Oxidation of LDL and extent of peripheral atherosclerosis.

Evidence has accumulated for oxidative modification of low-density lipoproteins (LDL) to play an important role in the atherogenic process. Therefore, we investigated the relation between susceptibility of LDL to oxidation and risk of peripheral atherosclerosis among 249 men between 45 and 80 years of age. The ankle-arm index was calculated for both legs as the ratio of systolic blood pressure in the leg divided by the arm systolic blood pressure. The lowest of both ankle-arm indices was used to categorize subjects. Thirty-nine men with an ankle-arm index < 1.00 (20% cut-off point of distribution) were classified as subjects with peripheral atherosclerosis. Subjects with peripheral atherosclerosis reported more often the use of a special diet and the use of antihypertensive medication, aspirin and coumarin derivatives. No significant differences in total, LDL and HDL cholesterol and triglycerides were present between groups. Resistance time and maximum rate of oxidation were measured ex vivo using copper-induced LDL oxidation. Subjects with peripheral atherosclerosis had a significantly lower resistance time, whereas the maximum rate of oxidation tended to be increased in subjects with peripheral atherosclerosis. Odds ratios (ORs, and 95% confidence interval) for the successive tertiles of resistance time were 1.00 (reference), 0.37 (0.15-0.89) and 0.37 (0.16-0.86) (p(trend) < 0.01). ORs for the successive tertiles of maximum rate of oxidation were 1.00 (reference), 1.34 (0.47-3.82) and 1.50 (0.55-4.15). This inverse association was borderline significant (p(trend) = 0.07). These results support an association between LDL oxidation and the development of peripheral atherosclerosis.

Effects of epanolol, a selective beta1-blocker with intrinsic sympathomimetic activity, in patients with ischemic left ventricular dysfunction.

Recently, different beta-blockers have been shown to be effective in the treatment of chronic heart failure (CHF), but the importance of their ancillary properties is not clear. Epanolol is a selective beta1-blocker with intrinsic sympathomimetic activity, which has been shown useful in angina pectoris, but its value in patients with left ventricular (LV) dysfunction and CHF is unknown. We examined the effects of epanolol in patients with LV dysfunction (n = 8; mean LV ejection fraction, 0.33 +/- 0.08) and compared them with patients with normal LV function (n = 8; mean LV ejection fraction, 0.52 +/- 0.04). Measurement of invasive hemodynamics and neurohormones was performed at rest and during myocardial ischemia, which was induced by atrial pacing. All measurements were performed before and after epanolol. Before epanolol, pacing-induced ischemia led to a similar increase in norepinephrine and coronary sinus blood flow in both groups. After epanolol, the increase in neurohormones was more pronounced in the group with LV dysfunction (norepinephrine, 1,130 +/- 164 pg/ml for patients with LV dysfunction vs. 637 +/- 41 pg/ml for normal subjects; p < 0.05). A similar effect was observed for angiotensin II. Further, in the LV-dysfunction group, coronary sinus blood flow increased less, and coronary vascular resistance decreased less (both values, p < 0.05). Despite the fact that the increase in double product was decreased to a similar extent in both groups, ischemia was reduced only in normal LV function (p < 0.05). In ischemic LV dysfunction, neurohumoral activation after epanolol may impair adequate coronary flow response, and this may limit its antiischemic properties. Because of the small size of the study, no definitive inference on the clinical benefit of epanolol in patients with ischemic LV function can be made from this study.

LDL oxidation and extent of coronary atherosclerosis.

