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To evaluate functional recovery in 20 consecutive patients with acute myocardial infarction who received recombinant tissue-type plasminogen activator, serial two-dimensional echocardiograms were performed before and immediately after tissue plasminogen activator administration and at 1 and 10 days postinfarction. Tissue plasminogen activator was administered intravenously (17 patients) or by intracoronary infusion (3 patients) after angiographic confirmation of total occlusion. Reperfusion, documented by angiography, occurred in 13 of the 20 patients. The mean time from onset of chest pain to thrombolysis was 5.1 +/- 1.1 hours. Echocardiograms were evaluated for regional function with a visual semiquantitative scoring system by two independent observers who had no knowledge of patient identity, temporal sequence, therapy or effect of therapy. There was no immediate or 24 hour improvement in wall motion. At day 10 compared with pretreatment, 28 of 33 reperfused infarct zone segments versus 6 of 20 nonreperfused infarct segments demonstrated improved wall motion (p = 0.01). This improvement did not relate to time from onset of chest pain to successful thrombolysis. Of reperfused infarct zone segments in the distribution of coronary artery balloon dilation, 19 of 23 segments exhibited improvement versus 7 of 17 (reperfused, no angioplasty) and 6 of 20 (nonreperfused, no angioplasty) segments (p = 0.001). Infarct zone segments reperfused at the time of ongoing chest pain demonstrated functional recovery compared with segments reperfused in the absence of chest pain (18 of 23 versus 10 of 20, respectively; p = 0.05). Thus, in this uncontrolled series, there was echocardiographically detectable improvement in function of reperfused infarct segments 10 days after coronary thrombolysis with recombinant tissue plasminogen activator.

This study was designed to evaluate the sensitivity of changes in myocardial carbon dioxide and oxygen tensions as indicators of regional myocardial ischemia and also to determine to what extent these changes can be related to changes in intramyocardial ST segment voltage. Changes in ST segment voltage recorded in unipolar epicardial electrodes proved to be a less-sensitive indicator of underlying myocardial ischemia than were changes in ST segment voltage recorded in unipolar intramyocardial electrodes. In 9 dogs, regional ischemia was produced by placing a variable constrictor on the left circumflex coronary artery; circumflex flow was monitored. Myocardial carbon dioxide and oxygen tensions were measured using a mass spectrometer. Unipolar electrograms were recorded using a multicontact plunge electrode. With progressive degrees of proximal stenosis, ranging from a critical stenosis, which is associated with a decrease in mean flow of less than 15%, to a severe stenosis associated with and 80% decrease, ST voltage increased 21 mv and carbon dioxide tension increased 84 mm Hg, but oxygen tension decreased only 7 mm Hg. The study suggests that increases in intramyocardial ST segment voltage, an index of myocardial ischemia, are associated with parallel increases in myocardial carbon dioxide tension, each providing a more sensitive quantitative correlate of regional myocardial ischemia than do decreases in oxygen tension. The local accumulation of carbon dioxide may be an important pathophysiological mechanism in myocardial ischemia.

Sublingual nitroglycerin has been the time-honored therapy for angina pectoris for nearly a century. Sustained-action oral forms and cutaneous ointment have been used for perhaps ten years for prophylactic treatment of angina and even more recently have been recommended for use in congestive failure. For the past six years investigators at Johns Hopkins Hospital have been administering intravenous nitroglycerin to patients with acute myocardial infarction with and without left ventricular failure. More recently, we have employed intravenous nitroglycerin to manage acute hypertension developing in patients before and after coronary artery bypass graft surgery. I would like to review with you the current indications for intravenous nitroglycerin and the beneficial effects that would be expected in each clinical situation. I will draw on our own clinical experience obtained in nearly 200 patients and, when necessary, on the recent medical literature.

