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.

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.

Acute hemodynamic effects and preload-dependent cardiovascular profile of the partial phosphodiesterase inhibitor nanterinone in patients with mild to moderate heart failure.

Nanterinone (UK-61,260) is a novel positive inotropic and balanced-type vasodilating drug, only partially based on phosphodiesterase III inhibition. Preliminary data from controlled studies suggest satisfactory long-term efficacy and safety. As its acute hemodynamic effects in humans are unknown, an oral dose of 2 mg nanterinone was studied in 14 patients with heart failure (NYHA class II-III) on chronic diuretic and angiotensin-converting enzyme (ACE) inhibitor treatment. Before the study, patients were on a 2 g salt-balanced diet, and they received their last medication 16 hours before each study day. Hemodynamic measurements were carried out before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours after administration of the study drug. All patients received placebo and nanterinone on 2 consecutive days. Following nanterinone, systemic vascular resistance decreased immediately from 1699 +/- 82 (mean +/- SEM) at baseline to 1368 +/- 80 at 1 hour. Changes persisted for 12 hours. Concomitantly, there was an immediate and significant fall in pulmonary wedge pressure to 38% of baseline at 1.5 hours, together with a 20% reduction in pulmonary artery pressure. Heart rate remained unchanged and arterial pressures showed only a short, significant decrease. Cardiac index rose significantly from 2.28 +/- 0.15 at baseline to a highest value of 2.65 +/- 0.14 1/min/m2 at 1 hour. Changes persisted for 3 hours. Placebo had no effect on these variables. As, in view of its potential venodilating properties, hemodynamic improvement by nanterinone may depend on pre-existing left ventricular filling pressure, patients were subsequently grouped according to baseline pulmonary wedge pressure of > 12 mmHg (H-PCWP) and < or = 12 mmHg (L-PCWP). Cardiac index improved by 26% in H-PCWP and by 17% in L-PCWP (NS). In contrast, PCWP fell more markedly in H-PWCP than in L-PCWP (40% and 23%, respectively, p < 0.05). Thus, oral nanterinone results in a significant acute hemodynamic improvement and is well tolerated. Although changes in left ventricular filling pressure are more pronounced in patients with elevated pre-existing PCWP, cardiac pump function improves equally in patients with normal or low left ventricular filling pressure at baseline.

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)

Cardiotoxicity as a dose-limiting factor in a schedule of high dose bolus therapy with interleukin-2 and alpha-interferon. An unexpectedly frequent complication.

BACKGROUND: In a group of patients with metastatic melanoma treated with high dose immunotherapy, there was an unexpectedly high incidence of severe cardiac adverse effects. METHODS: Sixteen patients with metastatic melanoma were treated with high dose interleukin-2 (IL-2) and alpha-interferon (alpha-IFN). Each treatment cycle consisted of IL-2 at a dose of 12 MIU/m2 and alpha-IFN at a dose of 3 MIU/m2, given as intravenous bolus injections every 8 hours on Days 1-5, every 3 weeks for a total of three cycles. Before treatment, careful cardiologic screening was performed, including electrocardiogram (ECG), stress test, cardiac multiple uptake-gated acquisition (MUGA) scan, and echocardiography. During therapy, patients were monitored with daily ECG and creatine phosphokinase measurements. Once cardiac damage was suspected, IL-2 and alpha-IFN were discontinued, and echocardiography, stress test and MUGA-scan were repeated. If indicated, cardiac catheterization with endomyocardial biopsies was performed. RESULTS: Despite pretreatment cardiac screening, seven patients (44%) exhibited myocardial injury. Acute myocardial infarction occurred in one patient, cardiomyopathy developed in four, asymptomatic ECG changes appeared in one, and 1 patient died of acute cardiac arrest. Echocardiography showed hypokinesis and decreased left ventricular ejection fraction. These abnormalities disappeared within 6 months. Cardiac catheterization in four affected patients revealed normal coronary arteries, but endomyocardial biopsies showed interstitial edema, vacuolation, and degeneration of myocytes. Electron-microscopic examination showed fragmentation of myofibrils, swelling of mitochondria and loss of mitochondrial cristae. CONCLUSIONS: This intensive treatment schedule of IL-2 and alpha-IFN is prohibited by severe and life-threatening cardiac toxicity.

