Comparison of a 60- versus 90-minute determination of ST-segment resolution after thrombolytic therapy for acute myocardial infarction. In TIME-II Investigators. Intravenous nPA for Treatment of Infarcting Myocardium Early-II.

Determination of ST-segment resolution 60 minutes after the administration of thrombolytic therapy allows accurate risk stratification for mortality and congestive heart failure. Patients with complete ST resolution at 60 minutes tended to be at lower risk for 30-day mortality than patients with complete ST resolution at 90 minutes.

Effect of isradipine on cardiopulmonary baroreflex function, regional blood flow, and vascular responsiveness in hypertensive patients.

Calcium channel antagonists, when used to treat hypertension, may modulate baroreflex function and vascular responsiveness to endogenous vasoconstrictors. We studied regional blood flow, cardiopulmonary baroreflex function, and pressor responses in nine hypertensive patients (mean age of 44 +/- 7 years), eight males and one female, treated with isradipine (ISR), a dihydropyridine calcium channel antagonist, in a placebo-controlled, crossover trial. Each patient underwent determination of blood pressure and forearm, splanchnic, and renal blood flows (by strain gauge plethysmography and indocyanine green and p-aminohippurate clearances, respectively) at baseline and during cardiopulmonary unloading by lower body negative pressure (LBNP) at -10 and -20 mm Hg. ISR decreased the mean arterial pressure from 105 +/- 2 to 93 +/- 2 mm Hg (p less than 0.01). ISR did not change supine forearm or splanchnic vascular resistances, but renal vascular resistance fell 30% during treatment (from 0.12 +/- 0.02 to 0.09 +/- 0.01 mm Hg min/ml, p less than 0.05). Cardiopulmonary baroreceptor unloading by LBNP elicited comparable effects on forearm, splanchnic, and renal vascular resistance before and during ISR treatment. Baroreceptor unloading during placebo did not change plasma NE or PRA; during ISR, LBNP elicited a progressive rise in these hormones. The pressor response to NE was potentiated during ISR treatment (p less than 0.05); in contrast, the pressor response to angiotensin II infusion was blunted by calcium blockade (p less than 0.05). The present study, therefore, demonstrates that calcium channel blockade with ISR preserves, and may even augment, cardiopulmonary baroreflex function. These physiologic responses may contribute to the relatively low incidence of symptomatic orthostatic hypotension observed during chronic treatment with this agent.

Baroreflex regulation of regional blood flow in congestive heart failure.

In patients with congestive heart failure (CHF), the distribution of the cardiac output is altered. Cardiopulmonary and arterial baroreceptors normally can regulate regional blood flow, but their contribution in heart failure is not known. To examine the role of baroreceptors in the regulation of regional blood flow in CHF, the effect of lower body negative pressure (LBNP) on forearm, renal, and splanchnic blood flow was evaluated in 12 patients with heart failure. Incremental LBNP at -10 and -40 mmHg decreased central venous pressure but had not effect on systolic blood pressure or pulse pressure. Renal blood flow decreased from 505 +/- 63 to 468 +/- 66 ml/min during LBNP -10 mmHg (P less than 0.05) and to 376 +/- 74 ml/min during LBNP -40 mmHg (P less than 0.01). Splanchnic blood flow decreased from 564 +/- 76 to 480 +/- 62 ml/min during LBNP -10 mmHg (P less than 0.01) and to 303 +/- 45 ml/min during LBNP -40 mmHg (P less than 0.01). Forearm blood flow did not decrease during LBNP -10 mmHg or -40 mmHg. To determine whether the absence of limb vasoconstriction during LBNP was confined to abnormalities in the baroreflex arc or was secondary to impaired end-organ responsiveness, six patients with heart failure and six normal subjects received an intrabrachial artery infusion of phenylephrine. Phenylephrine increased forearm vascular resistance comparably in each group. These data demonstrate that baroreceptors can regulate splanchnic and renal but not limb vascular resistance in patients with congestive heart failure and may contribute to the redistribution of blood flow that occurs in this disorder.

Internal carotid artery stenosis: accuracy and reproducibility of color-Doppler-assisted duplex imaging.

