ECG in neonate mice with spinal muscular atrophy allows assessment of drug efficacy.

Molecular technologies have produced diverse arrays of animal models for studying genetic diseases and potential therapeutics. Many have neonatal phenotypes. Spinal muscular atrophy (SMA) is a neuromuscular disorder primarily affecting children, and is of great interest in translational medicine. The most widely used SMA mouse models require all phenotyping to be performed in neonates since they do not survive much past weaning. Pre-clinical studies in neonate mice can be hindered by toxicity and a lack of quality phenotyping assays, since many assays are invalid in pups or require subjective scoring with poor inter-rater variability. We find, however, that passive electrocardiography (ECG) recording in conscious 11-day old SMA mice provides sensitive outcome measures, detecting large differences in heart rate, cardiac conduction, and autonomic control resulting from disease. We find significant drug benefits upon treatment with G418, an aminoglycoside targeting the underlying protein deficiency, even in the absence of overt effects on growth and survival. These findings provide several quantitative physiological biomarkers for SMA preclinical studies, and will be of utility to diverse disease models featuring neonatal cardiac arrhythmias.

Rate-dependent and site-specific conduction block at the posterior right atrium and drug effects evaluated using a noncontact mapping system in patients with typical atrial flutter.

INTRODUCTION: Conduction block in the posterior right atrium (RA) plays an important role in perpetuating atrial flutter (AFL). Although conduction blocks have functional properties, it is not clear how the block line changes with the pacing rate, pacing site, and administration of antiarrhythmic drugs. METHODS AND RESULTS: Forty patients with typical AFL were enrolled. Pacing (110, 170, 230 ppm) from the coronary sinus ostium (CSo) and low lateral RA was performed. After 1 mg/kg pilsicainide (pure sodium channel blockade) administration, the pacing protocol was repeated. Conduction block was assessed based on a color-coded isopotential map and 20 points of virtual unipolar electrograms in the posterior RA using noncontact mapping. Block line proportion was defined as the percentage of length of the block line between the superior and inferior vena cava. The pacing rate-dependent extension of the block proportion was significant during pacing from both sides (pacing from the CSo: 59 ± 17% at 110 ppm, 69 ± 16% at 230 ppm, P < 0.05; pacing from the low lateral RA: 43 ± 19% at 110 ppm, 55 ± 22% at 230 ppm, P < 0.05). The block line was significantly longer during CSo pacing than during low lateral RA pacing at each rate (all P < 0.05). After pilsicainide administration, the block line extended further. CONCLUSION: In addition to pacing rate-dependent and site-dependent changes in the block line, pilsicainide further extended the block line length. This phenomenon explains the clinical observation that counterclockwise AFL occurs more frequently than clockwise AFL, and the mechanism of class IC AFL.

[Successful treatment by 4--aminopyridine of three cases of severe verapamil poisoning]. / Skuteczna terapia 4-aminopirydyna trzech przypadków ciezkiego zatrucia werapamilem.

Three cases of verapamil intoxication were presented. In all cases shock and circulatory insufficiency were observed. In case no. 1 respiratory insufficiency and confusion were observed, in case no. 3 second-degree atrioventricular block was noted. The protracted hypotension (shock), circulatory insufficiency and atrioventricular block did not respond to calcium therapy, high dose of vasopressor amines and atropine. The addition of 4-aminopyridine (4-AP) infusion resulted in fast receding of poisoning symptoms; receding of atrioventricular block, cardiogenic shock and circulatory insufficiency. These cases suggest the usefulness of 4-AP in the treatment of verapamil poisoning. However, confirmation of the effectiveness of this substance for pharmacotherapy of calcium antagonists poisoning requires further clinical research. The influence of 4-AP on calcium channels is indirect. It blocks potassium channels K1 in cytoplasm side which makes potassium to stay inside the cell leading to depolarisation and opening of voltage-dependent calcium channels.

Comparison of the in vivo electrophysiological and proarrhythmic effects of amiodarone with those of a selective class III drug, sematilide, using a canine chronic atrioventricular block model.

Amiodarone effectively blocks both the sodium and calcium channels and beta-adrenoceptors, in addition to blocking several potassium currents including IKr, IKs, Ito, IK1, IKACh and IKNa. The incidence of clinical torsade de pointes (TdP) associated with amiodarone has been reported to be low and the present study compared the proarrhythmic potential of amiodarone with that of a selective IKr channel blocker, sematilide, using a canine chronic atrioventrucular block model. Amiodarone or sematilide (3 and 30 mg/kg; n=4 for each group) was administered orally without anesthesia under continuous ECG monitoring. Both drugs prolonged the QT interval, although the onset was faster for sematilide. The high dose of sematilide induced TdP in 3 of 4 animals, which caused their death, but neither the low dose of sematilide nor the 2 dosages of amiodarone induced lethal ventricular arrhythmias. These results suggest that IKr channel inhibition by amiodarone with its additional ion channel blocking action may contribute to the prevention of TdP.

