Tsuneaki Sadanaga

Assessment of reverse use-dependent blocking actions of class III antiarrhythmic drugs by 24-hour holter electrocardiography

OBJECTIVESnThis clinical study was designed to compare rate-dependent effects of class III agents on QT prolongation.nnnBACKGROUNDnClinical data that compare the electrophysiologic differences among class III agents with different selectivity for potassium channels are still lacking.nnnMETHODSnQT intervals were measured over a wide range of preceding RR intervals during sinus rhythm by 24-h Holter electrocardiography before and after oral administration of four class III agents: E4031, dofetilide, MS551 and d-sotalol. Rate-dependent changes in the QT interval were assessed by the slope of the linear regression line estimating the QT-square root of RR relation.nnnRESULTSnAll agents significantly increased the mean slope: E4031 increased the mean [+/- SD] value from 0.32 +/- 0.05 to 0.42 +/- 0.13 (p < 0.01), dofetilide from 0.32 +/- 0.03 to 0.50 +/- 0.12 (p < 0.03), MS551 from 0.35 +/- 0.06 to 0.45 +/- 0.10 (p < 0.02) and d-sotalol from 0.31 +/- 0.05 to 0.33 +/- 0.04 (p < 0.05). However, in those patients given either E4031, dofetilide or MS551, the degree of QT prolongation was smaller at shorter square root of RR intervals and was better preserved at shorter square root of RR intervals by d-sotalol, with a smaller increase in slope (p < 0.02 vs. dofetilide and MS551).nnnCONCLUSIONSnOn ambulatory electrocardiography, reverse use dependence in QT prolongation was least prominent with d-sotalol among the four study drugs. In the range of physiologic heart rates, class III agents could manifest different profiles of rate dependence in their QT-prolonging effect.

Ischemia enhances use-Dependent sodium channel blockade by pilsicainide, a class IC antiarrhythmic agent

OBJECTIVESnThe aim of this study was to elucidate whether the electrophysiologic properties of pilsicainide, a novel class IC drug with slow kinetic properties, could be altered in the presence of acute myocardial ischemia.nnnBACKGROUNDnAn increase in the rate of sudden death in patients taking flecainide and encainide has been reported by the Cardiac Arrhythmia Suppression Trial (CAST), implying a proarrhythmic effect that may be due to the interaction between ischemia and class IC antiarrhythmic drugs.nnnMETHODSnThirty-five patients and 16 age-matched control patients performed a treadmill exercise test and were assigned to four study groups: group A = 16 control patients; group B = 15 patients with ischemic ST segment depression; group C = 11 patients receiving pilsicainide without ST segment depression; and group D = 9 patients receiving pilsicainide with ischemic ST segment depression. The QRS duration was measured at rest and at heart rates of 80, 100 and 120 beats/min.nnnRESULTSnThere were no changes in the QRS duration as heart rates increased to 120 beats/min in the control patients. Ischemia, however, independently caused a significant increase in QRS duration at a heart rate of 120 beats/min. Pilsicainide produced a rate-dependent prolongation of the QRS duration in patients without ST segment depression as the heart rate increased to 100 beats/min. The combination of ischemia and pilsicainide led to a much greater rate-dependent prolongation of the QRS duration.nnnCONCLUSIONSnCombination of a class IC drug and acute ischemia could lead to additive rate-dependent ventricular conduction slowing. This may be one plausible mechanism for the induction of proarrhythmias noted in the CAST study.

B-type natriuretic peptide levels are decreased by reducing dietary salt intake in patients with compensated heart failure with preserved ejection fraction.

Dietary salt restriction is believed to be a mainstay in the management of patients with heart failure. However, the effect of salt intake on heart failure has not been well evaluated in outpatient medical practice.

Enalapril-induced cough is associated with non-severe heart failure

The incidence of enalapril-induced cough was evaluated in 199 patients with congestive heart failure. Cough was more frequent in class I or II patients (28%) than in class III (4.1%, p<0.01) and class IV (0%, p<0.01) patients. Brain natriuretic peptide level was lower in patients in the cough (+) group than in the cough (-) group (170+/-107 vs. 538+/-637 pg/ml, p<0.01). The incidence of enalapril-induced cough is low in patients with severe congestive heart failure and a cough can be a marker of non-severe heart failure.

High B-type natriuretic peptide levels predict a hypercoagulable state in otherwise low-risk patients with atrial fibrillation

The D‐dimer and B‐type natriuretic peptide (BNP) levels in relation to CHADS2 and CHA2DS2–VASc scores in 59 patients with atrial fibrillation who were not receiving anticoagulant therapy were analyzed. Among 19 patients with CHADS2 scores of 0–1, 3 of the 7 patients with elevated BNP levels also had elevated D‐dimer levels. Among 8 patients with CHA2DS2–VASc scores of 1, 2 of the 3 patients with elevated BNP levels also had elevated D‐dimer levels. Therefore, D‐dimer levels can be elevated in low‐risk patients when BNP levels are high, and anticoagulation therapy should be considered for these patients.

Rate-dependent anisotropic conduction property in the epicardial border zone of canine myocardial infarcts and its modification by moricizine

SummaryWe evaluated anisotropic conduction properties, different conduction velocities depending on fiber orientation, in normal and infarcted myocardium and the effects of moricizine on anisotropic conduction. Various cycle lengths of stimulation were applied to 15 mongrel dogs, and epicardial mapping was performed using a 96-channel mapping electrode. Moricizine was then administered to seven dogs and the same procedure was performed. Conduction velocities were calculated from these maps. Programmed electrical stimulations were performed before and after moricizine administration to induce ventricular arrhythmias. Before moricizine administration, a rate-dependent decrease in longitudinal conduction velocity was observed in the infarcted zone. Moricizine suppressed longitudinal conduction in the normal zone significantly at 300 msec pacing, but not at slower rates. Moricizine at a dose of 4 mg/kg, on the other hand, suppressed longitudinal conduction in the infarcted zone significantly at all pacing cycle lengths. The effect of moricizine on transverse conduction was inconsistent. In three dogs, sustained ventricular tachycardia (VT) was induced either before or after moricizine administration. The mean cycle length of sustained VT was prolonged from 202 msec to 291 msec after 4 mg/kg of moricizine. Thus, the changes in cycle length of ventricular tachycardia observed were most likely the result of slowing of conduction velocity, especially in the longitudinal direction, in the infarcted myocardium. We conclude that the electrophysiologic nature of the subacute ischemic model was modified by moricizine, leading to depression of the conduction velocity of longitudinal conduction and the inducibility of ventircular arrhythmias.