The role of oral 1C antiarrhythmic drugs in terminating atrial fibrillation

PURPOSE: To investigate a possible relationship between evisceration and sympathetic ophthalmia. METHODS: Data from Mt. Sinai Medical Center and University Hospitals of Cleveland were collected and histopathologic specimens were reviewed for 51 of 90 patients who underwent evisceration between 1980 and 1996 and who returned for follow-up examinations. Additionally, a survey was sent to members of the American Society of Ophthalmic Plastic and Reconstructive Surgery, the Uveitis Society, and the Eastern Ophthalmic Pathology Society to determine the number of enucleations and eviscerations performed and the documented incidence of sympathetic ophthalmia after evisceration. RESULTS: No clinical or histopathologic evidence of sympathetic ophthalmia after evisceration was found among patients treated at the two medical centers. The collective surveys showed a strong preference for enucleation over evisceration, but did not document evidence of sympathetic ophthalmia after evisceration. CONCLUSIONS: Evisceration is an effective and safe procedure with a low risk for sympathetic ophthalmia.     

Negative dromotropic effects of class I antiarrhythmic drugs in anisotropic ventricular muscle

OBJECTIVE: In a computer simulation study to mimic cardiac action potential, the total open time of the sodium channel at each excitation has been shown by other authors to be longer during propagation parallel (longitudinal, L) to fiber orientation than perpendicular (transverse, T) to that. If this is the case in actual cardiac tissue, the Class I antiarrhythmic drug action on conduction would be affected by their mode of sodium channel block. The present study was designed to test this hypothesis. METHODS: Effects of flecainide (F), quinidine (Q), aprindine (A) and SD3212 (S) on conduction velocity (theta), amplitude of extracellular potentials (phi e), and maximum upstroke velocity (Vmax) of action potentials were examined in isolated rabbit ventricular muscles with microscopic anisotropy. RESULTS: F (0.1-1 microM) or Q (2-10 microM), which blocks the sodium channel mainly during the activated state, caused a concentration- and frequency-dependent decrease in theta and phi e. The reduction was more prominent during L than T propagation, giving rise to a decrease in their anisotropic ratio (theta L/theta T). A (1-5 microM) or S (3-10 microM), which blocks the channel during the inactivated state, also decreased theta and phi e. However, the reduction was similar during L and T propagation, and the anisotropic ratio of theta and phi e remained unaffected. The decrease of maximum upstroke velocity (Vmax) of action potential by F or Q was greater during L than T propagation; VmaxL/VmaxT was decreased significantly. In contrast, the Vmax reduction by A(3 microM) or S (10 microM) was similar during L and T propagation. CONCLUSION: Different state-dependence of sodium channel block may underlie different negative dromotropic effects of Class I drugs in anisotropic cardiac muscle.     

Con: antiarrhythmic drugs should not be used to suppress ventricular ectopy in the perioperative period

The alterations in autonomic tone imposed by the conduct of anesthesia and surgery predispose patients to ventricular ectopy. It is important to initially view any ectopy as a warning sign and promptly check the adequacy of ventilation and oxygenation. Most commonly an inadequate depth of anesthesia, surgical manipulation or electrolyte abnormality will be causative. Treatment of this underlying problem will usually suffice to terminate the ectopy. Importantly, many patients have preexisting, chronic, complex ventricular ectopy that gets revealed because of perioperative electrocardiographic monitoring. All available pharmacologic agents have significant adverse side effects. To date, all investigations examining outcome of suppression of ventricular ectopy show that successful suppression of ventricular ectopy was associated with an increased mortality. Although the prognosis for patients is worse when complex ventricular ectopy is associated with cardiac structural abnormalities, the optimal therapeutic approach to such patients remains undefined. Unless new data supporting the use of antiarrhythmic drugs in the perioperative setting become available, the risk to benefit ratio is considered unfavorable.     

