C. Thomas Peter

Verapamil: A Review of its Pharmacological Properties and Therapeutic Use

SummarySynopsis: Verapamil is a novel antiarrhythmic and antianginal agent which, although introduced in 1962, has only recently gained prominence not only as a significant agent in cardiovascular therapeutics but also as a powerful tool to examine the nature of some of the biophysical phenomena at the membrane of cardiac and other excitable tissues. Verapamil is the prototype of those agents which selectively inhibit membrane transport of calcium, an action which accounts for the drug’s peripheral and coronary vasodilator properties, its effect on excitation-contraction coupling and hence its negative inotropic propensity, as well as its depressant effects on the sinus node and atrioventricular conduction. Its pharmacological effects are largely independent of the autonomic nervous system. The main therapeutic uses of the drug are in the management of atrial tachyarrhythmias, angina, and possibly hypertension. The overall experimental and clinical data suggest that verapamil will become an important and safe addition to existing drug regimens, especially as an agent of choice for the short-term treatment of most cases of paroxysmal supraventricular tachycardias. The initial experience in other arrhythmias, angina and hypertension, is also sufficiently encouraging to justify further detailed clinical trials to define its potential role in cardiovascular therapeutics. Pharmacodynamic Properties: Verapamil is a weak local anaesthetic; it does not depress the upstroke velocity of the cardiac action potential, nor does it prolong the action potential duration in heart muscle. It selectively depresses nodal tissues, presumably by an effect on the calcium-mediated slow response, an action distinct from that of all other antiarrhythmic agents. Pharmacokinetics: Preliminary pharmacokinetic studies reveal major discrepancies between the duration of the electrophysiological and haemodynamic effects of verapamil and the presence of unchanged drug in the plasma, raising the possibility of active metabolites. Plasma protein binding of verapamil approaches approximately 90%. Despite almost complete gastrointestinal absorption following oral administration, the overall bioavailability of the drug is about 10 to 22% reflecting substantial first pass hepatic metabolism which may account for the 8 to 10-fold greater oral compared with intravenous doses needed to produce comparable pharmacodynamic effects. Therapeutic Trials: The antiarrhythmic effects of verapamil are explained largely by its action on the atrioventricular node: intravenously administered verapamil (10mg in adults, 3.5 to 5mg in children) produces prompt reversion to sinus rhythm of 80 to 100% of cases with paroxysmal supraventricular tachycardias, especially those due to AV nodal re-entry. The drug has little effect on the anomalous pathways in the Wolff-Parkinson-White syndrome so that atrial fibrillation or flutter complicating this disorder are not affected by verapamil, in contrast to other cases of atrial fibrillation or flutter in which the ventricular response is consistently reduced in most cases and sinus rhythm restored in a few. The role of oral verapamil used alone or in combination with other agents in the prophylaxis of paroxysmal supraventricular tachycardias and in the maintenance of sinus rhythm following cardioversion of atrial fibrillation remains to be defined. Verapamil is of little value in the control of ventricular arrhythmias.Verapamil is also effective in angina pectoris in doses in excess of 120mg 3 times daily orally. At this dose schedule, its efficacy is comparable with that of 80mg 3 times daily of oral propranolol, although the latter produces a significant degree of bradycardia whereas verapamil does not. The mode of antianginal action of verapamil is therefore not understood, but unlike propranolol the drug has no effects on lung function. Experimental studies suggest that verapamil might reduce myocardial infarct size and preliminary clinical studies raise the possibility that the drug may be of value in the management of acute hypertensive crisis as well as of treatment of essential hypertension. Side-effects: Orally administered verapamil is extremely well tolerated and few side-effects have been encountered following intravenous administration of the drug, especially when it is given slowly. Transient hypotension and prolongation of AV conduction time or even AV dissociation may occasionally be seen. Haemodynamic effects in patients with cardiac disease include short-lived decreases in mean arterial pressure, first derivative of the left ventricular pressure, systemic resistance and a rise in left ventricular filling pressure, but with little change in stroke volume, cardiac index or heart rate. Rarely, severe hypotension, bradycardia, or asystole have been reported, most cases occurring in patients previously treated with β-adrenoceptor blocking drugs. Precautions: Prior digitalisation is not a contraindication to the use of intravenous or oral verapamil, except in the case of the sick sinus syndrome in which verapamil alone or in combination with other depressant drugs which influence automaticity or conduction may produce severe bradycardia or atrioventricular block. The drug is also contraindicated in unstable atrioventricular block, heart failure (especially that complicating acute myocardial infarction), cardiogenic shock or other hypotensive states. Side-effects resulting from verapamil may be reversed, at least in part, by atropine, isoprenaline, intravenous calcium or glucagon, with ventricular pacing being required occasionally.

