David Tepper

QT prolongation and the antiarrhythmic efficacy of amiodarone

Amiodarone is an antiarrhythmic agent known to cause prolongation of action potential duration which is reflected in the electrocardiogram as a prolongation of the QT interval. Prolongation of the QT interval in patients dying suddenly was compared with that in patients who remained alive to determine whether a difference existed between these two groups. The electrocardiogram and amiodarone levels were evaluated in 33 patients who presented with cardiac arrest and symptomatic ventricular tachycardia in whom no other antiarrhythmic agent was found effective in preventing induction of ventricular tachycardia during electrophysiologic studies. There were 30 men and 3 women (mean age 52 +/- 10 years). Twenty-three are alive after a mean follow-up period of 12 +/- 7 months. Ten died: six suddenly, three of non-cardiac causes and one of congestive heart failure. Using a two-way analysis of variance, the percent change in QT, QTc, JT and JTc intervals before and after amiodarone therapy was analyzed. Marked prolongation in the QT interval was present in patients who remained alive with amiodarone therapy. A significant difference in percent QT prolongation was seen between the latter patients and those who died suddenly (p less than 0.005). No difference was observed in the percent change in QRS interval between the two groups. The levels of amiodarone (2.5 versus 3.2 micrograms/ml) and its metabolite (desethylamiodarone) were not significantly different between the living patients and those who died suddenly. These findings suggest that a prolongation of the QT interval may be a marker for the therapeutic antiarrhythmic effect of amiodarone.

Adenosine and its cardiovascular effects

Adenosine is a new antiarrhythmic agent recently released with the permission of the Food and Drug Administration. It is an endogenously occurring nucleoside indicated for use in the diagnosis and treatment of supraventricular tachycardia. Its greatest utility is in patients with AV nodal reentry. Its antiarrhythmic action is mediated at the cellular level through the potassium channel, causing hyperpolarization of the myocyte membrane potential. In addition to its current indication as an antiarrhythmic agent, adenosine is now being used under an investigational protocol for pharmacologic stress testing. It can be given in conjunction with thallium or used in echocardiography as an imaging tool for patients who can not be adequately exercised. Adenosines side effect profile is relatively benign and the agents extremely short half-life makes most adverse reactions clinically insignificant. In this report we attempt to highlight this agents clinical utility and discuss its future in the cardiovascular pharmacopeia.

Prolonged repolarization: A historical perspective

This symposium will more fully discuss QT prolongation--an area of controversy--prolonged QT syndromes, and new groups of agents that prolong repolarization and the QT interval (calcium blockers and antiarrhythmic agents). This is an important evolving field with old biases confronting a new and more thorough understanding of the phenomenon of prolonged repolarization.

Enhancement of myocardial vulnerability by atrial fibrillation.

Certain groups are known to have an increased risk for sudden cardiac death. Epidemiologic studies have suggested that patients with atrial fibrillation may be at higher risk. The authors hypothesize that atrial fibrillation may increase myocardial vulnerability. To test this hypothesis, 37 dogs were studied using programmed electrical stimulation techniques to determine myocardial vulnerability as assessed by the ability to provoke ventricular tachycardia. Prior to atrial fibrillation, programmed electrical stimulation did not induce ventricular tachycardia. Aconitine was then topically applied to the right atrial appendage with care taken not to make contact with the ventricle. Application of aconitine caused atrial fibrillation with an increase in ventricular rate, but did not affect arterial blood pressure. Ventricular tachycardia was induced by programmed electrical stimulation studies in 25 of 26 dogs in atrial fibrillation. The enhanced vulnerability was noted following atrial fibrillation, not after aconitine application to the great veins, which did not cause atrial fibrillation. To further exclude the possibility that aconitine application may cause changes in ventricular threshold, atrial fibrillation was induced by pacing techniques in five dogs. Prior to atrial fibrillation induction, programmed electrical stimulation did not induce ventricular tachycardia. Following atrial fibrillation, ventricular tachycardia could be repeatedly induced. Mean heart rate following atrial fibrillation increased, while pacing animals at this increment in rate did not change the noninducibility of dogs in sinus rhythm. Six patients with a history of atrial fibrillation and ventricular tachycardia were studied to determine if AF lowered myocardial threshold to VT induction. Ventricular tachycardia could only be induced by PES techniques in four of five patients when the patients’ rhythm was AF (P < 0.05). This study suggests that atrial fibrillation lowers myocardial threshold for ventricular tachycardia induction and thus enhances myocardial vulnerability. The association of AF with a higher incidence of sudden death may be due to an enhanced electrical instability.

