Subsets of ambulatory myocardial ischemia based on heart rate activity. Circadian distribution and response to anti-ischemic medication. The Angina and Silent Ischemia Study Group (ASIS)

BACKGROUND: Identification of whether episodes of ambulatory ischemia are caused by increases in myocardial oxygen demand or to episodic coronary vasoconstriction in patients with stable coronary disease may be important to guide selection of optimal anti-ischemic therapy and to gain insight into mechanisms responsible for adverse cardiac events. METHODS AND RESULTS: Mean minute heart rate activity during ambulatory ECG (AECG) monitoring was determined for 50 patients treated with propranolol, diltiazem, nifedipine, or placebo in a randomized, double-blind, crossover trial. Periods of heart rate increases of various magnitudes and durations and starting at various baseline heart rates on each therapy were identified throughout each 48-hour AECG recording, and the proportion of these periods associated with an ischemic episode was determined. The circadian variation of ischemic episodes categorized by the presence or absence of an increase in heart rate was analyzed. Eighty-one percent of ischemic episodes were preceded by an increase in heart rate > or = 5 beats per minute. The likelihood of developing ischemia associated with a heart rate increase was proportional to the magnitude and duration of the heart rate increase and the baseline heart rate before the increases in heart rate: likelihood ranged from 4% when the heart rate increased 5-9 beats per minute and lasted < 10 minutes to 60% when the heart rate increased > or = 20 beats per minute and lasted > or = 40 minutes. The likelihoods of developing ischemia based on changes in the heart rate variables were similar for each of the therapies. Propranolol therapy significantly reduced the magnitude and duration of heart rate increase and the baseline heart rate compared with therapy with placebo, diltiazem, or nifedipine (P < .001). Ischemic episodes associated with a heart rate increase displayed a daytime peak, whereas ischemia occurring without a heart rate increase occurred evenly throughout the day. Propranolol reduced the proportion of heart rate-related ischemic episodes and increased the proportion of non-heart rate-related episodes compared with placebo (P < .02), and nifedipine exerted the opposite effect (P = .005). Multivariate analysis indicated that the probability of developing ischemia was strongly associated with heart rate variables and was unaffected by time of day. CONCLUSIONS: Most episodes of ambulatory ischemia are associated with a preceding period of increased heart rate. The likelihood of developing ischemia is predicted by heart rate variables and unaffected by time of day. Anti-ischemic efficacy is generally a result of the medication's efficacy in reducing heart rate variables. A minority of ischemic episodes are not associated with preceding periods of increased heart rate, may be caused by episodic coronary vasoconstriction, and are more effectively reduced by nifedipine than propranolol.

Effects of diltiazem on the pharmacokinetics of nifedipine.

To evaluate the effect of diltiazem pretreatment (60 mg three times a day for 3 days) on pharmacokinetics and pharmacodynamic effect of nifedipine, six healthy subjects received 20 mg nifedipine orally on two occasions using a double-blind cross-over, placebo-controlled method. Diltiazem induced a marked increment of the area under the plasma concentration-time curve (AUC) for nifedipine by a mean of 140% and reduced the total body clearance (Cl) from 0.0043 +/- 0.0019 to 0.0017 +/- 0.0006 ml/min/kg (p less than 0.05, mean +/- SD). The biological half-life (t1/2) of nifedipine was prolonged from 2.46 +/- 0.65 to 3.21 +/- 0.92 h (p less than 0.05) without any changes in indocyanine green (ICG) clearance. Diltiazem did not produce significant changes of AUC, Cl, and t1/2 for the acid metabolite of nifedipine. Blood pressure (BP) after nifedipine administration with diltiazem pretreatment was more decreased than that without diltiazem. Both a decreased hepatic clearance and an increased bio-availability of nifedipine by diltiazem probably explain the significant changes in pharmacokinetics and hemodynamics of nifedipine. A clinically important drug interaction may occur with nifedipine when diltiazem is administered concurrently.

Dose dependent effect of diltiazem on the pharmacokinetics of nifedipine.

The effect of diltiazem pretreatment on the pharmacokinetics of nifedipine were determined in six healthy male volunteers. Placebo or diltiazem (30 mg and 90 mg) was given orally three times daily for 3 days in a double-blind, Latin square method. On the fourth day, a 20-mg nifedipine was given orally 1 hour after the last dose of placebo or diltiazem. The mean elimination half-life of nifedipine prolonged significantly following diltiazem (2.54 hours on placebo vs 3.40 hours on 30 mg diltiazem and 3.47 on 90 mg diltiazem, both P less than .01). The mean AUC of nifedipine increased during diltiazem (1726.6 nmol X hr/ml on placebo vs 3838.0 on 30 mg diltiazem, and 5370.0 on 90 mg diltiazem, both P less than .05, 30 mg vs 90 mg, 0.1 less than P less than .05). The ratio of the AUC of primary metabolite (nitropyridine form) to the AUC of nifedipine was reduced by diltiazem pretreatment in a dose-dependent manner. ICG clearance was not influenced following diltiazem. These results indicate that diltiazem dose-dependently alters the pharmacokinetic profiles of nifedipine. The ICG clearance test showed that the liver blood flow did not decrease during diltiazem therapy, therefore, the reduction in the metabolic clearance of nifedipine might be caused by inhibiting effect of diltiazem on the activity of drug oxidizing enzymes.