Discrimination of ventricular tachycardia from sinus tachycardia and atrial fibrillation in a tiered-therapy cardioverter-defibrillator

OBJECTIVES This study was conducted to evaluate criteria for discrimination of ventricular tachycardia from atrial fibrillation and sinus tachycardia in a tiered-therapy cardioverter-defibrillator (Medtronic PCD). BACKGROUND Interval stability algorithms discriminate ventricular tachycardia from atrial fibrillation. Onset algorithms discriminate ventricular tachycardia from sinus tachycardia. Neither has been validated clinically. METHODS The stability criterion requires that a ventricular tachycardia interval not vary from any of the three previous intervals by more than the programmable stability value. The onset criterion detects initiation of ventricular tachycardia only if the ratio of an interval to the mean of four previous intervals is less than a programmed onset ratio and either the second or third preceding interval exceeds the ventricular tachycardia detection interval. We evaluated these criteria in 100 patients at electrophysiologic study and exercise testing (65 patients) and during a mean (+/- SD) follow-up of 16.2 +/- 7.9 months. The PCDs were programmed to tiered therapy in 54 patients. In the remaining 46 patients, the PCDs memory for detected ventricular tachycardia was used to study the specificity of the chosen onset criterion for rejecting sinus tachycardia. We used stored intervals preceding appropriate (n = 99) and inappropriate (n = 54) detections to test a new onset criterion that was less sensitive to a single index interval. RESULTS Programmed stability of 40 ms decreased detection of induced atrial fibrillation by 95% (20 patients), paroxysmal atrial fibrillation by 95% (6 patients) and chronic atrial fibrillation by 99% (9 patients); all episodes of spontaneous (n = 877) and induced (n = 339) ventricular tachycardia were detected. A programmed onset ratio of 87% rejected sinus acceleration (98%) but caused underdetection of 0.5% of ventricular tachycardias. The onset criterion permitted inappropriate detection of premature ventricular complexes during sinus tachycardia, but the new criterion reduced these inappropriate detections by 98%. CONCLUSIONS The PCDs onset and stability criteria reduced inappropriate detection of atrial fibrillation and sinus acceleration while detecting 99.5% of ventricular tachycardias.

Simultaneous Biatrial Computerized Mapping During Permanent Atrial Fibrillation in Patients with Organic Heart Disease

Activations in Permanent Atrial Fibrillation. Introduction: Activation patterns during permanent atrial fibrillation (AF) in patients with organic heart diseases are unclear.

Underdetection of ventricular tachycardia by algorithms to enhance specificity in a tiered-therapy cardioverter-defibrillator

OBJECTIVES The goal of this study was to determine the incidence and clinical significance of underdetection in 125 patients treated with a tiered-therapy cardioverter-defibrillator, the Medtronic PCD. BACKGROUND Underdetection, distinct from undersensing, is a unique, potential complication of new algorithms that enhance specificity in tiered-therapy cardioverter-defibrillators. These algorithms may delay or prevent recognition of ventricular tachycardia even though electrograms are sensed accurately and RR intervals meet the programmed interval criterion. METHODS Underdetection was defined as delay in detection > 5 s at electrophysiologic study or symptomatic delay or detection failure at follow-up of 15 +/- 8 months. RESULTS We identified six specific mechanisms of underdetection caused by algorithms to discriminate sustained ventricular tachycardia from sinus tachycardia, atrial fibrillation, ventricular fibrillation and nonsustained ventricular tachycardia. Underdetection caused detection delays in 13 (1.9%) of 677 induced ventricular tachyarrhythmia episodes in 12 patients (9.6%). During follow-up, underdetection occurred in 7 (9.9%) of 71 patients in whom ventricular tachycardia therapies were programmed. Failure to detect ventricular tachycardia occurred in 6 (0.6%) of 988 spontaneous ventricular tachycardia episodes in four patients (5.6%); 2 episodes required external cardioversion. After defibrillator reprogramming, underdetection did not occur. CONCLUSIONS Algorithms to enhance specificity cause underdetection of ventricular tachycardia in a significant minority of patients with tiered-therapy cardioverter-defibrillators. Optimal programming can minimize underdetection.

The frequency and prognostic significance of electrocardiographic abnormalities in clinically normal individuals

