DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model.
Myotonic dystrophy (DM) is the most common form of muscular dystrophy and is caused by expansion of a CTG trinucleotide repeat on human chromosome 19. Patients with DM develop atrioventricular conduction disturbances, the principal cardiac manifestation of this disease. The etiology of the pathophysiological changes observed in DM has yet to be resolved. Haploinsufficiency of myotonic dystrophy protein kinase (DMPK), DM locus-associated homeodomain protein (DMAHP) and/or titration of RNA-binding proteins by expanded CUG sequences have been hypothesized to underlie the multi-system defects observed in DM. Using an in vivo murine electrophysiology study, we show that cardiac conduction is exquisitely sensitive to DMPK gene dosage. DMPK-/- mice develop cardiac conduction defects which include first-, second-, and third-degree atrioventricular (A-V) block. Our results demonstrate that the A-V node and the His-Purkinje regions of the conduction system are specifically compromised by DMPK loss. Importantly, DMPK+/- mice develop first-degree heart block, a conduction defect strikingly similar to that observed in DM patients. These results demonstrate that DMPK dosage is a critical element modulating cardiac conduction integrity and conclusively link haploinsufficiency of DMPK with cardiac disease in myotonic dystrophy. (+info)
Junctional ectopic tachycardia evolving into complete heart block.
Transition from congenital junctional ectopic tachycardia to complete AV block was observed in an 8 month old girl, over a 36 hour period, during initial hospital admission. Two years later she had evidence of a rapidly increasing left ventricular end diastolic diameter, associated with lowest heart rates during sleep of < 30 beats/min. A transvenous permanent pacemaker was therefore implanted. This finding supports the idea that a pathological process in the area of the AV junction, initially presenting as junctional ectopic tachycardia may later extend to sudden complete atrioventricular block. (+info)
Modulation of AV nodal and Hisian conduction by changes in extracellular space.
Previous studies have demonstrated that the extracellular space (ECS) component of the atrioventricular (AV) node and His bundle region is larger than the ECS in adjacent contractile myocardium. The potential physiological significance of this observation was examined in a canine blood-perfused AV nodal preparation. Mannitol, an ECS osmotic expander, was infused directly into either the AV node or His bundle region. This resulted in a significant dose-dependent increase in the AV nodal or His-ventricular conduction time and in the AV nodal effective refractory period. Mannitol infusion eventually resulted in Wenckebach block (n = 6), which reversed with mannitol washout. The ratio of AV nodal to left ventricular ECS in tissue frozen immediately on the development of heart block (n = 8) was significantly higher in the region of block (4.53 +/- 0.61) compared with that in control preparations (2.23 +/- 0.35, n = 6, P < 0.01) and donor dog hearts (2.45 +/- 0.18, n = 11, P < 0.01) not exposed to mannitol. With lower mannitol rates (10% of total blood flow), AV nodal conduction times increased by 5-10% and the AV node became supersensitive to adenosine, acetylcholine, and carbachol, but not to norepinephrine. We conclude that mannitol-induced changes in AV node and His bundle ECS markedly alter conduction system electrophysiology and the sensitivity of conductive tissues to purinergic and cholinergic agonists. (+info)
Atrioventricular block occurring several months after radiofrequency ablation for the treatment of atrioventricular nodal re-entrant tachycardia.
Atrioventricular (AV) block following radiofrequency (RF) ablation for the treatment of AV nodal re-entrant tachycardia (AVNRT) is a rare but well recognised complication of the procedure--the reported incidence ranges from 1% to 21%. Almost all cases of AV block occur during or shortly after the procedure, are transient, and recover quickly. Two patients (a 22 year man and a 72 year old woman) with symptomatic AV block occurring several months after slow pathway RF ablation, requiring permanent pacemaker implantation, are described. Both patients had had several 24 hour Holter recordings before the procedure, and in neither case was there any evidence of intermittent or persistent AV block. This is a rare complication with no definitive predictors; however, all efforts should be made to exclude AV block in patients presenting with suggestive symptoms following RF ablation. With the wide use of RF ablation for the treatment of AVNRT, more cases are likely to occur. A registry should allow documentation of the incidence of this complication. (+info)
Catheter-induced mechanical trauma to accessory pathways during radiofrequency ablation: incidence, predictors and clinical implications.
