Biomedical subjects
Publications and source records attributed to C R Lambert.
The pathophysiology of stable angina is discussed with respect to anatomic substrate, coronary and systemic hemodynamic mechanisms, the dynamic nature of coronary artery stenoses, and determinants of myocardial oxygen consumption. Cellular mechanisms involved in ischemia and the transduction of these changes into angina are also reviewed.
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Single-plane left coronary angiograms in 18 patients were prospectively analyzed using videodensitometry (XR-70 system) and handheld digital calipers to compare arterial dimensions, stenosis dimensions, intraobserver variability and interobserver variability for the methods. A total of 648 arterial segments were measured, yielding a highly significant correlation between videodensitometry and caliper-determined cross-sectional area (r = 0.96, p = 0.0001). Similarly, a highly significant linear relation was observed between videodensitometry and caliper-determined diameter (r = 0.95, p = 0.0001). When data subsets for small, medium and large arterial segments were examined, higher variability in the correlation between videodensitometry and caliper-determined area was observed in the large segments (greater than 10 mm2). In addition, caliper-estimated areas tended to be slightly smaller than videodensitometry-estimated areas in these segments. For diameter estimations, correlations between caliper and videodensitometry data were similar for the entire range of arterial segment sizes. Intra- and interobserver variability was low for both caliper and videodensitometry determination of diameter or area. Thus, over a wide range of arterial dimensions, results obtained with caliper estimates of luminal area and diameter are comparable to those obtained with videodensitometry using the XR-70 system.
Circadian variations of transient myocardial ischemia and heart rate have been identified, but the rhythms and their response to beta blockade have not been fully characterized. Time-series analysis, a mathematical technique to describe oscillatory activity occurring within a continuous data set was used, to address these issues. Nine men with coronary artery disease underwent 72 hours of ambulatory electrocardiographic monitoring during therapy with placebo or metoprolol. During administration of placebo, ischemic time and heart rate showed a primary peak with a periodicity of approximately 24 hours with a tight coupling between the 2 variables and a secondary peak with a periodicity of 5 to 8 hours. During metoprolol therapy, heart rate and ischemic variation were reduced and the 24-hour periodicity for heart rate only remained. The 24-hour periodicity for ischemia was eliminated, but the data with 5- to 8-hour periodicity became the major component of the signal.
The value of right-sided cardiac catheterization was assessed prospectively in 200 patients undergoing left-sided catheterization for evaluation of known or suspected coronary artery disease. Before catheterization, data from right-sided catheterization was not felt to be necessary for clinical management. There were 6 +/- 2 extra minutes of procedure time and 86 +/- 63 extra seconds of fluoroscopy time used. Abnormalities were detected in 69 (35%) patients. These findings were unexpected in 37 of these patients and in 3 patients, further evaluation was prompted. However, management was altered in only 3 (1.5%) patients as a result of data obtained by right-sided catheterization. In conclusion this additional procedure rarely adds clinically useful information about patients undergoing left-sided catheterization and angiography for coronary artery disease without a clinical indication for right-sided catheterization.
To define the short-term effects of intravenous nicardipine on exercise- and pacing-induced myocardial ischemia, 15 men with coronary artery disease were studied. Nicardipine was administered as a 2 mg bolus followed by an infusion, titrated to maintain a 10 to 20 mm Hg decrease in systolic arterial pressure. At rest, nicardipine significantly decreased systemic and coronary vascular resistances and left ventricular end-diastolic pressure but increased coronary blood flow, heart rate, and myocardial oxygen consumption. With bicycle exercise performed to evoke myocardial ischemia, nicardipine prolonged exercise duration, time to of 1 mm ST segment depression, and increased cardiac work to onset of angina in most patients. These changes in cardiac performance were not associated with alteration in the product of systolic pressure and heart rate or with increased left ventricular end-diastolic pressure. During increased heart rate induced by atrial pacing to cause ischemia, the heart rate threshold for myocardial ischemia was not changed by nicardipine. This occurred despite decreased myocardial oxygen consumption, unchanged coronary blood flow, and otherwise similar hemodynamic changes as those observed during exercise. However, left ventricular end-diastolic pressure remained lower and stroke volume increased more after nicardipine with pacing stress when compared with observations before nicardipine with the same heart rate stress. These findings support beneficial antiischemic actions of nicardipine with possible prevention of ischemia-related left ventricular dysfunction.
