Usefulness of low-level exercise testing early after acute myocardial infarction in patients taking beta-blocking agents.

The value of low-level exercise testing early after acute myocardial infarction (AMI) in 207 patients taking beta-blocking drugs was evaluated in a multicenter study of prognosis after AMI. After stratifying patients according to the absence of significant rales upon admission or pulmonary congestion on the admitting chest x-ray, the results of the exercise test (ability to complete the 9-minute protocol) permitted a large cohort (108 patients, 52% of exercising patients) with no deaths from cardiac causes in the year after AMI to be identified. The results suggest that even in patients taking beta-blocking agents, low-level exercise testing together with clinical stratification has value in identifying a large group of patients with a good prognosis after AMI.

Low-level exercise testing after myocardial infarction: usefulness in enhancing clinical risk stratification.

Of 866 patients enrolled in our multicenter study, 667 performed a low-level exercise test early after myocardial infarction, most before discharge. Excluding seven patients who died before the test could be considered, there was a 14% 1 year cardiac mortality in 192 patients who did not take the test (150 for medical and 42 for logistic reasons) compared with 5% in those who did (p less than .0001). Of those who took the test, 12% subsequently underwent bypass grafts surgery compared with 14% of those who did not (p greater than .05). Decreased mortality in the year after the infarction in those taking the test was associated with an increase in blood pressure to 110 mm Hg or higher (3% vs 18%; p less than .001), ability to complete the 9 min test (3% vs 8%; p less than .01), and the absence of couplets (4% vs 13%; p less than .05) or any ventricular ectopic depolarizations (4% vs 7%, p less than .05) before, during, or after exercise. Achievement of a blood pressure of 110 mm Hg or higher during exercise in patients with no evidence of pulmonary congestion on the chest x-ray identified a group of 454 patients (70% of those taking the test) with a 1 year cardiac mortality of 1% compared with 13% in the remaining patients (p less than .0001). Logistic models showed that the exercise test contributed independent prognostic information for cardiac death, new infarction, and bypass surgery. Results of low-level exercise testing before hospital discharge combined with clinical features of the infarction can effectively identify patients at low risk for subsequent cardiac mortality.

Prognosis after recovery from acute myocardial infarction.

Left ventricular (LV) dysfunction, ventricular arrhythmias, and ischemic jeopardy independently determine outcome after recovery from acute myocardial infarction. Because death and reinfarction are most common early after hospital discharge, predischarge assessment of risk is optimal. Noninvasive methods can adequately detect LV dysfunction and ventricular arrhythmias, but coronary angiography is needed to assess ischemic risk in several subsets of patients. Management should be guided by the magnitude and functional nature of risk factors.

Effect of CO2 laser on the luminal surface of blood vessels in vivo.

The use of lasers as surgical tools may open up new possibilities for the treatment of atherosclerotic occlusive vascular disease. However, basic information regarding the effect of laser radiation to the lumen of normal blood vessels is needed prior to clinical application. This work investigates the nature of the CO2 laser-induced vascular wound and the time course of its healing in the rabbit aorta. The chief short-term problem with CO2 laser radiation of the luminal surface of blood vessels is thrombosis.

Which postinfarction ventricular arrhythmias should be treated?

There is still no consensus on which arrhythmias should be treated in the 6- to 12-month high-risk period after acute myocardial infarction. To examine this question, we analyzed 24-hour ECG recordings in 430 patients who survived for at least 2 weeks after myocardial infarction and studied these patients for at least 1 year. During the year after infarction, 63 cardiac deaths occurred. High ventricular premature depolarization (VPD) frequency increased the risk of dying; 26% of the patients had greater than or equal to 10 VPDs/hr and were 2.6 times as likely to die within a year as those with lower frequencies. Repetitive VPDs (pairs or ventricular tachycardia) also were strongly associated with mortality. Thirty-one percent had repetitive VPDs, and these patients were 3.2 times as likely to die as those who lacked this characteristic. Frequent or repetitive VPDs were strongly associated with many other important postinfarction risk factors (e.g., left ventricular dysfunction or digitalis treatment). Nevertheless, frequent or repetitive VPDs contributed significantly to death in the first year after infarction independent of other risk factors; about 90% of these arrhythmias can be controlled satisfactorily with antiarrhythmic drugs. As yet, no definitive trial has been conducted to show whether controlling frequent or repetitive VPDs will significantly reduce the mortality in the first year after infarction. The principal design features for such a trial are discussed.