The accuracy, rapidity, and reproducibility of color-Doppler-assisted duplex sonography in the diagnosis of significant internal carotid artery stenosis were prospectively evaluated. Only the point of maximal color shift on the color map was used for spectral analysis. When compared with angiography in 60 carotid bifurcations, a measured peak systolic velocity above 1.25 m/sec was 87% accurate in the detection of significant internal carotid artery stenoses greater than 50%. Determination of maximal internal carotid artery velocity was 40% faster with color-Doppler-assisted duplex sonography than with nonassisted duplex ultrasound. The correlation coefficient for interobserver agreement was .90. It increased to .97 when cases of extensive (greater than 1 cm) acoustic shadowing (7% of bifurcations) were excluded. The authors conclude that the color flow map is an accurate and reproducible means of depicting the point of maximal stenosis within the internal carotid artery.

Regional vascular responses to prolonged lower body negative pressure in normal subjects.

The purpose of this study was to determine the effects of sustained unloading of baroreceptors in humans. The regional hemodynamic responses to lower body negative pressure (LBNP) were determined in 20 normal subjects. LBNP at -10 mmHg for 1 h decreased central venous pressure (CVP) without affecting blood pressure or heart rate, suggesting that only cardiopulmonary baroreceptors were unloaded. Forearm blood flow (FBF) and splanchnic blood flow (SBF) both decreased. Renal blood flow (RBF) did not change, but glomerular filtration rate (GFR) increased. Plasma renin activity rose slightly, whereas plasma norepinephrine levels did not change. Peak LBNP (either -20 or -40 mmHg for 1 h) caused a further decline in CVP and narrowed pulse pressure, thus unloading both arterial and cardiopulmonary baroreceptors. FBF returned to base-line values and SBF decreased further. RBF fell and the GFR remained increased. Plasma renin activity increased further, and plasma norepinephrine level rose. Thus the forearm and splanchnic circulations are sensitive to sustained unloading of cardiopulmonary baroreceptors; renal vasoconstriction occurs with additional unloading of arterial baroreceptors. Renin-angiotensin system activation during LBNP may be pertinent to the preservation of glomerular filtration.

Responsiveness of atrial natriuretic factor to reduction in right atrial pressure in patients with chronic congestive heart failure.

In patients with congestive heart failure, atrial natriuretic factor may serve as a counter-regulatory hormone, offsetting the vasoconstrictive and volume-retentive effects of the sympathetic nervous system, the renin-angiotensin-aldosterone system and vasopressin. Indeed, the plasma levels of atrial natriuretic factor and the vasoconstrictor hormones are often simultaneously elevated in these patients. It is not known, however, whether atrial natriuretic factor remains responsive to sudden reductions in atrial pressure in patients with chronic heart failure, or is unresponsive like the vasoconstrictor systems. To examine this issue, the plasma concentrations of atrial natriuretic factor and the vasoconstrictor hormones were measured in 20 normal subjects and 12 patients with chronic congestive heart failure during incremental lower body negative pressure, an intervention that lowers atrial pressure. In the normal subjects, incremental lower body negative pressure at -10, -20 and -40 mm Hg decreased central venous pressure and pulse pressure. At maximal lower body negative pressure, plasma atrial natriuretic factor levels decreased from 51 +/- 5 to 27 +/- 3 pg/ml (p less than 0.01), whereas increases occurred in plasma levels of norepinephrine (194 +/- 11 to 385 +/- 70 pg/ml, p less than 0.01), renin activity (1.4 +/- 0.2 to 3.9 +/- 0.1 ng/ml per h, p less than 0.01) and vasopressin (1.3 +/- 0.1 to 6.4 +/- 2.4 pg/ml, p less than 0.05). In the patients with congestive heart failure, lower body negative pressure also reduced central venous pressure. Baseline plasma atrial natriuretic factor levels were markedly elevated, averaging 438 +/- 138 pg/ml, and decreased to 317 +/- 87 pg/ml at maximal lower body negative pressure (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of cardiac chamber volume to baroreflex activity in normal humans.

