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The QUO VADIS study was designed to explore whether 1 year of angiotensin-converting enzyme inhibition with quinapril (40 mg/day) would decrease ischemia in patients who underwent coronary artery bypass grafting (CABG). Patients (n = 149) scheduled for CABG were randomized 4 weeks before surgery. Study medication was used from randomization up to 1 year after CABG. Exercise testing was performed at randomization; the exercise test was repeated 1 year after CABG and patients underwent 48-hour Holter monitoring. Clinical ischemic events were recorded and defined as death, revascularization, myocardial infarction, recurrence of angina pectoris, ischemic stroke, or transient ischemic attack. Baseline characteristics were similar between groups. Total exercise time increased overall by 75 +/- 76 seconds 1 year after CABG (placebo +79 +/- 75 seconds, quinapril +72 +/- 79 seconds, p = 0.6). All patients had ischemic ST-segment changes at randomization; 33% of patients had ischemic ST-segment changes 1 year after CABG (placebo 29%, quinapril 37%, p = 0.4). On Holter monitoring, the number of patients experiencing > or = 1 episodes of ischemia was equal in both groups. Treatment with quinapril significantly reduced clinical ischemic events after CABG: 15% in patients on placebo versus 4% of patients on quinapril (hazard ratio 0.23, 95% confidence interval 0.06 to 0.87, p = 0.02). Long-term quinapril treatment significantly reduced clinical ischemic events within 1 year after CABG, although ischemia at exercise testing and Holter monitoring was unchanged.

Erectile dysfunction is a frequent condition in cardiovascular patients. Since the arrival of oral erection-supporting medication, patients want to know how safe sexual activity is in cardiovascular disease in general and during use of erection-supporting medication in particular. Sexual intercourse with a steady partner causes no more cardiovascular risk than normal daily activities such as ironing, 2 kilometers of walking without climbing, paperhanging, playing golf or gardening. The relative risk of myocardial infarction during sexual activity is not significantly higher than for healthy persons. The incidence of cardiovascular morbidity and mortality is not higher among users of sildenafil. Sildenafil is contraindicated in patients using long-acting nitrates or who may need to use short-acting nitrates, because the combination may cause a sharp fall of the blood pressure. No interactions have been observed with beta-receptor blockers, calcium antagonists, thiazide and loop diuretics and ACE inhibitors. Before prescribing a symptomatic (pharmaceutical) treatment for patients with an erection disorder, attention should be given tot the sexological, psychological and medical backgrounds of the disorder. Secondary prevention of atherosclerotic risk factors is also important: regulation of blood pressure and blood sugar level, hyperlipidaemia and obesity, as well as a change of lifestyle (giving up smoking, adapting of diet and more physical exertion). Patients with a very low cardiac capacity should be advised to refrain from treatment of the erection disorder.

Objectives: We sought to investigate the effect of angiotensin-converting enzyme (ACE) inhibition <9 h after myocardial infarction (MI) on left ventricular (LV) dilation in patients receiving thrombolysis., Background: The ACE inhibitors reduce mortality after MI. Attenuation of LV dilation has been suggested as an important mechanism., Methods: The data of 845 patients with three-month echocardiographic follow-up after MI were combined from three randomized, double-blind, placebo-controlled studies. The criteria for these studies included: 1) thrombolytic therapy; 2) ACE inhibition within 6 to 9 h; and 3) evaluation of LV dilation as the primary objective., Results: The ACE inhibitor was started 3.2+/-1.7 h after the patients' first (mainly, 85%) anterior MI. After three months, LV dilation was not significantly attenuated by very early treatment with an ACE inhibitor. The diastolic volume index was attenuated by 0.5 ml/m2 (95% confidence interval [CI] -1.5 to 2.5, p = 0.61), and the systolic volume index by 0.5 ml/m2 (95% CI -1.0 to 1.9, p = 0.50). Subgroup analysis demonstrated that LV dilation was significantly attenuated by ACE inhibitor treatment for patients in whom reperfusion failed. In contrast, LV dilation was almost unaffected by ACE inhibitor treatment in successfully reperfused patients., Conclusions: We could not demonstrate attenuation of LV dilation in patients receiving thrombolysis by ACE inhibitor treatment within 6 to 9 h after MI. We speculate that very early treatment with an ACE inhibitor has a beneficial effect on LV remodeling only in patients in whom reperfusion failed. Other mechanisms may be responsible for the beneficial effects of ACE inhibitors in successfully reperfused patients after MI.

The QUO VADIS (the effects of QUinapril On Vascular Ace and Determinants of ISchemia) study was a randomized, double-blind, placebo-controlled trial designed to evaluate the effects of long-term angiotensin-converting enzyme (ACE) inhibition on angiotensin II formation in human vasculature. Patients (n = 187) scheduled for coronary artery bypass surgery used study medication 27 +/- 1 days before surgery. Segments of internal mammary arteries were exposed to increasing doses (0.1 nM-1 microM) of angiotensin I and II in organ baths. The rate of local angiotensin II formation is a function of the reciprocal of the difference between the pEC50's of the dose response curves to angiotensin I and II (-log/mol) and of the area between the curves (units). Quinapril (40 mg) and captopril (3 x 50 mg) similarly and significantly reduced mean blood pressure compared with placebo (p = 0.04). Difference between pEC50's was 0.90 +/- 0.08 in quinapril patients compared with 0.60 +/- 0.08 for placebo (p = 0.01); the area between curves was 91 +/- 8 for quinapril patients compared with 67 +/- 8 for placebo (p = 0.03). Angiotensin II formation was decreased to a lesser extent with captopril and was not statistically different from placebo (p = 0.3); the difference between pEC50's was 0.83 +/- 0.15; the area between curves was 84 +/- 12. This is the first randomized study to demonstrate that long-term oral treatment with an ACE inhibitor reduces vascular angiotensin II formation in humans.

Objective: To describe the causes and circumstances of death regarding patients who died in 1994 and 1995 while on a waiting list for cardiac surgery in the Netherlands., Design: Retrospective multicentre case study., Setting: 11 Dutch cardiac surgery centres., Patients: All patients reported as dying while on the waiting list for cardiac surgery in 1994 and 1995., Main Outcome Measures: Classification of death by an independent adjudication committee into "erroneously reported", "waiting list related" or "not waiting list related". Death was judged as "waiting list related" if the clinical course would have been substantially different if there had been unrestricted surgical capacity., Results: 138 and 129 deaths were reported in 1994 and 1995, respectively. 43 deaths (16%) were considered as erroneously reported. 181 of the remaining 224 cases were adjudicated as waiting list related. Median time from acceptance for surgery to death was 35 days (interquartile range 14-75 days). 97 of 181 deaths occurred within six weeks following addition to the waiting list. The estimated incidence of death ranged from 1.33 per 1000 patient-weeks during weeks 2-4 to 0.68 per 1000 patient-weeks after 12 weeks., Conclusions: The causes and circumstances of death are waiting list related for approximately 100 patients per year in the Netherlands. At least half of the deaths may occur within the first six weeks. Waiting lists for cardiac surgery engender high risks for the patients involved.

His-bundle ablation followed by pacemaker implantation is today a widely accepted therapeutic choice when drug refractoriness of symptomatic AF is evident. The selection of pacing mode in patients suffering from paroxysmal AF is still controversial. Preservation of AV synchrony is an attractive option in patients with paroxysmal AF who undergo His-bundle ablation. The purpose of this study was to examine prospectively the contribution of VDDR pacing for preservation of AV synchrony. After His-bundle ablation a VDDR pacing system was implanted in 17 patients with paroxysmal AF, and all antiarrhythmic drugs were withdrawn. The endpoint of the study was defined as the onset of chronic AF. To document the onset of chronic AF 48-hour Holter recordings were made every 6-8 weeks. After a mean followup of 18.2 (range 14-21) months, VDDR pacing is still operative in 13 patients (77%). Four patients developed chronic AF after a mean follow-up of 6 months. Of several baseline characteristics, only the intraatrial P wave at implantation was significantly smaller in patients developing chronic AF than in patients in whom the VDDR mode is still operative. This pilot study suggests that VDDR pacing is an attractive pacing method for patients with paroxysmal AF after His-bundle ablation. A low intraatrial P wave electrogram at implant was associated with a higher risk for the development of chronic AF.

