Michael V. Cohen

Production of free radicals and lipid peroxides in early experimental myocardial ischemia.

Free radicals and lipid peroxides have recently been identified by us [1, 2, 3] as metabolic intermediates during acute myocardial ischemia. The mechanisms by which evolving myocardial ischemia initiates free radical production are not clear. Based on studies in vitro, it is feasible to consider the following possibilities: (a) dissociation of intramitochondrial electron support system and altered phospholipid integrity with inactivation of cytochrome oxidase, which results in release of ubisemiquinone, flavoprotein and superoxide radicals; (b) accumulation and increased release of intra/extracellular metabolites like NADH, lactate flavoproteins and catecholamines which react either with themselves or with O2 and ascorbic acid; (c) interaction of the metabolic product hypoxanthine with O2 in the presence of xanthine oxidase and (d) activation of phospholipase by calcium influx with enhanced arachidonic acid metabolism and superoxide radical production. Detailed in vitro radiobiological studies [4] have demonstrated that free radical reactions occur even at very low O2 tensions (83% of maximum rate of PO2 approximately 6 mmHg and 50% at PO2 approximately 1 mmHg), and Smith [5] has demonstrated that free radical peroxidation takes place quite rapidly in rat brain homogenates incubated in gas mixtures containing only 5% O2. Thus, the low oxygen tensions in ischemic tissue are adequate to support free radical reactions. The free radicals thus produced may initiate and enhance lipid peroxidation by attacking polyunsaturated membrane lipids.

Dobutamine echocardiography and resting-redistribution thallium-201 scintigraphy predicts recovery of hibernating myocardium after coronary revascularization

The value of dobutamine echocardiography and resting thallium-201 scintigraphy to predict reversal of regional left ventricular wall motion dysfunction after revascularization in patients with chronic coronary artery disease was assessed. Improvement in wall motion during dobutamine echocardiography and normal or mildly decreased uptake on thallium-201 scanning are strong predictors of reversible left ventricular dysfunction. Dobutamine echocardiography and resting thallium-201 scanning are simple and safe methods of assessing hibernating myocardium.

Effects of thyroid hormone on left ventricular function in patients treated for thyrotoxicosis

Systolic time intervals, echocardiographic indexes of left ventricular contractile function and serum triiodothyronine and thyroxine levels were measured before treatment in nine patients with hyperthyroidism, and again every 2 weeks for the first 2 months after therapy and then every 4 weeks until the subjects were clinically and chemically euthyroid. Six of the nine became transiently hypothyroid. Although the preejection period corrected for heart rate (preejection period index) increased as the patients became euthyroid, the change was not significant. Preejection period index increased dramatically in the patients becoming hypothyroid (p less than 0.005). Corrected left ventricular ejection time (left ventricular ejection time index) also increased as the patients became euthyroid (p less than 0.001), and increased again with the appearance of hypothyroidism (p less than 0.05). There was a linear correlation between velocity of circumferential fiber shortening and serum triiodothyronine level (r - 0.77) and between velocity of circumferential fiber shortening and serum thyroxine level (r = 0.70) at all stages of thyroid function. Thus thyroid hormone definitely enhances left ventricular function in human beings, and both excess and deficiency cause predictable reversible changes in myocardial contractile function. Thus thyroid hormone definitely enhances left ventricular function in human beings, and both excess and deficiency cause predictable reversible changes in myocardial contractile function. Furthermore echocardiographic measurements of velocity of circumferential fiber shortening provide rapid estimates of the chemical status of thyrotoxic patients before and after treatment.