The objectives of this study were to examine the effect of incremental lower body negative pressure (LBNP) on cardiac chamber volume and assess the relationship between cardiac chamber volume and baroreflex activation of the neurohormonal axis. Accordingly, echocardiographic determination of cardiac chamber volume and neurohormonal responses were studied in 14 normal subjects during incremental LBNP. LBNP -10 mm Hg decreased left atrial diameter and left ventricular systolic volume index, but did not alter heart rate, systolic or pulse pressure, or stroke volume. During LBNP -10 mm Hg, plasma norepinephrine levels increased, suggesting activation of the sympathetic nervous system. LBNP -40 mm Hg caused a significant decrease in left atrial diameter and left ventricular systolic, diastolic, and stroke volume indices. During LBNP -40 mm Hg, heart rate increased, and systolic and pulse pressure fell. With this more negative level of LBNP, norepinephrine, angiotensin II, aldosterone, and arginine vasopressin concentrations and PRA all increased. The findings that left atrial diameter decreased and plasma norepinephrine concentration increased during LBNP -10 mm Hg suggest that the sympathetic nervous system is sensitive to changes in atrial receptor activity. At higher levels of LBNP (-40 mm Hg), activation of the renin-angiotensin system and release of vasopressin were associated with a fall in left ventricular diastolic volume as well as a decrease in the pressure input to the arterial baroreceptors. Under this condition, the differential contribution of the cardiopulmonary and arterial baroreceptors to the regulation of the renin-angiotensin system and vasopressin release cannot be distinguished.

Efficacy of sustained-release verapamil in chronic stable angina pectoris.

The effectiveness of a sustained-release preparation of verapamil (verapamil-SR) was compared with the regular formulation of verapamil and with placebo in 12 patients with chronic stable angina pectoris. All patients completed an 8-week, double-blind, double-crossover, randomized protocol with 2-week treatment periods of verapamil-SR, 240 mg twice daily; regular-formulation verapamil, 120 mg 4 times daily; and 2 placebo therapies. The frequency of weekly anginal episodes was reduced from 7.6 +/- 10.0 with placebo to 3.1 +/- 4.2 after the regular formulation of verapamil (p = 0.09) and from 6.4 +/- 7.6 with placebo to 2.8 +/- 4.8 after verapamil-SR (p = 0.06). Treadmill time increased from 384 +/- 144 seconds during the first placebo phase to 468 +/- 138 seconds after the regular formulation of verapamil (p less than 0.01) and from 354 +/- 102 seconds during the second placebo phase to 462 +/- 138 seconds after verapamil-SR (p less than 0.01). Time to the onset of angina was similarly prolonged by formulations of verapamil. There were no significant adverse effects after 1 year in any patient taking verapamil-SR, 240 mg twice daily. Thus, a twice-a-day verapamil-SR dose regimen is safe and is as effective for treatment of angina of effort as the regular formulation given 4 times a day.

Contribution of vasopressin to vasoconstriction in patients with congestive heart failure: comparison with the renin-angiotensin system and the sympathetic nervous system.

Ten patients with advanced congestive heart failure were treated with an arginine vasopressin V1 antagonist during hemodynamic monitoring to determine the contribution of vasopressin to vasoconstriction in this disorder. The vasopressin antagonist caused a decrease in systemic vascular resistance in the three patients whose plasma vasopressin was greater than 4.0 pg/ml (average for the group was 2.4 +/- 0.6). Plasma vasopressin concentration correlated with the percent decrease of systemic vascular resistance (r = 0.70, p less than 0.025), serum sodium (r = 0.72, p less than 0.02) and serum creatinine (r = 0.85, p less than 0.005). To compare the relative roles of vasopressin, the renin-angiotensin system and the sympathetic nervous system, these patients also received captopril and phentolamine. Captopril decreased systemic vascular resistance by 20% (p less than 0.05), mostly in patients with high plasma renin activity. Levels of plasma renin activity ranged between 1 and 46 ng/ml per h (average 14.7 +/- 5.7) and correlated with serum sodium (r = 0.77, p less than 0.025), serum creatinine (r = 0.73, p less than 0.025) and right atrial pressure (r = 0.67, p less than 0.05). Phentolamine decreased systemic vascular resistance in all patients (average 34%, p less than 0.01), but the decrease did not correlate with the pretreatment norepinephrine concentration. Norepinephrine levels were elevated in all patients (694 +/- 110 pg/ml) and correlated with baseline stroke volume index (r = 0.75, p less than 0.025) and plasma renin activity (r = 0.67, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy and safety of sustained-release diltiazem in stable angina pectoris.