There are conflicting reports on the interaction of aspirin with angiotensin-converting enzyme inhibitors in heart failure and systemic hypertension. A post hoc analysis of the Captopril and Thrombolysis Study (CATS) study was conducted. At randomization, 94 patients (31.5%) took aspirin. In patients who took aspirin, the cumulative alpha-hydroxy butyrate dehydrogenase release was 1,151 +/- 132 IU/L in patients randomized to captopril compared with 1,401 +/- 136 IU/L in patients randomized to placebo (difference -250 +/- 189 [95% confidence interval (CI) -620 to 120]). This difference was comparable to the difference in patients who did not use aspirin (-199 +/- 147 [95% CI -488 to 897]). One year after acute myocardial infarction, an increase in left ventricular end-diastolic volume index of 2.2 +/- 3.0 ml/m2 in captopril-treated and 1.9 +/- 2.9 ml/m2 in placebo-treated patients was observed in patients who took aspirin (difference 0.4 +/- 4.2 [95% CI -8.2 to 8.9]). This difference was also comparable to the difference in patients who did not take aspirin (2.2 +/- 3.8 [95% CI -5.2 to 9.7]). One year after acute myocardial infarction, patients who did take aspirin had a mean change in LV end-diastolic volume index of 2.1 +/- 2.1 ml/m2 compared with 8.4 +/- 1.9 ml/m2 in patients who did not use aspirin (p = 0.02). Thus, aspirin does not attenuate the acute and long-term effects of angiotensin-converting enzyme inhibition after acute myocardial infarction, but independently reduces LV dilation after myocardial infarction.

Aims: To study the absorption kinetics of sotalol following administration of different formulations. A formulation which results in fast absorption might be useful in the episodic treatment of paroxysmal supraventricular tachycardia (SVT), atrial fibrillation (Afib) or atrial flutter (Afl)., Methods: In an open randomized crossover study seven healthy male volunteers were given an intravenous infusion of 20 mg sotalol, for assessing the absolute bioavailability, an oral solution containing 80 mg sotalol, an oral solution containing both 80 mg sotalol and 20 mg cisapride and an 80 mg sotalol tablet, which was taken sublingually., Results: The addition of cisapride decreased the time at which maximum serum concentrations were reached (tmax) from 2.79 (1.85-4.34) h to 1.16 (0.68-2.30) h (P=0.009) [95% CI: -2.59, -0.55] and increased the absorption rate constant (ka) from 0.49 (0.31-0.69) h(-1) to 1.26 (0.52-5.61) h(-1) (P=0.017). The absolute bioavailability of sotalol was reduced by cisapride from 1.00+/-0.15 to 0.70+/-0.26 (P=0.006), while maximum serum concentrations of both oral solutions were not significantly different. Compared with the sublingually administered tablet with a median tmax of 2.12 (0.89-3.28) h, the sotalol/cisapride oral solution gave a smaller tmax (p=0.009) [95% CI: -1.64, -0.36]. The ka of the sotalol/cisapride solution was significantly (P=0.010) larger than the ka of 0.56 (0.33-0.75) h(-1) found after sublingual administration of the tablet., Conclusions: The sotalol/cisapride oral solution might be suitable for the episodic treatment of SVT, Afib or Afl.

Objectives: This study was conducted to test the hypothesis that angiotensin-converting enzyme (ACE) inhibition reduces myocardial ischemia and related events after myocardial infarction (MI)., Background: The oxygen demand/supply ratio of the myocardium is influenced by angiotensin II as a result of its arterial vasoconstrictive and inotropic effects and through its interaction with the sympathetic nervous system., Methods: We studied 244 patients who had been included in a double-blind, randomized, placebo-controlled, post-MI, ACE inhibition intervention study (Captopril and Thrombolysis Study [CATS]). All patients underwent exercise testing before and 3 and 12 months after hospital discharge. After 1-year double-blind treatment, all patients continued receiving single-blind placebo for 1 month., Results: Total exercise time increased in both groups after 3 months (placebo: +86 +/- 13 s; captopril: +69 +/- 12 s, p = 0.8 between groups) and increased further after 1 year (placebo: +13 +/- 11 s; captopril: +33 +/- 13 s, p = 0.7 between groups). There were also no differences in mean ST segment depression. During the 12 months, significantly fewer ischemia-related events occurred in the captopril group (82 vs. 52, p = 0.015). This difference was found between 3 and 12 months but not during the first 3 months. After withdrawal from double-blind medication, nine ischemic events were reported in teh captopril group compared with one in the placebo group (p = 0.006 between groups)., Conclusions: The present data show that captopril may reduce the incidence of ischemia-related events after MI, which becomes apparent after 3 months. However, no anti-ischemic effect was observed during exercise testing. After withdrawal from ACE inhibition, a high incidence of clinical events occurred, suggesting a rebound phenomenon.

Aims: Angiographic studies on the natural course of both focal and diffuse coronary atherosclerosis have not been performed before, but can both be assessed by quantitative coronary angiography. The objective of this study was to describe the natural course of focal and diffuse coronary atherosclerosis over time., Methods and Results: In 129 patients with mild coronary artery disease, but not on lipid-lowering medication, three coronary angiograms were made each 2 years apart. Nine hundred and sixty five angiographically diseased and non-diseased segments were analysed by quantitative coronary angiography. Mean lumen diameter and minimal lumen diameter were used as measures of diffuse and focal coronary atherosclerosis. Mean lumen diameter and minimum lumen diameter decreased by 0.02 and 0.03 mm per year. The rate of progression was similar in the angiographically non-diseased, as in the mildly and moderately diseased segments. Progression of diffuse coronary atherosclerosis was largest in severely stenosed lesions (percentage diameter stenosis > or = 50%) and in the right coronary artery with a loss of 0.19 mm and 0.16 mm in mean lumen diameter. Progression of focal disease was most prominent in new and mild lesions and the right coronary artery, with a decrease in minimum lumen diameter of 0.34 mm and 0.22 mm. In most subgroups, progression occurred gradually over time. On a per segment level, progression and the occurrence of new lesions occurred in 4.4% and 4.2%. Regression and disappearance of a lesions was found in 2.3% and 1.9%. On a per patient level, 36% were progressors, 12% had a mixed response, 36% were stable, and 16% were regressors., Conclusion: Diffuse and focal coronary atherosclerosis progressed at the same rate in the first and second 2 years in stenosed and non-stenosed segments. The rate of coronary atherosclerosis progression was small, but was higher for focal than for diffuse disease. A minority of lesions progressed and spontaneous regression was rare.

Background: Left ventricular dilation after acute myocardial infarction (MI) is mainly determined by infarct size. In addition, this detrimental structural adaptation seems to be augmented in patients with the ACE DD genotype. The ACE DD genotype is associated with increased ACE activity. The aim of the present study was to evaluate whether ACE activity per se may carry prognostic significance for subsequent left ventricular dilation as assessed by echocardiography during 1-year follow-up after acute MI., Methods and Results: Left ventricular end-systolic and end-diastolic volume indexes were assessed by two-dimensional echocardiography. In 102 consecutive patients, plasma ACE activity was determined 3.7 +/- 0.1 hours after the onset of MI. In 64 of these patients, left ventricular volume indexes obtained at baseline and 1 year after MI were used for the present analysis. Patients were divided ino a group having low ACE activity (< or = IU/L, n = 15) and a group having high ACE activity (> 12 IU/L, n = 49). Infarct size was a significant predictor of the increase in left ventricular volume indexes (P = .0001) in these patients. Multivariate regression analysis, after correction for infarct size, demonstrated that elevated plasma ACE activity is a significant predictor of the increase in left ventricular end-diastolic and end-systolic volume indexes (P = .0006 and P = .02, respectively) 1 year after MI., Conclusions: Elevated plasma ACE activity determined soon after the onset of MI may be a significant predictor of the development of left ventricular dilation and may identify patients at risk.

