The positive inotropic effects of milrinone but not of digoxin are attenuated at short cycle lengths.

The effects of inotropically active agents on the left ventricular force-interval relation are a potential determinant of their clinical utility and safety. However, little information is available concerning the effects of noncatecholamine positive inotropic agents on this relation. Therefore this study compared the short-term effects of digoxin and milrinone on resting hemodynamics, frequency potentiation (FP), and mechanical restitution (MR) in patients undergoing nonemergency cardiac catheterization. Both digoxin and milrinone produced similar increases in LV + dP/dt at rest (12.2 +/- 1.3%, p < 0.000001 and 11.4 +/- 3.2%, p < 0.01, respectively). The positive inotropic effects of digoxin were marginally attenuated during FP (by 8.5 +/- 4.2% and 4.6 +/- 2.9% at 10 and 60 s, respectively, both p = NS compared with baseline). Similarly, on MRC analysis, the parameter c (a measure of sensitivity of contractile performance to reductions in cycle length) increased by 3.6 +/- 3.7% (p = NS). Whereas the positive inotropic effects of milrinone were not significantly attenuated during FP, they were abolished and possibly reversed at short cycle lengths on MR curve construction (6.8 +/- 5.9% negative inotropic effect at 60% of resting cycle length; p = NS; p < 0.05 vs. resting cycle length). In conclusion, in patients with well-preserved left ventricular systolic function, the positive inotropic effects of milrinone but not of digoxin are markedly dependent on heart rate. These properties may influence both relative safety and efficacy of both agents.

Short-term myocardial uptake of d- and l-sotalol in humans: relation to hemodynamic and electrophysiologic effects.

The myocardial concentration of many cardioactive drugs has been identified as an important determinant of their short-term effects in previous studies. Although sotalol is frequently administered via short-term intravenous injection, no previous studies had sought to correlate its uptake by the heart with its various effects. We determined the time course of short-term uptake of d,l-sotalol by human myocardium in vivo and investigated the relation between myocardial content of sotalol and the short-term hemodynamic, electrocardiographic, and electrophysiologic effects of the drug. Sixteen patients received a 20-mg intravenous bolus of sotalol at the time of diagnostic cardiac catheterization. Myocardial content of d- and l-sotalol (by using a paired transcoronary sampling technique) and the short-term hemodynamic and electrophysiologic effects of the drug were determined < or = 20 min after injection. Myocardial accumulation of sotalol was not enantioselective, proceeded very rapidly (maximal at 0.74 +/- 0.10 min, representing 2.05 +/- 0.45% of the total injected dose), and was not significantly influenced by left ventricular systolic function or the extent of coronary artery disease. Approximately one third of peak myocardial content was still present 17.5 min after sotalol administration. Maximal effects of the drug (reduction in spontaneous heart rate, p < 0.005; reduction in maximal rate of LV pressure increase (LV+dP/dtmax, p < 0.005); and prolongation of PR intervals, p < 0.02) were delayed by approximately 10 min relative to maximal myocardial sotalol content. The significant prolongation of AH intervals (p < 0.01) and atrioventricular nodal effective refractory periods (p < 0.0002) that was observed was also maximal 10 min after administration of sotalol. Thus a consistent delay between myocardial sotalol content and the short-term effects of the drug was observed. In conclusion, the accumulation of both d- and l-sotalol by the human myocardium is more rapid than that of any other agent studied to date, with considerable hysteresis between myocardial drug uptake and subsequent cardiac effects.

Relationship between myocardial milrinone content and its acute hemodynamic and electrophysiologic effects.