Mechanisms of quinidine-induced depression of maximum upstroke velocity in ovine cardiac Purkinje fibers.

A major advance in understanding how quinidine depresses maximum upstroke velocity (Vmax) is the Hondeghem-Katzung mathematical model which incorporates voltage-independent rate constants for binding to and unbinding from resting, open, and inactive Na channels, and a voltage shift of -40 mV for the Hodgkin-Huxley h-kinetics of quinidine-associated Na channels. Using a double microelectrode voltage clamp technique to control transmembrane voltage and apply conditioning pulses, we found that quinidine blockade increased as transmembrane voltage became more positive in the range -60 to +40 mV, and that the rate of quinidine dissociation increased as transmembrane voltage became more negative in the range -60 to -140 mV. The relationship of Vmax to transmembrane voltage obtained at drive cycles from 500 msec to 20 seconds conformed to the model modified to include voltage-dependent rate constants without the postulated -40-mV shift for quinidine-associated channels. Thus binding of quinidine to inactive Na channels and unbinding from resting channels are both voltage-dependent and can explain frequency and voltage dependent actions of quinidine on Vmax without any voltage shift for quinidine-associated channels.

Prevalence, characteristics and significance of ventricular tachycardia (three or more complexes) detected with ambulatory electrocardiographic recording in the late hospital phase of acute myocardial infarction.

A 24 hour electrocardiographic recording was performed before hospital discharge in 430 patients who survived the cardiac care unit phase of acute myocardial infarction. Fifty patients (11.6 percent) had ventricular tachycardia, that is, three or more consecutive ventricular complexes. In 25 (50 percent) of these 50 patients, there was only one episode of ventricular tachycardia and, in 15 patients (30 percent), the longest run of ventricular tachycardia was only three consecutive ventricular premature depolarizations. The average rate of tachycardia was 119/min. Tachycardia rarely started with R on T ventricular premature complexes (4 of 1,370 episodes in 50 patients). There was no difference between the groups with and without ventricular tachycardia with respect to age and sex, but the patients with tachycardia had a significantly greater prevalence of previous myocardial infarction, left ventricular failure in the cardiac care unit, atrial fibrillation, ventricular tachycardia or ventricular fibrillation in the cardiac care unit and significantly more frequent use of digitalis and diuretic and antiarrhythmic drugs at the time of hospital discharge. The group with tachycardia had a 38.0 percent 1 year mortality rate compared with the rate of 11.6 percent in the group without tachycardia. Ventricular tachycardia had a strong association with 1 year mortality (odds ratio = 4.7). Although ventricular tachycardia had a significantly association with many other postinfarction risk factors, it was still significantly associated with the 1 year mortality (p less than 0.05) when other important risk variables were controlled statistically using a multiple logistic regression model. The 36 month cumulative mortality rate was 54.0 percent in the group with ventricular tachycardia compared with 19.4 percent in the group without tachycardia.

Risk stratification with low-level exercise testing 2 weeks after acute myocardial infarction.

We enrolled 250 patients with acute myocardial infarction after they had been discharged from the cardiac intensive care unit. Among 236 patients who performed a low-level exercise test just before hospital discharge, 52 (22%) had exercise-induced ST depression of at least 0.1 mV in ECG lead V5, 102 (43%) had ventricular arrhythmias, and 121 (51%) had an exercise capacity of shorter than 6 minutes. We used multiple logistic regression analysis to investigate the association of exercise variables with 1-year cardiac mortality. Exercise duration and ventricular premature depolarizations (VPDs) were significantly associated with 1-year mortality after acute myocardial infarction, both with and without control of the influence of other exercise variables statistically; the association of exercise-induced ST depression with 1-year cardiac mortality was not statistically significant. Standardized regression coefficients showed that the variables ranked in the following order in terms of predictive value: exercise duration, VPD frequency and ST depression. Jackknife techniques showed that multiple logistic regression using the three exercise variables was highly accurate in predicting 1-year mortality.

