Effect of nifedipine and AQ-A 39 on the sinoatrial and atrioventricular nodes of the rabbit and their antiarrhythmic action on atrioventricular nodal reentrant tachycardia.

The effects of two drugs that apparently block slow inward current--nifedipine and the new compound AQ-A 39--were studied on the isolated sinoatrial (SA) and atrioventricular (AV) nodes of the rabbit heart using intracellular microelectrodes. Nifedipine and AQ-A 39 both slowed the sinus rate associated with a decrease in the rate of diastolic depolarisation. Conduction through the AV node was consistently impaired; this effect was enhanced with increasing atrial rates or with decreasing coupling intervals of premature beats. The action potential amplitude was significantly reduced in SA nodal and upper (AN) AV nodal fibres but was not significantly affected in lower (NH) AV nodal and in atrial fibres. The maximum diastolic potential showed little or no alteration. In all fibre types studied, the action potential duration was shortened with nifedipine but was significantly prolonged with AQ-A 39. Prevention of AV nodal reentrant tachycardia by nifedipine was related to an increase in the effective refractory period of the AV node. AQ-A 39 prevented the tachycardia by both slowing of AV nodal conduction and by prolongation of action potential duration in the AV nodal and atrial compartments of the reentrant circuit associated with the appearance of different gap phenomena of the AV conduction. The maximum possible A-H interval was, however, not shortened by either drug and single atrial echo beats could still be initiated. The results suggest that nifedipine and AQ-A 39 both have a direct depressant action on the slow inward current-dependent electrical activity of the SA and AV node but have opposite effects on the repolarisation phase resulting in different antiarrhythmic mechanisms.

Electrophysiological effects of glucose-insulin-potassium on sinus node function in patients with and without sinus node dysfunction.

The electrophysiological effects of glucose (100 g)-insulin (20 U)-potassium (10 mmol X litre-1) infusion (GIK) on three parameters of sinus node function were studied in 14 control subjects (mean age 53 +/- 14 yr) and 11 patients (mean age 50 +/- 17 yr) with sinus node dysfunction (SND). In a first series of experiments the response to GIK was examined in nine control and 11 SND patients. Following GIK, the mean spontaneous cycle length decreased by 17% (671 to 560 ms; P less than 0.01) in the control group and by 33% (1066 to 715 ms; P less than 0.001) in the SND patients; this difference between both groups was statistically significant (P less than 0.01). In the control group mean corrected sinus node recovery time (CRST) and calculated sinoatrial conduction time (SACT; n = 6) were not significantly altered after GIK. In SND patients GIK decreased the mean value of CSRT by 40% (693 to 416 ms; P less than 0.05) and of calculated SACT (n = 6) by 27% (130 to 95 ms; P less than 0.05); prolonged secondary pauses following termination of rapid atrial pacing in SND patients were also shortened. In a second series of experiments, mannitol (100 g, iv) was administered in five control patients but had no significant effect on the electrophysiological parameters tested. Plasma levels of glucose were significantly increased, by 500% (P less than 0.01), after GIK; plasma potassium and sodium concentrations decreased by 7 and 5% (P less than 0.05). The results indicate that GIK had a beneficial effect on sinus node dysfunction.

Differential effects of sotalol and metoprolol on induction of paroxysmal supraventricular tachycardia.

Seventeen patients with recurrent paroxysmal supraventricular tachycardia (SVT) underwent serial electrophysiologic studies to compare the effects of i.v. sotalol (1.5 mg/kg) and i.v. metoprolol (0.15 mg/kg). The plasma concentrations of sotalol (2.1 +/- 1.1 microgram/ml) and metoprolol (67 +/- 15 ng/ml) were within the therapeutic range. Before drug administration, sustained SVT could be reproducibly induced in all patients. Sotalol prevented induction of sustained SVT in 10 of 17 patients (59%) and metoprolol in 4 (28%) (p less than 0.05). In 6 of 8 patients with atrioventricular (AV) nodal reentrance, the site of action of sotalol was the anterograde or the retrograde limb, reflecting an increase in refractoriness in both pathways of the circus movement. In 4 of 9 patients with AV reentrance, the site of action of sotalol was exclusively the AV nodal pathway; conduction through the extranodal accessory tract appeared to be unchanged, but its anterograde effective refractory period was prolonged (from 285 +/- 25 to 322 +/- 28 ms, p less than 0.001; mean +/- standard deviation). In the 7 patients in whom sotalol did not prevent sustained SVT, the tachycardia cycle length increased from 347 +/- 42 to 392 +/- 45 ms (p less than 0.01). Compared with sotalol, metoprolol had qualitatively similar but quantitatively less potent effects on the AV nodal pathways; however, different from sotalol, metoprolol had no effect on extranodal accessory tracts. The study suggests that at therapeutic plasma concentrations, sotalol would be effective in preventing clinical SVT in a significant proportion of patients refractory to metoprolol; because sotalol not only has beta-blocking properties but also results in acute prolongation of the action potential duration, this combination of class II and III activity may contribute to its superior prophylactic efficacy compared with pure beta blockade.