Accumulated evidence indicates that oxidative modification of LDL plays an important role in the atherogenic process. Therefore, we investigated the relation between coronary atherosclerosis and susceptibility of LDL to oxidation in a case-control study in men between 45 and 80 years of age. Case subjects and hospital control subjects were selected from subjects undergoing a first coronary angiography. Subjects with severe coronary stenosis (> or = 85% stenosis in one and > or = 50% stenosis in a second major coronary vessel) were classified as case subjects (n=91). Hospital control subjects with no or minor stenosis (< or = 50% stenosis in no more than two of the three major coronary vessels, n=94) and population control subjects free of plaques in the carotid artery (n=85) were pooled for the statistical analysis into one control category. Enrollment procedures allowed for similar distributions in age and smoking habits. Case subjects had higher levels of total and LDL cholesterol and triglycerides and lower levels of HDL cholesterol. Resistance time, maximum rate of oxidation, and maximum diene production were measured ex vivo using copper-induced LDL oxidation. A borderline significant inverse trend was observed for coronary atherosclerosis risk at increasing resistance time. Odds ratios (95% confidence interval) for the successive quartiles were 1.0 (reference), 0.77 (0.39 to 1.53), 0.67 (0.33 to 1.34), and 0.55 (0.27 to 1.15) (ptrend=0.07). No relation with maximum rate of oxidation was found, and higher maximum diene levels were found in control subjects (P<.01). The main determinant of oxidation was the fatty acid composition of LDL. No effect of smoking or use of medication was observed. We conclude that although LDL resistance to oxidation may be a factor in atherogenesis, the ex vivo measure is not a strong predictor of severity of coronary atherosclerosis.

Early administration of ramipril in acute myocardial infarction: neurohormonal and hemodynamic effects and tolerability.

Although several large studies indicate a beneficial effect of angiotensin-converting enzyme (ACE) inhibitors after myocardial infarction, the optimal timing of therapy in terms of safety and the effects on neurohormones during myocardial infarction are less well known. In order to investigate the effect of ramipril, administered within 24 h after myocardial infarction, on hemodynamics and neurohormones and its safety, 20 patients with a myocardial infarction were studied. Nine patients had an anterior, 10 an inferior, and 1 a non-Q-wave infarction. Fourteen patients received thrombolytic therapy, whereas 6 did not. The initial dose of ramipril was 1.25 mg, but was gradually increased to 5 mg during the next 4 days. Side effects did not occur. The mean arterial pressure decreased 8 h after the first dose from 84 +/- 2 mm Hg (control) to 77 +/- 2 mm Hg (p < 0.05) and remained decreased thereafter. This was accompanied by a reduction in systemic resistance of 8% after 8 h and of 12% on day 2. Heart rate, cardiac and stroke indexes, and pulmonary artery and wedge pressures did not change. The ACE activity decreased within 1 h of ramipril administration with a maximum of 71% at 4 h after the second dose and remained at this level throughout the study. Angiotensin II decreased by 34% (day 2) and by 41% (day 5). The renin activity gradually increased from 33 +/- 7.5 to 75.4 +/- 11.5 microM/ml on day 5, whereas epinephrine was reduced from day 2 onwards, with a maximal reduction of 71% on day 5. Arginine vasopressin was significantly reduced 5 h after ramipril administration until the end of the study, with a maximum of 77% on day 3. Moreover, a late but significant decrease in norepinephrine occurred on day 5. Thus, oral ramipril results in early ACE inhibition, followed by progressive attenuation of the neuroendocrine activation and a reduction in afterload during the acute phase of myocardial infarction. It is well tolerated, also in combination with nitroglycerin and thrombolytic therapy.

Prevalence, determinants, and misclassification of myocardial infarction in the elderly.

We evaluated the prevalence, determinants, and misclassification of different types of myocardial infarction in 3,272 men and women age 55 years or older. We defined self-reported myocardial infarction with electro-cardiographic evidence as "typical myocardial infarction." We defined self-reported myocardial infarction without electrocardiographic evidence, but verified with additional clinical information, as "non-Q-wave myocardial infarction." Finally, we defined myocardial infarction detected by electrocardiogram that was not self-reported as "silent myocardial infarction," after verification of absence of symptoms. Overall, the prevalence of typical myocardial infarction was 4.1% [95% confidence interval (CI) = 3.5-4.9], of non-Q-wave myocardial infarction 2.8% (95% CI = 2.2-3.4), and of silent myocardial infarction 3.9% (95% CI = 3.2-4.5). Silent myocardial infarction was more prevalent in women, hypertensives, cigarette smokers, and those with higher post-load blood glucose. Self-reported myocardial infarction without electrocardiographic characteristics could be verified as myocardial infarction by means of additional clinical information in 56% of the cases. We conclude that myocardial infarction occurs frequently in the elderly without typical symptoms or electrocardiographic changes. As all these manifestations of myocardial infarction convey an increased risk of symptomatic heart disease or death, they require further attention. Misclassification due to limited sources of information can be considerable and should be taken into account in the design and interpretation of epidemiologic studies.