The development and reversal of tolerance to antianginal effect of isosorbide dinitrate in patients with effort angina.

The development and reversal of tolerance to the hemodynamic and anti-anginal effects of isosorbide dinitrate in a sustained release form (ISDN-SR) were investigated in 11 male patients (mean age 58.9 y.o.) with stable effort angina. Treadmill exercise test, evaluation of hemodynamic parameters and measurement of plasma ISDN concentrations were performed during the control period, on the 1st, 7th and 14th days of therapy with 40 mg of ISDN-SR orally every 8 h and, subsequently, on the day when ISDN-SR was re-administered after a 72 h placebo period (17th day). Initially, exercise tolerance time (ETT) was prolonged significantly (p less than 0.001) by ISDN-SR from 257 +/- 50 sec in the control period to 434 +/- 55 sec on day 1. This prolongation was significantly reduced with sustained therapy and ETT was shortened to 332 +/- 69 sec on the 7th day (p less than 0.01 vs day 1) and 326 +/- 73 sec on the 14th day (p less than 0.01 vs day 1). The effects of ISDN-SR initially observed were restored after a 72 h placebo period and ETT was prolonged to 432 +/- 57 sec on the 17th day. The resting heart rate was increased significantly (p less than 0.01 vs control) and systolic blood pressure was decreased (p less than 0.001 vs control) by ISDN-SR on day 1. These changes were also diminished significantly (p less than 0.01 vs day 1) with sustained therapy and were restored after a 72 h nitrate-free interval.(ABSTRACT TRUNCATED AT 250 WORDS)

Combination therapy with diltiazem and nifedipine in patients with effort angina pectoris.

The antianginal effects of diltiazem and nifedipine alone and in combination were evaluated in a double-blind, randomized, placebo-controlled trial in 11 patients (nine men and two women, 57 +/- 8 years old) with stable effort angina. Each patient received placebo, 30 mg of diltiazem, 10 mg of nifedipine, and 30 mg of diltiazem plus 10 mg of nifedipine four times daily for 1 week each. Antianginal efficacy was assessed by means of a treadmill exercise test. The exercise tolerance time was significantly prolonged from 235.1 +/- 52 (placebo period) to 342.2 +/- 101 sec by diltiazem (p less than .01) and to 325.6 +/- 73 sec by nifedipine (p less than .01). The drug combination further prolonged exercise time to 451.1 +/- 103 sec, which was significantly longer than the interval attained with either diltiazem (p less than .01) or nifedipine (p less than .01) alone. The plasma concentration of diltiazem was unaffected by the addition of nifedipine, whereas the plasma nifedipine concentration was significantly increased from 34.8 +/- 11 to 106.4 +/- 37 ng/ml (p less than .001) by the concomitant administration of diltiazem. These data suggest that exercise tolerance in patients with effort angina is increased by the concomitant administration of diltiazem and nifedipine associated with an increase in the nifedipine plasma concentration.

Evaluation of diseased coronary arterial branches by polar representations of thallium-201 rotational myocardial imaging.

The perfusion territories in polar representations of stress Tl-201 rotational myocardial imaging in patients with angina pectoris who had one diseased coronary segment were analyzed. The lesions proximal or distal to the first major septal perforator in left anterior descending arteries were detected by the presence or absence of defects at the base of the anterior septum. Right coronary artery lesions were detected by the presence of defects at the basal posterior septum, in contrast to the preservation of myocardial uptake at this portion in lesions of the left circumflex artery. The specific defect patterns were detected in cases with lesions at the first diagonal, obtuse marginal, and posterolateral branches. Recognition of these defects in the polar maps allows detailed detection of diseased coronary arterial branches.

[Serial changes in cardiovascular dimensions and left ventricular function after surgery of valvular heart disease: a follow-up study by echocardiography].