Chronic amiodarone evokes no torsade de pointes arrhythmias despite QT lengthening in an animal model of acquired long-QT syndrome.

BACKGROUND: Amiodarone is an effective antiarrhythmic drug rarely associated with torsade de pointes arrhythmias (TdP). The noniodinated compound dronedarone could resemble amiodarone and be devoid of the adverse effects. In the dog with chronic complete atrioventricular (AV) block (CAVB) and acquired long-QT syndrome, the electrophysiological and proarrhythmic properties of the drugs were compared after 4 weeks of oral treatment. METHODS AND RESULTS: Amiodarone (n=7, 40 mg. kg(-1). d(-1)) and dronedarone (n=8, 20 mg/kg BID) were started at 6 weeks of CAVB (baseline). Six dogs served as controls. Surface ECGs and endocardially placed monophasic action potential catheters in the left (LV) and right (RV) ventricles were recorded to assess QTc time, action potential duration (APD), interventricular dispersion (DeltaAPD=LV APD minus RV APD), early afterdepolarizations (EADs), ectopic beats, and TdP. Both amiodarone (+21%) and dronedarone (+31%) increased QTc time. Amiodarone showed no increase in DeltaAPD in 4 of 7 dogs, whereas dronedarone augmented DeltaAPD in 7 of 8 animals. After dronedarone, TdP occurred in 4 of 8 dogs with the highest DeltaAPD (105+/-20 ms). TdP was never seen with amiodarone, not even in the dogs that had DeltaAPD values comparable to those with dronedarone. Furthermore, a difference existed in EADs and ectopic activity incidence (dronedarone 3 of 8; amiodarone 0 of 7), which was also seen during an epinephrine challenge. CONCLUSIONS: In the CAVB dog model, both amiodarone and dronedarone prolong QT time (class III effect). The absence of TdP with amiodarone seems to be related to homogeneous APD lengthening in the majority of dogs and the lack of EADs and/or ventricular ectopic beats in all.

Clinical experience with nisoldipine in patients with atrio-ventricular blocks.

The effect of the 1,4-dihydropyridine calcium antagonist nisoldipine (Bay k 5552) on the atrio-ventricular (AV) conduction was studied in 9 patients with AV blocks. The impuls propagation through the AV node (A-H time) and the bundle of His (H-V time) was determined before, 1-3 min and 10-15 min after the intravenous injection of nisoldipine (1.5 micrograms/kg body weight). Except for one patient, A-H and H-V times almost remained unaffected by the calcium antagonist. In this patient with an AV block II, Mobitz type I, A-H time transiently increased from 290 to 410 ms. Nisoldipine did not aggravate an AV block I or II to an AV block II or III, respectively. Furthermore, ventricular heart rates did not change significantly. It is concluded that, in general, nisoldipine does not impair the impulse propagation of the AV node in patients with AV blocks although a transient increase of the A-H time may occur.

[Effect of vasodilator agents on the character and incidence of cardiac arrhythmia in chronic heart failure]. / Einfluss der Vasodilatatoren auf den Charakter und die Häufigkeit von Herzrhythmusstörungen bei der chronischen Herzinsuffizienz.

In 50 patients with chronic congestive heart failure (CCHF, III or IV class), aged 62.8 +/- 9.1 years, who were treated with digoxin (Dx) and furosemide (F) (investigation A), continuous 24-hour ecg registration was performed according to Holter. Next, this treatment was extended by two-week administration of nifedipine (N) or isosorbide dinitrate (S) (investigation B), followed by one-month addition of captopril (Cp) (investigation C). During the last two weeks Dx, F, N or Dx, F, S were administered with Cp being withdrawn (investigation D). At the end of each stage of the treatment ecg registration was repeated according to Holter. At the same time, during the investigation A there were performed determinations of blood serum sodium, potassium and digoxin concentrations, two-dimensional echocardiography and evaluation of submaximal exercise tolerance. In 96 per cent of patients with CCHF, treated with Dx and F, cardiac rhythm disturbances were found. In 53.3 per cent life-threatening ventricular arrhythmias occurred, including unstable ventricular tachycardia in 11.1 per cent of patients. Addition of N or S to the classical treatment did not decrease either patient number or amounts of cardiac rhythm disturbances in individual classes according to Lown. Also Cp did not affect numbers of patients with cardiac rhythm disturbances, but it decreased numbers of patients with life-threatening ventricular arrhythmias from 53.3 per cent to 28.9 per cent (from 24/45 to 13/45). At the same time, Cp significantly decreased numbers of ventricular arrhythmias in class 3 and 4a (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Non-invasive electrophysiological evaluation of calcium antagonist long-term therapy.