Myocardial stunning in dogs: Preconditioning effect and influence of coronary collateral flow

In open-chest dogs the left anterior descending (LAD) coronary artery diagonal branch was encircled with a pneumatic occluder. Pairs of ultrasonic crystals were inserted into LAD myocardium and remote normal muscle. The coronary artery was occluded for 5 minutes, followed by 10 minutes of reperfusion. This occlusion-reperfusion cycle was repeated 12 times, and after a final 90-minute reperfusion period the hearts were removed and stained with triphenyltetrazolium chloride. No heart had evidence of necrosis. Baseline shortening normalized for end-diastolic length averaged 10.4 +/- 1.0% in the LAD area and 7.4 +/- 0.8% in the remote normal myocardium. When analyzed as a percentage of baseline, segment shortening in the normal myocardium was not significantly altered by LAD occlusion and reperfusion. In contrast, during occlusions the LAD myocardium paradoxically lengthened. With the initial reperfusion, shortening was significantly depressed to 28.6 +/- 8.6% of baseline. Although with subsequent reperfusions the return of function progressively decreased, the rate of deterioration was markedly attenuated after the first occlusion. By the end of the protocol many LAD segments lengthened paradoxically even after reperfusion, but in five hearts in which active contraction was preserved there was no significant change in regional function after the third cycle, suggesting a protective or preconditioning effect of earlier ischemia. There was a moderately good correlation between collateral blood flow and the degree of dysfunction following the initial 10-minute reperfusion (r = -0.73). This correlation deteriorated during subsequent reperfusion periods, implying that collateral blood flow can be a predictor of the extent of myocardial stunning only after the initial one or two reperfusion cycles. Thereafter other as yet unidentified factors make baseline collateral flow unimportant.

Constrictive pericarditis: early and late complication of cardiac surgery.

Constrictive pericarditis is not considered a complication of cardiac surgery. However, three cases are presented in which equalization of diastolic pressures and the ventricular pressure pattern of early diastolic dip-late diastolic plateau, characteristic of restrictive disease, appeared after cardiac surgery. In one patients cardiac constriction developed less than 2 weeks after surgery, and loculated clotted and unclotted viscous blood was removed from the pericardial space. In the other two patients the pericardial space was obliterated by dense adhesions. Thus constrictive pericarditis should be considered in postoperative patients who either do not recuperate satisfactorily after surgery or whose condition deteriorates after initial recovery.

Angiographic-echocardiographic correlation in mitral valve prolapse.

Abstract Although mitral valve prolapse is easily identified with echocardiography, the angiographic diagnosis has been poorly understood. To determine relative specificity and sensitivity of recently established radiologic diagnostic criteria, prospective comparison of left ventriculograms with echocardiograms and clinical observations in patients undergoing routine cardiac catheterization from 1975 to 1977 and retrospective review of earlier catheterization data have been performed. Four types of normal mitral valve configurations were determined during protodiastole in the right anterior oblique (RAO) projection of left ventriculograms by identifying the fulcrum, the point of attachment of the mitral leaflets to the annulus fibrosus, and the fornix, that part of the left ventricular wall between the fulcrum and papillary muscles. Prolapse was present when mitral leaflet tissue extended inferiorly and posteriorly to the fulcrum during systole. Angiographic prolapse of the posteromedial commissural scallop of the posterior leaflet was diagnosed in RAO ventriculograms in 21 patients, approximately 1.9 per cent of the adult catheterization population. All of these patients also had positive echocardiograms. Three other patients had positive echocardiograms despite normal ventriculograms. In one of these three, isolated prolapse of the middle commissural scallop of the posterior leaflet was present. No patient with a normal mitral valve echocardiogram had an abnormal ventriculogram. The proposed angiographic criteria for mitral valve prolapse have eliminated false-positive diagnoses, and permitted accurate identification in approximately 88 per cent of cases. Improved imaging and additional left ventriculographic projections will probably improve sensitivity. The frequencies of angiographic, echocardiogrphic, and clinical diagnoses of mitral valve prolapse are not significantly different.

Activation of Protein Kinase C is Critical to the Protection of Preconditioning

The phenomenon of cardiac preconditioning was first clearly described in 1986 by Murry et al1 when they announced that brief ischemia could actually make the heart more tolerant to further ischemia. In dogs infarct size following a 40 minute coronary occlusion was reduced by 75% if four cycles of 5 minute occlusion/5 minute reperfusion preceded the 40 minute ischemia. Perhaps not unpredictably these data received little attention until a series of reports appeared in 1990-1991 confirming and extending Murry’s observation.2–4 In the succeeding 3–4 years the preconditioning phenomenon has been well characterized and many laboratories have been attempting to determine the mechanism. The latter has not yet been fully characterized, but efforts to date have strongly suggested the participation of protein kinase C (PKC).5 In this review the evidence for involvement of this important cell enzyme will be outlined, and our current hypothesis of the mechanism of preconditioning will be detailed.