Therapeutic drug monitoring: antiarrhythmic drugs

Two experiments were carried out to test the hypothesis that follicles recovered from Meishan animals may provide a more favourable environment for oocyte maturation in vitro than follicles recovered from Large-White hybrid animals. In Experiment 1, all follicles > or = 4 mm were recovered from six Meishan and seven Large-White hybrid gilts in the late follicular phase and healthy oocyte cumulus complexes recovered. Cumulus oocyte complexes were randomly divided into two groups, and each group cultured for 27 or 34 h (62 and 64; 56 and 56 for Meishan and Large-White hybrid, respectively) in defined medium in the presence of either of the two largest follicle shells per animal. Subsequent examination of oocyte nuclear maturation showed that although maturation did not differ significantly between the breeds after 27 h, more (P < 0.01) Meishan oocytes co-cultured with Meishan follicles developed to metaphase II stage than Large-White hybrid oocytes co-cultured with Large-White hybrid follicles after 34 h. The next eight largest follicles per animal were cultured for 34 h to produce conditioned media. In Experiment 2, oocytes recovered from the slaughterhouse were matured for 46 h in the presence of conditioned media from Meishan (612 oocytes) or Large-White hybrid (731 oocytes) follicles, or in fresh medium in the presence of a follicle shell from slaughterhouse ovaries. Oocytes were then inseminated and 12 h later examined for penetration and male pronuclear formation. A higher (P < 0.05) percentage of oocytes cultured in Meishan follicle conditioned medium underwent sperm penetration and male pronuclear formation than oocytes cultured in conditioned media from Large-White hybrid animals. Concentration of oestradiol and progesterone in the conditioned media did not differ between the breeds (P > 0.1). In conclusion, these results suggest that (1) Meishan oocytes have advanced maturational capacity when cultured with Meishan preovulatory follicle shells and (2) differences in follicle maturation in the Meishan compared to the Large-White hybrid pig may result in an improved ability of the follicles, via conditioned media, to support oocyte maturation and fertilization in vitro.     

New evolvement of antiarrhythmic drugs

The Cardiac Arrhythmia Suppression Trial (CAST) casted serious doubts on the usefulness of Class I antiarrhythmic drugs, causing us to turn our attention from drugs impairing conduction of excitation in the myocardium by blocking sodium channels toward those producing increased refractoriness of myocardial cells by blocking potassium channels. This change in the direction of thinking from the "Na+ channel paradigm" to "K+ channel paradigm" resulted in the generation of newly synthetized Class III drugs that have the common electrophysiological property of suppressing outward K+ currents (IK, IK1, Ito) without affecting inward currents (INa, ICa). However, their reversed use-dependence of action potential duration prolonging effect contributes to their untoward action of proarrhythmias. It is still controversial if ion channel blockers acting solely on a certain kind of ion channels are more beneficial than drugs having compound actions such as amiodarone or sotalol. Molecular biology, if combined with arrhythmology, is expected to provide new chemical and pharmacological bases for creating novel antiarrhythmic drugs.     

Postrepolarization refractoriness versus conduction slowing caused by class I antiarrhythmic drugs: antiarrhythmic and proarrhythmic effects

BACKGROUND: Conduction block may be both antiarrhythmic and proarrhythmic. Drug-induced postrepolarization refractoriness (PRR) may prevent premature excitation and tachyarrhythmia induction. The effects of propafenone and procainamide on these parameters, and their antiarrhythmic or proarrhythmic consequences, were investigated. METHODS AND RESULTS: In 11 isolated Langendorff-perfused rabbit hearts, monophasic action potentials (MAPs) were recorded simultaneously from six to seven different right and left ventricular sites, along with a volume-conducted ECG. All recordings were used to discern ventricular tachycardia (VT) or ventricular fibrillation (VF) induced by repetitive extrastimulation (S2-S5) or 10-second burst stimulation at 25 to 200 Hz at baseline and after addition of procainamide (20 micromol/L) or propafenone (1 micromol/L) to the perfusate. MAPs were analyzed for action potential duration at 90% repolarization (APD90), conduction times (CT) between the pacing site and the other MAPs, and PRR (effective refractory period-APD90=PRR) and related to the induction of VT or VF. During steady-state pacing, procainamide and propafenone prolonged APD90 by 12% and 14%, respectively. Procainamide slowed mean CT by 40% during S2-S5 pacing, whereas propafenone slowed mean CT by up to 400% (P<0.001 versus baseline and procainamide). Wavelength was not changed significantly by procainamide but was shortened fourfold by propafenone at S5. Both drugs produced PRR, which was associated with a 70% decrease in VF inducibility with procainamide and elimination of VF with propafenone. Despite this protection from VF, monomorphic VT was induced with propafenone in 57% of burst stimulations. CONCLUSIONS: Drug-induced PRR protects against VF induction. Propafenone promotes slow monomorphic VT, probably by use-dependent conduction slowing and wavelength shortening.     