To evaluate the myocardial protection afforded by multiple-dose versus single-dose administration of potassium cardioplegic solution, we studied 24 isolated feline hearts before, during, and after 1 hour of ischemic arrest. Intramyocardial gas tensions, ventricular function, histologic preservation, and postischemic myocardial edema were compared in hearts maintained at 27 degrees C during the ischemic period. Equal groups of hearts received no infusion of cardioplegic solution, a single dose of potassium solution at the onset of ischemia, or multiple infusions of the cardioplegic solution throughout the arrest period. During ischemia, single-dose cardioplegic administration resulted in less accumulation of myocardial carbon dioxide (Pmco2) than did hypothermia alone, reflecting a reduction in metabolic activity during ischemia. The fact that multiple-dose cardioplegia further reduced Pmco2 accumulation suggests an intermittent washout of metabolic end products. During reperfusion, hearts protected by multidose cardioplegia demonstrated superior preservation of ventricular performance compared to hearts protected by single-dose cardioplegia or hypothermia alone. In addition, multiple infusions of the cardioplegic solution resulted in optimal structural preservation in both light and electron microscope studies.

Nifedipine, a slow-channel calcium blocker, is thought to provide useful myocardial protection during prolonged total ischemia and reperfusion. An isolated, isovolumic, feline heart model was used to asses the effectiveness of nifedipine in both cardioplegic (100 microgram/10 ml) and noncardioplegic (10 microgram/10 ml) doses for providing myocardial preservation during 90 minutes of hypothermic ischemic arrest and 45 minutes of normothermic reperfusion. Use of nifedipine was compared to hypothermia (27 degrees C) alone and to hypothermia with potassium cardioplegia. Ventricular function was assessed by recovery of isovolumic left ventricular developed pressure and dP/dt. Myocardial carbon dioxide tension (PCO2) and myocardial oxygen tension (PO2) were measured by mass spectrometry. Potassium cardioplegia and the higher dose of nifedipine resulted in immediate asystole. The rates of rise of PCO were greatest in the group receiving 10 microgram nifedipine and in the control group. The rates of rise in the two cardioplegic groups were significantly lower. Recovery of ventricular function was significantly lower with low-dose nifedipine than with potassium cardioplegia. Higher dose nifedipine resulted in a return of function, which was no different than with potassium cardioplegia. Morphologic protection was better with higher dose nifedipine and potassium cardioplegia than with either low-dose cardioplegia or hypothermia alone. These results demonstrate that nifedipine in a cardioplegic dose results in preservation of myocardial structure and function that is similar to that obtained with potassium cardioplegia. In lower noncardioplegic dose, nifedipine does not appear to offer additional protection compared to hypothermia alone. Whether persistent depression of ventricular contractility will limit nifedipine's clinical usefulness as a myocardial protection agent will require further study.

Most corrective procedures as well as myocardial revascularization require a period of cardiac arrest, and numerous methods have been proposed to protect the myocardium during this ischemic episode. Potassium-induced cardioplegia is one method that appears to be of benefit in this setting. Since it is recognized that myocardial necrosis may result at very high doses of potassium, we examined the effect of varying concentrations of potassium on myocardial anoxic injury. Using an isolated rat heart preparation, we evaluated anoxic injury occurring with cardioplegic solutions containing various concentrations of K+, ranging from 15 to 200 mEq. per liter, during a 50 minute normothermic arrest followed by 60 minutes of reperfusion. The transverse histologic sections of the left ventricular myocardium were analyzed for contraction band injury by morphometric and qualitative methods. Among the 62 animals studied the least severe anoxic injury was seen with K+ cardioplegia at concentrations of 25 and 30 mEq. per liter. At lower and higher concentrations there was little difference between the hearts exposed to anoxia with or without K+ cardioplegia. Potassium administered in very high doses, i.e., 100 or 200 mEq. of K+ per liter, led to contracture and extensive myocardial cell injury. This study suggests that potassium-induced cardioplegia is effective in reducing cell injury due to anoxia, and in this model an optimal concentration range was 25 to 30 mEq. per liter.