Evolutionary pattern and prognostic importance of heart rate variability during the early phase of acute myocardial infarction.

AIMS: To investigate the evolution of time domain heart rate variability in the early phase of acute myocardial infarction (MI) and assess its prognostic ability. METHODS: We analysed several measures of heart rate variability (SDNN, SDANN, SDNN index, RMSSD) in 138 patients at days 0, 1 and 5+/-1 after hospital admission for acute MI. Results were correlated with infarct site, clinical variation and clinical outcome (death, MI, PTCA, CABG surgery). RESULTS: Measures of heart rate variability (SDNN, SDANN and SDNN index) declined during the first 24 h after acute MI (P<0.01) and increased to admission levels after about 5 days. SDNN values on day 0, 1 and 5 respectively were: 86+/-35, 75+/-28 and 87+/-27 ms. Patients with anterior infarction had lower heart rate variability than patients with inferior infarction on all test days but similar evolution patterns. After 3 years of follow-up there were 12 cardiac deaths (8.7%) and six resuscitated arrests and 33 (24%) new MIs, or revascularisation procedures. The evolutionary pattern of heart rate variability was similar in survivors to those who died although values were generally lower. Mortality was significantly higher in the group with SDNN<50 ms at day 1 (P<0.01) and 5 (P<0.05), but not at day 0. CONCLUSIONS: Our findings show that autonomic imbalance, already evident on the day of the acute event, progresses further over the next 24 h and recovers over the next few days. Low heart rate variability as early as 24 h after acute MI may be a useful predictor of cardiac mortality and contribute to the early risk stratification and therapeutic management of patients.

Coronary artery ectasia, aneurysm of the basilar artery and varicose veins: common presentation or generalized defect of the vessel wall? A case report.

A young man who suffered from an acute myocardial infarction is presented. He presented coronary artery ectasia along with coronary artery disease. Further evaluation revealed the presence of both a saccular aneurysm of the basilar artery as well as varicose veins of the lower limbs. A common pathogenic mechanism is discussed since all these findings are characterized by similar histologic substrate with the most profound defect being destruction of the myoelastic elements of the media.

Hypertension and paroxysmal atrial fibrillation: a novel predictive role of high sensitivity C-reactive protein in cardioversion and long-term recurrence.

The role of inflammation in maintenance of paroxysmal atrial fibrillation (PAF) in patients with hypertension and no other heart disease has not been fully elucidated yet. We investigated the association of various inflammatory markers with cardioversion and recurrence of PAF in patients with hypertension. We studied 75 patients (44 male, mean age 67.9+/-9.9 years) with PAF (duration from onset of symptoms<24 h) secondary to hypertension. None had heart failure or any other ongoing inflammatory process. All patients received anticoagulation and intravenous amiodarone for cardioversion. High sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and tumour necrosis factor (TNF)-alpha were measured on admission and 48 h later. By 48 h from admission 61/75 patients (81.3%) regained sinus rhythm (cardioverted), whereas 14/75(18.7%) remained in AF (non-cardioverted). hsCRP, IL-6 and TNF-alpha serum levels on admission were similar between groups. hsCRP at 48 h was the most significant factor correlated with cardioversion outcome (OR: 0.06, 95% CI: 0.01-0.47, P=0.008). During a 1-year follow-up, AF recurred in 28/61(45.9%) patients. The strongest factor associated with AF recurrence was hsCRP at 48 h > or =2.27 mg l(-1) (hazard ratio: 6.2, 95% CI: 2.2-17.6, P=0.001). hsCRP at 48 h after admission correlates with cardioversion outcome and may predict long-term AF recurrence.

Molecular diagnosis of the viral component in cardiomyopathies: pathophysiological, clinical and therapeutic implications.