Nicardipine, a new 1-4 dihydropyridine calcium antagonist, has chemical properties that allow oral and stable intravenous preparations. It is the first intravenous dihydropyridine calcium antagonist available in the United States. Among its drug class it has a unique chemical structure that affords properties useful in the treatment of acute cardiovascular conditions, such as myocardial ischemia, congestive heart failure, hypertension, cerebrovascular disease, and other related disorders. In patients with coronary artery disease, intravenous nicardipine has been found to reduce myocardial oxygen demand by reducing afterload and increasing myocardial oxygen supply through coronary vasodilatation. It enhances left ventricular performance and augments coronary blood flow beyond that required by increased myocardial oxygen consumption. Nicardipine may also offer protection from ischemic injury to the heart and central nervous system. Alone and in combination with other antihypertensive agents, nicardipine has been shown to be effective in the treatment of mild to moderate hypertension. It is safe for use in patients with certain types of conduction disturbances because it does not greatly affect sinoatrial and atrioventricular conduction. Additional advantages for nicardipine's use in the management of acute cardiovascular disorders are its rapid onset and short duration of action.
Nicardipine is a second-generation dihydropyridine calcium antagonist with relative coronary and cerebrovascular selectivity. To study the effects of nicardipine on systolic and diastolic myocardial function, we used three experimental models. In isolated feline papillary muscle, nicardipine produced a dose-dependent calcium antagonistic effect manifested by depressed indexes of contraction and relaxation. In an autoregulating blood-perfused isolated rabbit heart preparation, nicardipine markedly increased coronary blood flow and slightly decreased systolic pressure at a given end-diastolic pressure. The systolic pressure and +dP/dt versus volume curves, however, were shifted to the left during nicardipine administration, indicating improved systolic function. This increase was accompanied by decreased volume elastance and is probably due, at least in part, to the coronary turgor effect. In humans at rest, intravenous nicardipine administration produced pronounced coronary and systemic vasodilation with improved left ventricular systolic performance and enhanced relaxation accompanied by reflex sympathetic activation. With exercise to ischemia, nicardipine preserved the salutary effects on left ventricular function seen at rest and significantly blunted the increase in left ventricular end-diastolic pressure observed in the control setting. Administration of intracoronary nicardipine to patients produced a slight and transient depression of systolic and diastolic left ventricular function that was accompanied by a pronounced coronary vasodilator response and later by improved ventricular function. This improvement was manifested by decreased end-systolic volume and increased +dP/dt without changes in heart rate, arterial pressure, end-diastolic pressure, or end-diastolic volume. Global diastolic function indexes, including the time constant for isovolumic relaxation, peak filling rate normalized for stroke volume, and volume elastance, were unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)
The systemic and coronary hemodynamic effects of nicardipine, a calcium antagonist, were studied in 30 patients. Increased coronary blood flow (from 102 +/- 9 to 147 +/- 13 ml/min; p less than 0.001), heart rate (from 69 +/- 3 to 81 +/- 3 beats/min; p less than 0.001), stroke volume (108 +/- 6 to 123 +/- 6 ml; p less than 0.001) and cardiac output (from 7.3 +/- 0.5 to 9.9 +/- 0.5 liters/min; p less than 0.001) were demonstrated in 15 patients administered intravenous nicardipine (2 mg bolus given over 1 minute, followed by infusion of 50 micrograms/min to maintain 10 to 20 mm Hg decrease in systolic blood pressure). Systemic vascular resistance decreased (from 1,183 +/- 70 to 733 +/- 33 dynes s cm-5) as did coronary resistance (from 1.47 +/- 0.1 to 0.7 +/- 0.1 mm Hg/ml/min; p less than 0.001). Other hemodynamic parameters such as left ventricular end-diastolic pressure, stroke volume and work, aortic blood flow and acceleration, ejection and external power, myocardial oxygen consumption and time constant for left ventricular isovolumic relaxation also were evaluated. To distinguish between direct myocardial effects of nicardipine and peripheral effects, 15 patients were given intracoronary nicardipine (0.1 or 0.2 mg) during cardiac catheterization. Nicardipine produced slight depression of left ventricular contractile function and impairment of left ventricular relaxation; but these changes were mild and transient compared with the marked and sustained increase in coronary blood flow that persisted 7 minutes after administration. Thus, nicardipine is a relatively selective vasodilator with minimal direct myocardial depressant activity n humans.