Diagnostic interpretation of electrocardiograms in population-based research: computer program research physicians, or cardiologists?

We assessed the performance of diagnostic electrocardiogram (ECG) interpretation by the computer program MEANS and by research physicians, compared to cardiologists, in a physician-based study. To establish a strategy for ECG interpretation in health surveys, we also studied the diagnostic capacity of three scenarios: use of the computer program alone (A), computer program and cardiologist (B), and computer program, research physician, and cardiologist (C). A stratified random sample of 381 ECGs was drawn from ECGs collected in the Rotterdam Study (n = 3057), which were interpreted both by a trained research physician using a form for structured clinical evaluation and by MEANS. All ECGs were interpreted independently by two cardiologists; if they disagreed (n = 175) the ECG was judged by a third cardiologist. Five ECG diagnoses were considered: anterior and inferior myocardial infarction (MI), left and right bundle branch block (LBBB and RBBB), and left ventricular hypertrophy (LVH). Overall, sensitivities and specificities of MEANS and the research physicians were high. The sensitivity of MEANS ranged from 73.8% to 92.9% and of the research physician ranged from 71.8% to 96.9%. The specificity of MEANS ranged from 97.5% to 99.8% and of the research physician from 96.3% to 99.6%. To diagnose LVH, LBBB, and RBBB, use of the computer program alone gives satisfactory results. Preferably, all positive findings of anterior and inferior MI by the program should be verified by a cardiologist. We conclude that diagnostic ECG interpretation by computer can be very helpful in population-based research, being at least as good as ECG interpretation by a trained research physician, but much more efficient and therefore less expensive.

Contrasting preload-dependent hemodynamic and neurohumoral effects of isomazole, a partial phosphodiesterase inhibitor and calcium sensitizer.

BACKGROUND: Currently evaluated positive inotropic agents that act predominantly through phosphodiesterase III-inhibiting properties, have been disappointing in the treatment of heart failure. Lack of efficacy as a result of diminished cellular cyclic adenosine monophosphate and vasodilating tolerance and side effects are prevalent. In contrast, calcium sensitization is preserved in heart failure and agents that combine phosphodiesterase-inhibiting and calcium-sensitizing properties may be more efficacious. Isomazole is such a novel agent with combined properties. This study investigated the acute hemodynamic and neurohormonal effects of intravenous isomazole (3 micrograms/kg/min for 30 minutes). METHODS AND RESULTS: The effects of preexisting preload were evaluated in 18 patients with heart failure, New York Heart Association class II/III, and elevated (> 15 mmHg, n = 11, group I) and normal; (n = 7, group II) pulmonary wedge pressure at baseline. In the overall group, isomazole increased myocardial contractility and relaxation and decreased systemic resistance by 20%. Left and right filling pressures fell by 35-45%, accompanied by a 69% reduction in cardiac atrial natriuretic peptide release. In contrast, levels of arterial norepinephrine and renin both increased by 27%. Cardiac output increased in group I (23%), but fell in group II (18%), accompanied by a 51% increase in arterial norepinephrine. Cardiac atrial natriuretic peptide decreased in group I, but not in group II. CONCLUSIONS: Isomazole induced positive inotropic and lusitropic effects and arterial vasodilation in all patients. Cardiac pump function improved only in group I, accompanied by a reduction in sympathetic activity and renin-angiotensin and aldosterone levels and a more pronounced decrease in cardiac atrial natriuretic peptide release. In contrast, in patients with normal to low preload, the further reduction in preload led to a deterioration of pump function and increased sympathetic tone.

Autoantibodies against MDA-LDL in subjects with severe and minor atherosclerosis and healthy population controls.