BACKGROUND: Myocarditis is defined as the inflammation of myocardium associated with cardiac dysfunction. Despite this clear-cut definition, diagnosis and etiologic treatment continue to create considerable debate. Viral infections are frequent causes of myocarditis and there is evidence that persistent viral infection is associated with poor prognosis in different subtypes of cardiomyopathy. OBJECTIVE: To review methods for diagnosis of viral myocarditis and present the use of polymerase chain reaction (PCR)-based protocols for evaluating viral infection in myocarditis/cardiomyopathies. METHODS: A review of published literature. RESULTS/CONCLUSION: There is increasing evidence that PCR-based protocols can provide reliable molecular evidence for the presence of viral infection in myocardium. Thus application of molecular techniques will allow collection and analysis of more information on the epidemiology of viral cardiomyopathies, patient risk stratification and appropriate medical treatment.

Three-year survival of patients with heart failure caused by dilated cardiomyopathy and L-carnitine administration.

We examined the efficacy of long-term L-carnitine administration for the treatment of heart failure caused by dilated cardiomyopathy in adult patients. To accomplish this, we studied 80 patients with moderate to severe heart failure (New York Heart Association classification III to IV) caused by dilated cardiomyopathy. This article reports on the nearly 3 years of follow-up data on patient mortality. Primary results will be published in the future. After a period of stable cardiac function up to 3 months, patients were randomly assigned to receive either L-carnitine (2 g/d orally) or placebo. There were no statistical differences between the 2 groups at baseline examination in clinical and hemodynamic parameters, such as ejection fraction, Weber classification, maximal time of cardiopulmonary exercise test, peak VO(2) consumption, arterial and pulmonary blood pressure, and cardiac output. After a mean of 33.7 +/- 11.8 months of follow-up (range 10 to 54 months), 70 patients were in the study: 33 in the placebo group and 37 in the L-carnitine group. At the time of analysis, 63 patients were alive. There were 6 deaths in the placebo group and 1 death in the L-carnitine group. Survival analysis with the Kaplan-Meier method showed that patients' survival was statistically significant (P <.04) in favor of the L-carnitine group. L-carnitine appears to possess considerable potential for the long-term treatment of patients with heart failure attributable to dilated cardiomyopathy.

Serum lipoprotein(a) levels in a Greek population sample without a history of premature myocardial infarction.

OBJECTIVE: To investigate lipoprotein(a) levels in a Greek population sample. METHOD: Serum apolipoprotein [Apo(a)] concentrations were measured in 220 men and 190 women aged 55-65 years without a history of effort angina or myocardial infarction. RESULTS: The distributions of Apo(a) and lipoprotein(a) [LP(a)] levels were highly skewed both in men and in women. The level of 30 mg/dl Lp(a) corresponded to the 77th percentile of the Lp(a) distribution in men but to the 66th percentile in women. Women had significantly higher values of Apo(a) or Lp(a) concentration than men. High-density lipoprotein cholesterol levels tended to be higher in women, but not in men, belonging to the fourth and fifth quintiles of the Lp(a) distribution than in those belonging to the three lower quintiles.

Amiodarone in patients with recurrent sustained ventricular tachyarrhythmias: results of programmed electrical stimulation and long-term clinical outcome in chronic treatment.

Thirty-three patients with clinically recurrent ventricular tachyarrhythmias were treated with amiodarone (200 to 600 mg/day) during a mean follow-up period of 23.7 months. Prior to amiodarone therapy, sustained ventricular tachycardia or ventricular fibrillation was initiated in all patients at control electrophysiologic study; patients failed a mean of 5.7 drugs, as assessed by programmed electrical stimulation. At electrophysiologic study after a loading phase (1000 mg/day for 10 days), 10 patients had no inducible ventricular tachycardia, nine patients had nonsustained ventricular tachycardia, 13 patients had persistent sustained ventricular tachycardia, and one patient had ventricular fibrillation. Patients were continued on amiodarone alone regardless of the findings at the electrophysiologic study, and during follow-up patients with no inducible sustained ventricular tachycardia or fibrillation on amiodarone had no recurrent arrhythmias or sudden death. Six of 14 patients (43%) with sustained ventricular tachyarrhythmias still inducible had recurrent ventricular tachycardia/fibrillation, and four of them died suddenly (29%). Programmed electrical stimulation predicts a good clinical long-term outcome during amiodarone therapy. Patients with persisting fast tachyarrhythmias (cycle length less than or equal to 300 msec) on amiodarone and a low ejection fraction (less than 35%) seem to have a higher incidence of sudden death. In these patients, therapeutic approaches such as antiarrhythmic surgery or implantation of antitachycardia devices should be considered.

[Programmed stimulation in patients with malignant ventricular arrhythmia. II: Individual optimization of anti-arrhythmia therapy]. / Programmierte Stimulation bei Patienten mit malignen Kammerarrhythmien. Teil II: Individuelle Optimierung der antiarrhythmischen Therapie.