One of the major determinants of the short-term effects of many cardioactive drugs is the concentration of the drug specifically within the myocardium. However, no information regarding the disposition of the phosphodiesterase inhibitor milrinone in the heart is available. We therefore determined the time course of short-term myocardial milrinone uptake from paired transcoronary sampling and simultaneous coronary sinus blood flow after a 1-mg intravenous bolus in patients undergoing diagnostic cardiac catheterization. In accordance with this intention, a sensitive, reproducible method for the determination of milrinone in human whole-blood samples was developed. The reverse-phase high-performance liquid chromatographic method described used a C18 column with UV-absorbance detection at 326 nm, with a limit of detection of 0.6 ng/ml, and was highly reproducible. The short-term hemodynamic and electrophysiologic effects of the drug also were determined. Significant increases in spontaneous heart rate and LV+dP/dtmax (at constant heart rate) were observed, accompanied by reductions in mean arterial pressure, systemic vascular resistance, and PR interval, without significant changes in atrioventricular nodal or ventricular effective refractory periods. Peak content (1.89 +/- 0.30% of injected dose) was rapidly attained, 0.56 +/- 0.06 min after milrinone injection. Time of peak effects was significantly delayed (7-10 min after injection) relative to time of peak myocardial milrinone content. Residual myocardial milrinone content was 69.1 +/- 5.7% of maximum 12.5 min after injection. It is concluded that both myocardial uptake and the onset of positive inotropic effects after intravenous injection of milrinone were very rapid. However, there was significant hysteresis between peak myocardial content and subsequent hemodynamic effects.

Antiarrhythmic drug effects on QT interval dispersion in patients undergoing electropharmacologic testing for ventricular tachycardia and fibrillation.

The effects of antiarrhythmic drugs on QT interval dispersion as a predictor of antiarrhythmic drug therapy has not been rigorously assessed. This study was performed to determine whether the effects of antiarrhythmic drugs on QT interval dispersion predict antiarrhythmic drug response in patients undergoing electropharmacologic testing for ventricular tachycardiarrythmias. Precordial QT intervals and QT interval dispersions were measured at baseline and during steady-state antiarrhythmic drug therapy in 72 consecutive patients with documented coronary artery disease and remote myocardial infarction presenting with spontaneous sustained ventricular tachyarrhythmias who underwent electropharmacologic studies to assess arrhythmia suppression. QT interval dispersion was similar at baseline in drug responders (42 +/- 21 ms) and drug nonresponders (46 +/- 21 ms), whereas during antiarrhythmic therapy QT interval dispersion was shorter in drug responders (33 +/- 15 ms) than in drug nonresponders (55 +/- 29 ms, p <0.001). QT interval dispersion was shorter in 7 drug responders during their effective drug trials (27 +/- 14 ms) than during their ineffective drug trials (47 +/- 24 ms, n = 9, p <0.05). QT dispersion < or = 50 ms (p <0.002) and a patent infarct-related artery (p <0.003) were independent predictors of antiarrhythmic therapy. The positive and negative predictive value of QT interval dispersion during drug therapy to predict a successful drug response was 32% and 96%, respectively. QT interval dispersion predicted the outcome of electropharmacologic studies independent of infarct-related artery patency. QT interval dispersion >50 ms during drug therapy was associated with ineffective drug therapy.

Feasibility and safety of a minimally invasive approach to catheter ablation for atrioventricular nodal reentrant tachycardia.

This study assessed the feasibility and safety of a minimally invasive approach to catheter ablation in 72 consecutive patients with AV nodal reentrant tachycardia. A 3-catheter approach was used in the first 19 patients. In the other 53 patients, a 2-catheter approach was employed. Ablation was successful in all patients after a mean of 3 +/- 3 RF applications. Procedure and fluoroscopy times were 62 +/- 20 mins and 8 +/- 5 mins respectively. Slow pathway was ablated in 43 patients (60%). Transient AV block occurred in 6 patients; there was no permanent AV block. These results suggest that it is feasible to perform ablation for AV nodal reentrant tachycardia safely and with high efficacy using a minimally invasive approach. This has the potential to lessen patient discomfort and to further shorten procedure and radiation exposure times.

Outcomes of empiric antiarrhythmic drug therapy for ventricular tachyarrhythmias: a comparison of amiodarone and sotalol

The aim of this study is to review the long-term outcomes of a series of patients with ventricular tachyarrhythmias who commenced empiric treatment with either amiodarone or sotalol in the period before electrophysiologic studies were used routinely at our institution. We compared these two class III drugs as first line therapy in survivors of sustained ventricular tachycardia or cardiac arrest. Between April 1987 and August 1992, 68 male patients (mean age 68 + ou - 11 years) who had either documted sustained ventricular tachycardia (VT), cardiac arrest due to ventricular fibrillation, or syncope in the presence of underlying heart for 27-80 months (mean follow-up of 39 +/- 23 monts). The major findings in this retrospective, non-randomized study include: (1) no significant differences between sotalol and amiodarone groups with respect to total mortality, sudden death, or combined VT and sudden death: (2) a significantly higher incidence of recurrent non-fatal VT in the sotalol group; and (3) ageater incidence of adverse drug reactions in patients receiving sotalol therapy.