Objective: To evaluate exercise capacity of patients with chronic atrial fibrillation in whom His bundle ablation followed by ventricular rate response pacing (VVIR) was carried out because of drug refractoriness., Design: Prospective study., Patients: 25 consecutive patients, all with chronic symptomatic drug refractory atrial fibrillation, underwent His bundle ablation. Before this intervention all patients were on antiarrhythmic drugs to attain acceptable heart rate control and to relief symptoms., Main Outcome Measures: Exercise capacity, including measurements of VO2, was examined before and after a mean interval of seven months following His bundle ablation., Results: Exercise capacity after His bundle ablation increased from a mean of 109 (SD 49) W to 118 (46) W (P < 0.002), but VO2 at peak exercise did not change significantly. Maximum exercise capacity was achieved with a significantly lower maximum driven heart rate than the spontaneous heart rate before ablation., Conclusions: Exercise capacity of patients who underwent His bundle ablation followed by VVIR pacing remained unchanged or improved during a mean follow up of seven months. Larger patient populations with longer follow up are necessary to examine determinants of improved exercise capacity.

The gastrointestinal therapeutic system formulation of nifedipine enables a once-daily dosing resulting in predictable, relatively constant plasma concentrations. To evaluate the efficacy and safety of this formulation and to compare this with the beta-blocker atenolol, we conducted a double-blind, randomised, multi-centre study in 129 male patients with documented exercise induced angina pectoris. After 4 weeks' treatment, nifedipine (60 mg), improved time to onset of 0.1 mV ST-segment depression from 536 s by 72 +/- 117s, time to onset of pain from 619 s by 56 +/- 120 s, and total exercise time from 685 s by 40 +/- 88 s. Atenolol 100 mg, had a comparable effect, time to onset of 0.1 mV ST-segment depression improved from 496 s by 53 +/- 129 s, time to onset of pain from 572 s by 57 +/- 118 s, and total exercise time from 653 s by 33 +/- 99 s. Between group analysis revealed no statistically significant differences for these exercise parameters. Atenolol, but not nifedipine, significantly reduced heart rate and systolic blood pressure at rest and during exercise (P < 0.001 between groups), indicating different modes of action of the drugs. With regard to safety, both drugs were generally well tolerated. There were significantly (P = 0.01) more vasodilation related side effects with nifedipine. These data demonstrate that gastrointestinal therapeutic system formulation of nifedipine and atenolol as once-daily monotherapy are equally effective and safe, but with different effects on exercise parameters.

Objectives: In this study we sought to investigate the effect of intervention with captopril within 6 h of the onset of myocardial infarction on left ventricular volume and clinical symptoms of heart failure in relation to infarct size during a 1-year follow-up period., Background: Remodeling of the heart starts in the early phase of myocardial infarction and is associated with an adverse prognosis. Angiotensin-converting enzyme inhibition started in the subacute or late phase after myocardial infarction has been shown to improve prognosis., Methods: In the Captopril and Thrombolysis Study, 298 patients with a first anterior myocardial infarction treated with intravenous streptokinase were randomized to receive either oral captopril (25 mg three times a day) or placebo. The left ventricular volume index was assessed by two-dimensional echocardiography within 24 h, on days 3, 10 and 90 and after 1 year., Results: A small but significant increase in left ventricular volume indexes was observed after 12 months. Using a random coefficient model, no significant treatment effect on left ventricular volumes could be detected. In contrast, when survival models were used, the occurrence of left ventricular dilation was significatnly lower in captopril-treated patients (p = 0.018). In addition, the incidence of heart failure was lower in the captopril group (p < 0.03). This effect appeared early and was most obvious in patients with a medium-sized infarct (p = 0.04) and was not present in large infarcts., Conclusions: Very early treatment with captopril after myocardial infarction significantly reduces the occurrence of early dilation and the progression to heart failure. These data underscore the importance of early treatment. Furthermore, patients with intermediate infarct size benefit the most from this treatment strategy.

To recognize patients prone to subsequent left ventricular dilation after the acute phase of a myocardial infarction treated with thrombolysis, we studied 233 patients with a first anterior infarction, treated with thrombolysis, with 2-dimensional echocardiography within 12 hours after admission and 3 months later. A wall motion score index (WMSI) and left ventricular volumes were assessed, and enzymatic infarct size was expressed as cumulative alphahydroxybutyrate dehydrogenase determined in the first 72 hours after infarction. Patients who died (17 of 233, 7%) after a mean follow-up of 517 days had a significantly higher acute WMSI (2.1 +/- 0.3, mean +/- SD) than those who survived (1.9 +/- 0.4)(p=0.006). With use of this cutoff value for 2 WMSI, ventricles with an acute WMSI < or = 2 (62%) showed no increase in end-diastolic volume index (EDVI) or end-systolic volume index (ESVI), whereas ventricles with an acute WMSI >2 (38%) showed a significant increase in ESVI (6.1 +/- 12.2 ml/m2) and in EDVI (10.3 +/- 16.6 ml/m2) in the first 3 months. Using a cutoff value of 1,000 U/L for cumulative alphahydroxybutytrate dehydrogenase, only infarcts with a value of >1,000 U/L (52%) caused a significant increase in EDVI (10.8 +/- 14.3 ml/m2) and ESVI (6.5 +/- 10.0 ml/m2) in the first 3 months. Thus, acutely assessed WMSI of >2 can readily predict subsequent dilation in patients with a first anterior infarction treated with streptokinase and is a good predictor of mortality. Enzymatic infarct size also is a predictor of dilation, although not available until 3 days after infarction.

Objective: To estimate the costs and effects of preventive treatment with captopril compared with the current treatment policy in patients with asymptomatic left ventricular dysfunction after a myocardial infarction., Methods: Estimates of effects are based on the results of the SAVE trial. Costs are estimated on the basis of current treatment patterns in four Dutch hospitals. All knowledge is incorporated in a mathematical model extrapolating the SAVE results to 20 years., Results and Conclusions: Captopril treatment is expected to increase survival at certain costs. The average additional costs per patient are estimated at DF1 2,491 in 4 years and at DF1 8,723 in 20 years of treatment. Costs per additional survivor after 4 years are estimated at DF1 69,126. After extrapolation of the results of the SAVE trial to 20 years, costs per life-year gained can be estimated at DF1 15,799. From univariate sensitivity analysis it appears that the results are highly sensitive for the costs of treatment with captopril and the occurrence and prevention of clinical heart failure. Varying all estimates randomly between upper and lower limits-in 5,000 simulations-an estimate of costs per life-year gained of DF1 15,729 is made for 20 years of treatment, with 95% of all estimates between DF10 and DF1 50, 000. On a national level, undiscounted costs are expected to increase up to approximately DF1 42 million annually during the first 40 years after introduction of the preventative strategy.

Background: In patients with postinfarction sustained ventricular tachycardia showing one or more antiarrhythmic drug failures, the question is how long to proceed with new drug trials before deciding to perform map-guided arrhythmia surgery. Although the techniques of this surgery developed rapidly in the early 1980s, this therapy may be offset by damage to residual left ventricular function. However, surgery has been shown to be very effective in selected groups of patients., Methods: A randomized study was carried out in patients with postinfarction ventricular tachycardia and eligible for arrhythmia surgery based on residual left ventricular function. Therapy failure was defined by the occurrence of the following events: spontaneous recurrence of ventricular tachycardia or ventricular fibrillation, sudden cardiac death, inducibility of sustained ventricular tachycardia or ventricular fibrillation with programmed stimulation of the heart, symptomatic non-sustained ventricular tachycardia requiring therapy or side-effects of antiarrhythmic drugs requiring withdrawal. In the drug limb, failure of the first antiarrhythmic drug was accepted but failure of a second and different drug was regarded as true therapy failure., Results: After randomization, antiarrhythmic drug therapy was administered in 33 patients, and 30 patients underwent surgery. Neither group differed in baseline characteristics, and the mean number of drug failures before randomization was 2.7. The Kaplan-Meier therapeutic failure of antiarrhythmic drugs was 39 +/- 11%, 42 +/- 11% and 51 +/- 18% at 0.5-, 1- and 4-year follow-up, respectively, whereas the therapeutic failure of cardiac surgery was 37 +/- 11%, 37 +/- 11% and 50 +/- 20% at 0.5, 1 and 4 years, respectively, showing no statistical difference. The 1- and 4-year Kaplan-Meier survival of the antiarrhythmic drug-treated group was 91 +/- 6% and 78 +/- 15%, respectively, and of the surgical group 92 +/- 6% and 59 +/- 20%, respectively, and did not differ between either group. However, the relative risk for total cardiac death was higher in the surgical limb than in the drug limb (relative risk 2.2, CI 0.68-7.48)., Conclusion: This study demonstrated no difference between the therapeutic result of continuation of two different antiarrhythmic drugs and that of arrhythmia surgery. Despite the small number of patients studied, it is recommended that drug therapy should continue as long as this regimen is tolerated by the patient. When true drug refractoriness or side-effects of drugs arise, arrhythmia surgery offers a valuable alternative. However, when additional reasons for cardiac surgery exist, arrhythmia surgery should be undertaken earlier and may become the first choice of treatment of postinfarction ventricular tachycardia.