Analysis of prognostic significance of ventricular arrhythmias after myocardial infarction. Shortcomings of Lown grading system.

The Lown grading system for ventricular arrhythmias has been used in observational and experimental studies of ischaemic heart disease. This grading system uses three levels of ventricular premature depolarisation frequency and four complex features to assign patients to one of seven grades. We tested several of the major assumptions of the Lown grading system in a group of 400 patients who had recently experienced acute myocardial infarction. The Lown grading system assumes that the frequency of ventricular extrasystoles exerts a negligible risk force in patients who have complex ventricular extrasystoles. We found, however, that the frequency of ventricular extrasystoles contributed significant additional risk for cardiac death even in the three highest Lown grades, 4A, 4B, and 5. The Lown grading system assumes that, of the four complex features used, R on T ventricular extrasystoles have the greatest risk for subsequent cardiac death. We found that paired ventricular extrasystoles and ventricular tachycardia had more prognostic significance than R on T ventricular extrasystoles. It is important for prognostic stratification that subgroups which are merged into a given Lown grade should be relatively homogeneous with respect to outcome. We found a lack of homogeneity in the three highest Lown grades. Grade 5 contained 16 subgroups with a mortality risk which ranged from 0 to 75 per cent; statistically significant differences in subsequent mortality were found among these subgroups. Most of the shortcomings of the Lown grading system in our acute myocardial infarction population resulted from failure to give sufficient weight to ventricular extrasystoles frequency and to repetitive ventricular extrasystoles.

Shortcomings of the Lown grading system for observational or experimental studies in ischemic heart disease.

The Lown grading system uses three levels of frequency and four complex features to grade ventricular arrhythmias. The seven Lown grades are mutually exclusive (a patient can be in only one grade) and hierarchical (higher grades indicate increased likelihood of death). We evaluated the ability of the Lown arrhythmia grading system to predict death in 400 patients who were convalescing from acute myocardial infarction. Lown grading produced a poor distribution among grades of the population, lacked a monotonic increase in risk with increasing arrhythmia grade, lacked a substantial risk gradient between grades, and showed a lack of isometry in the higher grades. Also, the Lown grading system thwarts the use of standard multivariate techniques for relating the frequency and characteristics of ventricular premature depolarizations (VPDs) to cardiac death. We also examined the utility of the Lown arrhythmia equation for evaluating the results of antiarrhythmic drug therapy. The Lown grading system failed to reveal clearly the change in VPD frequency and characteristics as a function of drug dose. We propose an alternative grading system that is not mutually exclusive or hierarchical. This grading system lacks many of the flaws of the Lown grading system and is suitable for standard multivariate analyses but, like the Lown grading system, still fails to show the relationships among ventricular arrhythmias, time, drug dose, and activity.

Electrophysiological effects of mexiletine (Kö1173) on ovine cardiac Purkinje fibers.

To clarify the electrophysiological mechanisms of the antiarrhythmic effects of mexiletine, we examined the actions of mexiletine (0.1--30 mg/l) on action potential characteristics (phase 0 amplitude, overshoot, maximum upstroke velocity, maximum diastolic and activation voltages, duration at 50% and 90% repolarization) of cardiac Purkinje fibers using standard microelectrode techniques. In fibers stimulated at constant rate, mexiletine decreased phase 0 amplitude and Vmax and shortened the action potential. Mexiletine shortened action potential duration at lower concentrations than those which altered phase 0 depolarization. The effect of mexiletine on normal automaticity in cardiac Purkinje fibers was studied in fibers made automatic either by hypokalemia or by isoproterenol. Mexiletine suppressed normal automaticity by shifting activation voltage, so that spontaneous phase 4 depolarization reached a stable resting voltage without triggering regenerative phase 0 depolarization. The effects of mexiletine on abnormal automaticity were studied in Purkinje fibers intoxicated by ouabain. Mexiletine decreased the amplitude of or abolished either early or delayed after depolarizations induced by ouabain.