The major purpose of programmed ventricular stimulation in patients with malignant ventricular arrhythmias (sustained ventricular tachycardia/ventricular fibrillation) is not the diagnostic or prognostic evaluation but the individual optimization of antiarrhythmic therapy. For successful antiarrhythmic treatment, the choice of an adequate parameter of efficacy is of outstanding relevance: in patients with frequent daily episodes of malignant ventricular arrhythmias, proper treatment can be based on Holter monitoring; however, in patients with infrequent but life-threatening attacks, Holter monitory appears to be inadequate and programmed stimulation is the method of choice for proper treatment decisions. A total of 394 serial pharmaco-electrophysiological studies was performed in 82 patients with inducible sustained ventricular tachycardia or ventricular fibrillation. During the acute serial studies, one drug was tested each subsequent day using short-term intravenous infusions. The only criterion for drug efficacy was prevention of inducible sustained ventricular tachycardia or ventricular fibrillation that had been reproducibly initiated under control conditions before antiarrhythmic treatment. At least one preventive drug was found in approximately 2/3rd of the patients. Following serial acute studies using intravenous administration, an effective agent was selected and given orally. Programmed stimulation was repeated usually after three days demonstrating reproducibility of preventive efficacy in 90% of the trials. During a subsequent follow-up period of an average of 15 months, the number of acute events (9%) including sudden death or life-threatening recurrences of malignant ventricular arrhythmias was significantly reduced as compared to patients with non-optimized therapy (54%; p less than 0.05). The number of cardiac deaths due to progressive heart failures was not significantly different in patients placed on optimized or non-optimized antiarrhythmic treatment.

Role of some components of ischemia in the genesis of spontaneous ventricular arrhythmias.

The importance of single components of ischemia including hypoxia, lactic acidosis, high potassium, and sympathetic stimulation to the spontaneous occurrence of ventricular arrhythmias was studied in chloralose-anesthetized cats using systemic and local intracoronary administration. Hypoxia and acidosis provoked no spontaneous arrhythmias regardless of systemic or regional administration. Systemic or local hyperpotassemia induced regularly ventricular ectopic activity including recurrent ventricular tachycardias that were characterized by a sudden onset and termination and by a stable rate. Stimulation of the left, right or bilateral stellate ganglia failed to provoke ventricular arrhythmias during hypoxia or acidosis and had also no influence on the initiation or rate of K+-induced ventricular tachycardias. The results indicate that high extracellular K+ may be the predominant arrhythmogenic factor of the components of ischemia we studied and that sympathetic ganglia stimulation does not affect K+-induced ventricular tachycardia.

Arrhythmogenic effects of toxic concentrations of the antiarrhythmic drug lorcainide on the isolated canine ventricle.

The effect of the new antiarrhythmic drug lorcainide was studied on the specialized conducting system of isolated canine ventricle. Transmembrane action potentials were recorded simultaneously from three subendocardial sites within the ventricular basis, free wall and apex. At concentrations of 3 x 10(-6) and 2.4 x 10(-5) M, lorcainide caused a dose-dependent decrease in maximum rates of rise and in amplitude of the action potential; 0.6 x 10(-6) M had no significant effect, resting potential and action potential duration remained unchanged with 0.6 x 10(-6) M and 3 x 10(-6) M. The most prominent effect of 2.4 x 10(-6) M lorcainide was the appearance of an increasing notch resulting in clear separation of the action potential in an initial short spike depolarization (50-120 msec) with or without a subsequent plateau depolarization 280-370 msec). Both components demonstrated an independent and inhomogeneous conduction through functionally different pathways. Changes in stimulation rate or premature stimuli resulted in nonstimulated reexcitations resembling bigemini, ventricular tachycardia or regional ventricular fibrillation. The results indicate that dissociation of the action potential in two components is due to toxic alterations of ionic channels of the fiber membrane and that nonstimulated reexcitations are due to reentry via functionally fast and slow pathways.

[Programmed stimulation in patients with malignant ventricular arrhythmias. I: Diagnostic value]. / Programmierte Stimulation bei Patienten mit malignen Kammerarrhythmien. Teil I: Diagnostische Wertigkeit.

