R.Kirby Primm

Incidence and clinical features of the quinidine-associated long QT syndrome: Implications for patient care

Quinidine therapy is one of the most common causes of the acquired long QT syndrome and torsade de pointes. In reviewing clinical data in 24 patients with the quinidine-associated long QT syndrome, 20 of whom had torsade de pointes, we have delineated several heretofore unreported or underemphasized features. (1) This adverse drug reaction occurred either in patients who were being treated for frequent nonsustained ventricular arrhythmias or for atrial fibrillation or flutter. (2) In patients being treated for atrial fibrillation, torsade de pointes occurred only after conversion to sinus rhythm. (3) Although most patients developed the syndrome within days of starting quinidine, four had torsade de pointes during long-term quinidine therapy, usually in association with hypokalemia. (4) Because of the large experience with this entity at our institution, we have been able to estimate the risk as at least 1.5% per year. (5) Twenty of the 24 patients had at least one major, easily identifiable, associated risk factor including serum potassium below 3.5 mEq/L (four); serum potassium between 3.5 and 3.9 mEq/L (nine); high-grade atrioventricular block (four); and marked underlying, (unrecognized) QT prolongation (two). Plasma quinidine concentrations were low, being at or below the lower limit of the therapeutic range in half of patients. The ECG features typically included absence of marked QRS widening, marked QT prolongation (by definition), and a stereotypic series of cycle length changes just prior to the onset of torsade de pointes. Torsade de pointes started after the T wave of a markedly prolonged QT interval that followed a cycle that had been markedly prolonged (usually by a post ectopic pause).(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiologic Actions of High Plasma Concentrations of Propranolol in Human Subjects

The authors have previously shown that 40% of patients whose ventricular arrhythmias respond to propranolol require plasma concentrations in excess of those producing substantial beta-receptor blockade (greater than 150 ng/ml). However, the electrophysiologic actions of propranolol have only been examined in human beings after small intravenous doses achieving concentrations of less than 100 ng/ml. In this study, the electrophysiologic effects of a wider concentration range of propranolol was examined in nine patients. Using a series of loading and maintenance infusions, measurements were made at baseline, at low mean plasma propranolol concentrations (104 +/- 17 ng/ml) and at high concentrations (472 +/- 68 ng/ml). Significant (p less than 0.05) increases in AH interval and sinus cycle length were seen at low concentrations of propranolol, with no further prolongation at the high concentrations; these effects are typical of those produced by beta-blockade. However, progressive shortening of the endocardial monophasic action potential duration and QTc interval were seen over the entire concentration range tested (p less than 0.05). At high concentrations, there was significant (p less than 0.05) further shortening of both the QTc and monophasic action potential duration beyond that seen at low propranolol concentrations, along with a progressive increase in the ratio of the ventricular effective refractory period to monophasic action potential duration. No significant changes were seen in HV interval, QRS duration or ventricular effective refractory period. In summary, the concentration-response relations for atrioventricular conductivity and sinus node automaticity were flat above concentrations of 150 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration of prostacyclin prevents ventricular fibrillation following coronary occlusion in conscious dogs.

Summary The effects of prostacyclin (PGI2) on ventricular arrhythmias following 20 min of coronary occlusion and release wore studied in 34 conscious dogs. We administered PGI2 at 100 ng/kg/min and did not observe significant changes in heart rate, blood pressure, or systemic vascular resistance. During the control period, heart rate was 97 ± 30 (mean ± SEM) vs. 99 ± 28 in the PGI2-treated group. Mean arterial pressure was 115 ± 26 mm Hg and 109 ± 10 mm Hg in the control and PGI2 groups, respectively. Systemic vascular resistance declined minimally from 2.985 ± 221 dyn.s.cm5 to 2.484 ± 135 dyn.s.cm5 during the PGI2 infusion (p = NS). Following coronary occlusion, the frequency of ventricular fibrillation was reduced from 53% (9/17) in the control group to 6% (1/17) in the PGI2 group (p < 0.01). Overall 80-min postin-farction survival was 64% in the group receiving PGI2 infusion compared to 24% in the control group (p < 0.05). The effects of PGI2 in preventing ventricular fibrillation following acute coronary occlusion can be ascribed to a direct action of this prostaglandin on the myocardium, rather than to an indirect effect due to a reduction in systemic vascular resistance.

Spectrum of antiarrhythmic response to encainide

Encainide is effective in suppressing non-life-threatening ventricular arrhythmias; however, inconsistent results have been noted in patients with more serious ventricular arrhythmias. Thirty-seven patients with drug-resistant ventricular arrhythmias were studied. Patients in group I (n = 11) has sustained ventricular tachycardia and those in group II (n = 26) had nonsustained ventricular arrhythmias. In group I, 8 patients had remote myocardial infarction, congestive heart failure and sustained ventricular tachycardia requiring repeated cardioversion (group Ia). None of these patients responded to encainide treatment, but 6 did have an antiarrhythmic response (complete in 3 and only partial in 3) to other investigational antiarrhythmic agents. Three patients in group I, all without ischemic heart disease (group Ib), had an excellent antiarrhythmic response to encainide, as did 21 of 26 patients in group II. In 4 of 5 patients in group II who did not respond, the dosage was limited due to the development of sinus pauses, atrioventricular block or bundle branch block, and in 3 of these 4 patients preexisting conduction disease was evident (PR longer than 0.2 second or QRS longer than 0.12 second). Diplopia occurred while taking the maximal oral dosage in the fifth patient. At 21.5 months of follow-up, 14 of the original 24 patients who responded to encainide continue to receive it; 3 have died (all due to natural progression of left ventricular dysfunction) and encainide was discontinued in 7: in 2 because of syncope, in 2 because of new-onset atrial fibrillation, in 1 patient because of exercise-induced polymorphic ventricular tachycardia, in 1 because of diplopia and in 1 because of skin exanthem.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiologic and hemodynamic effects of chronic oral therapy with the α2‐agonists clonidine and tiamenidine in hypertensive volunteers

Clonidine can produce symptomatic sinus bradycardia or atrioventricular (AV) block in some patients. Electrophysiologic studies have been performed after intravenous clonidine in patients showing such side effects; these have demonstrated variable depression of sinus and AV nodal function. We have evaluated the electrophysiologic and hemodynamic effects of chronic oral treatment with either clonidine (0.2 to 0.5 mg every 12 hours; n = 7) or another centrally active α2‐agonist, tiamenidine (0.5 to 1.5 mg every 12 hours; n = 7), in otherwise healthy hypertensive human volunteers. At dosages that modestly lowered diastolic blood pressure, both agents significantly slowed sinus rate and increased the atrial pacing rate producing AV nodal Wenckebach. Clonidine also significantly increased corrected sinus node recovery time and lowered cardiac output while similar (but statistically insignificant) trends were seen with tiamenidine. We conclude that chronic oral treatment with these α2‐agonists depresses sinus and AV nodal function in virtually all subjects, including those without manifest conduction system disease.