Risk stratification after acute myocardial infarction.

One hundred patients admitted to the hospital with acute myocardial infarction who lived 10 days and agreed to enroll were studied. Data from the history, hospital course and a 24 hour Holter electrocardiographic recording were related to cardiac mortality in the 6 months after enrollment. Fifteen cardiac deaths occurred during this period; 12 of these were sudden. The univariates with the strongest association with mortality were (in descending order): blood urea nitrogen level, serum creatinine level, serum uric acid level, enlarged heart 2 weeks after infarction, ventricular tachycardia 2 weeks after infarction, peak creatine kinase level and left ventricular failure in the coronary care unit. The odds of dying if one of these factors was present rather than absent ranged from 3.6 to 11.5. Groups with two or these univariates had up to 20 times the odds of dying in 6 months. A period of greately enhanced risk for cardiac death persists for about 6 months after acute myocardial infarction. Relatively simple clinical variables can identify the groups at highest and lowest risk. This information is useful for designing management strategies.

The effect of lidocaine on diastolic transmembrane currents determining pacemaker depolarization in cardiac Purkinje fibers.

We studied the effects of lidocaine (1-5 mg/liter) on the diastolic currents of sheep Purkinje fibers by the two-microelectrode voltage clamp technique to obtain additional information on how lidocaine decreases the slope of spontaneous diastolic depolarization of mammalian Purkinje fibers. During voltage clamps we measured both the magnitude and time course of activation and deactivation of the time- and voltage-dependent potassium "pacemaker current" (iK2), and also the steady state current-voltage relationship throughout the pacemaker voltage range. At a concentration of 1 mg/liter lidocaine had no effect on the amplitude of iK2. In contrast, at 5 mg/liter, lidocaine diminished the magnitude of iK2 throughout the voltage range of pacemaker depolarization. Lidocaine (1-5 mg/liter) had no effect on either (1) the transmembrane voltage at which iK2 is half-activated, (2) the reversal voltage for iK2, or (3) the kinetics of iK2. Lidocaine (1-5 mg/liter) increased the steady state outward transmembrane current. This effect of lidocaine can be attributed to a variable contribution from both an increase in time-independent outward potassium current (iK1) and a decrease in background inward current.

Effect of lidocaine on the early inward transient current in sheep cardiac Purkinje fibers.

We used two experimental techniques to study the effect of lidocaine hydrochloride on the early inward transient (sodium) current as it is reflected by the maximum rate of change of action potential phase 0 (Vmax). We assessed the effect of lidocaine on Vmax as Purkinje fibers were slowly depolarized by increasing the extracellular potassium concentration from 4.0 to 16.0 mM; these voltage-dependent effects were compared with lidocaine's effect on membrane responsiveness (which measures both the time and the voltage dependence of Vmax). We also used a voltage clamp technique to establish the effect of lidocaine on the voltage dependence of Vmax by measuring Vmax 800-1000 msec after transmembrane voltage (Vm) had been changed in small steps. We studied the effect of lidocaine on the time course of early inward transient current reactivation by depolarizing the membrane to -25 +/- 5 mv for 100 msec to inactivate this current, clamping Vm to a repolarized test voltage for various periods, and then measuring phase 0 Vmax of action potentials elicited immediately after termination of the voltage clamp. We showed that lidocaine at 5 mg/liter, but not a 1 mg/liter, shifted the steady-state Vmax- Vm relationship to a more negative position on its voltage axis by about 5 mv and markedly slowed the reactivation of the measure early inward transient current.