Martin A. Josephson

Prognostic significance of silent myocardial ischemia in patients with unstable angina

Silent myocardial ischemia is common in unstable angina, but its prognostic significance is unknown. Fifty-two (42 with subsequent angiography) of 81 patients prospectively evaluated for unstable angina had ambulatory electrocardiographic (Holter) recordings analyzed by compact analog technique after they had received medical treatment (3 of the 52 had unanalyzable recordings and were excluded). From 1,103 hours of recordings, 298 ischemic episodes were identified, only 9% associated with angina. By Ridit analysis a significant correlation was found between the cumulative duration of transient myocardial ischemia and the number of diseased coronary vessels and indexes of proximal stenosis. During a 3 to 6 month follow-up period, there was one death and one patient was lost to follow-up among 20 patients without transient ischemia; in the group of 11 patients with a cumulative duration of transient ischemia less than 60 minutes/24 h, 7 were alive and well, 2 required coronary bypass surgery, 1 had coronary angioplasty for recurrence of angina and 1 was lost to follow-up. In the group of 18 patients with ischemia duration greater than 60 minutes/24 h, only 1 developed a stable angina pattern; 12 required coronary surgery (n = 11) or angioplasty (n = 1) and 5 developed myocardial infarction (2 died, 2 needed surgery for postinfarction angina and 1 recovered). A favorable clinical outcome occurred in only 6% of patients in the group with ischemia duration greater than 60 minutes/24 h; this rate was significantly lower (p less than 0.001) than that (70%) for the group with ischemia duration less than 60 minutes/24 h or that (95%) for the group without ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Noninvasive detection and localization of coronary stenoses in patients: comparison of resting dipyridamole and exercise thallium-201 myocardial perfusion imaging.

Two noninvasive tests to detect and localize coronary stenoses were compared in a fully blinded protocol. Thallium201 myocardial perfusion imaging (MPI) following maximal treadmill exercise and pharmacologic coronary vasodilation with intravenous dipyridamole (DP) was performed in 33 patients. Thallium201 imaging defects in six myocardial perfusion regions were correlated with stenoses in their respective vascular distributions. Disease severity was determined with coronary arteriograms using a computer-assisted method. 198 myocardial regions were evaluated; 101 were supplied by at least one major artery with a greater than or equal to 50% stenosis (luminal diameter narrowing). The sensitivity and specificity for detecting a greater than or equal to 50% stenosis were 85% and 64% (p less than 0.005), respectively, for DP and 84% and 68% (p less than 0.005) for exercise-thallium201 imaging. A particular combination of anterior and septal imaging defects was useful in detecting left anterior descending artery stenoses proximal to its first septal branch. DP administration was safe in this group of patients; however, 42% experienced transient chest pain. Although the overall sensitivity and specificity of the two methods were not significantly different, DP-MPI appeared more sensitive than exercise-MPI (70% vs 52%, p less than 0.01) in detecting coronary stenoses in the 40% to 60% range. DP-thallium201 MPI provides a useful alternative test for potential coronary disease patients unable to perform maximal exercise.

Myocardial Ischemia during Cocaine Withdrawal

STUDY OBJECTIVE To determine the prevalence of myocardial ischemia in patients with cocaine addiction. DESIGN Myocardial ischemia in chronic cocaine users was detected by serial 24-hour electrocardiographic ambulatory (Holter) monitoring and exercise treadmill testing in chronic cocaine users. The Holter tapes were coded, scanned in a blinded manner, and mixed with the tapes of 42 normal volunteers and 119 patients with either stable or unstable angina. SETTING A 28-day inpatient, substance abuse treatment program followed by an outpatient treatment program. PATIENTS Twenty-one consecutive male chronic cocaine users. MAIN RESULTS Eight of the 21 patients with cocaine addiction had frequent episodes of ST elevation during Holter monitoring; these episodes occurred almost exclusively during the first 2 weeks of withdrawal. None of the volunteers and patients with stable angina and only 4% of the patients with unstable angina had episodes of ST elevation during Holter monitoring (cocaine users compared with volunteers, P = 0.0004). Of the 20 cocaine patients who had exercise treadmill testing, only 1 had a positive test for ischemia. CONCLUSIONS Cocaine users frequently develop silent myocardial ischemia manifesting as episodes of ST elevation during the first weeks of withdrawal. The underlying mechanisms for these changes remain unknown, but our observations support the hypothesis that coronary vasospasm plays an important role in cocaine-related ischemic syndromes.