Serial changes in cardiac function after surgery were studied in 84 patients with various valvular heart diseases using M-mode and two-dimensional echocardiography (2-DE). The results were as follows: 1. Serial postoperative changes in cardiac dimensions and left ventricular functions were well documented by M-mode and 2-DE. 2. The change in left ventricular function became most pronounced one month after surgery, and remained unchanged in many patients during the subsequent observation periods. 3. Open mitral commissurotomy (OMC) and mitral valve replacement (MVR) were compared as to their benefits for patients with isolated mitral stenosis (MS) accompanied by left ventricular dysfunction, and MVR proved superior to OMC in terms of magnitude of functional improvement. 4. (a) Ejection fraction (EF) in patients with left ventricular volume overload was overestimated due to the influence of increased preload. Accordingly, EF which tended to be depressed one month after surgery was judged to reflect altered loading conditions; it did not represent myocardial damage caused by valve replacement. (b) In patients who had MVR or aortic valve replacement (AVR) without postoperative heart failure, EF remained unchanged in the MVR group after a lapse of one month postoperatively, while it tended to improve in the AVR group. This difference was thought to be caused by changes in left ventricular systolic overload resulting from correction of regurgitation. (c) In patients with MR and postoperative heart failure, there was a tendency for EF to decrease after a lapse of one month postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Earlobe crease and coronary heart disease in Japanese.

To evaluate whether a significant statistical correlation exists between earlobe crease (EC) and coronary heart disease (CHD), 1000 Japanese adult patients (573 males, 427 females) were examined for the presence or absence of EC, clinical or angiographic evidence of CHD, and the following coronary risk factors: male sex, age over 50 years, obesity, hypertension, diabetes mellitus, cigarette smoking, and hyperlipidemia. Patients were divided into two groups according to clinical evidence of CHD: 237 patients with angina pectoris and/or myocardial infarction (CHD+ group); 720 patients without evidence of CHD (CHD- group). Coronary angiography was performed on 200 patients from this sample population; these patients were also divided into two groups: 119 patients with greater than 50% luminal narrowing of at least one major coronary artery (stenosis+ group); 81 patients with no significant atherosclerotic changes in the coronary arteries (stenosis- group). EC was present in 58 of 237 CHD+ patients (24.5%) but in only 35 of 720 CHD- patients (4.8%; P less than 0.001); it was present in 31 of 199 stenosis+ patients (26.1%) but in only 3 of 81 stenosis- patients (3.7%; P less than 0.01). EC was also found to correlate significantly with some coronary risk factors; the correlations between the presence of EC and the presence of CHD and coronary risk factors were investigated by multivariate analysis. In a multivariate setting, the existence of CHD and an age of over 50 years was significantly related to the presence of EC. To investigate the relationship between EC and advancing age, all patients were separated into age-groups.(ABSTRACT TRUNCATED AT 250 WORDS)

[Prediction of coronary lesions by two-dimensional echocardiography in patients with healed myocardial infarction].

Regional left ventricular wall motion abnormalities were assessed by two-dimensional echocardiography (2-DE) in 66 patients with healed myocardial infarction (MI) and the results were compared with those of coronary angiography which was performed at nearly the same time as 2-DE. The left ventricular wall was divided into 14 segments and asynergy was assessed in each segment. To compare the severity of segmental asynergy with coronary artery lesions, relation between segments and coronary artery perfusion was assumed as follows: the anterior wall, anterior septum and apex corresponded to the anterior descending artery (LAD); the lateral and inferior walls corresponded to the left circumflex artery (LCX); and the posterior septum and inferior wall corresponded to the right coronary artery (RCA). One vessel disease: In all 24 patients with MI induced by LAD lesions, regional asynergy was identified in the anterior wall, anterior septum and apex. All patients had advanced asynergy (severe hypokinesis, akinesis or dyskinesis) except one with subendocardial infarction. Advanced asynergy was identified in the other segments including the lateral wall (one patient) and the posterior septum (11 patients), but such asynergy was not associated with that of the inferior wall. In four patients with MI induced by RCA lesions, regional asynergy appeared in localized segments of the posterior septum and inferior wall, and the asynergy was severe in all patients except one in whom collaterals were well-developed. In four patients with MI induced by LCX lesions, asynergy was observed in both the lateral and inferior walls. In only one patient, mild asynergy was identified in the apex. Multi-vessel disease: In both groups with double vessel (16 patients) and triple vessel (16 patients) disease, asynergy was recognized in the affected areas of the major coronary artery which was considered responsible for the infarction, irrespective of the severity of the coronary stenosis. Also, there was no significant correlation between the severity of coronary artery stenosis and segmental wall motion abnormalities in non-infarcted areas. No significant correlation was observed between the severity of regional wall motion abnormalities in the infarcted areas and the degree of development of collaterals. In patients with MI induced by LAD lesions, more extensive asynergy in the anterior wall and anterior septum at the basal portion was observed in the patient group with proximal stenosis than in the group with distal stenosis.(ABSTRACT TRUNCATED AT 400 WORDS)