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Experience gained during clinical trials at Johns Hopkins University Hospital has led to refinements in a commercial arrhythmia monitoring system. The performance capabilities and limitations are described for normal Coronary Care Unit use. The system evaluation spanned a time period of over 16 months and included 3,176 monitored patient days. The majority of both false and true arrhythmia alarms was found to be produced by two small, statistically independent segments of the patient population.

Impaired energy production has been proposed as one mechanism to explain the contractile abnormality in post-ischemic "stunned" myocardium. If energy production were impaired, administration of inotropic agents should result in a deterioration of cellular energy stores because of an inability of ATP synthesis to match the rate of increased utilization. In this study we correlated changes in myocardial high energy phosphates, measured by 31P-NMR spectroscopy, with changes in left ventricular function and energy requirement in buffer perfused rabbit hearts following ischemia and reperfusion, and during stimulation with isoproterenol. Hearts were stunned by 20 min of zero flow global ischemia at room temperature. After reperfusion, isovolumic developed pressure returned to 77.8 +/- 2.2% of baseline and ATP content was reduced to 80.9 +/- 4.1% of baseline. Isoproterenol (5 x 10(-8) M for 10 min) caused increases in developed pressure and rate-pressure product (to 134.1 +/- 12.6% and 195.0 +/- 21.4% of baseline, respectively) without a decrease in ATP or phosphocreatine (PCr) content (80.0 +/- 7.1% and 103.0 +/- 3.8% of preischemia, respectively), and without functional or metabolic deterioration of the hearts after discontinuation of the drug. Control hearts not subjected to ischemia showed similar functional and metabolic responses to isoproterenol. The phosphocreatine/inorganic phosphate (PCr/Pi) ratio, an index of the balance between energy production and utilization, was higher (not lower) than baseline in stunned hearts, thus confirming that energy production was not intrinsically impaired. Together these data indicate that despite reduced myocardial ATP content, mitochondrial function in stunned hearts is capable of sustaining a large increase in function and energetic requirements.

In parallel with experimental research into methods for salvage of ischemic myocardium after acute myocardial infarction (AMI) over the last decade, there has been a growing interest in prostaglandins (PG) and their inhibition by aspirin-like drugs or nonsteroidal anti-inflammatory drugs (NSAID). The finding of enhanced PG release during myocardial ischemia and its blockade by the NSAID indomethacin led to the hypothesis that PG might influence the infarction process. Because PG differ in vasoactive, cellular, and metabolic properties, and PG inhibitors also differ in their ability to inhibit synthesis of different PG and their metabolites, some PG inhibitors might be expected to reduce myocardial ischemic injury and infarct size. In addition, the NSAID may directly modify cellular events during infarction. Experiments with NSAID in the anesthetized and conscious animals have demonstrated a reduction of myocardial infarct size with ibuprofen, but an increase in infarct size with indomethacin. The opposite effects of these agents on infarct size might have been related to the different doses used, different degrees of inhibition of PG and their metabolites, and different effects on factors influencing myocardial oxygen supply and demand, metabolic and cellular events during infarction. It has recently been suggested that some of these agents might also influence the healing process after AMI and, therefore, late complications.

The effect of varying the site of acute regional ischemia on nonischemic myocardial function was examined by comparing regional thickening during 2-3 min circumflex (Circ) vs. left anterior descending (LAD) coronary artery occlusions in eight open-chest dogs. Cross-sectional midwall two-dimensional echocardiograms were obtained, and systolic thickening was measured at 16 equal-spaced points around the circumference. The distribution and extent of hypoperfusion was assessed by radiolabeled microspheres. The echo slice was subdivided into a hypoperfused region (Hypo), four adjacent nonischemic regions (ADJ1-4), and the remaining remote segments (Remote). The extent of hypoperfusion (%LV mass) was similar with both sets of occlusions (LAD, 29.4 +/- 2.8%; Circ, 26.0 +/- 4.4%; P = NS), as was endo- and epicardial flow in the nonischemic regions. Yet, even with like-sized Hypo regions, thickening of nonischemic myocardium was significantly greater during Circ than during LAD occlusions (P less than 0.001). These results are consistent with recently reported disparities of global functional impairment during LAD vs. Circ ischemia. The responses likely reflect differences in regional wall geometry, loading, and the three-dimensional distribution of coronary hypoperfusion between the two vascular territories.