Circadian variation in occurrence of transient overt and silent myocardial ischemia in chronic stable angina and comparison with prinzmetal angina in men

Circadian periodicity was examined in 68 patients with chronic stable angina and in 9 patients with Prinzmetal angina. The frequency and duration of transient ischemic episodes were determined from analysis of 1 or more 24-hour Holter recordings by the compact analog technique. Ninety percent of the episodes in both syndromes were silent; 80% of the episodes of Prinzmetal angina were associated with ST-segment elevation and all episodes of chronic stable angina had ST-segment depression. Ischemic episodes were shorter (3 +/- 2 vs 18 +/- 23 minutes, p less than 0.0005) but more frequent (21 +/- 18 vs 6 +/- 4 per 24 hours, p less than 0.0001) in patients with Prinzmetal angina than in those with chronic stable angina. In patients with chronic stable angina, both silent and painful episodes had a peak occurrence in the morning and early afternoon hours (between 8 AM and 3 PM); the fewest episodes were between 1 AM and 5 AM. This distribution was not random by chi-square test (p less than 0.001). Cosinor analysis of ischemic episodes periodicity showed the acrophase at 1 PM, which was not different from that (3 PM) of the circadian rhythmicity for heart rate. In case of Prinzmetal angina, the acrophase of heart rate changes was at 5 PM, but a clear periodicity in the distribution of the ischemic episodes was not found. These differences in the circadian periodicity may reflect differences in the mechanism of ischemia in chronic stable angina and in Prinzmetal angina and are likely to be of therapeutic significance.

Characteristics and clinical significance of silent myocardial ischemia in unstable angina

The frequency and duration of transient myocardial ischemia on Holter recordings, analyzed by the compact analog technique, were determined in 41 patients (all men, mean age 54) with unstable angina (33 with angiographic evidence). There were 781 episodes of ischemia: 392 (50%) with ST-segment depression, 242 (31%) with ST elevation, 45 (6%) with ST elevation and depression in different leads, 70 (9%) with pseudonormalization of T waves and 32 (4%) with T-wave augmentation. Ventricular arrhythmias were associated with 18% of the episodes. The mean duration of ischemic episodes was 14 minutes (range 30 seconds to almost 12 hours); most were less than 5 minutes. Only 154 (20%) of the 781 episodes of ischemia were associated with pain. Conversely, 77 episodes of chest pain were not associated with electrocardiographic changes. Analysis of the temporal sequence of heart rate during the development of ischemia (analyzed in 415 episodes) showed that in only 43 (10%) the heart rate at the beginning of ischemia was significantly (greater than 6 beats/min) higher than that at 5 minutes (baseline) before the onset of ischemia. At the peak of the ischemic abnormality, the mean heart rate increase was 10% and returned to baseline at the end of the ischemic episode. The data indicate that 80% of ischemic episodes in unstable angina are silent and over 90% are not triggered by increases in heart rate; apparently increased oxygen demand is an uncommon cause of ischemia in unstable angina. Although most of the episodes were short-lived, some were extremely protracted without the development of myocardial infarction. The findings are of therapeutic significance.

Reproducibility of equilibrium radionuclide ventriculography in patients with coronary artery disease: response of left ventricular ejection fraction and regional wall motion to supine bicycle exercise.

To evaluate the reproducibility of ejection fraction (EF) and regional wall motion (RWM) analyses by rest and exercise equilibrium radionuclide ventriculography (RNV) in the presence of coronary artery disease (CAD), 18 patients underwent two maximum, multistage supine bicycle exercise studies separated by an interval of 2 weeks. There were no significant differences in EF between the two studies, both at rest (56.0 +/- 13.8% vs 58.2 +/- 11.7%, p = NS) and with exercise (51.1 +/- 17.6% vs 54.3 +/- 17.6%, p = NS) and a highly significant correlation was shown between the two groups of values (rest r = 0.90, exercise r = 0.93, p less than 0.001). There was no significant difference in the change from rest to exercise (-4.9 +/- 12.0% vs -3.8 +/- 11.5%, p = NS) between the two studies and the correlation was highly significant (r = 0.69, p less than 0.01). The interstudy variabilities were 2.2 +/- 6.1% and 1.2 +/- 7.3% for rest and exercise, respectively, and 2.0 +/- 9.2% for the change from rest to exercise. Ninety-four percent of both rest and exercise regions had similar RWM. Eighty-one percent of the abnormally contracting regions were common to both exercise studies. Utilizing conventional criteria for the diagnosis of CAD, 11 patients had abnormal EF response and nine had abnormal RWM response to exercise on both studies. Combining EF and RWM criteria resulted in the diagnosis of CAD in 15 patients in both studies. We conclude that: (1) there were no significant differences in rest and exercise radionuclide EF and RWM between two supine bicycle exercise studies performed 2 weeks apart in patients with stable CAD and there were significant correlations between the two studies; (2) despite these correlations, the interstudy variabilities emphasize the need for the inclusion of reproducibility studies in all evaluations of interventions by exercise radionuclide ventriculography; and (3) the variations in EF and RWM response to exercise result in lack of uniformity between the two studies regarding the diagnosis of CAD based on conventional RNV criteria.

Severity of silent myocardial ischemia on ambulatory electrocardiographic monitoring in patients with stable angina pectoris: relation to prognostic determinants during exercise stress testing and coronary angiography.