Left ventricular lesions in arrhythmogenic right ventricular dysplasia and 12-lead electrocardiographic findings

Left ventricular lesions in arrhythmogenic right ventricular dysplasia have not been well described, and the relationship between the left ventricular lesions and the 12-lead electrocardiographic findings has not been analyzed. This study examined whether the presence of left ventricular lesions and the extent of right ventricular lesions due to arrhythmogenic right ventricular dysplasia are predictable by 12-lead electrocardiographic findings. The 12-lead electrocardiograms during sinus rhythm and left and right ventriculography were studied in 29 patients (27 males and 2 females, mean age 42.6 +/- 15.5 years) diagnosed by the current criteria for this disease. After evaluation, patients were divided into two groups: those with normal left ventricles (normal group) and those with left ventricular wall motion abnormalities (abnormal group). Seventeen of the 29 patients (59%) were classified into the abnormal group. Left ventricular wall motion abnormalities were located in the posterolateral (4 patients), apical (1), and posterolateral and apical regions (12). QS patterns of abnormal Q waves in lead I, aVL or V5, V6 rS patterns (R/S ratio < 1) in leads I and V6, and/or R or Rs patterns (R/S ratio > 1) in lead V1 were observed in all patients in the abnormal group, but in none in the normal group. There was a positive correlation between the right ventricular end-diastolic volume index and the number of precordial negative T waves (r = 0.746, p < 0.0001), and the time from onset of the QRS to the terminal portion of the epsilon wave in lead V1 (r = 0.627, p < 0.001). The correlation coefficients showed no significant differences between the groups. A left ventricular lesion associated with arrhythmogenic right ventricular dysplasia was not unusual (59%), and our study suggests that the posterolateral and apical regions are the most frequent sites. The presence of these lesions were predictable by the QRS abnormalities. Moreover, regardless of the presence of such a lesion, the extent of the right ventricular lesion is also predictable by the 12-lead electrocardiographic findings.     

Comparative electrophysiologic findings between responders and nonresponders to class III antiarrhythmic drugs among patients with ventricular tachyarrhythmia

Rabbits received conditional discrimination training using contextual stimuli to set the occasion for stimulus pairings during eyelid conditioning. Specifically, animals were exposed to either the presence or the absence of an oscillating chamber light throughout the intertrial interval (50 +/- 10 s). For half the animals, this light signaled paired presentations of a discrete tone conditioned stimulus (CS) and air puff unconditioned stimulus (US) while darkness signaled presentations of only the tone CS. The remaining animals experienced the opposite contextual relationship to the conditioning stimuli. These trial types occurred pseudo-randomly across a session, with all transitions between contextual settings (i.e., light or dark) taking place immediately at the CS-US offset. Under these conditions, animals successfully utilized the contextual stimuli as conditional cues for differential responding to the shared CS. Moreover, both light and dark were equally effective as discriminative stimuli. A subset of animals received further training in which the contextual contingency was removed by restricting all conditioning to the CS-alone context. Without the contingency in place, subsequent CS presentations (paired and CS-alone) evoked equivalent conditioned responding across three sessions of training. Following the reinstatement of the contextual contingencies, discriminatory responding was immediately observed and returned to previous levels within three sessions. Finally, animals appeared to use the static representation of the conditional cue, rather than the phasic transition between cues, for discriminatory responding. These findings are discussed in terms of current neurobiological models of eyelid conditioning.     

Ibutilide: an antiarrhythmic agent for the treatment of atrial fibrillation or flutter

The results of nineteen semiconstrained modified Coonrad-Morrey total elbow arthroplasties performed in nineteen patients to treat instability were evaluated at an average of seventy-two months (range, twenty-five to 128 months) postoperatively. Preoperatively, all patients had either a flail elbow or gross instability of the elbow that prevented useful function of the extremity. The instability of sixteen elbows was the result of a traumatic injury or of the treatment of such an injury. The most recent result was satisfactory for sixteen elbows and unsatisfactory for three. The average overall Mayo elbow performance score increased from 44 points preoperatively to 86 points postoperatively. At the most recent follow-up examination, no elbow was unstable. The average arc of flexion was from 25 degrees (range, 0 to 60 degrees) to 128 degrees (range, 30 to 142 degrees), which represented a 58-degree increase from the preoperative average arc. Sixteen patients had little or no pain after the arthroplasty. There were four complications in four patients. Three complications (loosening of the humeral component in one patient and a fracture of the ulnar component in two) occurred postoperatively; all three were treated with a revision procedure. The other complication (a fracture of the olecranon) occurred intraoperatively and was treated with tension-band fixation; the most recent outcome was not affected. Radiographically, one patient had complete (type-V) radiolucency about the humeral component. None of the nine patients for whom true anteroposterior radiographs were available had evidence of wear of the bushings. The bone graft behind the anterior flange of the humeral prosthesis was mature in fourteen elbows, incomplete in two, and resorbed in two. One patient was excluded from this analysis because radiographs were not available. Instability of the elbow resulting in the inability to use the extremity is a challenging clinical situation. However, in patients who are more than sixty years old and in selected patients who are less than sixty years old but who have extensive loss of bone as a result of severe injury, have had multiple operations, or have rheumatoid arthritis, total elbow arthroplasty with a linked, semiconstrained prosthesis reestablishes a mobile, stable joint without premature loosening or failure of the components. In our experience, the use of customized implants, maintenance of the muscular attachments to the epicondyles, and reconstruction of the epicondyles to the implant were unnecessary.     