Autoantibodies against oxidized low-density lipoprotein (LDL) have been reported to be associated with atherosclerosis. However, data are not consistent. We compared the titres of autoantibodies to malondialdehyde-modified LDL in three groups, a case group with angiographically documented severe coronary stenosis (> 80% stenosis in at least 1 vessel, n = 47), a hospital control group with minor stenosis on the coronary angiography (< 50% stenosis in all three major vessels, n = 47) and a healthy population control group with no history of coronary heart disease (n = 49). Age ranged from 26 to 68 years. Subjects were frequency-matched for gender distribution and storage time of the blood samples. No relevant differences in autoantibody titre between case and control groups were found. The mean autoantibody titres (+/- S.D.) were 1.44 +/- 1.82, 1.46 +/- 1.40 and 1.62 +/- 1.95 for cases, hospital controls and population controls, respectively. No correlations were found between autoantibody titre and age, number of cigarettes smoked and LDL or total cholesterol. Autoantibody titres were correlated with body mass index (r = 0.2) and high-density lipoprotein (HDL) (r = -0.2). Odds ratios (OR) were calculated by tertiles of autoantibody titres for the hospital control group and the population control group, respectively. Age-adjusted OR (95% confidence interval) for medium and high compared to low autoantibody titre were 0.76 (0.27-2.14) and 1.09 (0.39-2.95) for the comparison between cases and hospital controls and 1.09 (0.39-3.07) and 0.90 (0.32-2.56) for the comparison between cases and population controls. Adjustment for gender, body mass index, smoking habits and HDL yielded essentially the same results. This study does not support an association between autoantibody titres to oxidized LDL and the extent of coronary stenosis.

Anti-ischaemic efficacy of L-propionylcarnitine--a promising novel metabolic approach to ischaemia?

L-propionylcarnitine, a naturally occurring derivative of L-carnitine, essential for mitochondrial fatty acid transport and high-energy phosphate exchange, acutely reduces myocardial ischaemia and improves ischaemia-induced cardiac dysfunction following intravenous administration. This randomized, crossover study was designed to compare the long-term anti-ischaemic effects of oral L-propionylcarnitine with diltiazem in patients with stable, exercise-induced angina. After a 2-week washout phase of anti-anginal medication and a 2-week single-blind placebo period, 46 patients were included in the study, 23 of whom received 1500 mg L-propionylcarnitine daily for 6 weeks, and 23 diltiazem (180 mg daily for 3 weeks, followed by 360 mg daily for 3 weeks), crossing over to the other treatment after a 1-week washout period. Three patients on L-propionylcarnitine and two on diltiazem discontinued. Both treatments resulted in comparable exercise duration (582 +/- 35 s and 588 +/- 33 s, mean +/- SEM), time to 0.1 mV ST depression (436 +/- 38 s and 465 +/- 36 s), and increase in time to 0.1 mV ST depression from baseline (20% and 28%), L-propionylcarnitine and diltiazem, respectively. Diltiazem decreased the rate-pressure product at rest and exercise, L-propionylcarnitine did not. Both compounds significantly reduced ST depression at maximal exercise [23% (L-propionylcarnitine) vs 35% (diltiazem), P < 0.05 diltiazem vs L-propionylcarnitine]. Diltiazem increased the time to onset of angina by 22%. In contrast, no significant changes occurred with L-propionylcarnitine. During the study, anginal attacks were reduced by 70% and 57%, and nitroglycerin consumption decreased by 57% and 70%, L-propionylcarnitine and diltiazem, respectively. Thus, both L-propionylcarnitine and (high-dose) diltiazem result in anti-ischaemic effects and decrease anginal attacks in daily life. Although the effect of diltiazem on exercise-induced ischaemia appears more pronounced than that of L-propionylcarnitine, this novel metabolic approach to ischaemia warrants further development.

Additional antiischemic effects of long-term L-propionylcarnitine in anginal patients treated with conventional antianginal therapy.