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.

Hemodynamic tolerability and anti-ischemic efficacy of high dose intravenous diltiazem in patients with normal versus impaired ventricular function.

OBJECTIVES: This study was designed to compare the acute systemic and coronary hemodynamic effects of high doses of intravenous diltiazem in patients with normal versus impaired left ventricular function, investigate the safety of this drug and compare its anti-ischemic potential in these two patient groups during pacing-induced stress. BACKGROUND: Because coronary hemodynamic effects and negative inotropic properties of diltiazem are dose related, high dose intravenous diltiazem may improve anti-ischemic efficacy but may not be tolerated in patients with impaired cardiac function. METHODS: High dose intravenous diltiazem, 0.4 mg/kg for 5 min followed by 0.4 mg/kg for 10 min, was administered to 23 normotensive patients with coronary artery disease, 11 (group A) with normal and 12 (group B) with impaired ventricular function (ejection fraction < 45%) during two identical arterial pacing stress tests performed 30 min before (pacing test I) and immediately after diltiazem (pacing test II). RESULTS: Diltiazem was well tolerated despite high peak plasma levels, 869 +/- 152 micrograms/liter (group A) and 926 +/- 169 micrograms/liter (group B). It resulted in immediate but similar reductions in systemic resistance from 1,321 +/- 136 (control value) to 963 +/- 113 dynes.s.cm-5 (group A) and from 1,267 +/- 106 to 865 +/- 58 dynes.s.cm-5 (group B) and in mean arterial pressure from 107 +/- 3 to 93 +/- 4 mm Hg (group A) and from 103 +/- 4 to 86 +/- 4 mm Hg (group B), at 5 min after diltiazem (all p < 0.05 vs. control value). Diltiazem improved stroke output from 36 +/- 3 (control value) to 46 +/- 4 ml/beat per m2 in group B and from 44 +/- 4 (control value) to 49 +/- 5 ml/beat per m2 in group A, an effect that was significantly greater and more prolonged in group B than in group A. Although neither heart rate nor contractility was affected in either group, left ventricular end-diastolic pressure increased in group A (9 +/- 2 mm Hg to 12 +/- 1 mm Hg, p < 0.05) but not in group B. Despite similar reductions in coronary resistance and improvements in coronary flow, diltiazem consistently reduced myocardial oxygen extraction, but only in group B. Also, the anti-ischemic effects of diltiazem were more pronounced in group B. During pacing test II, myocardial lactate extraction normalized in group B (7 +/- 5% vs. -6 +/- 12% [pacing test I]) but not in group A, contractility indexes improved more and the increase in left ventricular filling pressure was reduced to a greater extent in group B. Moreover, the ischemia-induced increase in arterial pressures, observed in both groups during pacing test I, was prevented in group B but recurred in group A during pacing test II. CONCLUSIONS: High dose intravenous diltiazem is well tolerated, augments coronary flow and improves left ventricular pump function, particularly in patients with preexisting ventricular dysfunction. As its anti-ischemic effects also appear more pronounced in the latter group, high dose diltiazem may be particularly useful when ventricular function is depressed, for example, during prolonged ischemia at rest.

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)

Preload-dependent hemodynamic effects of milrinone in moderate heart failure.