Sudden cardiac death is a leading cause of death in industrially developed countries and accounts for approximately 90 000 deaths yearly in the FRG. While the majority of victims have severe coronary heart disease, sudden cardiac death is infrequently caused by acute myocardial infarction (20%) but is predominantly related to malignant ventricular arrhythmias (i.e., ventricular fibrillation or sustained ventricular tachycardia). Patients with a history of such malignant ventricular arrhythmias are at high risk for sudden death. Spontaneous occurrence of sustained ventricular tachycardia and of ventricular fibrillation is critically related to two factors: 1. trigger-arrhythmias consisting usually of complex ventricular extrasystoles (Lown classification IV to V); 2. increased vulnerability of the myocardium representing the target organ for trigger-arrhythmias. While trigger-arrhythmias can be easily recorded by noninvasive techniques including Holter monitoring or exercise and stress ECG, ventricular vulnerability is more difficult to determine and often requires ventricular stimulation with intracardiac electrocatheters. In patients with documented spontaneous malignant ventricular arrhythmias, two aspects of programmed stimulation must be considered: 1. diagnostic, and more importantly, 2. therapeutic purposes of this method. Diagnostic purposes include determination of the mode of initiation and unequivocal ventricular localization of the tachycardia excluding other arrhythmias with broad QRS complex. In patients with spontaneous sustained ventricular tachycardia, programmed stimulation can reproducibly initiate the clinical arrhythmia in 85% (sensitivity and specificity of the method approximately 90%). In patients with cardiac arrest due to ventricular fibrillation, programmed stimulation is less reliable (50%). However, the main purpose of programmed stimulation in patients with documented clinical malignant arrhythmias is not diagnostic or prognostic evaluation but is serial electrophysiological studies for individual optimization of antiarrhythmic therapy.

Electrophysiological mechanisms of action of the levorotatory isomer of sotalol in a canine infarct model of inducible ventricular tachycardia: comparison with the beta-1 receptor antagonist bisoprolol.

To evaluate the antiarrhythmic efficacy of l-sotalol and bisoprolol on inducible ventricular arrhythmias, conscious dogs with 4- to 8-day-old myocardial infarction were studied by programmed electrical stimulation. Direct recordings from infarcted and adjacent normal subepicardium were made using a specially designed composite electrode. From 18 dogs developing sustained ventricular tachycardia (sVT) during control stimulation, l-sotalol (1.5 mg/kg i.v.) prevented reinducibility of sVT in 10 animals, while in seven other animals it significantly reduced the rate of tachycardia. Bisoprolol (0.2 mg/kg i.v.), tested in a separate group of 10 dogs susceptible to sVT, was mostly ineffective in preventing or slowing the tachycardia. Both agents significantly prolonged conduction time and refractoriness within the atrioventricular conduction system, and decreased heart rate. However, while l-sotalol lengthened ventricular refractoriness and QT interval, bisoprolol exerted only a minor effect on these parameters. Neither of the drugs affected conduction in normal and infarcted myocardium, as indicated by almost unchanged QRS complex width and duration of ventricular late potentials, respectively. The results indicate that acute beta-blockade is ineffective against sVT induced during the subacute stage of myocardial infarction. The antiarrhythmic efficacy of l-sotalol may predominantly be related to its prolonging effect on ventricular refractoriness, supporting the concept of pure class III action.

Lidocaine converts inducible ventricular fibrillation into sustained ventricular tachycardia in conscious dogs with recent myocardial infarction.

The aim of the present study was to investigate the effect of lidocaine (L) on ventricular tachyarrhythmias with special reference to ventricular fibrillation (VF). Myocardial infarction (MI) was created in 39 dogs by doubly ligating the left anterior descending (LAD) coronary artery. All animals surviving the infarction (n = 33) were subjected to programmed ventricular stimulation 7.6 +/- 3.2 days later. Local electrical activity was recorded from the subepicardium of the left ventricular wall by means of a specially designed composite electrode. L (2 and 4 mg/kg i.v.) facilitated the induction of sustained monomorphic ventricular tachycardia (sVT) in 8 dogs with nonsustained polymorphic ventricular tachycardia (nsVT) in the control. In 13 dogs developing sVT during control stimulation, L slowed the rate of tachycardia in 8 animals (first-dose effect), while it abolished arrhythmia induction in 5 animals (second-dose effect). It was interesting that L (2 mg/kg) abolished reproduction of control VF in 12 animals by converting it into sVT. L significantly depressed conduction and prolonged ventricular refractoriness in the infarction zone. The results suggest that L facilitates induction of sVT in conscious dogs with recent MI, thereby decreasing susceptibility of infarcted myocardium to aggressive polymorphic nsVT or VF. The capability of L to exacerbate slow conduction in the infarction zone seems not to favor the development of VF during this stage of MI.