There is increasing evidence that class III antiarrhythmic agents may be superior to class I agents for the long-term treatment of life-threatening ventricular tachyarrhythmias. This open study evaluated the acute electrophysiologic effects, antiarrhythmic efficacy, and safety of different doses of intravenous dofetilide, a new class III drug, in 50 patients with sustained monomorphic ventricular tachycardia inducible by programmed electrical stimulation who had previously been unsuccessfully treated with 0 to 7 (median 3) other drugs. Intravenous dofetilide was administered over 60 minutes at the following dose levels: 1.5, 3.0, 6.0, 9.0, and 15.0 micrograms/kg. Significant class III activity was apparent at doses of 3.0 to 15.0 micrograms/kg, as evidenced by dose-related prolongation of the QTc interval by 13.4% to 14.2%, ventricular effective refractory period by 7.9% to 20.6%, and ventricular functional refractory period by 7.3% to 25.0%. The corresponding mean +/- SD plasma dofetilide concentrations ranged from 1.45 +/- 0.52 to 6.48 +/- 1.31 ng/ml. There was no evidence of reverse use-dependence. At these electrophysiologically active dose levels, intravenous dofetilide suppressed (complete response) or slowed (partial response) inducible ventricular tachycardia in 17 of 41 patients (41%) compared with 0 of 9 patients receiving only 1.5 micrograms/kg. The response rate was fairly uniform among the groups receiving 3.0, 6.0, 9.0, and 15.0 micrograms/kg. Intravenous dofetilide was hemodynamically well tolerated. Torsades de pointes (which was self-limiting) developed in only 1 patient, who was allocated to receive 15.0 micrograms/kg. There were no other proarrhythmic episodes or serious adverse effects. Further evaluation of the therapeutic potential of dofetilide in the management of life-threatening ventricular arrhythmias is justified.

In recent years, growing evidence has suggested a beneficial effect from the use of angiotensin converting enzyme (ACE) inhibitors after myocardial infarction. Since important differences between the structure and effects of the various ACE inhibitors exist, differences in outcome can be expected. This review discusses the structural, pharmacodynamic and pharmacokinetic differences between ACE inhibitors administered after myocardial infarction, both in experimental settings and in clinical practice.

Background: Progressive left ventricular dilatation after myocardial infarction is associated with a high mortality rate, the majority of which is arrhythmogenic in origin. The underlying mechanism of this relation remains unknown. It has been suggested, however, that left ventricular dilatation is accompanied by changes in repolarization characteristics that may facilitate the occurrence of life-threatening ventricular arrhythmias., Methods and Results: We examined 62-lead body surface QRST integral maps during sinus rhythm in 78 patients at 349 +/- 141 days after thrombolysis for a first anterior myocardial infarction. Visual map analysis was directed at discriminating dipolar (uniform repolarization) from nondipolar (nonuniform repolarization) patterns. In addition, the nondipolar content of each map was assessed quantitatively with the use of eigenvector analysis. Nondipolar map patterns were present in almost one third of the patients (32%). Left ventricular end-systolic and end-diastolic volumes were assessed echocardiographically before discharge and after 3 and 12 months with the use of the modified biplane Simpson rule. The increase in left ventricular end-systolic volume 1 year after myocardial infarction was more pronounced in patients with nondipolar QRST integral map patterns (14.47 +/- 14.10 versus 4.22 +/- 8.44 mL/m2, P = .017). In patients with an increase in end-systolic volume of more than 16 mL/m2 (upper quartile), the prevalence of nondipolar maps was 89% compared with 29% in patients with dilatation of less than 16 mL/m2. In addition, the nondipolar content of maps in patients in the upper quartile was significantly increased compared with the lower quartiles (49 +/- 14% versus 37 +/- 12%, P = .013). Logistic regression analysis revealed that an end-systolic volume of more than 42 mL/m2 after 1 year contributed independently to the appearance of nondipolar maps. Patients with high-grade ventricular arrhythmias showed a higher nondipolar content (49 +/- 17% versus 39 +/- 10%, P = .013). QTc dispersion did not discriminate between patients with and those without high-grade ventricular arrhythmias. Also, the association between left ventricular remodeling and nondipolar map patterns was confirmed prospectively in an additional group of 15 patients., Conclusions: Nondipolar map patterns are present in 32% of patients after thrombolysis for a first anterior myocardial infarction and are associated with increased left ventricular dilatation. These data support the hypothesis that left ventricular dilatation after myocardial infarction leads to changes in repolarization characteristics that may facilitate the occurrence of life-threatening ventricular arrhythmias.

To evaluate the efficacy and safety of hirudin, a direct thrombin inhibitor, in patients with acute myocardial infarction, a dose-finding, angiography study was carried out. After a pilot phase in 10 patients treated with a bolus of 0.1 mg.kg-1 and a continuous infusion of 0.06 mg.kg-1.h-1 (dose group I), two doses of hirudin, bolus 0.2 mg.kg-1.h-1 (DG II), and bolus 0.4 mg.kg-1 with 0.15 mg.kg-1.h-1 (DG III) were tested and compared with heparin as an adjunct to streptokinase and aspirin. This interim analysis was mandatory due to puncture-site related bleedings. Early and complete patency was achieved in 30% of 35 heparin patients, in 40% of 10 DG I, in 47% of 58 DG II and in 62% of 14 DG III patients. A dose-response relationship particularly between DG I and DG II, was also observed in the anti-thrombotic activity monitored by the aPTT. Apart from the catheter-related bleedings, there were low rates of serious adverse events.

Objectives: This study sought to determine whether patients who are homozygous for the deletion (D)-type allele of the angiotensin-converting enzyme gene display augmented ventricular dilation after myocardial infarction., Background: Recent evidence suggests that the deletion-type allele of the angiotensin-converting enzyme gene (DD genotype) is associated with an increased prevalence of myocardial infarction and myocardial hypertrophy. However, it is unknown whether the DD genotype is associated with adverse cardiac remodeling. To address this question we determined the genotype in patients enrolled in the Captopril and Thrombolysis Study (CATS), a prospective trial in which patients received either captopril or placebo during and after thrombolysis for a first anterior myocardial infarction., Methods: Cardiac volume was determined by echocardiography immediately after thrombolysis and at 1-year follow-up. The genotype for the angiotensin-converting enzyme was determined in 96 patients. Norepinephrine levels were assessed during and immediately after thrombolysis., Results: Immediately after thrombolysis, cardiac volume did not differ between genotype groups. However, at 1-year follow-up, both end-systolic and end-diastolic left ventricular volumes were significantly greater in the DD-genotype group. Norepinephrine increased to higher levels in the DD-genotype group that received placebo therapy. Captopril treatment effectively blunted both the norepinephrine increase and cardiac dilation in the DD-genotype group., Conclusions: This exploratory study suggests that homozygosity for the angiotensin-converting enzyme deletion-type allele is associated with augmented neurohumoral activation as well as augmented cardiac dilation after an acute anterior myocardial infarction, an effect that may be susceptible to angiotensin-converting enzyme inhibition.