The force-interval relationship of the left ventricle: a quantitative description in patients with ischemic heart disease.

Quantitative descriptions of the mechanical restitution curve as a description of variability in ventricular performance with coupling interval in isolated tissue preparations are widely available. In humans, however, in vivo examination of the force-interval relationship is restricted to test pulse intervals shorter than the sinus cycle length (i.e., incomplete mechanical restitution). The primary objectives in this investigation were therefore to examine this aspect of mechanical restitution in patients with ischemic heart disease and to develop a quantitative description of the phenomenon. Mechanical restitution curves were constructed in 40 patients, most of whom had well-preserved left ventricular (LV) systolic function, undergoing diagnostic cardiac catheterization for the investigation of chest pain, using a single premature test pulse interval during baseline atrial pacing. The mechanical restitution curve, the relationship between LV + dP/dtmax and test pulse interval, was fitted to a rectangular hyperbolic function. From this, the parameter c, the calculated proportional decrease in LV + dP/dtmax at 60% of the resting cycle length, was derived. The mechanical restitution curve-fitting model (involving determination of c) satisfactorily described the force-interval relationship in 37 of the 40 patients studied (as a rectangular hyperbola in 31 and with simple linear regression in 6 patients). The refractory period of the atria/atrioventricular node limited accurate use of the model in the remaining three patients. The parameter c was inversely proportional to both baseline atrial pacing cycle length (P < .001) and LV ejection fraction (P < .02) In patients with normal LV ejection fractions, the derived value of c at a cycle length of 800 ms (c800) was 29.0% baseline LV + dP/dtmax (95% confidence interval, 23.0, 35.0). The presence of hemodynamically significant ischemic heart disease was not a predictor of the parameters of the model. After intravenous injection of the beta-adrenoreceptor antagonist metoprolol in seven patients, there was a significant (P < .05) reduction in both c and LV + dP/dtmax at the baseline atrial pacing cycle length. Thus, the force-interval relationship can be quantitatively studied using incomplete mechanical restitution curves in humans in vivo. This quantitative description probably reflects relative intracellular calcium availability via slow channel activity and can be used to assess effects of cardioactive drugs on frequency-dependent inotropic mechanisms in humans. The predictive value of this mechanical restitution curve model for hemodynamic instability during tachycardia in patients with impaired LV function remains to be determined.

Catheter ablation using radiofrequency or low-energy direct current in pediatric patients with the Wolff-Parkinson-White syndrome.

Percutaneous ablation of accessory pathways was performed in 22 consecutive children and adolescents (9 boys and 13 girls, age range 8 to 18 years). Low-energy direct current (DC) was used exclusively in the first 6 patients, whereas ablation was performed with radiofrequency energy in the following 16. Accessory pathways were located in the left free wall in 15 patients, were posteroseptal in 3, were in the right free wall in 3 and were anteroseptal in 1. A concealed accessory pathway was present in 7 patients (32%). There was no significant difference in clinical or electrophysiologic variables between both groups. Catheter ablation was successful in the initial 6 patients using low-energy DC, as compared with 13 of 16 patients using radiofrequency ablation. Low-energy DC was successful as a backup power source in all 3 patients who had unsuccessful radiofrequency ablation. There was no complication. The median procedural and fluoroscopic times for successful ablation were 2.5 hours and 49 minutes, respectively (p = NS between both power sources). Accessory pathway conduction recurred in 2 patients (33%) who had low-energy DC as compared with 1 (6%) who had radiofrequency ablation (p = NS). These 3 patients had successful reablation of their accessory pathways. In children and adolescents with accessory pathways, both new power sources compare favorably, with an overall success rate of ablation of 100% (22 of 22 patients). Radiofrequency ablation should be used initially because it does not require general anesthesia and is associated with a lower rate of recurrence of accessory pathway conduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Results of a comparative study of low energy direct current with radiofrequency ablation in patients with the Wolff-Parkinson-White syndrome.