A GREAT deal is now known about the frequency and prognosis of electrocardiographic (ECG) abnormalities in patients with clinically overt heart disease. However, the physician in practice is often confronted with ECG abnormalities as an incidental finding during the routine screening of an asymptomatic individual without a clinically apparent cardiac disorder. The prognostic significance of such abnormalities have not been clearly established and therefore the physician’s conclusions and recommendations in such instances are based essentially on his knowledge of the outcome of patients with comparable ECG abnormalities occurring in the context of known heart disease. In recent years, ECG “abnormalities” in clinically “normal” individuals have assumed greater importance than ever before, since ECG examinations are now undertaken with increasing frequency during the course of an application for life insurance or employment, preoperative evaluation. or as an integral part of the popular routine periodic “check-up.” Furthermore, the use of continuous ECG recording on Holter monitor has revealed much more striking ECG abnormalities occurring with a greater frequency in apparently healthy individuals than those previously revealed on routine 12-lead ECG records. The identification of asymptomatic ECG abnormalities in apparently healthy individuals clearly raises the important issue of their prognostic significance especially in relation to the question of whether their mere presence on a rhythm strip or on the dynamic cardiogram merits therapy. A clear delineation of the natural history of such “lone” ECG deviatreatment can reasonably be formulated in an individual instance. To our knowledge, no attempt has previously been made to systematize the existing knowledge in this regard. In this article, the pertinent literature is therefore reviewed and conclusions regarding the prognostic significance of various ECG abnormalities occurring in subjects without clinical heart disease have been drawn in light of the published reports and of our own clinical experience and practice. The need for a better understanding of the natural history of asymptomatic abnormalities of rhythm has become more acute with the increasing plethora of new antiarrhythmic drugs that might be used in their prophylaxis.’

Atypical Atrioventricular Node Reciprocating Tachycardia Masquerading as Tachycardia Using a Left-Sided Accessory Pathway ☆

OBJECTIVES The study was performed to document that atrioventricular node reciprocating tachycardia (AVNRT) can be associated with eccentric retrograde left-sided activation, masquerading as tachycardia using a left accessory pathway. BACKGROUND The eccentric retrograde left-sided activation during tachycardia is thought to be diagnostic of the presence of a left free wall accessory pathway. However, it is not known whether AVNRT can occur with eccentric retrograde left-sided activation. METHODS We studied 356 patients with AVNRT who underwent catheter ablation. Retrograde atrial activation during tachycardia and ventricular pacing were determined by intracardiac recordings, including the use of a decapolar coronary sinus catheter. RESULTS The retrograde atrial activation was eccentric in 20 patients (6%). Eight of these patients had the earliest retrograde atrial activation recorded in the lateral coronary sinus leads, and 12 had the earliest retrograde atrial activation recorded in the posterior coronary sinus leads, with the most proximal coronary sinus electrode pair straddling the coronary sinus orifice. These tachycardias were either the fast-slow or the slow-slow form of AVNRT. The slow-fast form of AVNRT was also inducible in 17 of the 20 patients. Successful ablation of the slow pathway in the right atrial septum near the coronary sinus ostium prevented the induction and clinical recurrence of reciprocating tachycardia in all patients. CONCLUSIONS Atypical AVNRT with eccentric retrograde left-sided activation was demonstrated in 6% of all patients with AVNRT masquerading as tachycardia using a left-sided accessory pathway. Ablation of the slow pathway at the posterior aspects of the right atrial septum resulted in a cure in these patients.

Programming of Implantable Cardioverter-Defibrillators on the Basis of the Upper Limit of Vulnerability

BACKGROUND A patient-specific measure of defibrillation efficacy that requires a minimum number of ventricular fibrillation (VF) episodes would be valuable for programming implantable cardioverter-defibrillators (ICDs). The upper limit of vulnerability (ULV) is the weakest shock strength at or above which VF is not induced when a stimulus is delivered during the vulnerable phase of the cardiac cycle. It correlates with the defibrillation threshold (DFT) and can be determined with a single episode of VF. The objective of this study was to test the hypothesis that ICDs programmed on the basis of the ULV convert spontaneous ICD-detected VF reliably. METHODS AND RESULTS We studied 100 consecutive patients at ICD implantation and during follow-up of 20 +/- 7 months. At implantation, the ULV and DFT were determined, and the ICD system was tested at a shock strength equal to the ULV + 3 J. During follow-up, the strength of the first shock was programmed to the ULV + 5 J for arrhythmias detected in the VF zone (cycle length < 292 +/- 17 ms). We reviewed stored detection intervals and electrograms from spontaneous episodes of ICD-detected VF to determine the success rate for appropriate first shocks. The programmed first-shock strength was 17.5 +/- 5.2 J. During follow-up, there were 120 appropriate first shocks in 37 patients. The arrhythmia was rapid monomorphic ventricular tachycardia (VT) in 70% of episodes (31 patients), VF in 11% (13 patients), polymorphic VT in 1%, and unclassified in 17% (15 patients). The first shock was successful in 119 of 120 episodes (99%; 95% CI, 93% to 100%). One unclassified episode required two shocks. No patient had syncope associated with an ICD shock or arrhythmic death. CONCLUSIONS ICD shocks can be programmed on the basis of the ULV, a measurement made in regular rhythm, without a direct measure of defibrillation efficacy.