Cardiac L-carnitine content, essential for mitochondrial fatty acid transport and ATP-ADP exchange, decreases during ischemia. In animal models, administration of the natural derivative, L-propionylcarnitine, may reduce ischemia and improve cardiac function. To evaluate possible antiischemic effects of L-propionylcarnitine was compared with placebo in a randomized, double-blind, parallel design, in addition to preexisting therapy. Patients with > or = 2 anginal attacks per week and objective signs of ischemia with angina during bicycle exercise testing were included. After an initial 2-week, single-blind placebo phase, 37 patients received 500 mg L-propionylcarnitine tid, and 37 patients received placebo for 6 weeks. Both groups were comparable at baseline. Three patients discontinued the study while on placebo (two because of noncompliance, one because of palpitations) and one while on L-propionylcarnitine (noncompliance). Although heart rate, blood pressure at rest, and maximal exercise were not affected, L-propionylcarnitine increased the time to 0.1 mV ST-segment depression [44 +/- 3 vs. 8 +/- 2 seconds (mean +/- SEM) in the placebo group; p = 0.05], and exercise duration improved by 5% compared with placebo. Anginal attacks and the consumption of nitroglycerin were not affected in either group. Thus, following a 6 week treatment period, L-propionylcarnitine induced additional, albeit marginal, antiischemic effects in anginal patients who were still symptomatic despite maximal conventional antianginal therapy. It is questionable whether in these patients this form of metabolic treatment will achieve great benefit, although in some improvement can be expected.

Long-term vasodilator treatment with flosequinan does not lead to hemodynamic tolerance or neurohormonal activation in severe heart failure.

Flosequinan is a balanced-type vasodilator with a prolonged mode of action due to an approximate 38-hour half-life of its active first metabolite, BTS 53554. As this may lead to tolerance and neurohormonal activation, the acute and long-term pharmacokinetic, hemodynamic, and neurohormonal profile of flosequinan was evaluated. On three consecutive days, 23 patients with heart failure (New York Heart Association classes II-IV), despite digitalis and diuretics, underwent invasive hemodynamic studies after receiving 100 mg oral flosequinan (day 1), placebo (day 2), and 100 mg flosequinan (day 3), followed by repeat invasive evaluation after long-term flosequinan (100 mg daily) for 17 +/- 2 weeks. On each study day, plasma flosequinan levels increased to 1.9 +/- 0.2 mg/L after 1 hour, but returned to baseline levels at 24 hours. In contrast, BTS 53554 increased progressively, reaching relatively high plateau levels (6 mg/L) during chronic therapy. First-dose flosequinan decreased the pulmonary wedge, right atrial pressure, and systemic resistance by 50, 60, and 22%, respectively, whereas the cardiac index was increased by 40%; these effects lasted for 48 hours. During long-term treatment, baseline values of the pulmonary wedge and right atrial pressure were comparable to prestudy values, whereas systemic resistance had decreased by 22%, and the cardiac index and heart rate had increased by 22 and 14%, respectively. Readministration of flosequinan did not further affect hemodynamics, apart from a moderate reduction in the pulmonary wedge and right atrial pressure. Neurohumoral activation did not occur during acute or long-term therapy. Thus, although changes in left and right heart filling pressures are attenuated during long-term treatment, flosequinan induces sustained arterial dilatation and improves cardiac pump function without activation of circulating neurohormones.

Hemodynamic, neurohumoral, and myocardial energetic effects of pimobendan, a novel calcium-sensitizing compound, in patients with mild to moderate heart failure.