OBJECTIVE: To compare two new power sources for catheter ablation in patients with the Wolff-Parkinson-White syndrome. DESIGN: 120 consecutive patients with accessory pathways had catheter ablation. Low energy direct current (DC) was used in the first 60 patients and radio-frequency current in the next 60 patients. SETTING: Electrophysiological laboratory of a large heart institute. PATIENTS: 72 men and 48 women (mean (SD) age 35 (14) years (range 9-75)). The accessory pathways were in the left free wall in 73 patients. They were posteroseptal in 35 patients, in the right free wall in five, and anteroseptal in seven. There was no significant difference in the clinical or electrophysiological variables between the two ablation groups. RESULTS: Catheter ablation with low energy direct current was successful in 55/60 patients (92%) and radiofrequency energy was successful in 52/60 patients (87%). Low energy direct current was also successful in four of the eight patients in whom radiofrequency ablation had failed. Radiofrequency ablation was successful in two of the five patients in whom low energy direct current ablation had failed. The mean (SD) procedure and fluoroscopy times for successful ablation were 3.2 (1.5) h and 61 (40) min respectively. These times were similar for both power sources. Accessory pathway conduction recurred in 17 patients (28%) who had low energy direct current and four patients (7%) who received radiofrequency energy (p < 0.004). All patients with recurrence of an accessory pathway had successful re-ablation. CONCLUSIONS: Both new power sources successfully ablated accessory pathways, (overall success rate 94% (113/120 patients)). Radiofrequency ablation, however, did not require general anaesthesia and was associated with a significantly lower rate of recurrence of accessory pathway conduction. Therefore radiofrequency should be used initially for ablation. Low energy direct current may be most useful as a back-up in patients in whom radiofrequency ablation fails.

Risks of developing supraventricular and ventricular tachyarrhythmias after implantation of a cardioverter-defibrillator, and timing the activation of arrhythmia termination therapies.

The clinical courses of 39 consecutive recipients (mean age 61 +/- 12 years, and mean left ventricular ejection fraction 0.32 +/- 0.15) of an automatic implantable cardioverter-defibrillator (ICD) were examined to determine the risks of developing ventricular tachycardia (VT) and supraventricular tachyarrhythmias (SVT) after surgery, with ventricular response rates fulfilling ICD detection criteria. ICD system leads were implanted by thoracotomy in 25 patients and by using nonthoracotomy lead systems in 14. Six patients (18%) developed SVT after surgery, whereas 14 (36%) developed sustained VT. The median times to the development of both SVT and VT were 2 days. By actuarial analysis, the probability of developing VT after surgery was significantly greater than that of SVT during hospitalization (p = 0.04). This significant excess of postoperative VT over SVT was most marked in patients aged < or = 61 years, those who received nonthoracotomy rather than epicardial lead systems, those who presented with VT rather than ventricular fibrillation, and those who received > 20 intraoperative defibrillation shocks. These observations recommend the activation of ICD therapies immediately after implantation.

Infarct artery patency predicts outcome of serial electropharmacological studies in patients with malignant ventricular tachyarrhythmias.

BACKGROUND: Surviving myocardial cells near the infarct border zone form the arrhythmogenic substrate for sustained ventricular tachycardia (VT) in humans. Infarct-related artery (IRA) patency may modulate the electrophysiological function of this arrhythmogenic substrate and its response to antiarrhythmic drug therapy. We postulated that effective antiarrhythmic drug therapy selected during serial electrophysiological studies in patients with VT after a myocardial infarction would be identified more frequently when the IRA is patent than when chronically occluded. METHODS AND RESULTS: Consecutive patients (n = 64) with documented coronary artery disease and remote myocardial infarction presenting with spontaneous sustained VT or ventricular fibrillation (VF) were studied. These patients underwent 4 +/- 2 electropharmacological studies identifying effective antiarrhythmic drug therapy in 16 (25%) patients. Drug responders did not differ significantly from nonresponders in demographic, electrocardiographic, angiographic, or hemodynamic measurements. A patent IRA was associated with antiarrhythmic drug response significantly more frequently than was an occluded IRA (45% versus 9%, p = 0.001). Patency of the IRA was the only independent predictor of response to antiarrhythmic drug therapy in this study population. The sensitivity and specificity of using a patent IRA to predict successful drug testing were 81% and 67%, respectively. CONCLUSIONS: The outcome of electropharmacological studies was predicted by the patency of the IRA. A patent IRA was associated with a greater probability of finding effective drug therapy.