The safety and efficacy of a sustained-release preparation of diltiazem (diltiazem-SR), with dose levels of 240 and 360 mg/day, were assessed in 18 patients with stable angina of effort. A double-blind, placebo-controlled, randomized, crossover protocol was used. Diltiazem-SR, when given twice daily, reduced the frequency of weekly anginal attacks from 9.3 +/- 10.4 with placebo to 3.7 +/- 4.7 with 240 mg/day and to 3.1 +/- 4.7 with 360 mg/day (both p less than 0.01 compared with placebo). Treadmill time was increased from 410 +/- 180 seconds during the placebo phase to 519 +/- 177 seconds during the 240-mg/day dose and to 506 +/- 182 seconds during the 360-mg/day dose of diltiazem-SR (both p less than 0.01 compared with placebo). The time to the onset of angina and ischemic ST-segment depression were similarly prolonged by both doses of diltiazem-SR. The beneficial effects of diltiazem-SR appeared partly due to a reduction in the heart rate during submaximal exercise. Diltiazem-SR is effective and safe for the treatment of angina of effort when given twice daily.

The efficacy and safety of high-dose verapamil and diltiazem in the long-term treatment of stable exertional angina.

The efficacy and safety of high-dose verapamil (480 mg/day) and diltiazem therapy (360 mg/day) were compared in separate cohorts of 26 and 20 patients, respectively. All patients had stable exertional angina and underwent an initial 6-week double-blind, placebo-controlled, randomized phase followed by a 12-month open-label period. Angina attacks were reduced by verapamil (6.3 +/- 7.5 to 2.5 +/- 4.1 attacks per week, p less than 0.001) and by diltiazem (9.2 +/- 7.5 to 3.0 +/- 3.1 attacks per week, p less than 0.001), while treadmill time increased with both verapamil (372 +/- 132 to 444 +/- 108 s, p less than 0.001) and diltiazem (412 +/- 175 to 536 +/- 164 s, p less than 0.001) during the short-term study. Both agents continued to show similar salutory effects at the end of one year. The beneficial effects of both drugs appeared to be related in part to a reduction of the rate-pressure product during submaximal exercise (12% by verapamil, 7% by diltiazem, both p less than 0.05). Adverse effects were few and consisted primarily of mild constipation in six patients taking verapamil, and pedal edema and transient flushing in 2 patients each using diltiazem. Thus, high-dose verapamil and diltiazem have similar beneficial effects and are safe for the long-term treatment of effort-related angina pectoris.

Plasma verapamil levels and exercise performance.

Our study in 10 patients with stable, exercise-related angina under a double-blind, placebo-controlled protocol correlated plasma verapamil levels after single oral doses of 120 and 240 mg and exercise performance. Plasma verapamil levels peaked at 2 hr in seven patients and 4 hr in three patients and declined thereafter, with a mean plasma t1/2 of 3.22 and 4.54 hr after the 120- and 240-mg dose. Despite the relatively short t1/2s, total exercise duration and time to onset of angina and S-T segment depression were longer than placebo values for 4 hr after the 120-mg dose and for 8 hr after the 240-mg dose. Percentage increase in treadmill time and log of plasma verapamil levels correlated. All patients with plasma levels above 100 ng/ml had at least a 50% increase in exercise duration. Thus measurement of plasma verapamil levels are useful in patients who fail to respond to a dose of verapamil. If the level is below 100 ng/ml, increasing the dose of verapamil may improve response.

Efficacy and safety of incremental doses of diltiazem for the treatment of stable angina pectoris.

The safety and efficacy of incremental doses of diltiazem in treating angina pectoris were assessed in 20 patients with functional class II to III exertional angina. During an initial single-blind dose titration phase, dilitiazem produced a dose-related improvement in anginal frequency and exercise capacity. Weekly anginal attacks were reduced to 7.5 +/- 8.9, 5.6 +/- 7.8 and 4.9 +/- 7.3 on diltiazem, 120, 240 and 360 mg per day, respectively, as compared with 11.9 +/- 8.7 on placebo (all p less than 0.001). Treadmill time was significantly enhanced by high dose (360 mg per day) as compared with moderate dose (240 mg per day) diltiazem: 473 +/- 149 versus 424 +/- 146 seconds (p less than 0.05). Time to ischemic ST segment depression was similarly changed: 344 +/- 132 versus 298 +/- 142 seconds (p less than 0.05) by high dose as compared with moderate dose diltiazem. During a subsequent double-blind phase, high dose diltiazem significantly reduced weekly anginal frequency when compared with placebo: 3.1 +/- 3.0 versus 9.3 +/- 7.1 (p less than 0.001); and increased treadmill exercise time: 508 +/- 158 versus 418 +/- 172 seconds on placebo (p less than 0.05). Subjective and objective benefits of high dose diltiazem were sustained during a follow-up period of 6 months without major drug side effects.