Milrinone, a bipyridine derivative with positive inotropic and balanced type vasodilating properties, acutely improves cardiac pump function in patients with severe and moderate to severe heart failure. Whether it has similar effects in patients with mild to moderate heart failure is unknown. A hemodynamic evaluation of oral milrinone in dosage of 2.5, 5 and 10 mg was carried out on 3 consecutive days in 18 patients with NYHA class 2.7 heart failure. Patients continued with diuretics and digitalis, administered 15 h before each hemodynamic study. Peak milrinone plasma levels ranged from 77 to 252 micrograms/ml and were attained at 60-90 min following administration. Concomitantly, milrinone significantly reduced pulmonary wedge and right atrial pressures with 24, 47 and 44, and 25, 42 and 38% with the 2.5-, 5- and 10-mg doses, respectively. Milrinone had no effect on cardiac or stroke indices with either dose. Moreover, systemic vascular resistance only decreased by 12% with the highest dose, together with a 7% fall in mean arterial pressure and a 13% rise in heart rate (all p less than 0.05 vs. baseline). Patients were subsequently grouped depending on baseline pulmonary wedge pressure greater than or equal to 18 mm Hg (Gr I, n = 9) or less than 18 mm Hg (Gr II, n = 9). Changes in pulmonary wedge, pulmonary artery and right atrial pressure were similar in both groups following each dose. In contrast, the effect on cardiac pump function clearly differed in patients with high versus normal baseline wedge pressure. In Gr I, cardiac index increased significantly by 16% (5 and 10 mg). In Gr II, cardiac index decreased with 13% following the 10-mg dose (p less than 0.05 vs. baseline). When maximal individual changes in cardiac index were compared, 10 mg milrinone resulted in an improvement of cardiac index in all patients with baseline wedge pressures greater than 15 mm Hg, but in a decrease in cardiac index in patients with lower wedge pressures. It is concluded that milrinone induces contrasting effects on cardiac pump function in patients with mild to moderate heart failure, which may negatively affect its early and, possibly, also late efficacy in this patient group.

Hemodynamic effects and tolerability of intravenous amiodarone in patients with impaired left ventricular function.

Acute hemodynamic effects and tolerability of intravenous amiodarone, 5 mg/kg administered over 5 minutes, were compared in patients with coronary artery disease and either a normal (left ventricular [LV] ejection fraction greater than or equal to 45%, n = 10, group N) or impaired LV function (ejection fraction less than 45%, n = 9, group L). Amiodarone reduced systemic vascular resistence and LV and aortic pressures in both groups (13%, 18%, and 13%, respectively [group N], and 15%, 17%, and 15%, respectively [group L]) over the short term. Heart rate initially increased (18%, group L, and 10% group N), but was followed by a late 6% decrease in group N only, and by a progressive reduction in contractility (Vmax), together with a rise in LV end-diastolic pressure (19% and 38%, respectively [group N] and 17% and 58%, respectively [group L]; all values p less than 0.05 versus control). Coronary flow increased significantly by 20% (group N) and 31% (group L), but only during amiodarone administration, accompanied by a 26% and 25% reduction in myocardial oxygen extraction in groups N and L, respectively. Stroke work decreased in both groups (20% [group N] and 19% [group L], p less than 0.05 versus control). In contrast, cardiac output only improved (10%) in patients with impaired ventricular function. Significant side effects did not occur. Thus relatively high dosages of intravenous amiodarone are well tolerated and improve cardiac pump function in patients with an impaired, but not with a normal cardiac function. However, the tendency to increase LV end-diastolic pressures necessitates careful monitoring in patients in whom preexisting LV filling pressure may be elevated.

Determinants of prognosis in symptomatic ventricular tachycardia or ventricular fibrillation late after myocardial infarction. The Dutch Ventricular Tachycardia Study Group of the Interuniversity Cardiology Institute of The Netherlands.

In a multicenter study, 390 patients with sustained symptomatic ventricular tachycardia or ventricular fibrillation late after acute myocardial infarction were prospectively followed up to assess determinants of mortality and recurrence of arrhythmic events. Patients were given standard antiarrhythmic treatment, which consisted primarily of drug therapy. During a mean follow-up period of 1.9 years, 133 patients (34%) died; arrhythmic events and heart failure were the most common cause of death (41 patients [11%] died suddenly, 31 [8%] died because of recurrent ventricular tachycardia or ventricular fibrillation and 23 [6%] died of heart failure). One hundred ninety-two patients (49%) had at least one recurrent arrhythmic event; 85% of first recurrent arrhythmic events were nonfatal. Multivariate analysis of data from patients who developed the arrhythmia less than 6 weeks after infarction identified five variables as independent determinants of total mortality: 1) age greater than 70 years (risk ratio 4.5); 2) Killip class III or IV in the subacute phase of infarction (risk ratio 3.5); 3) cardiac arrest during the index arrhythmia (risk ratio 1.7); 4) anterior infarction (risk ratio 2.2); and 5) multiple previous infarctions (risk ratio 1.6). Multivariate analysis of data from patients developing the arrhythmia greater than 6 weeks after infarction identified four variables as independently predictive of total mortality: 1) Q wave infarction (risk ratio 2.1); 2) cardiac arrest during the index arrhythmia (risk ratio 1.7); 3) Killip class III or IV in the subacute phase of infarction (risk ratio 1.7); and 4) multiple previous infarctions (risk ratio 1.4). The results of the two multivariate analyses were used in a model for prediction of mortality at 1 year. The average predicted mortality rate varied considerably according to the model: for 243 patients (62%) with the lowest risk, it was 13%, corresponding to an observed mortality rate of 12%; for 92 patients (24%) with intermediate risk, it was 27%, corresponding to an observed rate of 28%; for 55 patients (14%) with the highest risk, it was 64%, corresponding to an observed rate of 54%. This study shows that patients with symptomatic ventricular tachycardia or ventricular fibrillation late after myocardial infarction who are given standard antiarrhythmic treatment have a high mortality rate. The predictive model presented identifies patients at low, intermediate and high risk of death and can be of help in designing the appropriate diagnostic and therapeutic strategy for the individual patient.