Background: Reduced heart rate variability has been identified as an important prognostic factor after myocardial infarction. This factor is thought to reflect an imbalance between sympathetic and parasympathetic activity, which may lead to unfavourable loading conditions and thus promote left ventricular dilatation., Patients and Methods: 298 patients in a multicentre clinical trial were randomised to captopril or placebo after a first anterior myocardial infarction. All patients were treated with streptokinase before randomisation. In the present substudy full data including heart rate variability and echocardiographic measurements were available from 80 patients. Patients were divided into two groups: those with a reduced (< or = 25) heart rate variability index and those with normal heart rate variability index (> 25). Heart rate variability was evaluated by 24 h Holter monitoring before discharge. Left ventricular volumes were assessed by echocardiography before discharge and three and 12 months after myocardial infarction. Extent of myocardial injury, severity of coronary artery disease, functional class, haemodynamic variables, and medication were also considered as possible determinants of left ventricular dilatation., Results: Before discharge end systolic and end diastolic volumes were not different in the two groups. After 12 months in patients with a reduced heart rate variability, end systolic volume (mean (SD)) had increased by 6 (14) ml/m2 (P = 0.043) and end diastolic volume had increased by 8 (17) ml/m2 (P = 0.024). Left ventricular volumes were unchanged in patients with a normal heart rate variability. Also, patients with left ventricular dilatation had a larger enzymatic infarct size and higher heart rates and rate-pressure products. A reduced heart rate variability index before discharge was an independent risk factor for left ventricular dilatation during follow up. Measurement of heart rate variability after three months had no predictive value for this event., Conclusion: Assessment of the heart rate variability index before discharge, but not at three months, gave important additional information for identifying patients at risk of left ventricular dilatation.

Objectives: This study examined the performance of the 62-lead body surface electrocardiogram (ECG) in identifying the site of origin of ventricular tachycardia in patients with a previous myocardial infarction., Background: Because the accuracy of ECG localization of ventricular tachycardia using standard 12-lead recordings is restricted to the identification of rather large ventricular areas, application of multiple torso lead recordings may augment the resolving power of the surface ECG and result in more discrete localization of arrhythmogenic foci., Methods: Thirty-two patients were selected for electrophysiologically guided ablative therapy for drug-resistant postinfarction ventricular tachycardia. In these patients, QRS integral maps of distinct monomorphic ventricular tachycardia configurations were correlated with a previously generated infarct-specific reference data base of paced QRS integral maps. Each paced pattern in the data base corresponded with ectopic endocardial impulse formation at 1 of 18 or 22 discrete segments of the left ventricle with a previous anterior or inferior myocardial infarction, respectively. Electrocardiographic localization was compared with the results obtained during intraoperative or catheter endocardial activation sequence mapping., Results: Body surface mapping was performed during 101 distinct ventricular tachycardia configurations. Compared with the activation mapping data that were acquired in 64 of 101 ventricular tachycardias, body surface mapping identified the correct segment of origin in 40 (62%) of 64 tachycardias, a segment adjacent to the segment where the arrhythmia actually originated in 19 (30%) of 64 tachycardias and a segment disparate from the actual segment of origin in 5 (8%) of 64 tachycardias. With respect to infarct location, the segment of origin was correctly identified in 28 (60%) of 47 ventricular tachycardias in patients with anterior, 7 (70%) of 10 tachycardias in patients with inferior and 5 (71%) of 7 tachycardias in patients with combined anterior and inferior myocardial infarction., Conclusions: This study shows that body surface mapping enables precise localization of the origin of postinfarction ventricular tachycardia in 62% and regional approximation in 30% of tachycardias. The multiple-lead ECG may be used to guide and shorten catheter-based mapping procedures during ventricular tachycardia and to provide relevant information on the origin of tachycardias that cannot be mapped with conventional single-site mapping techniques because of unfavorable characteristics.

In atrial flutter, chemical conversion with class I drugs is often unsuccessful, whereas class III drugs seem more promising. The different electrophysiological effects of these drugs may explain this discrepancy. To date, only experimental data show the differential effects of these drugs on conversion rate and atrial flutter cycle length. This study evaluates the effects of the class IC antiarrhythmic drug flecainide, and of dofetilide, a new class III drug, on conversion rate and flutter cycle length in patients with atrial flutter. Flecainide (11 patients) was given as an intravenous bolus of 2 mg.kg-1 in 10 min and dofetilide (10 patients) as a maximum intravenous bolus of 8 micrograms.kg-1 in 15 min. Baseline characteristics were comparable between both groups. Only one patient treated with flecainide converted to sinus rhythm. This patient showed the largest flutter cycle length increase (280 to 420 ms). By contrast, seven of the 10 patients treated with dofetilide converted to sinus rhythm. Patients treated with flecainide showed a significantly larger increase in atrial flutter cycle length at the end of the infusion compared to the dofetilide-treated patients (from 226 +/- 28 to 317 +/- 52 ms vs from 221 +/- 26 to 239 +/- 39 ms, respectively). In conclusion, dofetilide is more effective than flecainide in the conversion of atrial flutter to sinus rhythm, despite the fact that flecainide produced a more prolonged flutter cycle length. Thus, action potential prolongation in the absence of conduction slowing seems more effective in terminating human atrial flutter than depression of the excitability.

Progressive left ventricular dilatation is an important determinant of prognosis after myocardial infarction. The association of this process with the occurrence of ventricular arrhythmias is less well established. Of 153 patients with a first anterior myocardial infarction treated with thrombolytic therapy, 34 (22%) had high-grade ventricular arrhythmias (Lown 4A and B) during Holter monitoring after 1 year. Patients with high-grade ventricular arrhythmias had a larger end-systolic volume (38 +/- 12 vs 25 +/- 11 mL/m2; P < .001) at hospital discharge and more left ventricular dilatation (10 +/- 18 vs 1 +/- 9 mL/m2; P = .011) during the follow-up period. Increased end-systolic volume at discharge and subsequent dilatation proved to be independent predictors of high-grade ventricular arrhythmias. Six patients died suddenly during the first 12 months after myocardial infarction. Four of these patients had an enlarged end-systolic volume (> 22 mL/m2) at discharge, and the three patients who died suddenly after 3 months showed a significant increase in end-systolic volume from discharge to 3 months compared to survivors (16 +/- 6 vs 2 +/- 9; P = .008). Left ventricular remodeling after myocardial infarction is an independent predictor of the occurrence of ventricular arrhythmias late after myocardial infarction.

In two patients with a symptomatic posteroseptally localized accessory atrioventricular pathway, but with distinct electrocardiographic patterns, a coronary sinus diverticulum appeared to be the site of this connection. Radiofrequency catheter ablation in the diverticulum was implemented to interrupt the pathway in both cases. This study demonstrates the necessity to perform coronary sinus angiography when ablation attempts in the posteroseptal region are not immediately successful, or optimal signals are not detected.