Right ventricular arrhythmia in the absence of arrhythmogenic dysplasia: MR imaging of myocardial abnormalities

PURPOSE: To evaluate right ventricular abnormalities with magnetic resonance (MR) imaging in patients with arrhythmia but without arrhythmogenic dysplasia. MATERIALS AND METHODS: In 53 patients being evaluated for right ventricular arrhythmia and 15 control subjects, MR imaging was performed to evaluate fixed thinning, fatty replacement, or reduced systolic wall thickening or motion. A diagnosis of idiopathic right ventricular outflow tract tachycardia or indeterminate was assigned for each patient, and the severity of arrhythmia was categorized. RESULTS: Right ventricular abnormalities were revealed in 32 (60%) of the 53 patients: fixed thinning in 27 (84%), fatty replacement in eight (25%), and reduced wall thickening or motion in 31 (97%). Right ventricular abnormalities were found in 35 (76%) of 46 patients with idiopathic right ventricular outflow tract tachycardia and in seven (39%) of 18 patients with indeterminate diagnoses (P = .022). CONCLUSION: Mild right ventricular abnormalities are likely sources for arrhythmias, even in the absence of arrhythmogenic right ventricular dysplasia.     

Contrast media-induced ventricular fibrillation: an experimental study of the effects of dimeric contrast media during wedged catheter injection in dogs

Expression/induction of the 72 and 60 kDa heat shock proteins (HSPS 72 and 60) in cultured human keratinocytes by high calcium was studied with immunofluorescent staining and the flow cytometric method. Normal human keratinocytes cultured in serum free, low calcium medium (Ca2+, 0.1 mM) at 3-passage weakly expressed HSP 60, but not HSP 72, as fine granules in the cytoplasm. HSP 72 was induced in the perinuclear cytosomal area and then in the nucleus after transferring the cells in high calcium medium (Ca2+, 1.8 mM). Whereas the nuclear accumulation began to decrease 24 h after the treatment, the perinuclear cytosomal staining continued. High calcium also augmented the expression of HSP 60 as coarse granules in the cytoplasm. Flow cytometric analyses quantitatively revealed the induction of HSP 72 and the upregulation of HSP 60 by high calcium treatment. Our results clearly demonstrated that extracellular calcium concentration modifies the level of expression of HSP 72 and 60 in normal human keratinocytes, indicating the importance of the careful attention to medium condition in evaluating the expression of HSPS 72 and 60 in cultured keratinocytes.     

The ionic mechanisms of early after depolarization in mouse ventricular myocytes: the role of IK1

The occurrence of early after depolarization (EAD) in single mouse ventricular myocytes was observed and its ionic mechanisms were studied using the patch clamp technique. Under treatment with perfusion of Tyrode's solution containing 3 mM KCl and 3 mM CsCl, 3/6 cases exhibited EAD, while with 3 mM KCl or 3 mM CsCl alone, EAD was not induced. The background steady-state current-voltage (I-V) curves of the myocytes showed no negative slope, i.e., the slope in the range of 50 mV positive to the reversal potential was virtually flat and stayed at a low current level. Under perfusion of 3 mM KCl and 3 mM CsCl, the outward current in the above region decreased nearly to 0: in the myocytes which exhibited EAD, a net inward current (crossover) was displayed in the same region, which was abolished by 10 microM TTX and 10 microM nifedipine. The results of whole-cell inward rectifier current I-V curves were similar to the above background steady-state I-V curves. In mouse ventricular myocytes, transient outward current was very strong with a peak current density of 63 +/- 19 pA/pF, whereas low K+ and Cs+ had no significant effect. 11/30 cases showed obvious delayed rectifier current, but the tail current recorded by envelope method was relatively weak (1.19 +/- 0.35 pA/pF) and insensitive to CsCl or changing of the KCl concentration. The results suggest that under treatment with low K+ and Cs+, the inhibition of inward rectifier current is the basis of the formation of second plateau, while Na and Ca currents contribute to the generation of triggered bursts.     