Flecainide: A new antiarrhythmic agent

PVCs (trigger mechanisms) and the vulnerability of the myocardium to sustain a life-threatening ventricular tachycardia (substrate) are two variables in the sudden death equation. Physicians treating patients at risk for sudden death should consider PVC frequency and vulnerability as interrelated variables. Risk assessment must take into consideration both variables. Antiarrhythmic drug efficacy can be assessed in terms of a reduction in trigger mechanisms (PVCs) as well as decreasing myocardial vulnerability (induction of VT at PES). Flecainide acetate, at a reduced dosage of 100 mg twice daily, is effective in both aspects, markedly decreasing PVC frequency and preventing VT induction at PES testing. Holter monitoring and electrophysiologic testing evaluate different aspects of the problem. With the addition of an agent as potent as flecainide, which is devoid of many of the bothersome side effects previously limiting antiarrhythmic therapy, an agent is now available that may be useful to treat both the trigger mechanism and the substrate in sudden death. We must be careful not to worsen the situation through the profound effects of flecainide on depolarization and refractoriness that in some patients cause life-threatening arrhythmias to be more frequent.

The effect of bepridil, verapamil, and quinidine in the prevention of ventricular tachycardia induced by programmed electrical stimulation in the digitalized dog

Bepridil, a new antianginal agent, has calcium channel-blocking activity and antiarrhythmic properties. To test the efficacy of bepridil as an antidysrhythmic agent, we looked at its effect on the induction of ventricular tachycardia (VT) in dogs, utilizing programmed electrical stimulation (PES). Incremental doses of bepridil up to 20 mg/kg were given to five nondigitalized dogs and verapamil up to 20 mg, and PES was performed at each dose. Both drugs were not found to facilitate arrhythmia induction. Seventeen dogs were chronically digitalized and following digitalization, VT could be induced in all animals by PES. Six dogs were given bepridil and PES was reperformed at each dose. An average of 1.8 mg/kg was found to protect against induction of VT. Five dogs received verapamil and none was protected (all had VT induced), while five of six dogs given quinidine were protected at an average dose of 15.4 mg/kg. Bepridil produced a significant decrease in heart rate. A significant correlation was found at the effective antiarrhythmic dose of bepridil between percentage change in the effective refractory period for the first extrastimulus (ERP S2) and QTc (r = 0.96), suggesting that a parallel and homogeneous prolongation in repolarization and refractoriness is essential for the antiarrhythmic effect of bepridil. Bepridil is thus an effective antiarrhythmic agent that affords protection against induction of VT, and this action is similar to the conventional class I antiarrhythmic agent, quinidine, while lacking in another calcium channel blocker, verapamil.

Digitalis: Historical Development in Clinical Medicine

t is now 200 years since Withering first reported his I careful clinical pharmacologic observations on the use of digitalis. An Account of the Foxglove and Some of Its Medicinal Uses-Practical Remarks on Dropsy and Other Diseases remains one of the most comprehensive presentations on the introduction of a drug based on a case studies appr0ach.l This text carefully details the clinical experience Withering had with digitalis, administering the drug to 163 patients over nine years. The identification of the active digitalis ingredient from a herbal preparation was one of Withering’s accomplishments, but of equal significance was his establishing a standardized preparation for his clinical testing, developing a doseresponse relationship, and careful chronicling of the drug‘s clinical toxicity. Withering had the intuitive judgment of a great clinical pharmacologist, and his treatise was a model of clinical pharmacologic investigation. He indeed had to be this to overcome the vagaries of human nature that, both before and after his time, led to the misuse of the cardiac glycosides to such an extent as to make them useless to those who treat as well as dangerous to those being treated. Excessive and indiscriminate dosing is not unique to digitalis, but its history is testimonial to the need for clinical pharmacology if therapeutics are to succeed in benefiting patients. It is most fitting that the JOURNAL OF CLINICAL PHARMACOLOGY, dedicated to the principles of rational drug research and therapeutics, is the forum for this review of the history of digitalis. ’