OBJECTIVES: To evaluate the incidence, predictors and clinical implications of nonintentionally catheter-induced mechanical trauma to accessory pathways during radiofrequency ablation procedures. BACKGROUND: Data on the incidence and significance of catheter-induced trauma to accessory pathways are scarce. METHODS: Consecutive patients (n = 381) undergoing radiofrequency ablation of accessory pathways at two different institutions were closely monitored for appearance of mechanical block of accessory pathways during catheter manipulation. RESULTS: Mechanical trauma to accessory pathways was observed in 37 (9.7%) patients. According to a multivariate analysis, the only independent variable associated with this phenomenon was the anatomical pathway location (p = 0.0001). The incidence of trauma of either right anteroseptal (38.5%) or right atriofascicular pathways (33.3%) was significantly greater than that of pathways (< or =10%) at all remaining locations (p < 0.0001). The duration of conduction block observed ranged from < or =1 min to >30 min in 19% and 35% of patients, respectively. "Immediate" application of radiofrequency pulses at sites of mechanical block (<1 min after occurrence) was associated with a 78% long-term success rate at follow-up. This contrasted with a 25% long-term success rate in patients in whom pulses were delivered 30 min after occurrence of block ("delayed pulses"). Finally, in 24% of patients persistent trauma-induced conduction block led to discontinuation of the ablation procedure. CONCLUSIONS: Trauma to accessory pathways is more common than previously recognized and frequently results in prolongation or discontinuation of the ablation procedure and in lower success rates. The only independent predictor of catheter-trauma to accessory pathways is the pathway location. (+info)
Conduction disturbances and increased atrial vulnerability in Connexin40-deficient mice analyzed by transesophageal stimulation.
BACKGROUND: Recently, it has been reported that connexin40 (Cx40) deficiency in targeted mouse mutants is associated with a prolongation of P-wave and QRS complex duration on surface electrograms. The specific effects of Cx40 deficiency on sinus node function, sinoatrial, and atrioventricular conduction properties as well as on atrial vulnerability have not yet been investigated systematically by electrophysiological analysis. METHODS AND RESULTS: Fifty-two mice (18 Cx40(+/+), 15 Cx40(+/-), and 19 Cx40(-/-) mice) were subjected to rapid atrial transesophageal stimulation after anesthesia with avertin. A significant prolongation of sinus node recovery time was noticed in Cx40(-/-) mice compared with Cx40(+/-) and Cx40(+/+) mice (287.8+/-109.0 vs 211.1+/-61.8 vs 204.4+/-60.9 ms; P<0.05). In addition, Wenckebach periodicity occurred at significantly longer atrial pacing cycle lengths in Cx40(-/-) mice than in Cx40(+/-) or Cx40(+/+) mice (93. 3+/-11.8 vs 83.9+/-9.7 vs 82.8+/-8.0 ms, P<0.05). Analysis of 27 Cx40(-/-) mice showed a significant increase in intra-atrial conduction time and atrioventricular conduction time compared with 52 Cx40(+/-) and 31 wild-type (Cx40(+/+)) mice. Furthermore, in Cx40(-/-) mice, atrial tachyarrhythmias could be induced frequently by atrial burst pacing, whereas no atrial arrhythmias were inducible in heterozygous or wild-type mice. CONCLUSIONS: This study demonstrates that Cx40 deficiency is associated with sinoatrial, intra-atrial, and atrioventricular conduction disturbances. In atrial myocardium of the mouse, Cx40 deficiency results in increased atrial vulnerability and might contribute to arrhythmogenesis. (+info)
Reversion to sinus rhythm 11 years after surgically induced heart block.
A patient is presented in whom the heart reverted spontaneously to sinus rhythm 11 years after surgical closure of a ventricular septal defect complicated by complete heart block. It seems unlikely that regeneration of fibres in the bundle of His, if these had indeed been destroyed, could account for the restoration of sinus rhythm after so long an interval. (+info)
Electrophysiological effects of mexiletine in man.
The electrophysiological effects of intravenous mexiletine in a dose of 200 to 250 mg given over 5 minutes, followed by continuous infusion of 60 to 90 mg per hour, were studied in 5 patients with normal conduction and in 20 patients with a variety of disturbances of impulse formation and conduction, by means of His bundle electrography, atrial pacing, and the extrastimulus method. In all but 2 patients the plasma level was above the lower therapeutic limit. Mexiletine had no consistent effects on sinus frequency and atrial refractoriness. The sinoatrial recovery time changed inconsistently in both directions; however, of the 5 patients in whom an increase was evident, 3 had sinus node dysfunction. In most patients mexiletine increased the AV nodal conduction time at paced atrial rates and shifted the Wenckebach point to a lower atrial rate. The effective refractory period of the AV node was not consistently influenced, while the functional refractory period increased in 12 out of 14 patients. The HV intervals increased by a mean of 11 ms in 8 patients and were unchanged in 17. Both the relative and effective refractory period of the His-Purkinje system increased after mexiletine. Non-cardiac side effects occurred in 7 out of 25 patients, and cardiac side effects, including one serious, in 2. The results indicate that mexiletine shares some electrophysiological properties with procainamide and quinidine, when given to patients with conduction defects, and that the drug should not be used in patients with pre-existing impairment of impulse formation or conduction. It has additional effects on AV nodal conduction which may be of value in the treatment of re-entrant tachycardias involving the AV node. (+info)