Precordial QT interval dispersion as a marker of torsade de pointes. Disparate effects of class Ia antiarrhythmic drugs and amiodarone.

BACKGROUND: Patients with a history of class Ia drug-induced torsade de pointes have been treated with chronic amiodarone without recurrence of torsade de pointes despite comparable prolongation of the QT interval. We hypothesized that in such patients, class Ia drugs cause nonhomogeneous prolongation of cardiac repolarization times, whereas amiodarone causes homogeneous prolongation of cardiac repolarization times. METHODS AND RESULTS: Thirty-eight consecutive patients who received both class Ia drug therapy and chronic amiodarone therapy were evaluated. Standard 12-lead ECGs at baseline and during each therapy were used to calculate precordial QT interval dispersion (maximum QT in leads V1 through V6 minus minimum QT leads V1 through V6) as a measure of regional variabilities in ventricular repolarization times. Nine of these patients had torsade de pointes during class Ia drug therapy. In these nine patients, class Ia drug therapy and amiodarone significantly prolonged the maximum QT interval to comparable extents. However, class Ia drug therapy but not amiodarone therapy significantly increased precordial QT interval dispersion (101 +/- 37 versus 49 +/- 26 msec; baseline, 44 +/- 12 msec; p = 0.002). In the 29 patients without class Ia drug-induced torsade de pointes, neither class Ia drug therapy nor amiodarone therapy significantly increased QT interval dispersion (50 +/- 6 versus 69 +/- 7 msec; baseline, 54 +/- 5 msec). None of the patients with class Ia drug-induced torsade de pointes had recurrent torsade de pointes during chronic amiodarone therapy. CONCLUSIONS: An increase in regional QT interval dispersion during class Ia antiarrhythmic drug therapy is associated with torsade de pointes. Chronic amiodarone therapy in patients with a history of class Ia drug-induced torsade de pointes produces comparable maximum QT interval prolongation but does not increase QT interval dispersion. This characteristic may explain its apparent safe use in patients with a history of class Ia drug-induced torsade de pointes.

Comparison of atrial overdrive pacing with and without extrastimuli for termination of atrial flutter.

Atrial overdrive pacing has been successfully used to terminate atrial flutter. This study compared the efficacy of atrial extrastimuli following a rapid pacing train to overdrive pacing without atrial extrastimuli for the termination of atrial flutter. Patients were randomized to treatments of short or long burst atrial overdrive pacing or atrial overdrive pacing followed by atrial extrastimuli in a crossover study design. A total of 22 patients (73%) had successful conversion of atrial flutter to sinus rhythm. The success rates in patients exposed to each therapy, including crossover therapies, were 62% with the atrial extrastimuli method, 8% with the short burst pacing method, and 8% with the long burst pacing method (p less than 0.001). Transient atrial fibrillation developed in 15 patients and in 9 of these this arrhythmia preceded conversion to sinus rhythm. Sustained atrial fibrillation was induced in 3 additional patients but never with the atrial extrastimuli method. In conclusion, the method of delivering atrial extrastimuli after a rapid pacing train is highly efficacious for the termination of atrial flutter. Furthermore, this method is more effective than atrial overdrive pacing methods delivered at the same pacing cycle length. These observations have important implications for the programming of antitachycardia pacemakers.

Sotalol-induced torsade de pointes: management with magnesium infusion.