Hemodynamic profile of amiodarone during acute and long-term administration in patients with ventricular dysfunction.

One of the potential adverse effects of anti-arrhythmic agents is an impairment of cardiac function as a result of their intrinsic negative inotropic properties. Amiodarone, in animals, also induces dose-related negative inotropic effects, in addition to coronary and systemic vasodilatation and slowing of the heart. Likewise, in most human studies, intravenous amiodarone gives rise to early systemic and coronary vasodilatation, followed by a reduction in contractility. Depending on the relative impact of these opposing effects on the left ventricle, the changes in heart rate, cardiac output and left ventricular filling pressure are variable. Particularly in patients with pre-existing ventricular dysfunction, cardiac pump function is impaired further when relatively high dosages of amiodarone are used without its solvent Tween 80. In contrast, fast bolus administrations, eg. 5 mg/kg amiodarone in 5 minutes, result in an improvement of cardiac output, albeit at the expense of an increase in left ventricular filling pressure. The latter observation suggests that intravenous amiodarone should be given with caution in patients with heart failure and elevated left ventricular filling pressures. When given by mouth, amiodarone does not have significant hemodynamic effects, other than a moderate reduction in heart rate and, occasionally, in diastolic blood pressure. Cardiac pump function is not affected, even in patients with ventricular dysfunction or heart failure, in whom chronic oral administration of the drug is well tolerated.

Neurohumoral activation during acute myocardial ischaemia. Effects of ACE inhibition.

ACE inhibition may be useful in several manifestations of ischaemic heart disease, such as heart failure due to ischaemic cardiomyopathy. Recent evidence suggests that these effects may also be present in normotensive patients with ischaemic heart disease without heart failure. Theoretically, converting-enzyme inhibition, through coronary and systemic vasodilating effects and negative inotropic properties, should have a favourable effect on the myocardial oxygen supply/demand ratio and, hence, affect the incidence and severity of myocardial ischaemia. It is doubtful, however, whether these cardiac and extracardiac properties of ACE inhibitors really underlie its potential antiischaemic effects, at least in the average patient with ischaemic heart disease without concomitant heart failure and hypertension. Recent animal and human studies indicate that converting-enzyme inhibitors may modulate myocardial ischaemia by reducing ischaemia-induced circulating neurohumoral activation. It has been shown that, depending on the severity of ischaemia, the circulating renin-angiotensin system may become activated together with an increase in circulating catecholamine levels. ACE inhibition suppresses this neuroendocrine stimulation during ischaemia and modulates subsequent systemic and, presumably, also coronary vasoconstriction. In addition to these effects on circulating neurohormones, ACE inhibition could affect myocardial ischaemia through a number of local actions, e.g. modulation of tissue (cardiac) angiotensin II formation and bradykinin breakdown, stimulation of prostaglandin synthesis and, in the use of sulphydryl compounds, by affecting EDRF formation. Whether ACE inhibitors have clear antiischaemic effects in all clinical conditions is uncertain. Their efficacy to limit exercise-induced ischaemia has been questioned. In contrast, pacing-induced ischaemia in patients at rest is clearly prevented by ACE inhibition. This differential effect may be related to a more pronounced difference in circulating neurohormones during exercise per se. It also suggests that ACE inhibitors may be particularly useful as (additional) antiischaemic therapy in patients with angina at rest, e.g. unstable angina and the acute phase of myocardial infarction.