The study was designed to examine the safety and efficacy of acute interventional use of captopril on left ventricular volumes, ventricular arrhythmias and neurohormones during thrombolysis in patients with a first anterior myocardial infarction, within 6 h of onset of symptoms. Left ventricular dysfunction and prognosis after myocardial infarction can be improved by angiotensin converting enzyme inhibition started after the ischaemic phase. Experimental evidence suggests that intervention during thrombolysis may lead to even further benefit. In a randomized, double-blind placebo-controlled trial, 298 patients with a first anterior myocardial infarction, eligible for thrombolytic therapy were treated with captopril 6.25 mg or placebo, started immediately upon streptokinase infusion and titrated to 25 mg t.i.d.. The efficacy of captopril by an intention-to-treat-analysis to reduce left ventricular volumes, ventricular arrhythmias, neurohumoral activation and enzymatic infarct size was measured. During dose titration, mean blood pressure and heart rate were similar in both groups. However, hypotension after the first dose was reported in 18 patients on placebo and 31 patients on captopril (P < 0.05). At discharge, 80% of patients were on study medication. Left ventricular volumes were significantly increased in both groups at 3 months, but they tended to be lower in the captopril group; however, the differences were not statistically significant. The incidence of accelerated idioventricular rhythm and non-sustained ventricular tachycardia in captopril patients was lower than in placebo patients (P < 0.05), parallelled by transiently lower norepinephrine levels (P < 0.05) upon thrombolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To investigate the long-term results of the corridor operation in the treatment of symptomatic atrial fibrillation refractory to drug treatment., Background: The corridor operation is designed to isolate from the left and right atrium a conduit of atrial tissue connecting the sinus node area with the atrioventricular node region in order to preserve physiological ventricular drive. The excluded atria can fibrillate without affecting the ventricular rhythm. This surgical method offers an alternative treatment when atrial fibrillation becomes refractory to drug treatment., Patients: From 1987 to 1993, 36 patients with drug refractory symptomatic paroxysmal atrial fibrillation underwent surgery. The in hospital rhythm was followed thereafter by continuous rhythm monitoring and with epicardial electrograms. After discharge Holter recording and stress testing were regularly carried out to evaluate the sinus node function and to detect arrhythmias; whereas Doppler echocardiography was used to measure atrial contraction and size., Main Outcome Measures: Maintained absence of atrial fibrillation without drug treatment after operation; preservation of normal chronotropic response in the sinus node., Results: The corridor procedure was successful in 31 (86%) of the 36 patients. After a mean (SD) follow up of 41 (16) months 25 (69%) of the 36 patients were free of arrhythmias without taking drugs (mean (SE) actuarial freedom at four years 72 (9)%)). Paroxysmal atrial fibrillation recurred in three patients; paroxysmal atrial flutter (two patients) and atrial tachycardia (one patient) developed in the corridor in three others. Among the 31 patients in whom the operation was successful sinus node function at rest and during exercise remained undisturbed in 26 and 25 patients respectively (mean (SE) actuarial freedom of sinus node dysfunction at four years (81(7)%)). Pacemakers were needed in five (16%) of the 31 patients for insufficient sinus node rhythm at rest only. Doppler echocardiography showed maintenance of right atrial contribution to right ventricle filling in 26 of the 31 patients after operation in contrast to the left atrium, which never showed such contribution. His bundle ablation was performed and a pacemaker implanted in the five patients in whom the corridor operation was unsuccessful., Conclusion: These results substantiate the idea of this surgical procedure. Modification of the technique is, however, needed to achieve a reliable isolation between left atrium and corridor, which would make this experimental surgery widely applicable in the treatment of drug refractory atrial fibrillation.

The adjunctive use of ACE-inhibitors with thrombolytic therapy early during acute myocardial infarction offers theoretic advantages. In the acute phase, captopril may scavenge free radicals, blunt the catecholamine response, elicit coronary vasodilation and increase prostacyclin and bradykinin levels. In the chronic phase remodelling may be attenuated. At present, a large number of controlled clinical trials mainly focussing on the effects of ACE-inhibition in the chronic phase is under way. Only few studies concentrate on the effect of acute intervention with ACE-inhibitors in ischemia-reperfusion i.e. thrombolysis in myocardial infarction. In the Captopril And Thrombolysis pilot study (CAT pilot-study) 3 mg and 6.25 mg captopril was tolerated well as adjunctive therapy to intravenous streptokinase. Decrease in mean arterial blood pressure (36 +/- 11%) after 6.25 mg was comparable to the control group (30 +/- 7%). Furthermore noradrenaline levels decreased dose dependently to 47 +/- 6 and 38 +/- 7% from baseline respectively. These results prompted a large nationwide acute intervention trial with captopril in 300 patients receiving thrombolytic therapy: the Captopril And Thrombolysis Study (CATS). The primary hypothesis of CATS supposes a very early effect of converting enzyme inhibition on evolving myocardial damage due to ischemia and the consequences of early reperfusion. This will be evaluated by serial echocardiography, Holter monitoring and neurohumoral measurements immediately upon thrombolysis and during the first year after myocardial infarction. Blinded data show a favourable blood pressure response, with systolic hypotension below 100 mm Hg occurring only in 0.2% of patients.

Background: The purpose of this study was to assess the value of body surface mapping and the standard 12-lead ECG in localizing the site of origin of postinfarction ventricular tachycardia (VT) during endocardial pace mapping of the left ventricle., Methods and Results: Simultaneous recordings of 62-lead body surface QRS integral maps and scalar 12-lead ECG tracings were obtained in 16 patients with prior myocardial infarction during a total of 26 distinct VT configurations and during subsequent left ventricular catheter pace mapping at 9 to 24 different endocardial sites. Anatomic pacing site locations were computed by means of a biplane cineradiographic method and plotted on a polar projection of the left ventricle. The QRS integral map and the QRS complexes of the 12 standard leads of each VT morphology obtained in a particular patient were compared independently with the different paced QRS integral maps and paced QRS complexes of the 12-lead ECG generated in that same patient. The stimulus site locations of the best matching paced QRS integral map and paced QRS complexes of the 12-lead ECG were indicated on the polar projection and subsequently compared with the endocardial location of the corresponding site of VT origin identified during intraoperative (surgical ablation) or catheter activation sequence mapping (catheter ablation). The localization resolution of pace mapping was established separately for each electrocardiographic technique by computing the size of endocardial areas with similar morphological features of the QRS complex. Pace mapping advocated with body surface mapping or the 12-lead ECG enabled adequate reproduction of the VT QRS morphology in 24 of 26 VTs (92%) and 25 of 26 VTs (96%), respectively. Activation sequence mapping identified the site of origin in 12 of 26 previously observed VT configurations (46%). Ten and 11 VTs were localized by activation sequence mapping and pace mapping combined with body surface mapping or the 12-lead ECG, respectively. Pace mapping applied with body surface mapping identified the site of origin correctly (distance < or = 2 cm) in 8 of 10 compared VTs (80%); an adjacent site (distance between 2 and 4 cm) or a disparate site (distance > or = 4 cm) was identified in the remaining 2 of 10 VTs (20%). Pace mapping used with the 12-lead ECG localized the site of origin correctly in 2 of 11 VTs (18%); the site of origin was identified correctly next to an additional adjacent site in 5 of 11 VTs (55%); and an adjacent site or a disparate site was found in 1 of 11 VTs (9%) and 2 of 11 VTs (18%), respectively. The difference in localization accuracy of both electrocardiographic techniques was statistically significant (P = .02). The mean size of endocardial areas where a comparable QRS morphology was obtained during pace mapping was 6.0 +/- 4.5 cm2 with the application of body surface mapping and 15.1 +/- 12.0 cm2 with the use of the 12-lead ECG., Conclusions: These results demonstrate that application of the 62-lead instead of the 12-lead ECG during endocardial pace mapping enhances the localization resolution of this mapping technique and enables more precise identification of the site of arrhythmogenesis in the majority of compared postinfarction VT episodes.

Introduction: The mechanism of wide QRS complex tachycardias during dofetilide infusion was studied in a patient with atrial fibrillation., Methods and Results: Endocardial recordings from the intraventricular conduction system showed that dofetilide caused "classic" aberrant conduction (Ashman phenomenon, typical QRS morphology) at high prematurity ratios (preceding interval = 1.78 x coupling interval--290), thus mimicking ventricular ectopy. In addition, there was frequent sequential bilateral bundle branch block, caused by a significant difference in preceding bundle-to-bundle intervals (mean difference +/- 1 SD: 74 +/- 26 msec)., Conclusion: The present findings may prove helpful in the clinical assessment of wide QRS complex rhythms after dofetilide and possibly other "pure" Class III antiarrhythmics.

Self-terminating ventricular fibrillation was recorded in a 47 year old woman without coronary artery or other structural heart disease. Reperfusion was thought to be responsible for the ventricular fibrillation because the arrhythmia started while the ST segment was returning to the baseline during an episode of silent ischaemia that was probably caused by coronary spasm. This case shows that potentially lethal arrhythmias can arise during reperfusion and that ventricular fibrillation during reperfusion may be self-terminating.