The relation of silent ischemia in patients with stable angina to known predictors of severity of coronary disease on exercise stress testing and coronary angiography is poorly defined. This issue was therefore examined with use of Holter electrocardiographic (ECG) recordings, treadmill exercise tests and angiographic indexes in 102 patients (not taking antianginal therapy) and the results were compared with Holter and treadmill findings in 42 volunteers. A total of 159 ischemic episodes (90% silent) were identified during 2,503 h on Holter recording in 97 patients (mean duration per episode 22.7 +/- 147 min; range 1 to 234). Holter recordings had a 92% specificity and an 80% positive predictive value, but a sensitivity of only 37% and a negative predictive value of 27% for coronary disease. Sixty-three patients (Group I) had no ischemia on Holter recording, 22 (Group II) had a cumulative duration of 1 to 60 min/24 h and in 12 (Group III) ischemia exceeded 60 min/24 h. There was no significant correlation between cumulative ischemia duration on Holter recording and exercise duration or time to ST segment depression on treadmill exercise. In general, the greater the number of coronary vessels involved and the higher the proximal coronary artery stenosis score, the greater the likelihood of ischemia and the longer the cumulative ischemia duration on Holter recording. Irrespective of the severity of coronary disease, in about 25% of Holter recordings in each angiographic category there were no ischemic episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical pharmacology, pharmacokinetics, and hemodynamic effects of nicardipine

The dihydropyridine derivatives constitute a distinct subcategory of calcium channel blockers that have marked peripheral vascular effects with minimal or no electrophysiologic actions when administered to intact animals or humans. These dihydropyridine derivatives are structurally similar to nifedipine, the most widely studied dihydropyridine. The derivatives have varying affinities for different regional circulations, and there may be an important relationship between structure and activity of these compounds with respect to the predilection of the site of their action in vascular tissue. It is possible that such differences may be of clinical significance. As a class, the dihydropyridines exert reasonably distinct hemodynamic changes that may be of particular importance in the treatment of hypertension, cardiac failure, and regurgitant valvular lesions. Nicardipine hydrochloride is a newer agent that has undergone extensive evaluation in recent years. Pharmacologically and electrophysiologically, it resembles other dihydropyridines. Unlike nifedipine, however, it can be administered by both the intravenous and oral routes. There are additional differences between its properties and those of other calcium channel blockers. For example, nicardipine appears to produce a greater increase in coronary sinus blood flow than other calcium channel blockers. The clinical significance of this finding is unclear. In addition, nicardipine appears to increase myocardial contractility, even in patients with severe congestive cardiac failure. Nicardipine produces a dose-dependent decrease in blood pressure and systemic vascular resistance with increases in heart rate, left ventricular dP/dt, LV ejection fraction, cardiac output, and stroke work index, but no significant change in LV end-diastolic pressure. Clearly, the drug has negligible venodilator actions.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation of continuous-wave doppler assessment of chronic aortic regurgitation with hemodynamics and angiography

Fifteen patients with chronic aortic regurgitation (AR) were studied by cardiac catheterization and continuous-wave (CW) Doppler echocardiography. The slope of the AR CW Doppler signal was higher in patients with severe AR (5.7 +/- 2.1 m/s2) than in those with moderate (2.5 +/- 1.3 m/s2) or mild (1.8 +/- 0.7 m/s2) AR (p less than 0.05). The slopes in patients with mild (less than or equal to 18 mm Hg), moderate (19 to 24 mm Hg) and severe (greater than 24 mm Hg) elevation of left ventricular end-diastolic pressure were significantly different (1.9 +/- 0.6, 3.3 +/- 1.2 and 7.1 +/- 0.4 m/s2, respectively, p less than 0.05). Patients with severe AR had shorter pressure half-times than those with mild AR (283 +/- 141 vs 820 +/- 393 ms, p less than 0.05). There was a significant correlation between the slope and left ventricular end-diastolic pressure (r = 0.80, p less than 0.001) and a weaker inverse correlation between pressure half-time and left ventricular end-diastolic pressure (r = -0.59, p less than 0.05). The end-diastolic pressure gradient estimated from CW Doppler using a simplified Bernoulli equation correlated poorly with the catheter measured gradient (r = 0.59, p less than 0.02). The slope of the CW Doppler signal is a better predictor of severity than pressure half-time and is affected by left ventricular end-diastolic pressure in addition to angiographic severity of AR.

Use of calcium antagonists in ventricular dysfunction.

Calcium antagonists are now widely used in a variety of cardiocirculatory disorders, many of which are associated with varying levels of depressed myocardial function. Thus, the hemodynamic effects of calcium antagonists in patients with normal as well as depressed ventricular function are clinically relevant. None of the 3 agents verapamil, nifedipine or diltiazem exerts significant negative inotropic effects in patients with relatively normal myocardial function, although increases in left ventricular end-diastolic pressure may occur with verapamil and possibly diltiazem. In a setting in which ischemia, hypertension or arrhythmias contribute to cardiac failure, all 3 agents may ameliorate myocardial decompensation if they reverse the precipitating causes. In patients with depressed myocardial function, the effects of diltiazem are not known; verapamil may depress myocardial function, especially if the ventricular filling pressure is increased. Nifedipine generally has little depressant action in this setting and usually improves cardiac function, especially if the sympathetic reflexes are intact. However, hemodynamic deterioration after nifedipine administration has been reported. Thus, the available data do not support the use of calcium antagonists as afterload-reducing agents in heart failure and suggest caution in the use of these agents in patients with impaired ventricular performance.