Selective atrionodal input ablation for induction of proximal complete heart block with stable junctional escape rhythm in patients with uncontrolled atrial fibrillation

AbstractBackground: The study tests the hypothesis that ablating all inputs to the atrioventricular (AV) node can result in complete heart block with stable junctional escape rhythm. Methods and Results: We attempted atrionodal input ablation in 76 consecutive patients with uncontrolled atrial fibrillation. Fast and slow pathways were first ablated. If there was no AV block, additional energy applications were done between fast and slow pathway locations. The patients were followed for 42 ± 11 months. Group I (n = 57) comprised patients with complete heart block and junctional escape rhythm (53 ± 4 beats/min) at the end of the procedure. The escape rhythm remained stable throughout follow-up. Group II (n = 15) were patients who failed the stepwise atrionodal input ablation and required AV junctional ablation guided by His bundle potential to achieve complete heart block. Four patients showed a slow escape rhythm after ablation (33 ± 4 beats/min). Others had no escape rhythm. All 15 pts remained pacemaker dependant. The total death rate of groups I and II was 18/57 (31.6%) vs 10/15 (66.7%), respectively (p < 0.02). These differences could not be explained by a difference of left ventricular ejection fraction (0.42 ± 0.07 vs 0.41 ± 0.04, respectively, p = NS). Conclusions: (1) In most patients, ablation of both fast and slow pathways did not result in complete heart block, indicating the presence of multiple atrionodal inputs. (2) Ablation of all atrionodal inputs may result in complete heart block with stable junctional escape rhythm. (3) As compared with AV junctional ablation, atrionodal input ablation was associated with a lower mortality rate on long-term follow up.

Effects of voltage and respiration on impedance in nonthoracotomy defibrillation pathways

The effects of applied voltage and phase of respiration on impedance of pathways used by implantable cardioverter-defibrillators were investigated. Patients were studied at implantation of cardioverter-defibrillators using epicardial (n = 12) or transvenous and subcutaneous (SQ) (n = 30) electrodes. Transvenous-SQ pathways were right ventricular cathode to SQ anode and coronary sinus cathode to SQ anode. Transvenous-transvenous pathways were right ventricle to coronary sinus and right ventricle to superior vena cava. Patients with nonthoracotomy electrode systems were studied at end-expiration and end-inspiration. Five shocks of 65 to 745 V (0.2 to 34 J) were given in random order in sinus rhythm. Over this range, end-expiratory impedance decreased monotonically for all pathways. This effect was greatest for transvenous-SQ pathways (13 +/- 3% to 17 +/- 4%, p < 0.001), intermediate for transvenous-transvenous pathways (5 +/- 4% to 8 +/- 5%, p < 0.001), and least for epicardial pathways (3 +/- 3%, p = 0.006). Paired data in inspiration and expiration showed that inspiration increased impedance in transvenous-SQ pathways (p < 0.001) but not in transvenous-transvenous pathways. Further, the effects of respiration and voltage on impedance in transvenous-SQ pathways were interactive (p < 0.001): Inspiration increased voltage-dependence of impedance. The magnitude of the inverse relationship between voltage and impedance depends on type of defibrillation pathway. The effect of respiration on impedance suggests that voltage-dependence of impedance is greatest in the lungs. These findings have potential relevance for intraoperative testing of cardioverter-defibrillators and selection of pathways for low-energy cardioversion.

Optimal electrode configuration for pectoral transvenous intplantable defibrillator without an active can

A new 83 cm3 implantable cardioverter-defibrillator (ICD) designed for pectoral implantation has been implanted most frequently using right ventricular and superior vena cava (RV-->SVC) electrodes; a patch electrode (RV-->patch + SVC) has been added when necessary to decrease the defibrillation threshold (DFT). The goal of this prospective study was to compare biphasic waveform DFTs for 3 electrode configurations: RV-->patch, RV-->SVC, and RV-->patch + SVC in 25 consecutive patients. The patch was positioned in a left retro-pectoral pocket, and the SVC electrode was positioned with the tip at the junction of the SVC and innominate vein. In the first 15 patients, all 3 electrode configurations were tested in random order; in the last 10 patients, only the RV-->patch and RV-->patch + SVC configurations were tested. In the first 15 patients, the stored-energy DFT for the RV-->SVC configuration (15.2 +/- 7.7 J) was higher (p < 0.001) than the DFT for the RV-->patch configuration (11.3 +/- 6.2 J) and the RV-->patch + SVC configuration (10.0 +/- 5.8 J). For all 25 patients, the DFT was lower for the RV-->patch + SVC configuration (9.7 +/- 5.1 J) than for the RV-->patch configuration (12.4 +/- 6.6 J, p = 0.005). The pathway resistance was highest for the RV-->patch configuration (72 +/- 9 omega), lower for the RV-->SVC configuration (63 +/- 6 omega, p < 0.01), and lowest for the RV-->patch + SVC configuration (46 +/- 3 omega, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)