A 69 year old woman was treated with sotalol (320 mg daily) for intermittent atrial fibrillation. Sotalol was initially well tolerated and reversion to sinus rhythm with sinus bradycardia occurred 4 weeks after initiation of therapy. Shortly thereafter, the patient developed recurrent syncope due to torsade de pointes. This was treated successfully with intravenous magnesium infusion and withdrawal of sotalol. Subsequently, the atrial fibrillation was adequately managed using amiodarone, with no recurrence of torsade de pointes. Development of bradycardia associated with reversion to sinus rhythm represents a potential cause of 'late' pro-arrhythmic effects of sotalol.

Propafenone-induced torsade de pointes: cross-reactivity with quinidine.

A 77-year-old female with new onset atrial fibrillation occurring in the absence of structural heart disease developed torsade de pointes during therapy with quinidine bisulfate 500 mg orally every 8 hours. Ten days after quinidine therapy had been discontinued she developed torsade de pointes while receiving propafenone 300 mg orally every 8 hours. This case demonstrates that propafenone may be associated with torsade de pointes and suggests a cross-reactivity between this effect and prior occurrence of torsade de pointes on Class IA antiarrhythmic drug therapy.

Acute heart failure: determinants of outcome.

We prospectively studied 69 consecutive patients hospitalized with a primary diagnosis of acute left ventricular failure so as to assess the impact of vasodilators on incidence and morbidity of acute symptomatic left ventricular failure. The determinants of duration of hospitalization, in-hospital mortality and symptomatic status 2 months after discharge were examined. There were 9 in-hospital deaths (13%), and survival at 60 days was 77%. Median duration of hospitalization was 9 days, and 33% of the surviving patients remained in New York Heart Association functional class III-IV 60 days subsequent to discharge. Of the patients, 49 (76%) had previously received treatment for left ventricular failure: 30 (61%) of these had received vasodilators, most commonly angiotensin converting enzyme inhibitors and nitrates. Ischaemic chest pain was present in 34 (49%) of the patients. Acute utilization of vasodilators (45% of patients) was largely limited to nitrate therapy associated with ischaemic chest pain (P less than 0.01). Multiple logistic regression revealed previous left ventricular failure, advanced age and hypokalaemia as significant correlates of prolonged hospitalization (greater than 9 days). Previous left ventricular failure was also predictive of persistent severe disability two months subsequent to discharge. No factor was a significant predictor of in-hospital death. Although preceding treatment with digoxin and incremental angiotensin converting enzyme inhibitor therapy tended to predict brief hospitalization, the parameter of acute ischaemia, other biochemical anomalies and modes of acute or chronic therapy were not significant correlates of any end point. We conclude that preceding disability, rather than mode of treatment, predicts an adverse outcome in acute left ventricular failure.

Clinical pharmacokinetics of propafenone.

Propafenone is a class 1C antiarrhythmic agent which is administered as a racemate of S(+)- and R(-)-enantiomers. It is well absorbed and is predominantly bound to alpha 1-acid glycoprotein in the plasma. The enantiomers display stereoselective disposition characteristics, the R-enantiomer being cleared more quickly. The hepatic metabolism of propafenone is polymorphic and genetically determined: about 10% of Caucasians have a reduced capacity to hydroxylate the drug. This polymorphic metabolism accounts for the marked interindividual variability in the relationships between dose and concentration, and between concentration and pharmacodynamic effects. During long term administration, the metabolism is saturable in patients with the 'extensive metaboliser' phenotype, leading to accumulation of the parent compound. Propafenone blocks fast inward sodium channels in a frequency-dependent manner, and also has moderate beta-blocking effects. Both the enantiomers and the 5-OH metabolite have a potency to block sodium channels comparable with that of the parent compound. The S-enantiomer is a more potent beta-antagonist than the R-enantiomer. Propafenone typically slows conduction markedly but only modestly prolongs refractoriness. These cardiac effects are determined by the extent of its myocardial accumulation. The drug should be used with caution in patients with serious structural heart disease, as it may cause or aggravate life-threatening arrhythmias. Significant interactions occur when propafenone is coadministered with other drugs. It increases the plasma concentrations of digoxin, warfarin, metoprolol and propranolol as well as enhancing their respective pharmacodynamic effects. Doses of these drugs should therefore be decreased if they are coadministered with propafenone.