Dofetilide may induce aberrant intraventricular conduction due to its Class III effect. This report describes an atrial fibrillation patient in whom intraventricular conduction was studied before and after dofetilide using multiple endocardial recordings. Dofetilide provoked aberrant conduction during atrial fibrillation, and aberrancy could be mimicked with programmed atrial stimulation after restoration of sinus rhythm. However, during right ventricular stimulation, isolated bundle branch reentrant beats were recorded after induction of critical retrograde conduction delays. This occurred in the setting of relatively large differences in refractoriness between the right bundle branch and the right ventricular myocardium. This favored distal retrograde bundle branch block during ventricular extrastimulation, in turn enhancing bundle branch reentry. This potential proarrhythmic mechanism deserves close attention in the further development of dofetilide and also of other new "pure" Class III agents.

One hundred twenty-four consecutive patients (85%) with paroxysmal atrial fibrillation (AF) and 21 (15%) with atrial flutter (AFI) were studied immediately after pharmacologic or electrical cardioversion to sinus rhythm. Mean age was 59 +/- 13 years (range 23 to 79). Patients with reduced left ventricular function were excluded from the study. After restoration to sinus rhythm, the clinical course of all patients was followed for the first recurrence of paroxysmal AF or AFI irrespective of the therapeutic approach. Mean follow-up was 23 +/- 16 months. After 12 months of follow-up, 50% of all patients remained in sinus rhythm. Univariate analysis indicated that coronary artery disease (relative risk 1.9; 95% confidence interval 0.9-3.9), history of paroxysmal AF or AFI (2.3; 1.1-5.0), female sex (2.3; 1.1-4.6), pulmonary disease (3.9; 1.9-7.6) and valvular heart disease (4.4; 2.2-8.8) were associated with an increased risk for recurrent or frequent episodes of paroxysmal AF or AFI. No predictors were found to be associated with a decrease in length of the recurrence-free period after successful conversion to sinus rhythm. Multivariate analysis identified history of AF or AFI (odds ratio 2.5; 95% confidence interval 0.9-6.4), coronary artery disease (3.1; 1.1-8.2) and female sex (3.4; 1.3-8.9) as independent predictors for recurrent or frequent episodes of paroxysmal AF or AFI. The presence of these risk factors should be taken into account when prophylactic therapy with antiarrhythmic drugs is being considered in the treatment of paroxysmal AF or AFI.

To improve electrocardiographic localization of the site of origin of ectopic left ventricular (LV) impulse formation in the heart with prior myocardial infarction, 62-lead body surface QRS integral maps were studied during LV pacing at a total of 221 endocardial sites in 14 patients with previous anterior (AMI), inferior (IMI), lateral (LMI), or anterior and inferior (AMI/IMI) myocardial infarction. The anatomic location of each pacing site was computed using digitized biplane fluoroscopic images and plotted on standardized LV endocardial polar projections. A data base of characteristic AMI and IMI mean QRS integral maps was developed after visually selecting subgroups with nearly identical QRS integral morphology from the ectopic activation sequences produced at 110 sites in eight patients with AMI and at 66 sites in four patients with IMI. Intrasubgroup pattern uniformity and intersubgroup pattern variability were statistically verified. The endocardial pacing site locations belonging to each AMI and IMI subgroup were depicted as segments on the respective LV polar projections. In patients with AMI, a total of 18 typical mean QRS integral patterns were obtained, whereas 22 different mean total QRS integral patterns showing more substantial intersubgroup variation were acquired in patients with IMI. Posterolateral regions exhibited a relatively low electrocardiographic sensitivity (six AMI and five IMI patterns) as compared with anteroseptal regions (12 AMI and 17 IMI patterns). Total QRS integral patterns obtained at 24 sites in one patient with LMI were largely compatible with the IMI mean total QRS integral patterns, whereas the majority of total QRS integral patterns acquired at 21 sites in one patient with AMI/IMI corresponded with the AMI mean total QRS integral patterns. The results show that total body surface QRS integral maps generated during LV pacing in patients with prior myocardial infarction cluster by pattern and that each QRS integral pattern is related to a circumscribed endocardial segment of ectopic impulse formation. The relation between a given QRS integral pattern and the position and size of the corresponding paced segment is dependent on infarct location. The present infarct-specific data base of characteristic total body surface QRS integral patterns provides a clinical tool to obtain detailed electrocardiographic localization of ventricular arrhythmias in patients with previous myocardial infarction.

Efficacy and safety of intravenous flecainide (2 mg/kg body weight in 10 minutes), verapamil (10 mg in 1 minute), and propafenone (2 mg/kg body weight in 10 minutes) were investigated in 90 consecutive patients with atrial fibrillation (AF) or flutter (AFL). In the first 40 patients, flecainide and verapamil were evaluated; in the second 50 patients, flecainide and propafenone were compared, both in a single-blind randomized study design. The primary end point was sinus rhythm occurring within 1 hour after start of infusion. Sinus rhythm was attained in 32 of 37 patients (86%) with AF treated with flecainide and in 11 of 20 patients (55%) with AF treated with propafenone. In recent onset AF (less than or equal to 24 hours) conversion rates were 24 of 25 patients (96%) in the flecainide group and 8 of 14 patients (57%) in the propafenone group (p less than 0.05). Conversion of AFL occurred in only 1 of 8 patients (13%) in the flecainide-treated patients and in 2 of 5 patients (40%) treated with propafenone (difference not significant). Verapamil was almost ineffective, since only 1 of 20 patients (5%) responded within 1 hour. Time to conversion was 21 +/- 17 minutes in the flecainide group and 16 +/- 10 minutes in the propafenone group. QRS widening occurred in flecainide-treated patients (83 +/- 15 to 99 +/- 20 msec; p less than 0.001), but not after propafenone (83 +/- 11 to 86 +/- 12 msec). Significantly higher plasma levels were found in patients with conversion within 1 hour using propafenone.(ABSTRACT TRUNCATED AT 250 WORDS)

Patients with paroxysmal atrial fibrillation may be extremely disabled despite medical therapy. Based on recent concepts of atrial fibrillation, a surgical open heart procedure was designed to isolate a "corridor" from the right and the left atrium. The corridor consists of the sinus node area, the atrioventricular nodal junction, and the connecting right atrial mass, small enough to prevent atrial fibrillation. Between 1987 and 1990, 20 patients with severely disabling symptoms due to frequent paroxysmal atrial fibrillation underwent the corridor operation, with permanent success in 16 patients. In 8 patients, left atrium to corridor conduction reappeared shortly after the procedure. Reoperation was performed in these patients without extracorporeal circulation. The site of persistent conduction between the left atrium and the corridor could consistently be localized adjacent to the coronary sinus. Nevertheless, reoperation failed to isolate permanently the corridor in 4 patients. During a mean follow-up of 20 months, atrial fibrillation dominating the ventricles was never observed nor inducible in the corridor in the 16 patients with a successful operation. In all cured patients, sinus node function remained undisturbed. Paroxysmal atrial flutter inside the corridor arose in 1 patient and a paroxysmal focal tachycardia in another. All 16 cured patients experienced a clear improvement in quality of life. Refinement of the surgical technique to obtain persistent isolation between the left atrium and the corridor is needed. These results demonstrate that the concept of the corridor operation is sound and justify its use in the treatment of drug-refractory paroxysmal atrial fibrillation.

A total of 1124 consecutive patients who were selected for coronary artery bypass graft surgery were studied. Of patients awaiting surgery (mean waiting time 98 days) 25 patients (2.2%) died before operation (mean waiting time 63 days). To assess patient characteristics predictive for early mortality before surgery, 25 deceased patients were analysed and compared to 50 controls matched for age, gender, type of surgery and waiting-list priority. Univariate analysis showed that the deceased patients had a higher rate of severe angina pectoris class III-IV (odds ratio (OR) 2.9), unstable angina prior to angiography (OR 4.8), cardiac enlargement on chest X-ray (OR 13.5), positive exercise testing of short duration (less than or equal to 6 min) (OR 6.0), coumarin treatment (OR 4.2), smoking (OR 3.0), severe left main or three-vessel disease (OR 4.1), abnormal end-diastolic volume (OR 3.1) and an abnormal left ventricular wall motion score (OR 3.0). Using multivariate analysis, cardiac enlargement (OR 14.4), positive exercise testing of short duration (OR 13.3), smoking (OR 8.7), coumarin treatment (OR 7.1), unstable angina (OR 6.5) and/or left main or three-vessel disease (OR 5.4) were independent predictors for death while awaiting coronary revascularisation. Thus, patients with the above mentioned independent characteristics have an increased short-term mortality while awaiting coronary bypass graft surgery. These indicators may contribute important information for determination of priority in high risk patients awaiting coronary artery bypass graft surgery.