Acute hemodynamic and antiischemic properties of intravenous bepridil in coronary artery disease.

The acute hemodynamic and antiischemic effects of intravenous bepridil (3 mg/kg/5 minutes followed by 1 mg/kg/hour) were studied in 19 patients with coronary artery disease under basal conditions and during 2 identical pacing stress tests 30 minutes before (pace test I) and 15 minutes after (pace test II) onset of infusion. Bepridil immediately decreased coronary and systemic vascular resistance (26 and 17%, respectively). This resulted in a 19 and 21% reduction in left ventricular systolic and mean aortic pressures and a 15% increase in coronary flow and stroke index (p less than 0.05 vs control for each). These vasodilating effects were short lasting, persisting for 5 minutes after the bolus infusion, followed by significant reductions in heart rate (15%) and contractility (10%) and a temporary 46% increase in left ventricular filling pressure. During both pace tests heart rate, contractility, coronary flow and myocardial O2 consumption were comparable. In contrast, bepridil prevented the significant increase in systemic resistance and mean aortic pressure observed during pace test I (11 and 15%, respectively). Subsequently, myocardial O2 demand was significantly less during pacing after bepridil, due to an 11% reduction in left ventricular systolic pressure (p less than 0.05 vs control and pacing test II vs I). This resulted in marked antiischemic effects: normalization of lactate extraction and reduction in ST-segment depression (-14 +/- 7 vs 3 +/- 6% and 0.2 +/- 0.02 vs 0.13 +/- 0.02 mV, respectively, pace test I vs II, p less than 0.05), and in less or no angina in 18 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Cost benefit analysis of early thrombolytic treatment with intracoronary streptokinase. Twelve month follow up report of the randomised multicentre trial conducted by the Interuniversity Cardiology Institute of The Netherlands.

The costs and benefits of early thrombolytic treatment with intracoronary streptokinase in acute myocardial infarction were compared in a randomised trial. All hospital admissions were recorded and the functional class was assessed at visits to the outpatient clinic during a 12 month follow up of 269 patients allocated to thrombolytic treatment and of 264 allocated to conventional treatment. Mean survival during the first year was calculated for patients with inferior and with anterior infarction and adjusted for impaired quality of life in cases where there were symptoms or hospital admission. In patients with inferior infarction mean survival was 337 days (out of a total follow up of 365 days) for patients allocated to thrombolytic treatment and 327 days for controls. Quality adjusted survival was seven days longer in the thrombolysis group (307 vs 300 days in controls). In patients with anterior infarction mean survival was significantly longer (35 days) in the thrombolysis group than in the control group as was quality adjusted survival (38 days) (304 vs 266 days in controls). The gain in life expectancy with thrombolytic treatment was 0.7 years for patients with inferior infarction, 2.4 years for patients with anterior infarction, and 3.6 years for the subset of patients with large anterior infarction who were admitted within two hours of the onset of symptoms. The costs of medical treatment, including medication, hospital stay, cardiac catheterisation, coronary angioplasty, and bypass surgery, in the first year follow up were higher inpatients allocated to thrombolytic treatment (an additional cost ofDfl 7000 in inferior and Dfl 9000in anterior infarction (1 pounds sterling approximately Dfl 3.3.)) than in conventionally treated patients. The additional costs per year of life gained were Dfl 10 000 in inferior infarction, Dfl 3 800 in anterior infarction, and only Dfl 1 900 in patients with large anterior infarction admitted within two hours of onset of symptoms. Intracoronary thrombolysis can be recommended as a cost effective treatment in patients with extensive anteroseptal infarction.

Acute antiischaemic properties of high dosages of intravenous diltiazem in humans in relation to its coronary and systemic haemodynamic effects.