Studies on the possible mechanisms of lidoflazine arrhythmogenicity

Lidoflazine is a calcium channel blocking agent that is effective and safe in the treatment of angina pectoris, but has been reported to be associated with sudden death when administered for the treatment of supraventricular arrhythmias. Studies were performed in dogs to determine if lidoflazine caused a rise in serum digoxin concentration that could cause arrhythmias or if it was directly arrhythmogenic. Dogs received chronic injections of digoxin and then digoxin in combination with lidoflazine. No increase in digoxin concentration was found. Dogs also underwent programmed electrical stimulation while not receiving medications and then after incremental doses of lidoflazine administered intravenously. Lidoflazine did not cause spontaneous ventricular tachycardia and did not lower the threshold of ventricular tachycardia induction. Combined administration of lidoflazine and digoxin did not facilitate arrhythmia induction. These studies do not support a digoxin-lidoflazine interaction or a direct arrhythmogenic action of lidoflazine.

Renal hypertensive hypertrophy in the rat: a substrate for arrhythmogenicity

SummaryWe investigated the ability of ouabain to produce lethal arrhythmias in rats with myocardial hypertrophy resulting from chronic renal hypertension. A gradual pressure overload was produced in female Wistar rats by left renal artery stenosis (two kidney, one clip, Goldblatt hypertension). Hypertension (systolic blood pressure >150 mm Hg) developed within three weeks after clipping of the left renal artery and blood pressure continued to increase for the next five weeks. At ten weeks after the onset of hypertension animals were anesthetized with sodium pentobarbital (40 mg/kg) and artificially ventilated with room air while ECG was continually monitored and recorded. Continuous infusion of ouabain was maintained (0.7 mg/kg/min) through the inferior vena cava. Body weight and heart rate of control animals (C) was not significantly different from hypertensive (H) values, while systolic blood pressure in animals hypertensive for ten weeks was considerably greater (187±8.4 mm Hg) than their age-matched normotensive counterparts (123±6.0 mm Hg). Heart weight in hypertensive animals was elevated by 69%±2.5 by time of study. Serological evaluation of both groups of animals revealed no significant differences in electrolytes and blood gases while significant differences were noted in glucose, BUN and creatinine. The average time to the first premature ventricular contraction was significantly shorter in H animals (3.5±0.2 min) when compared to c rats (6.0±0.2 min). The average time to ventricular tachycardia, ventricular fibrillation and death were also significantly shorter in H rats when compared to C animals (7.5±0.6 vs. 13.5±0.3; 13.5±0.5 vs. 21.0±0.5; 15.6±0.4 vs. 24.0±0.6 min). Thus, the hypertensive hypertrophied myocardium displays an increased propensity for lethal cardiac arrhythmias due to ouabain.

Effects of Amrinone on Atrioventricular Conduction in the Intact Canine Heart

Abstract: The effects of amrinone on conduction in the intact canine heart were studied. Intracardiac His‐electrode catheter recordings were used to measure the functional refractory period (FRP) of the AV node and conduction time through the AV node (A2H2 interval) and in the His‐Purkinje system (H2V2 interval). Amrinone (2.5 to 10 mg/kg) shortened the FRP and A2H2 in a dose‐dependent manner but had no significant effect on H2V2. In hearts where AV conduction was depressed by treatment with verapamil, propranolol, or ouabain, amrinone partially reversed this depression. Amrinone also shortened the recovery time of spontaneous sinoatrial (SA) node activity following a train of rapid atrial stimulation. This effect was also observed after depression of SA nodal recovery with verapamil, propranolol, or ouabain. These results indicate that amrinone enhances AV conduction and SA nodal activity in the normal heart and may favorably influence depressed AV conduction and SA nodal activity induced by a variety of cardioactive agents.