Extended (72-hour) ambulatory electrocardiographic monitoring was used to enable time series analysis of heart rate and asymptomatic ST-segment depression in 9 patients with severe coronary artery disease. The effects of beta 1-adrenergic blockade with optimal dose metoprolol were then assessed. Data were analyzed using Fourier transformation, autocorrelation and cross-correlation to examine possible coupling between heart rate and ischemic electrocardiographic changes. A marked circadian pattern was observed for both heart rate and ambulatory myocardial ischemia, with a period of approximately 24 hours by both Fourier and autocorrelation methods. Cross-correlation revealed heart rate and ischemia to be tightly coupled with a lag of 0 hours during placebo. During beta 1 adrenergic blockade the marked circadian variation in heart rate was diminished, although some periodicity in the 24-hour region remained. Ambulatory ischemia was also markedly diminished during beta 1-adrenergic blockade; however, some residual ischemia remained that was characterized by a peak spectral activity shifted to a period of 5 to 7 hours. Heart rate and ischemia were not coupled during beta 1-adrenergic blockade, as evidenced by lack of significant cross-correlation. Thus, time series analysis suggests close coupling between the variation in heart rate and ambulatory ischemia in patients with severe coronary artery disease. Beta 1-adrenergic blockade can markedly alter the periodic characteristics of and coupling between heart rate and ischemia. Ischemia remaining during beta 1-adrenergic blockade may have different spectral characteristics than that predominating during placebo administration. These differences may be manifestations of the heterogenous pathophysiologic mechanisms responsible for ambulatory ischemia and may have therapeutic implications.
From the studies and observations reviewed in this chapter, it can be appreciated that there is considerable direct and circumstantial evidence to implicate coronary artery spasm as a primary phenomenon in some patients with myocardial infarction. Although currently available data indicate that the number of acute myocardial infarctions due primarily to "pure" coronary artery spasm is relatively small, it should be emphasized that essentially very little if any data exist at "time zero" or at the actual onset of infarction. Most myocardial infarctions are probably multifactorial in etiology. To what extent coronary artery spasm, atherosclerosis, platelets, in situ thrombosis, endothelial mediators, and passive influences on vascular caliber interact in the pathogenesis of acute myocardial infarction remains incompletely understood.
Contrast media may lead to adverse reactions during cardiac catheterization. Hexabrix has less hemodynamic and electrophysiologic effects than Renografin-76. To assess relative complication rates using these agents, 82 patients with heart failure or "unstable" ischemic syndromes and undergoing catheterization were prospectively randomized to receive either Hexabrix or Renografin. Clinical diagnoses, hemodynamics before contrast media administration, left ventricular ejection fraction, case duration, contrast volume and cine film quality were similar in the 2 groups. The condition of 1 patient assigned to receive Renografin was deemed too unstable and Hexabrix was safely used. In the other patients, a total of 17 adverse reactions occurred (7 before administration of contrast and thus unrelated: 4 Hexabrix- and 3 Renografin-assigned patients, difference not significant). Three contrast-induced adverse reactions were considered minor (Hexabrix 2, Renografin 1, difference not significant). Severe adverse reactions requiring intervention, such as pulmonary edema and hypotension, were more frequent in patients who received Renografin (6 of 38, 16%) as compared with Hexabrix (1 of 43, 2%) (p less than 0.05). It is concluded that in high-risk patients undergoing cardiac catheterization, Hexabrix is tolerated better than Renografin and should be considered for routine use.
Recent studies show that in many coronary artery disease patients with any form of angina, myocardial infarction, or positive exercise tests but no symptoms, most of the ischemic episodes are silent. Furthermore, evidence is building to suggest that in many patient groups, silent ischemia relates to prognosis. Numerous therapies, including nitroglycerin or isosorbide dinitrate, have been shown to modify silent ischemia and its associated risks. Studies indicate that frequency and perhaps duration of silent ischemic episodes can be modified by treatment with beta-adrenergic blockers or calcium antagonists alone or, even more effectively, with a combination of both types of agent. Many ischemic episodes persist, however, when therapy is directed only at reduction of angina. Evidence suggests that some characteristics of silent ischemia predict prognosis, whereas angina characteristics do not. Until additional data about prognosis and the influence of treatment on prognosis are available, the appropriate focus seems to be improvement of outcome in those patients who are at highest risk, rather than only reduction of chest pain.
The systemic and coronary hemodynamic effects of combined alpha- and beta-adrenergic blockade produced by labetalol were assessed in 24 normotensive patients with angina pectoris and an ischemic electrocardiographic response to exercise stress. Both the intravenous (0.5 mg/kg) and oral (200 mg) formulations of labetalol were evaluated. At rest, labetalol produced systemic vasodilation (systemic vascular resistance -16% after intravenous and -8% after oral labetalol, both p less than 0.05) without change in heart rate. Aortic pressure usually was lower and cardiac output preserved or increased. Left ventricular end-diastolic pressure was unchanged. Coronary sinus flow was usually unchanged after either route of administration. Exercise duration was prolonged in 14 of the 20 patients with severe coronary artery disease. During exercise, tachycardia was blunted (-12% after intravenous, -7% after oral labetalol, both p less than 0.05) as was the increase in mean aortic pressure (-12% and -13% intravenous and oral labetalol respectively, both p less than 0.05), left ventricular end-diastolic pressure [-7% and -1%, respectively, both p = not significant (NS)] was unchanged. Coronary sinus flow (-16% and -25%, respectively, both p less than 0.05) was decreased as heart rate and aortic pressure were lower. Cardiac output, systemic vascular resistance, and coronary vascular resistance were similar to control exercise. The hemodynamic effects of intravenous and oral labetalol are, in general, similar. Hemodynamic responses differ from those produced by other beta-blockers and by calcium antagonists.