The antiischaemic properties of intravenous diltiazem in recommended therapeutic doses are disputed. In 17 patients with coronary artery disease the systemic and coronary haemodynamic effects of diltiazem were assessed during a high-dose infusion (0.4 mg kg-1 per 5 min, followed by 0.4 mg kg-1 per 10 min). In addition, its potential antiischaemic properties were investigated during identical pacing stress tests, 30 minutes before (P1) and immediately after diltiazem administration (P2). Diltiazem reduced left ventricular systolic pressure from 133 +/- 5 to 116 +/- 5 mmHg (P less than 0.005, means +/- SEM), persisting until after P2. It decreased systemic and coronary resistance by 32% (P less than 0.001) and 29% (P less than 0.005), respectively, with a sustained increase in cardiac output from 5.9 +/- 0.4 to 7.3 +/- 0.6 l min-1 (P less than 0.01), but a brief 20% rise in coronary flow (P less than 0.05), after the bolus infusion only. Heart rate, contractility, left ventricular filling pressure and myocardial O2 consumption remained unchanged. Despite high plasma levels (673 +/- 81 micrograms l-1) diltiazem was well tolerated. During identical maximal pacing rates diltiazem considerably reduced myocardial O2 demand (double product: 16.3 +/- 0.8 (P2) vs 21.1 +/- 1.1 (P1), P less than 0.005), due to an 18% decrease in left ventricular systolic pressure, resulting in diminished coronary flow and myocardial O2 consumption during P2 (14% and 15%, respectively, P less than 0.05 vs P1). Diltiazem also significantly reduced pacing-induced ischaemia, indicated by normalization of myocardial lactate extraction (1 +/- 8% (P2) vs -41 +/- 12% (P1), P less than 0.05), and left ventricular filling pressure (13 +/- 2 (P2) vs 27 +/- 3 mmHg (P1), P less than 0.01), less ST-segment depression (0.12 +/- 0.01 (P2) vs 0.24 +/- 0.02 mV (P1), P less than 0.01) and improved contractility (Vmax 59 +/- 5 (P2) vs 48 +/- 3 s-1 (P1), P less than 0.05). Angina was absent or less in 15 patients during pacing after diltiazem. Thus, diltiazem, in high dosages, induces continuing systemic but short lasting coronary vasodilation, improves pump function without negative chronotropic and inotropic effects and has pronounced antiischaemic properties, predominantly due to diminished myocardial O2 demand.

Dose related coronary and systemic haemodynamic effects of intravenous bepridil in patients with coronary artery disease.

The acute coronary and systemic haemodynamic effects of intravenous bepridil were investigated in 27 patients with coronary artery disease; 13 (group 1) received 2 mg kg-1 and 14 (group 2) 4 mg kg-1 over 5 min. An immediate systemic and coronary vasodilation occurred in both groups during and immediately after the infusion. Changes were dose-related with a maximal decrease in left ventricular (LV) systolic pressure of 11% (group 1) and 18% (group 2), in mean aortic pressure of 11% (group 1) and 19% (group 2), and in coronary resistance of 23% (group 1) and 41% (group 2). Coronary flow increased by 17% (group 1) and 47% (group 2) (all changes significantly different from control (C) values and between groups). Cardiac output, measured immediately after bepridil, was unaltered, although in group 2 stroke volume index increased (14%) and systemic resistance decreased (16%), both P less than 0.05 vs C. In group 2, heart rate (HR) and contractility initially increased (8% and 10%, respectively, P less than 0.05 vs C), secondary to the greater fall in afterload, followed by a significant reduction at 5 and 10 min after bepridil (9% and 10%, respectively), accompanied by a 36% increase in LV enddiastolic pressure (P less than 0.05 vs C). No such changes were observed in group 1, apart from a simultaneous decrease in HR (9%, P less than 0.05 vs C). Thus, in humans, a dose-related, biphasic haemodynamic pattern is observed with intravenous bepridil, consisting of an acute, short-lasting vasodilation, followed by late negative chronotropic and inotropic effects, which, with longterm bepridil administration, may be beneficial during myocardial ischaemic.

Temporal relation of changes in regional coronary flow and myocardial lactate and nucleoside metabolism during pacing-induced ischemia.

