronary occlusion. IABC was also effective in reducing myocardial ischemic injury which had been increased by isoproterenol infusion. Employing a noninvasive technic, which utilizes 35 electrodes on the thorax, the effects of IABC were examined in two patients with cardiogenic shock associated with acute myocardial infarction. Preliminary observations in these patients confirmed the experimental results indicating that IABC reduced myocardial ischemic injury.

Precordial S-T segment elevation mapping: An atraumatic method for assessing alterations in the extent of myocardial ischemic injury: The effects of pharmacologic and hemodynamic interventions

A noninvasive technique for evaluating the extent of myocardial ischemic injury after experimental coronary artery occlusion was devised and applied to study alterations in the extent of injury produced by hemodynamic and pharmacologic interventions. The technique was then extended to the assessment of myocardial ischemic injury in patients with acute myocardial infarction. In 7 closed chest dogs, electrocardiograms were recorded from 15 sites on the chest wall before and after intermittent occlusions of the left anterior descending coronary artery. There was no S-T segment elevation before the occlusion; 15 minutes after occlusion the sum of S-T segment elevations (ΣS-T) averaged 15.0 ± 3.0 mm (SEM, 1 mm deflection = 0.1 mv), and an average of 4.2 ± 0.6 sites exhibited elevations exceeding 0.1 mv (NS-T). Occlusions occurring during administration of isoproterenol (0.25 μg/kg per min) increased ΣS-T to 51.0 ± 9.0 mm and NS-T to 10.6 ± 0.9, whereas occlusions occurring after administration of propranolol (1 mg/kg) decreased ΣS-T to 3.0 ± 1.5 mm and NS-T to 0.2 ± 0.2. In 8 dogs the extent of ischemic injury, manifested by S-T segment changes, was decreased by propranolol and norepinephrine and increased by hemorrhagic hypotension and isoproterenol, applied up to 6 hours after occlusion. Reproducible S-T segment maps, using 35 surface electrodes, were obtained in 19 patients with acute myocardial infarction. In 15 patients studied serially, ΣS-T decreased from 54.25 ± 7.00 to 38.50 ± 6.30 mm and NS-T from 18.7 ± 2.5 to 12.3 ± 2.8, respectively, during a 24 hour period. However, in 3 patients in whom ventricular fibrillation, arterial hypotension and further ischemic pain occurred, ΣS-T and NS-T increased whereas in another patient propranolol decreased ΣS-T and NS-T. Thus, precordial mapping, both in dogs and patients, shows changes parallel to those measured by the epicardial technique and should provide a useful clinical tool for determining acute changes in the extent of ischemic injury.