In contrast to cyclic AMP-dependent positive inotropes, the calcium-sensitizer and partial phosphodiesterase (PDE) inhibitor pimobendan may induce beneficial effects in heart failure. However, its effect on relaxation, myocardial energetics and neurohormones are unknown. Twelve patients with heart failure, New York Heart Association (NYHA) classification II-III, due to ischemic cardiomyopathy, were studied for 1 h after they received 5 mg pimobendan intravenously (i.v.). Pimobendan progressively reduced systemic resistance and left ventricular end-diastolic pressure (LVEDP) (22 and 50%, respectively) and improved isovolumetric contractility and relaxation parameters by 30% (all p < 0.05 vs. control). LV end-diastolic and end-systolic volumes (LVEDV, LVESV) decreased significantly by 20 and 19%, respectively. Cardiac output (CO) increased by 17% due to a simultaneous increase in heart rate (HR) from 75 +/- 3 to 86 +/- 5 beats/min (mean +/- SEM, p < 0.05). Pimobendan did not change coronary hemodynamics, but myocardial O2 extraction and consumption were decreased significantly by 18 and 20%, respectively. Catecholamines, angiotensin II (AII), and aldosterone levels did not change significantly. In contrast, arterial and coronary venous renin increased significantly from 57 +/- 17 and 53 +/- 14.7 microM/h at control to 69 +/- 20 and 69 +/- 20 microM/h, respectively, 60 min after pimobendan administration. Simultaneously, cardiac renin uptake at baseline (0.449 +/- 0.185 mumol/min) changed to release (-0.071 +/- 0.145 mumol/min, p < 0.05). Serious side effects did not occur. Thus, pimobendan had progressive positive inotropic and lusitropic effects, diminished preload and afterload despite modest stimulation of plasma renin activity (PRA), and reduced systemic vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of L-propionylcarnitine on ischemia-induced myocardial dysfunction in men with angina pectoris.

To identify the effect of L-propionylcarnitine (LPC) on ischemia, 31 fasting, untreated male patients with left coronary artery disease were studied during 2 identical pacing stress tests 45 minutes before (atrial pacing test I [APST I]) and 15 minutes after (APST II) administration of 15 mg/kg of LPC or placebo. Hemodynamic, metabolic, and nuclear angiographic variables were studied before, during, and for 10 minutes after pacing. After LPC administration, arterial total carnitine levels increased from 47 +/- 1.7 mumol/liter (control) to 730 +/- 30 mumol/liter. Hemodynamic and metabolic variables were comparable in LPC and placebo during APSI I, and reproducible in placebo during both tests. Although LPC did not affect myocardial oxygen demand and supply, it diminished myocardial ischemia, indicated by a significant 12% and 50% reduction in ST-segment depression and left ventricular end-diastolic pressure, respectively, during APST II. Moreover, during APST II, left ventricular ejection fraction increased by 18% (p < 0.05 vs APST I). Furthermore, LPC improved recovery of myocardial function after pacing, with a reduction in the time to peak filling and a 21% increase in both peak ejection and filling rates 10 minutes after pacing (all p < 0.05). Thus, LPC prevents ischemia-induced ventricular dysfunction, not by affecting the myocardial oxygen supply-demand ratio but as a result of its intrinsic metabolic actions, increasing pyruvate dehydrogenase activity and flux through the citric acid cycle. Because it is well tolerated, it may be a valuable alternative or addition to available antiischemic therapy.

Acute systemic and antiischemic effects of epanolol in patients with coronary artery disease.

Antiischemic effects of beta 1-blocking agents are based on intrinsic negative inotropic and chronotropic properties. Partial beta 1-agonistic activity, although useful in preserving cardiac function, may counteract such antiischemic properties by modulating the intrinsic negative cardiac effects of beta-blockade. To investigate the acute hemodynamic and antiischemic profile of epanolol, a cardioselective beta 1-antagonist and partial agonist, 20 patients with left coronary artery disease underwent two incremental atrial pacing tests, 45 minutes before (APST I) and 15 minutes after (APST II) 4 mg intravenous epanolol, administered over 5 minutes. Additional measurements were carried out at 1, 3, 5, 10, and 15 minutes after epanolol, at basal and fixed heart rates. Epanolol immediately reduced heart rate with a maximum of 10% at 15 minutes and decreased contractility (Vmax) by 7% (both p < .05), whereas cardiac output fell temporarily by 9% (p < .05). Other hemodynamic parameters did not change, except for a significant 11% reduction in myocardial oxygen demand. Despite comparable pacing conditions, both the double product and contractility decreased significantly less during APST II, resulting in a 17% lower myocardial oxygen consumption (p < .05). Myocardial ischemia was markedly reduced, indicated by normalization of lactate metabolism [lactate extraction 16 +/- 7% vs. -7 +/- 8% (APST I)], less ST depression (21%), and modulation of LV end-diastolic pressure postpacing (all p < .05 vs. APST I), whereas angina was absent or less in 14 patients. None of the patients reported an adverse effect. Thus, under resting conditions intravenous epanolol induces moderate, short-lasting negative chronotropic and inotropic effects, but does not alter cardiac pump function or vascular resistance, reflecting its additional beta 1-agonistic properties. Alternatively, during pacing it still reduces ischemia through negative inotropic effects and diminishes myocardial oxygen demand, reflecting its beta 1-antagonistic profile.