Efficacy and safety of verapamil in patients with angina pectoris after 1 year of continuous, high-dose therapy.

The long-term efficacy and safety of high-dose verapamil therapy (480 mg/day) was assessed in 26 patients with chronic stable angina pectoris during a 3-phase protocol: Phase 1--an initial, 6-week placebo-controlled, double-blind crossover assessment; Phase 2--an open label, 1-year follow-up; and Phase 3--a final drug withdrawal and rechallenge 10-week study. Three patients withdrew during Phase 2 (1 had hepatitis and 2 underwent coronary bypass surgery). Adverse effects during Phase 2 were mild, consisting of constipation (6 patients) and prolongation of the P-R interval (5 patients); however, no patient required alteration of the 480 mg/day dosage. At the end of Phase 2, 10 patients underwent the Phase 3 study, commencing with a 2-week period in which verapamil was either tapered gradually or abruptly discontinued. This was followed by an 8-week double-blind, placebo-controlled crossover rechallenge study with verapamil. The clinical and exercise responses to verapamil compared with placebo were similar during the Phase 3 protocol and the initial Phase 1 study (treadmill time increased by 55% and anginal attacks per week decreased by 63% during Phase 3, compared with a 28% increase and a 42% decrease, respectively, during Phase 1, p = not significant [NS]). Withdrawal of verapamil produced a similar return of anginal symptoms whether the drug was abruptly discontinued or its administration tapered. No patient had unstable angina pectoris or acute myocardial infarction. These investigations demonstrate that verapamil is safe and effective when evaluated after 1 year of continuous therapy using a dosage of 480 mg/day. There is no evidence of drug tachyphylaxis, nor does verapamil appear to cause an abrupt withdrawal syndrome in patients with chronic stable angina pectoris.

Cardiokymography during exercise testing: a new device for the detection of coronary artery disease and left ventricular wall motion abnormalities.

The cardiokymograph (CKG) is a device that has been shown to reflect left ventricular (LV) wall motion abnormalities. Its accuracy in detecting coronary artery disease (CAD) during treadmill exercise testing was assessed in 204 consecutive patients undergoing coronary arteriography. Of the 188 patients with a technically adequate CKG, 146 (78%) had significant CAD. The sensitivity and specificity were similar for both the exercise electrocardiogram (ECG) (66% and 86%, respectively) and the exercise CKG (73% and 95%, respectively). An abnormal exercise CKG was significantly more common in patients with 3-vessel CAD than in those with 1-vessel disease (97% versus 52%, respectively; p less than 0.001) and in patients with left anterior descending disease than in those without (85% versus 26%, respectively; p less than 0.001). Seventy patients showed both an abnormal exercise ECG and CKG; all had CAD and 86% had multivessel CAD. Forty-eight patients demonstrated a normal exercise ECG and CKG; 29% had CAD but only 6% had multivessel CAD. Among 55 patients who had simultaneous exercise radionuclide ventriculography, new septal or apical wall motion abnormalities were found in 79% (23 of 29) of patients with an abnormal CKG compared with 19% (5 of 26) of patients with a normal CKG (p less than 0.001). Thus, the CKG during exercise testing accurately reflects LV wall motion abnormalities and can be used to improve the diagnostic accuracy of exercise testing as an additional marker of myocardial ischemia.

Treatment of stable angina of effort with verapamil: a double-blind, placebo-controlled randomized crossover study.