A randomized prospective clinical trial compared combined treatment with intraaortic balloon pumping and intravenous nitroglycerin for 4 to 5 days with routine clinical management in 20 patients with extensive myocardium at risk for infarction as evidenced by a thallium defect score of 7.0 units or greater. No significant differences in mortality or clinical outcome were observed between the 10 patients receiving the combined treatment and the 10 receiving routine management. In 14 patients two-dimensional echocardiograms obtained 6 to 24 hours after the onset of symptoms and at follow-up 6 to 16 days later (after completion of combined intraaortic balloon pumping plus nitroglycerin therapy) were analyzed to determine whether infarct segment or noninfarct segment lengths were affected by therapy. Among these 14 patients, 5 (3 receiving the combined therapy and 2 receiving routine management) demonstrated an increase in infarct segment length of greater than 1.0 cm. Mean infarct segment length increased 0.30 +/- 0.44 cm in patients receiving the combined therapy and 0.29 +/- 0.36 cm in patients on routine management (p = NS). In contrast, noninfarct segment length increased greater than 1.0 cm (mean increase 1.20 +/- 0.39) in five of seven patients on routine management but in none of 7 patients receiving intraaortic balloon pumping plus nitroglycerin therapy (mean decrease 0.22 +/- 0.20 cm) (p less than 0.05). No significant differences were noted in left ventricular ejection fraction, as measured by gated blood pool scintigraphy, or thallium perfusion defect score in a comparison of day 1 (pretreatment) with day 4 thallium or day 7 to 14 gated blood pool scintigrams. Thus, in patients with extensive myocardium at risk, it is unlikely that a reduction in mortality or a significant improvement in myocardial perfusion or ventricular function can be obtained by early intervention with intraaortic balloon pumping in combination with nitroglycerin. Although this combined therapy failed to prevent infarct segment lengthening (infarct expansion), the combined afterload-lowering effects of intraaortic balloon pumping and nitroglycerin did appear to prevent dilation or remodeling of noninfarcted segments during the first 2 weeks after acute myocardial infarction.

The present study was designed to examine the safety and efficacy of titrating a nitroglycerin infusion to a fixed hemodynamic endpoint as initial therapy for patients admitted to a coronary care unit for medically refractory unstable angina, and to test the hypothesis that patients, responding to the addition of intravenous (i.v.) nitroglycerin to their previous antianginal regimen, could be crossed over to nitroglycerin administered by a new transdermal delivery system. In 9 patients the nitroglycerin infusion titrated upward at 3- to 10-minute intervals until a 10% reduction in mean arterial pressure was achieved. This titration schedule and hemodynamic endpoint proved safe and effective for controlling episodes of chest pain at rest in all 9 patients. Subsequently, this treatment strategy was tested in 17 consecutive patients with unstable angina treated in our coronary care unit during a 1-month period. In 10 of 15 successfully treated patients ischemia was the cause of chest pain as documented by cardiac catheterization. No change was made in antianginal or vasoactive drugs during the period of i.v. nitroglycerin administration or during crossover to transdermal therapy. In this well defined subgroup of patients with unstable angina, nitroglycerin infusion decreased the mean arterial pressure from 101 +/- 18 to 87 +/- 11 mm Hg (mean +/- standard deviation), using an infusion rate of 84 +/- 74 micrograms/min (range 10 to 200). The mean duration of i.v. therapy was 36 +/- 12 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Unstable angina can be defined by the development of chest pain at rest, usually with reversible S-T segment changes. It has been found in patients in whom angina developed at rest in the cardiac catheterization laboratory that a decrease in coronary sinus oxygen saturation preceded changes in left ventricular relaxation and contractility that preceded the development of chest pain and/or electrocardiographic changes. Increases in heart rate and/or blood pressure followed, rather than preceded, these ischemic episodes. These findings suggest that a decrease in oxygen supply, rather than an increase in oxygen demand, is the cause of episodes of angina at rest. Although principles of treatment of effort angina have emphasized the reduction of myocardial oxygen demand, treatment of rest angina should logically emphasize therapies that improve oxygen supply. A stepwise approach to the treatment of patients admitted to the Coronary Care Unit with unstable angina is proposed. The initial step consists of replacing oral and/or transcutaneous nitrates with an intravenous infusion of nitroglycerin while maintaining beta-blockers and calcium blockers at their previous doses. Nitroglycerin dilates coronary arteries and intercoronary collateral channels in addition to reducing preload and afterload. Intravenous administration allows faster titration to an effective dose and also more rapid reversal of hemodynamic effects, if the patient's status changes. The second step would consist of maintaining the nitroglycerin infusion and beta-blockers and adding or increasing the dose of calcium channel blockers. Slow channel calcium blockers dilate coronary arteries and prevent or reverse coronary spasm in addition to reducing afterload. The third step consists of adding or increasing the dose of beta-blockers in subgroups of patients with resting tachycardia and/or arterial hypertension. The fourth and final step would be to employ intra-aortic balloon counterpulsation therapy and/or to perform urgent coronary angiography. In patients with suitable coronary anatomy, angiography could be followed by percutaneous transluminal angioplasty or coronary artery bypass surgery.