Acute hemodynamic and electrophysiologic effects and safety of high-dose intravenous diltiazem in patients receiving metoprolol.

The anti-ischemic efficacy of diltiazem may improve with increments in dosage and with additional beta-blocking therapy. However, the combined administration could lead to adverse effects through amplification of negative inotropic and chronotropic properties. To evaluate hemodynamic tolerability and safety of high-dose intravenous diltiazem in patients with coronary artery disease receiving long-term metoprolol treatment, 9 such patients were studied for 30 minutes after onset of intravenous diltiazem administration (0.5 mg/kg for 5 minutes, followed by 15 mg/hour). Diltiazem plasma levels peaked at 5 minutes (641 +/- 74 micrograms/liter), decreasing to 177 micrograms/liter at 30 minutes. Average metoprolol levels (43 +/- 12 micrograms/liter) did not change. Diltiazem immediately decreased systemic vascular resistance, left ventricular systolic and mean aortic pressures (29, 21 and 20%, respectively, at 5 minutes), and they remained significantly reduced at 30 minutes. Heart rate initially increased by 11% during the bolus infusion (p < 0.05). Concomitantly, contractility indexes Vmax and Vce40, measured at fixed heart rates, also increased significantly by 11%. Both heart rate and contractility indexes returned to baseline levels thereafter. Cardiac output increased by 10% (p = not significant), stroke index remained unchanged, but stroke work decreased significantly by 20%. Also, the tension-time index was significantly reduced (23%). Diltiazem induced moderate negative lusitropic effects, the first derivative of negative left ventricular pressure decline decreased by 12% and Tau 2 lengthened by 13%. Concomitantly, left ventricular filling pressure increased from 19 +/- 2 to 23 +/- 3 mm Hg, but only at 5 and 15 minutes. PQ, QRS and QTc intervals were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic neurohumoral activation and vasoconstriction during pacing-induced acute myocardial ischemia in patients with stable angina pectoris.

To identify the effect of myocardial ischemia on systemic neurohormones and vascular resistance, 32 untreated, normotensive patients with coronary artery disease underwent incremental atrial pacing until angina. Arterial and coronary venous lactate and arterial values of catecholamines and angiotensin II were determined at control, at maximal pacing rates, and at 1, 2, 5 and 30 minutes after pacing. Based on pacing-induced ST-segment depression (greater than or equal to 0.1 mV) or myocardial lactate production, or both, patients were selected as ischemic (n = 25) or nonischemic (n = 7). Baseline clinical and hemodynamic data were comparable. During pacing, chest pain was similar (20 ischemic vs 7 nonischemic patients). Also, hemodynamic measurements were comparable, except for contractility, which did not improve, and left ventricular end-diastolic pressure, which significantly increased in ischemic patients. Moreover, during ischemia arterial pressures increased significantly (13%) and systemic resistance increased from 1,470 +/- 60 (control) to 1,632 +/- 76 dynes.s.cm-5 5 minutes after pacing (p less than 0.05) in ischemic but not in nonischemic patients. Pacing did not affect neurohormones in nonischemic patients. In contrast, norepinephrine in ischemic patients increased significantly from 1.7 +/- 0.2 (control) to 2.6 +/- 0.3 (maximal pacing) and to 3.0 +/- 0.4 nmol/liter (1 minute after pacing), whereas angiotensin II levels increased from 6.2 +/- 1.4 (control) to 9.3 +/- 2.1 pmol/liter (1 minute after pacing, p less than 0.05). Epinephrine only increased during maximal rates (0.9 +/- 0.1 vs 0.6 +/- 0.1 nmol/liter at control, p less than 0.05). Thus, myocardial ischemia activates circulating catecholamines and angiotensin II, accompanied by systemic vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)