The effects of verapamil were assessed in 26 patients with stable exertional angina pectoris in a double-blind, placebo-controlled, randomized crossover protocol using serial treadmill tests. Verapamil, 480 mg/day, reduced anginal frequency from 5.6 +/- 7.3 to 2.2 +/- 3.9 attacks per week (p less than 0.001) and nitroglycerin consumption from 3.4 +/- 4.9 to 1.2 +/- 2.5 tablets per week (p less than 0.05) compared with placebo. Treadmill time increased from 6.4 +/- 2.1 minutes during the placebo phase to 7.5 +/- 1.8 minutes during the verapamil phase (p less than 0.001). Verapamil's beneficial effect appeared to be related, in part, to a 10% reduction of the rate-pressure product at rest (p less than 0.05) and a 12% reduction during submaximal exercise (p less than 0.001). Verapamil also caused less marked ST-segment depressions at peak exercise (p less than 0.05) at a similar rate-pressure product, suggesting a favorable redistribution of coronary blood flow to the ischemic zone. Side effects from verapamil were minimal, consisting mainly of constipation (six patients). Verapamil appears to be a safe and effective drug for treating angina of effort.

Suppression of ischemic related ventricular tachycardia by verapamil during treadmill exercise testing.

A 35-year-old man with class 2 angina pectoris was enlisted in a serial exercise test protocol to evaluate oral verapamil therapy for angina pectoris. During both the single-blind open dose titration phase and the double-blind phase, short salvoes of ventricular tachycardia (VT) were followed by angina and ischemic ST segment depression during exercise with placebo. With verapamil therapy, no ventricular ectopy was noted during exercise, and the patient exercised longer before angina or ischemic ECG changes developed. Twenty-four hour ECG monitoring revealed multiform ventricular premature depolarizations and three-beat salvoes of VT with placebo and no ventricular ectopy whatsoever with verapamil. Verapamil's antiarrhythmic effect may be secondary to its anti-ischemic action, or, by inhibiting slow channel conduction (with its propensity for enhanced automaticity and reentry) induced by ischemia and the sympathetic response to exercise, exerts a primary antiarrhythmic action.

Decrease in systolic blood pressure during exercise testing: reproducibility, response to coronary bypass surgery and prognostic significance.

To investigate the reproducibility and prognostic significance of an exercise-induced decrease in systolic blood pressure, 47 patients were identified who manifested such a reduction below the pre-exercise standing level in a consecutive series of 436 patients who underwent treadmill exercise testing and cardiac catheterization during a 3 year period. The prevalence of this abnormal finding was 11 percent in the total group but 21 percent in the 124 patients with three vessel or left main coronary artery disease. Patients with an exercise-induced reduction in systolic blood pressure were more likely to be male, have typical angina pectoris with class III or IV functional limitation and to have had a prior myocardial infarction than were patients without this finding (p less than 0.05). Although no complications occurred during the exercise test of these 47 patients, the majority had severe ischemic responses and 14 (30 percent) showed complex repetitive ventricular arrhythmias. Of the 47 patients, 24 (group 1a) received medical treatment and 23 (group 1b) underwent coronary bypass surgery. On repeat exercise testing in 42 patients, a decrease in systolic blood pressure during exercise was consistently present in group 1a (17 of 20) but entirely absent (0 of 22) in group 1b (p less than 0.001). The mean treadmill time, peak heart rate and systolic blood pressure were not significantly different in the initial and on repeat exercise tests in patients in group 1a; however, in patients in group 1b, all of these variables were significantly higher in the repeat test (p less than 0.001). At a mean follow-up time of 37 months, the total cardiac mortality rate was 8 percent (2 of 24) in group 1a and 4 percent (1 of 23) in group 1b. It is concluded that a decrease in systolic blood pressure during exercise testing is highly reproducible and appears to be reversed by coronary bypass surgery.

Serial exercise testing after coronary artery bypass surgery.

To determine the duration of functional benefit from coronary bypass surgery, 111 patients with angina pectoris were serially evaluated by standard exercise testing prior to and for up to 4 years after surgery. Exercise testing 6 to 18 months after surgery showed greater heart rate-blood pressure product at peak work load, improved work capacity, and less symptomatic and electrocardiographic evidence of ischemia than was demonstrated preoperatively. Twenty patients were tested 37 to 48 months postoperatively and showed improved exercise performance in comparison with preoperative results, but the frequency of positive tests during this period no longer differed. Thus, improved exercise performance appears to persist for at least 4 years after coronary bypass surgery.