OPC-8212 is a new positive inotrope with a unique mechanism of action. To assess its clinical utility we administered 60 mg/day for 30 days to 10 patients with overt congestive heart failure, who had substantial limitations in exercise performance despite treatment with conventional therapy. Patients were evaluated by simultaneous respiratory gas exchange and radionuclide ventriculography measurements during graded maximal exercise testing. Improvement was demonstrated in both peak oxygen uptake and radionuclide-determined cardiac index after 30 days of treatment with OPC-8212. These changes were not associated with alterations in heart rate at rest or during peak exercise. Furthermore OPC-8212 significantly decreased ventricular ectopy in our patients. However, two patients had possible hematologic toxicity with prolonged use. The results of the present phase II study suggest that a larger randomized double-blind placebo study to evaluate the safety and clinical efficacy of this drug is warranted.

Sequential exercise-gated cardiac blood pool scintigrams provide a noninvasive technique for evaluating the effect of therapeutic interventions on cardiac volumes and function only if both exercise periods are equivalent in the absence of an intervention. To assess whether they are indeed equivalent, 14 healthy subjects underwent gated blood pool scintigraphy during two maximal upright exercise periods separated by 60 min without changing position. Although resting cardiac output and blood pressure returned to base-line values 60 min after the first exercise period, mean resting heart rate was markedly higher (89.4 +/- 2.7 vs. 66.5 +/- 2.5 beats/min, P less than 0.001) and upright cardiac volumes lower [39.1 +/- 4.9 vs. 56.3 +/- 6.0 ml, P less than 0.001, for end-systolic volume (ESV) and 112.6 +/- 8.0 vs. 144.9 +/- 9.0 ml, P less than 0.001, for end-diastolic volume (EDV)] than before the first exercise period. These differences persisted during low levels of the subsequent exercise but not at high and maximum work loads. Cardiac volumes and heart rate 60 min after an identical exercise protocol in a second group of 22 subjects who received propranolol, 0.15 mg/kg iv, after their initial exercise, however, were the same as those preexercise. Thus higher sympathetic tone may be responsible for the persistently higher heart rate and decreased cardiac volumes after exercise, and the assumption that cardiac volumes and function are similar during two closely spaced sequential exercise studies is not always valid.

The quantitative relationship between fractional myocardial thallium uptake and radioactive microsphere-determined flow was studied in 33 open chest dogs under baseline conditions during increased coronary flow (dipyridamole), decreased coronary flow (propranolol and coronary artery stenosis), inhibition of Na-K ATPase (ouabain), and regional infarction. Myocardial contents of thallium and microspheres were compared in left ventricular (LV) biopsies taken 5, 10, 15, 30, and 60 min after thallium injection, expressed as fractions of injected dose. Maximal LV thallium uptake occurred 10 min after injection and the 10-min values were therefore used for subsequent comparisons. Combining all dogs, fractional LV thallium content (% injected dose) correlated well with fractional LV blood flow (% cardiac output) (r = 0.95). However, for fractional LV flows in the low, normal, or moderately elevated range (LV flow/cardiac output less than 9%), thallium content consistently exceeded flow by about 15%. This relationship was not altered by ouabain or regional ischemia or infarction. For greatly elevated fractional LV flows (greater than 9%), thallium content was not significantly different from flow. To explain these differences, myocardial and systemic extraction fractions for thallium were determined in eight dogs with a dual tracer method. At baseline, myocardial extraction fraction was significantly greater than systemic (88 +/- 0.4% compared with 75 +/- 1%, p less than 0.001). During dipyridamole, myocardial extraction fraction decreased and myocardial and systemic values were no longer significantly different (82 +/- 1% compared with 79 +/- 1%). These results show that the fraction of injected thallium dose taken up by the LV myocardium exceeds the delivered fraction of cardiac output over a wide range of LV flows, and is not altered by ouabain-induced inhibition of sodium-potassium ATPase or regional myocardial infarction. This difference is explained by a greater myocardial than systemic extraction fraction for thallium. During high LV flows produced by dipyridamole, fractional LV thallium uptake and flow become similar as myocardial and systemic extraction fractions equalize.