It has been proposed that oxygen free radicals mediate damage that occurs during postischemic reperfusion. Recombinant human superoxide dismutase (r-h-SOD) has been shown to be effective at reducing reperfusion injury, but it is not known if this infused enzyme actually reduces oxygen free radical concentrations in the myocardial tissue. Electron paramagnetic resonance spectroscopy was used to directly measure the effect of r-h-SOD on free radical concentrations in the postischemic heart. Hearts were freeze clamped at 77 degrees K after 10 min of normothermic global ischemia followed by 10 s of reflow with control perfusate (n = 7) or perfusate containing 60,000 U r-h-SOD (n = 7). The spectra of these hearts exhibited three different signals: signal A isotropic, g = 2.004, identical to the carbon-centered ubiquinone free radical; signal B anisotropic with axial symmetry, g parallel = 2.033, g perpendicular = 2.005, identical to the oxygen-centered alkyl peroxyl free radical; and the signal C an isotropic triplet, g parallel = 2.000, an = 24 G, similar to a nitrogen-centered free radical such as a peroxyl amine. With r-h-SOD administration the concentration of the oxygen free radical, signal B, was reduced 49% from 6.8 +/- 0.3 microM to 3.5 +/- 0.3 microM (P less than 0.01) and the concentration of the nitrogen free radical, signal C, was reduced 38% from 3.4 +/- 0.3 to 2.1 +/- 0.3 microM (P less than 0.01). The concentration of the carbon-centered free radical, signal A, however, was increased 51% from 3.3 +/- 0.2 to 5.0 +/- 0.2 microM (P less than 0.01). Identical reperfusion with peroxide-inactivated r-h-SOD did not alter the concentrations of free radicals indicating that the specific enzymatic activity of r-h-SOD is required to decrease the concentrations of reactive oxygen free radicals. Additional measurements performed varying the duration of reflow demonstrate a burst of oxygen free radical generation peaking at 10 s of reperfusion. r-h-SOD entirely abolished this burst. These studies demonstrate that superoxide-derived free radicals are generated during postischemic reperfusion and suggest that the beneficial effect of r-h-SOD is due to its specific enzymatic scavenging of superoxide free radicals.