The temporal relation between myocardial lactate and hypoxanthine metabolism and regional changes in krypton-81m perfusion during pacing-induced ischemia was studied in 17 patients with coronary artery disease (CAD). During incremental atrial pacing, lactate production and hypoxanthine release occurred early and simultaneously, accompanied by ST-segment changes, but before angina and only few minutes after a significant (17%) reduction in krypton-81m perfusion in areas with more than 90% luminal diameter reduction. During maximal pacing heart rates, krypton-81m distribution decreased to 68 +/- 7% of control in areas with more than 90% diameter reduction and to 80 +/- 4% in 70 to 90% reduction (both p less than 0.05 vs control). Maximal lactate production occurred 15 seconds after pacing (extraction -15 +/- 7% vs 16 +/- 2% during control, p less than 0.05) and peak hypoxanthine release 1 minute after pacing (delta arteriovenous -2.64 +/- 0.8 microM vs 0.08 +/- 0.21 microM during control, p less than 0.05). Krypton-81m perfusion decreased in 20 of the 21 CAD areas. Angina, ST-segment changes, hemodynamic alterations and lactate production occurred in 15, 14, 9 and 15 patients, respectively. In contrast, hypoxanthine release was found in all cases. After pacing, lactate production and all general indexes of ischemia persisted for only 2 to 3 minutes. In contrast, krypton-81m perfusion was still significantly reduced 5 minutes after pacing and was only accompanied by hypoxanthine release (delta arteriovenous -1.41 +/- 0.6 microM, p less than 0.05 vs control).(ABSTRACT TRUNCATED AT 250 WORDS)

Bleeding complications of intracoronary fibrinolytic therapy in acute myocardial infarction. Assessment of risk in a randomised trial.

The risk of bleeding associated with intracoronary infusion of streptokinase in acute myocardial infarction was determined in a randomised controlled trial containing 302 patients under the age of 70. Intracoronary streptokinase infusion was given to 152 patients and 150 patients were treated conventionally. Bleeding was seen in 24 (16%) patients in the streptokinase group and in two of the conventionally treated patients. Bleeding was most common (28%) in patients over the age of 60 years. The groin was the site of bleeding in all patients except one. In the first 48 hours after admission the haematocrit in streptokinase treated patients with manifest bleeding fell by 0.07 (0.04) (mean (SD)). The fall in haematocrit in the streptokinase treated patients without manifest bleeding was 0.05 (0.04) and in the conventionally treated patients it fell by 0.03 (0.04). Sixty six units of packed cells were transfused in the streptokinase group (50 units to those who bled); the control group required only 17 units. There were no deaths due to bleeding. The occurrence of bleeding and the fall in haematocrit in the streptokinase group correlated with the occurrence of systemic fibrinolysis but not with the dose of streptokinase given. Thus, in about 15% of patients treatment with intracoronary streptokinase resulted in significant non-fatal bleeding from the femoral puncture site that required substantial transfusion support. Furthermore, there was a significant drop in haematocrit in patients without manifest bleeding. These results emphasise the need for more specific fibrinolytic agents.

Continuous determination of regional myocardial blood flow with intracoronary krypton-81m in coronary artery disease.

Pacing-induced changes in regional coronary flow were studied continuously with krypton-81m by intracoronary infusion in 25 patients: 21 with 50% or greater diameter narrowing of 1 or more left coronary arteries (group I) and 4 with less than 50% diameter reduction of a left coronary artery (group II). No changes occurred in group II. In group I, krypton-81m perfusion decreased progressively in all areas with more than 70% diameter narrowing, with a simultaneous increase in normal regions. At the end of pacing during angina, krypton-81m perfusion was reduced to 81 +/- 4% of control in areas with 71 to 90% diameter reduction (n = 8) and to 69 +/- 6% in areas with more than 90% diameter narrowing (n = 15). In contrast, in regions with 50 to 70% diameter reduction changes were variable (decrease in 4 regions, increase in 2 and an unchanged distribution in 1 region). Krypton-81m perfusion decreased early, before general signs of ischemia in areas with more than 90% diameter reduction, whereas this decrease occurred later in regions with 71 to 90% diameter narrowing, concurrently with ST-segment changes but before anginal pain. Although all signs of ischemia had disappeared between 2 and 5 minutes after pacing, changes in krypton-81m distribution persisted in most areas for 5 to 15 minutes after pacing. It is concluded that the functional significance of coronary arterial narrowing can be assessed with a continuous intracoronary infusion of krypton-81m. Changes in regional distribution persisted after cessation of pacing-induced ischemia, indicating an ongoing decrease in regional myocardial blood flow.