The evaluated effects of oral administration of verapamil, diltiazem, and nifedipine in patients with first degree A-V block by using a new noninvasive technique: signal averaged ECG. The study group consists of 5 females and 3 males ranging from 52 to 70 years old. All patients showed a first degree A-V block at surface ECG and an abnormal A-V time (suprahisian lengthening) during signal averaged ECG (SAECG). Verapamil 240 mg/daily, diltiazem 180 mg/day and nifedipine 30 mg/day were given separately for a week followed by a wash out period of 5 days before giving next drugs. An ECG and SAECG were performed before and after every administration. PR, A-H and H-V interval were evaluated in every recording. Verapamil and diltiazem induced a significant lengthening of A-V conduction (PR increase was 15.4% and 15.1%, respectively). No significant modification appeared after nifedipine. Our data, using a noninvasive technique, agreed with values of previous invasive evaluations. We suggest precaution in using verapamil and diltiazem in patients with BAV 1 degree and advise a selective use of calcium antagonist therapy.

[Effect of nifedipine on sinus node and atrioventricular node function following autonomic blockade in the human]. / Die Wirkung von Nifedipin auf die Sinusknoten- und AV-Knoten-Funktion unter autonomer Blockade beim Menschen.

The effect of intravenously administered nifedipine (7.5 micrograms/kg) on sinus node and atrioventricular (AV) node function was evaluated in 17 patients, 9 of whom had sinus node disease after autonomic blockade (propranolol 0.2 mg/kg and atropine 0.04 mg/kg i.v.). The patients' ages ranged from 18 to 77 years. After nifedipine there was a nonsignificant increase in the median values for sinus cycle length from 750 ms to 760 ms, for sinus node recovery time from 1150 ms to 1240 ms, for corrected sinus node recovery time from 440 ms to 460 ms, and for sinoatrial conduction time from 63 ms to 75 ms. Nevertheless, nifedipine produced a significant increase in the AV node refractory periods (median values): the effective refractory period lengthened from 300 ms to 305 ms (rate 100/min) and from 290 ms to 300 ms (rate 120/min) respectively. The functional refractory period increased from 380 ms to 400 ms (rate 100/min) and from 385 ms to 410 ms (rate 120/min) respectively. The Wenckebach period was significantly prolonged from 370 ms to 390 ms. We conclude, therefore, that in the absence of autonomic control intravenous administration of nifedipine exerts a mild depressive effect on AV node but not on sinus node function.

Clinical and electrophysiologic findings in patients with paroxysmal slowing of the sinus rate and apparent Mobitz type II atrioventricular block.

Over five years, 13 patients with episodic apparent type II atrioventricular (AV) block associated with sinus slowing were seen. This phenomenon occurred only transiently during an acute illness in eight patients (group I) but recurred chronically in five (groupII). For the group as a whole, the mean spontaneous cycle length was 42% longer during the period of AV block compared with periods of 1:1 AV conduction (800 +/- 116 msec to 1138 +/- 489 msec) (P less than 0.05). Electrophysiologic studies in four group I patients showed no abnormalities, whereas abnormalities in AV nodal conduction and refractoriness or provocation of intranodal Mobitz type II AV block (during carotid massage) were observed in three patients in group II and were totally abolished by atropine. In group I patients, apparent type II AV block was self-limited. In the chronic group, recurrent symptoms required insertion of permanent pacemakers in two patients. Simultaneous type II block and sinus slowing appeared to be related to the effects of increased vagal tone on both nodal structures. Intracardiac pacing is not indicated for patients with transient episodes associated with an acute illness, but may be required for symptomatic patients with recurrent episodes.

[Anti-arrhythmic therapy with verapamil by intravenous infusion]. / Terapia antiaritmica con il verapamil per infusione endovenosa

Rapid and slow venous infusion of various doses of Verapamil in a mixed series of 185 cases of arrhythmia since 1968 is reported. Results and electrophysiological and ECG changes observed for each type of arrhythmia examined are considered separately: atrial fibrillation-flutter, supraventricular paroxystic tachycardia (atrial and/or junctional), and hyperkinetic ventricular arrhythmia. An association of i.v. Verapamil and a quinidine salt per os is suggested as an alternative to cardioversion in cases of recent atrial fibrillation-flutter. Results obtained in the treatment of arrhythmia due to electrical instability following angina and of angina following arrhythmia are also described. A study of His potentials as the premiss for using Verapamil in subjects with stimulus conductivity changes, including W.P.W. syndrome, is also reported. I.v. Verapamil was used in association with atrial and/or ventricular electrostimulation, and/or with electrical counter-shock in cases of arrhythmia (mostly supraventricular) that were especially refractory. Attention is drawn to the use of Verapamil in the control of arrhythmia after electrical cardioversion.