The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43.

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1-2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex-influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre-symptomatic diagnosis has the greatest clinical utility.

Radiofrequency ablation of atrial tachycardia originating from the triangle of Koch.

Atrial tachycardia (AT) originating in the triangle of Koch is reported rarely and presents a potential risk of atrioventricular (AV) block during radiofrequency (RF) catheter ablation. Eight patients with AT in the triangle of Koch undergoing RF ablation are presented. There were five women and three men, ranging in age from 32 to 74 years. One patient had bicuspid aortic valve disease, and the other seven patients had no structural heart disease. At electrophysiological study, AT was inducible in all eight patients. In one patient, AV nodal re-entrant tachycardia was also inducible. The site of AT was located by recording the earliest atrial activation during AT and successful RF ablation. Fluoroscopy confirmed the corresponding site to the region of the triangle of Koch. The earliest atrial activation was 35+/-9 ms before the surface P wave, and was recorded at the apex of the triangle of Koch near the bundle of His in six patients and midway between the bundle of His and coronary sinus os in two patients. At the successful RF application site, His potential was not recorded in any patient. The mean AV ratio was 5:1 (range 1:1 to 12:1). RF ablation at the successful site resulted in accelerated junctional rhythm in four of the eight patients and successfully terminated AT in all eight patients, with first-degree AV block in one patient. In conclusion, AT from the triangle of Koch is a distinct entity and RF ablation can be successfully performed; however, a potential risk of AV block remains.

The positive inotropic effect of compound II, a novel analogue of sotalol, on guinea-pig papillary muscles and single ventricular myocytes.

1. Compound II is a novel analogue of sotalol which has been reported to be free of beta-adrenoceptor and L-type calcium channel blocking actions. The effects of compound II on the contraction of guinea-pig papillary muscles (at 2 microM) and single ventricular myocytes (at 100 nM) were investigated. 2. Exposure to compound II caused a significant increase in the contraction of both preparations. 3. Compound II prolonged the action potential of the single myocytes and increased the magnitude of the Ca-activated current which was used as a qualitative indicator of the intracellular calcium transient. 4. The ratio of first/steady state Ca-activated currents evoked by short action potentials was not modified. This may indicate that compound II does not influence the normal functioning of the sarcoplasmic reticulum stores. 5. The observations are consistent with the hypothesis that action potential prolongation by compound II reduces Ca2+ extrusion via the Na-Ca exchange. This in turn allows increased uptake of calcium into the sarcoplasmic reticulum stores so that more calcium is available for release by subsequent action potentials, leading to an increase in intracellular calcium transients and contractions.

Actions and mechanisms of action of novel analogues of sotalol on guinea-pig and rabbit ventricular cells.

1. The actions and mechanisms of action of novel analogues of sotalol which prolong cardiac action potentials were investigated in guinea-pig and rabbit isolated ventricular cells. 2. In guinea-pig and rabbit cells the compounds significantly prolonged action potential duration at 20% and 90% repolarization levels without affecting resting membrane potential. In guinea-pig but not rabbit cells there was an increase in action potential amplitude and in rabbit cells there was no change in the shape or position of the 'notch' in the action potential. 3. Possible mechanisms of action were studied in more detail in the case of compound II (1-(4-methanesulphonamidophenoxy)-3-(N-methyl 3,4 dichlorophenylethylamino)-2-propanol). Prolongation of action potential duration continued to occur in the presence of nisoldipine, and calcium currents recorded under voltage-clamp conditions were not reduced by compound II (1 microM). Action potential prolongation by compound II was also unaffected in the presence of 10 microM tetrodotoxin. 4. Compound II (1 microM) did not influence IK1 assessed from the current during ramp changes in membrane potential (20 mV s-1) over the range -90 to -10 mV. 5. Compound II (1 microM) blocked time-dependent delayed rectifier potassium current (IK) activated by step depolarizations and recorded as an outward tail following repolarization. When a submaximal concentration (50 nM) was applied there was no change in the apparent reversal potential of IK.6. Submaximal concentrations of compound II were without effect on activation of IK with time at a membrane potential of + 40 mV, and no changes were detected in the time constants of the two components of IK decay over the range of potentials - 60 to 0 mV. Compound 11 (50 nM) appeared to cause a small shift in the activation of IK with membrane potential (an apparent shift of approximately 10mV in the depolarizing direction at the mid-point of the curve).7. Log dose-response curves for action potential prolongation and for blockade of IK by compound II were similar. The IC50 for compound II was approximately 30 nM.8. It is concluded that this novel series of compounds prolongs action potential duration, and that in the case of compound II the evidence supports a potent selective effect on the time-dependent potassium current IK, an effect which can account for this prolongation.

The synthesis and potassium channel blocking activity of some (4-methanesulfonamidophenoxy)propanolamines as potential class III antiarrhythmic agents.

The synthesis of 22 (4-methanesulfonamidophenoxy)propanolamines and their testing on isolated guinea pig cardiac myocytes, on isolated preparations from guinea pig atria, and on rat blood pressure are described. Secondary amines in the series (11a-f) showed residual beta-blocking activity, whereas incorporation of N-methyl phenylalkyl and 4-phenyl alicyclic amine groups abolished beta-blocking activity but led to enhanced ability to block the channel conducting the delayed rectified potassium current, and hence produced an increase in the cardiac action potential duration (APD). Incorporation of hydrophobic Cl and CF3 groups further enhanced potassium channel blocking activity. Compounds 81 and 8m produced a significant increase in APD at nanomolar concentrations, with no effect on cardiac muscle conduction velocity, and hence merit further investigation as Class III antiarrhythmic agents. Methylation of the methanesulfonamido group abolished channel-blocking activity; 4-carboxy and 3-methanesulfonamido analogues retained activity but at a reduced level.