Long-term efficacy of d/l sotalol in patients with sustained ventricular tachycardia refractory to class I antiarrhythmic drugs

The efficacy of d/l sotalol was investigated in 50 patients (43 men, seven women; 33 with coronary artery disease, 15 with dilated cardiomyopathy; ejection fraction 33 +/- 10%) with inducible sustained ventricular tachycardia. Before d/l sotalol a mean of 2 +/- 1 (1 to 4) class I antiarrhythmic drugs were ineffective. In 24 patients (48%) oral d/l sotalol (320 +/- 47 mg.day-1) prevented induction of the ventricular tachycardia; in 23 patients the ventricular tachycardia remained inducible (d/l sotalol 326 +/- 50 mg.day-1). The electrophysiological effects of d/l sotalol did not differ between patients in whom d/l sotalol prevented induction of ventricular tachycardia and those in whom the ventricular tachycardia remained inducible. In two patients, torsade des pointes developed after oral application of d/l sotalol; one patient suffered from severe hypotension even with 80 mg of sotalol per day. During long-term follow-up (27 +/- 12 months) 5/24 patients (21%) had a non-fatal recurrence of ventricular tachycardia (1 week to 21 months), one patient died suddenly and another from progressive heart failure. In patients in whom the ventricular tachycardia could be induced despite oral application of d/l sotalol, control of the ventricular tachyarrhythmia was attempted by the use of sotalol in combination with mexiletine (n = 2), amiodarone (n = 9), catheter ablation (n = 2), antitachycardia surgery (n = 1) or the implantation of an automatic cardioverter defibrillator (n = 12). Recurrence of ventricular tachycardia was observed in four patients without an implanted cardioverter defibrillator. Seven out of 12 patients with an implanted cardioverter defibrillator received appropriate shocks or successful antitachycardia pacing. Although no patient died suddenly, overall mortality was 17% in this group. It is concluded that d/l sotalol is highly effective in the suppression of sustained monomorphic ventricular tachycardia inducible by programmed electrical stimulation. However during a mean follow-up of 27 +/- 12 months a recurrence of ventricular tachycardia was seen in 21% of patients, and one patient died suddenly.     

Atropine-induced ventricular fibrillation: case report and review of the literature

A bradycardic and mildly hypotensive acute myocardial infarction patient developed sinus tachycardia, ventricular tachycardia, flutter, and fibrillation following intravenous atropine. Previous case reports are reviewed and the literature regarding the advisability of this mode of therapy is discussed. In the light of conflicting opinion as to the necessity of atropine in the mildly hypotensive and bradycardic acute myocardial infarction patient, and in view of its potentially deliterious effects on ischemic myocardium, a cautious and selective application of this drug is advised.     

The role of neurochemical mechanisms in the pathogenesis of kinetoses and the therapeutic-prophylactic action of drugs]

Experimental and clinical data on the neurochemical and neurohumoral mechanisms underlying the pathogenesis and therapeutic and preventive effects of drugs are generalized. Literature data and the authors' own data concerning drugs used for the prevention and treatment of kinetoses are given. The possible mechanisms of their effect against motion sickness are suggested. New ideas of the means of search for substances possessing vestibuloprotective activity, and the principles of rational pharmacological correction of vestibuloautonomic disorders in motion sickness are discussed.     

Out-of-hospital ventricular fibrillation in children and adolescents: causes and outcomes

STUDY OBJECTIVE: To compare causes and outcomes of patients younger than 20 years with an initial rhythm of ventricular fibrillation versus asystole and pulseless electrical activity. DESIGN: Retrospective cohort study. SETTING: Urban/suburban prehospital system. PARTICIPANTS: Pulseless, nonbreathing patients less than 20 years who underwent out-of-hospital resuscitation. Patients with lividity or rigor mortis or who were less than 6 months old and died of sudden infant death syndrome were excluded. RESULTS: Ventricular fibrillation was the initial rhythm in 19% (29 of 157) of the cardiac arrests. Rhythm assessment was performed by the first responder in only 44% (69 of 157) of patients. All three rhythm groups were similar in age distribution, frequency of intubation (96%), and vascular access (92%); 93% of ventricular fibrillation patients were defibrillated. The causes of ventricular fibrillation were distributed evenly among medical illnesses, overdoses, drownings, and trauma, only two patients had congenital heart defects. Seventeen percent were discharged with no or mild disability, compared with 2% of asystole/pulseless electrical activity patients (P = .003). CONCLUSION: Ventricular fibrillation is not rare in child and adolescent prehospital cardiac arrest, and these patients have a better outcome than those with asystole or pulseless electrical activity. Earlier recognition and treatment of ventricular fibrillation might improve pediatric cardiac arrest survival rates.