Changes in myocardial carbon dioxide (PmCO2) and oxygen tension (PmO2) measured by mass spectrometry have been shown to reflect quantitatively progressive degrees of regional myocardial ischemia associated with stepwise reduction in coronary blood flow. The present study utilized mass spectrometry to assess the severity of regional myocardial ischemia developing during atrial pacing in the presence of a flow-limiting proximal critical coronary artend subendocardial layers was measured by the radioactive microsphere technique. Application of a "critical stenosis" resulted in a 6-mmHg decrease in PmO2 and a 17-mmHg increase in PmCO2 in the region of the myocardium supplied by the stenosed vessel. The addition of atrial pacing resulted in a 3-mmHg further decrease in Pmo2 and a 40-mmHg further increase in PmCO2. In the region of myocardium supplied by the critically stenosed vessel MBF increased in the subepicardial layer, but decreased or remained unchanged in the subendocardial layer. The failure of myocardial blood flow to increase in deeper myocardial layers in response to the increased myocardial oxygen demand of atrial pacing would provide a mechanism for the development of subendocardial ischemia in the presence of a critical coronary stenosis.

A new method for producing pulsatile flow during cardiopulmonary bypass is described. The method requires only the addition of a dilated segment in the tubing which passes beneath the arc of a standard roller pump. Preliminary studies demonstrate that pulsatile flow and pressure with physiologic contours can be produced by this "bubble tube" system. Furthermore, the new tubing causes less hemolysis than standard pump tubing.

Various dosing strategies to determine therapeutic effects of nitroglycerin (NTG) preparations are reviewed. The importance of individual patient titration in establishing an effective NTG dosage is emphasized by reviewing a nitroglycerin ointment study and a crossover study. Studies reporting the development of hemodynamic attenuation ("tolerance") with longterm nitrate therapy are also discussed. The results of these and other studies suggest that the magnitude of the hemodynamic response to NTG or isosorbide dinitrate diminishes over time, with acute or first-dose effects far exceeding those obtained during long-term therapy. However, patients on long-term therapy continue to respond to sublingual NTG, which suggests that this phenomenon is not true NTG tolerance. The effect of a nitrate-free interval as a mechanism for avoiding hemodynamic attenuation of NTG therapy is reviewed. The results of 4 studies discussed found that intermittent nitrate protocols were not associated with the attenuated hemodynamic effect observed during chronic therapy. Two possible mechanisms for the vasodilatory effects of nitroglycerin are discussed. The first relates to the production of cyclic guanosine monophosphate in the smooth muscle cells of arteries and veins; the second to the synthesis of prostaglandin I2 by vascular endothelial cells. A mechanism by which nitrate receptors could be manipulated to increase vascular responsiveness is theorized, as well as a means by which a nitrate-free interval might avoid the development of hemodynamic attenuation in terms of cellular mechanisms and receptors.

Recognition that myocardial infarction is caused by coronary thrombosis has stimulated a search for a safe, rapidly acting, and effective thrombolytic regimen. Tissue plasminogen activator (t-PA) can provide relatively clot-selective thrombolysis, but one quarter of patients fail to achieve reperfusion, lysis speed is not optimal, and higher doses have been associated with an increased incidence of hemorrhagic stroke. We report the results of a multicenter study of pro-urokinase, a second naturally occurring plasminogen activator that has structural similarities to t-PA but has a different mechanism of action. Pro-urokinase was administered 3.9 +/- 1.1 hours after the onset of chest pain to 40 patients with acute myocardial infarction with angiographically confirmed complete coronary occlusion (TIMI grade 0). After a 90-minute intravenous infusion of pro-urokinase (4.7-9 million units, 36-69 mg) 51% (20 of 39) of the patients demonstrated reperfusion (TIMI grade 2 or 3) occurring 64.8 +/- 22.3 minutes after initiation of therapy. Fibrinogen levels fell only 10 +/- 17% from baseline, confirming the fibrin specificity of pro-urokinase. As with t-PA, however, this specificity was only relative. alpha 2-Antiplasmin decreased to 39% and plasminogen decreased to 64% of initial values. Fibrinogen degradation products increased 63% and the fibrin-specific D-dimer increased 8.7-fold. Thus, pro-urokinase produces relatively clot-selective coronary thrombolysis similar to that produced by t-PA, but the use of either pro-urokinase or t-PA alone in higher doses would be likely to produce more nonspecific effects.