Cardiac tamponade in dogs with normal coronary arteries. I: Effect of changing intravascular volume on hemodynamics and myocardial blood flow

SummaryIntravascular volume expansion has been shown to improve cardiac output in experimental cardiac tamponade. To determine the limitations of intravascular volume manipulation, acute tamponade was created in 20 anesthetized, spontaneously breathing dogs. The intrapericardial volume causing tamponade was determined for each animal, and kept constant. Hemodynamics were recorded with and without tamponade at multiple levels of intravascular volume. During cardiac tamponade, intravascular volume expansion increased cardiac output only in animals which were initially volume-depleted. Volume expansion of normovolemic or hypervolemic animals caused minimal changes in cardiac output, but increased atrial and aortic pressures. Intravascular volume depletion of the normovolemic animal caused a significant decline in cardiac output, in contrast to the trend towards an increased output following phlebotomy of the volume-expanded animals. In general, the benefit of intravascular volume expansion during cardiac tamponade could only be demonstrated when atrial pressures were below 12 mm Hg.

Myocardial ischemia is not a prerequisite for the stimulation of coronary collateral development.

To understand better the temporal sequence of coronary collateral development and the factors that may govern that development, dogs were chronically instrumented with left circumflex (LCf) Doppler flow probe, ameroid constrictor, balloon occluder, and left atrial and aortic catheters. Collateral blood flow was measured at least weekly or when the coronary artery occluded. The reactive hyperemic response (RH) to a 15-second LCf occlusion was recorded three times per week. Most LCf arteries occluded during the 4th week after surgery. Two patterns of coronary collateral development were observed. In 11 animals collateral flow did not change for 2 or 3 weeks; peak RH and flow debt repayment, indexes of coronary vascular reserve, changed little. The next week there was an abrupt increase in collateral flow from approximately 15% of normal to 100%. This increase was coincident with a sudden loss of coronary vascular reserve and therefore suggests myocardial ischemia was the principal stimulus. However, in 11 dogs collateral flow increased gradually over 3 to 4 weeks as indexes of RH slowly decreased. The greatest increase in collateral flow occurred while peak RH was still approximately twice baseline flow, representing 80% of peak flow measured 1 week after surgery. Therefore in these animals ischemia is less likely to have been the major stimulus of coronary collateral development.

Myocardial blood flow during cardiac tamponade in dogs with coronary occlusion: Effects of isoproterenol

To determine the effects of cardiac tamponade in dogs with ligation of the left anterior descending coronary artery, fluid was introduced into the pericardial space to raise right and left atrial and pericardial pressures, first to 7 to 9 mm Hg and then to 11 to 12 mm Hg. Normal and ischemic myocardial blood flow fell approximately 20% to 25% during mild tamponade (1.27 +/- 0.16 to 1.00 +/- 0.06 ml/min/gm and 0.52 +/- 0.12 to 0.39 +/- 0.08 ml/min/gm, respectively) and by 50% during moderate tamponade (0.66 +/- 0.08 and 0.23 +/- 0.05 ml/min/gm, respectively). The inner/outer left ventricular wall blood flow ratio decreased modestly from 1.16 to 1.08 (p less than 0.025) in normal areas but increased from 0.53 to 0.61 (p less than 0.05) in the ischemic regions, suggesting possible epicardial vessel compression. Isoproterenol resulted in prompt decreases in pericardial and filling pressures, 16% increase in aortic pressure, and 200% rise in cardiac output. Normal myocardial blood flow more than doubled (1.55 +/- 0.12 ml/min/gm, p less than 0.001). Although average ischemic blood flow rose slightly to 0.042 +/- 0.10 ml/min/gm, the increase was not significant. Furthermore, changes in ischemic blood flow were heterogeneous with frank decrease in one dog. Therefore, although isoproterenol has salutary hemodynamic effects, its unpredictable action on myocardial blood flow should cause one to use it cautiously in those with tamponade who are believed to have coronary occlusive disease.