The hemodynamic effects of high- (diatrizoate meglumine/sodium) and low- (iopamidol) osmolar contrast administration for left ventriculography were compared in 15 patients with severe aortic valve stenosis. Patients were similar with respect to aortic valve gradient, aortic valve area, age, body surface area, and baseline hemodynamics as well as associated coronary disease and valvular insufficiency. Administration of diatrizoate meglumine/sodium was associated with a 22% increase in heart rate, and marked (27%) decrease in left ventricular systolic pressure, with a small (15%) increase in left ventricular end diastolic pressure. In contrast, administration of larger volumes of iopamidol was associated with only a slight (9%) increase in heart rate, a small (6%) decrease in left ventricular systolic pressure, and a smaller (6%) increase in left ventricular end diastolic pressure. In patients with severe aortic valve stenosis iopamidol may offer a safer hemodynamic profile than diatrizoate meglumine/sodium.
Nicardipine, a new 1,4 dihydropyridine calcium antagonist, has chemical properties that permit both oral and stable intravenous preparations. These preparations have prominent effects on indices of myocardial ischemia, coronary blood flow, and myocardial oxygen consumption. Data are reviewed from animal models of myocardial ischemia and patient studies that suggest that nicardipine has very prominent effects acting to increase coronary blood flow and reduce myocardial oxygen demand, in addition to favorable effects on myocardial metabolism and function.
Of 35 tuco-tucos (Ctenomys opimus) collected in Bolivia, South America, 31 (88%) had eimerian oocysts in their feces at the time they were examined. Eighteen (58%) of the 31 infected animals were concurrently infected with 2 or 3 eimerian species. Four species of Eimeria were recovered and are described as new species based on the characteristics of sporulated oocysts. Oocysts of Eimeria granifera n. sp. were ellipsoidal, 21.1 x 17.2 (15-26 x 11-20) micron with sporocysts ovoidal, 11.3 x 7.1 (8-14 x 5-9) micron. Oocysts of Eimeria montuosi n. sp. were spheroidal, 24.2 x 22.0 (21-28 x 18-25) micron with sporocysts ovoidal, 10.5 x 7.3 (8-14 x 6-9) micron. Oocysts of Eimeria opimi n. sp. were spheroidal to subspheroidal, 24.3 x 21.8 (18-29 x 15-26) micron with sporocysts ovoidal, 11.6 x 7.6 (10-13 x 6-9) micron. Oocysts of Eimeria oruroensis n. sp. were spheroidal to subspheroidal, 27.3 x 23.6 (23-32 x 20-28) micron with sporocysts ovoidal, 13.2 x 8.6 (10-16 x 8-11) micron.
Ambulatory ECG monitoring for detection of transient myocardial ischemia is useful because most ischemic episodes that occur outside the exercise laboratory are not accompanied by symptoms. Special considerations, not required for AEM when used for arrhythmia analysis, must be employed. Although many commercially available recorders provide excellent ST-segment reproduction, some playback systems may have a nonlinear phase response resulting in signal distortion, making ST-segment analysis difficult. Conventional Holter-type AEM devices do not allow for patient or physician intervention during acute myocardial ischemia. Considerable cost and time are required to analyze ST-segment data of prolonged monitoring periods from these tape-recorded signals, and human error and fatigue play an important role in diminishing accuracy of ST-segment interpretation. Automated analysis is done with computer and technician interaction but the accuracy and validation of the various systems for ST-segment analysis from tape recordings requires further detailed study. Newer, real-time ambulatory ECG analyzers are designed for prolonged monitoring periods and directed toward ST-segment analysis. Some devices also alert the patient to an acute ischemic or arrhythmic event allowing for intervention immediately. Some real-time systems have undergone some very encouraging validation studies. These recent studies suggest excellent sensitivity and specificity for detection of ischemic-type ST-segment depression. However, more work is needed before the accuracy of other such devices is known with certainty. As the central goal of therapy for patients with coronary artery disease evolves from simply controlling angina to reduction or elimination of ischemic episodes and their consequences, use of AEM devices will play an increasingly important role in management of these patients.