The adjunctive use of angiotensin-converting enzyme (ACE) inhibitors with thrombolytic therapy early during acute myocardial infarction offers theoretic advantages. In the acute phase, captopril may scavenge free radicals, blunt the catecholamine response, elicit coronary vasodilation, and increase prostacyclin and bradykinin levels. In the chronic phase, ventricular remodeling may be attenuated. At present, a large number of controlled clinical trials mainly focusing on the effects of ACE inhibition in the chronic phase are underway. Only a few studies concentrate on the effect of acute intervention with ACE inhibitors in ischemia-reperfusion, i.e., thrombolysis in myocardial infarction. In April 1990 under auspices of the Interuniversity Cardiology Institute of the Netherlands, a large nationwide acute intervention trial with captopril in 280 patients receiving thrombolytic therapy was started, the Captopril and Thrombolysis Study (CATS). The primary hypothesis of CATS supposes a very early effect of ACE inhibition on evolving myocardial damage due to ischemia and the consequences of early reperfusion. This will be evaluated by serial echocardiography, Holter monitoring and neurohumoral measurements immediately on thrombolysis and during the first year after myocardial infarction.

To investigate the effectiveness and safety of low-dose sotalol (a class III antiarrhythmic beta-blocking agent) in the prevention of supraventricular tachyarrhythmias (SVTs) and to identify predictors for the occurrence of these arrhythmias shortly after coronary artery bypass grafting, 300 consecutive patients were randomized in a double-blind, placebo-controlled fashion. Patients with severely depressed left ventricular function or other contraindications for beta blockers were excluded. Beginning at 4 hours and up to the sixth day after surgery, 150 patients received 40 mg of sotalol every 6 hours. SVT was observed in 24 (16%) of 150 low-dose sotalol-and in 49 (33%) of 150 placebo-treated patients [p less than 0.005]. In patients receiving sotalol, atrial fibrillation was the only noted tachyarrhythmia, whereas in the placebo group, 42 (28%) patients had atrial fibrillation, 3 (2%) atrial flutter, 1 (0.7%) atrial tachycardia and 3 (2%) sinus tachycardia. Drug-related adverse effects necessitating discontinuation of the drug were noted in only 2 (1%) sotalol-treated patients and 4 (3%) placebo-treated patients (p = not significant). For both groups, univariate analysis indicated that older age, 1- or 2-vessel coronary artery disease, long bypass (greater than or equal to 150 minutes) and aorta cross-clamp time (greater than or equal to 120 minutes) were predictive variables for the occurrence of SVTs. Multivariate analysis showed that male sex (odds ratio 2.3), 1- or 2-vessel coronary artery disease (odds ratio 2.0) and older age (odds ratio 1.1) were independent risk factors for increased occurrence of postoperative SVT.(ABSTRACT TRUNCATED AT 250 WORDS)

In animal studies reperfusion of coronary arteries is commonly accompanied by ventricular arrhythmias. It is not certain, however, whether ventricular arrhythmias can be used as a reliable non-invasive marker of reperfusion in humans. Two-channel Holter recordings were obtained from the start of an intravenous infusion of streptokinase until coronary angiography (2.8 (2.7) hours (mean SD)) afterwards) in 57 patients with acute myocardial infarction of less than four hours who were generally not treated with antiarrhythmic drugs. Ventricular arrhythmias occurred in 21 (37%) of the 57 patients: accelerated idioventricular rhythm in 13 patients and non-sustained ventricular tachycardia in 15 patients. Seven patients had both accelerated idioventricular rhythm and non-sustained ventricular tachycardia. Coronary angiography showed a patent infarct-related vessel in 12 (92%) of the 13 patients with accelerated idioventricular rhythm (95% confidence interval 66 to 99%), in 22 (50%) of the 44 patients without accelerated idioventricular rhythm (95% CI 34 to 66%), in 11 (73%) of the 15 patients with non-sustained ventricular tachycardia (95% CI 45 to 92%), and in 23 (55%) (95% CI 39 to 71%) of the 42 patients who did not have non-sustained ventricular tachycardia. Seventeen (81%) of the 21 patients with accelerated idioventricular rhythm, or non-sustained ventricular tachycardia, or both, had a patent infarct-related vessel (95% CI 58 to 94%) as did 17 (47%) of the 36 patients with no ventricular arrhythmia (95% CI 29 to 65%). In patients with accelerated idioventricular rhythm after thrombolysis the infarct-related vessel is almost certain to be patent; but the infarct-related coronary artery can still be patent when no arrhythmia is seen.

In a single-blind randomized study, the efficacy and safety of intravenous propafenone (2 mg/kg body weight per 10 min) versus flecainide (2 mg/kg per 10 min) were assessed in 50 patients with atrial fibrillation or flutter. Treatment was considered successful if sinus rhythm occurred within 1 h. Conversion to sinus was achieved in 11 (55%) of 20 patients with atrial fibrillation treated with propafenone and in 18 (90%) of 20 with atrial fibrillation treated with flecainide (p less than 0.02). If atrial fibrillation was present less than or equal to 24 h, conversion to sinus rhythm was achieved in 8 (57%) of 14 patients in the propafenone group and 13 (93%) of 14 in the flecainide group (p less than 0.05). Atrial flutter was converted in two (40%) of five patients treated with propafenone and in one (20%) of five with flecainide (p = NS). Mean time to conversion was 16 +/- 10 min in the propafenone group versus 18 +/- 13 min in the flecainide group (p = NS). QRS lengthening (83 +/- 15 to 99 +/- 20 ms) was observed only in the patients treated with flecainide (p less than 0.001). Patients successfully treated with propafenone showed significantly higher plasma levels than those whose arrhythmia did not convert to sinus rhythm. Transient adverse effects were more frequent in the flecainide group (40%) than in the propafenone group (8%) (p less than 0.01). In conclusion, at a dose of 2 mg/kg in 10 min, flecainide is more effective than propafenone for conversion of paroxysmal atrial fibrillation to sinus rhythm. However, considering the propafenone plasma levels and very few adverse effects, the dose or infusion rate, or both, used in the propafenone group may not have been sufficient to achieve an optimal effect. Neither drug seems very effective in patients with atrial flutter.

Supraventricular tachyarrhythmias are reported in up to 40% of patients early after coronary artery bypass graft operations. In a randomized study, we compared the efficacy and safety of the class III antiarrhythmic beta-blocking drug sotalol versus propranolol at low and high doses in the prevention of supraventricular tachyarrhythmias in 429 consecutive patients after coronary artery bypass graft operations. Patients with severely depressed left ventricular function and other contraindications for beta-blockers were excluded. From the fourth hour up to the sixth day after coronary artery bypass, 74 patients received low-dose sotalol (40 mg every 8 hours), 66 patients low-dose propranolol (10 mg every 6 hours), 133 patients high-dose sotalol (80 mg every 8 hours), and 156 patients high-dose propranolol (20 mg every 6 hours). Baseline characteristics were comparable in all groups. Supraventricular tachyarrhythmia was observed in 10 of 72 (13.9%) who received low-dose sotalol, 12 of 64 (18.8%) who received low-dose propranolol, 13 of 119 (10.9%) who received high-dose sotalol, and 19 of 139 (13.7%) who received high-dose propranolol (not significant). Drug-related adverse effects necessitating discontinuation of the drug occurred in four receiving low doses (2.9%) and in 31 receiving high doses (10.7%) (p less than 0.02). In conclusion, no medication was found to be superior, although supraventricular tachyarrhythmias tended to be less prevalent in patients treated with sotalol than in those treated with propranolol. Moreover, significantly fewer adverse effects were noted in both low-dose groups. Therefore, low-dose beta-blocking treatment, especially low-dose sotalol, seems preferable.