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The structure and functioning of the atrioventricular (AV) node has remained mysterious owing to its high degree of complexity. In this review article, we integrate advances in knowledge regarding connexin expression in the AV node. Complex patterning of 4 different connexin isoforms with single channel conductances ranging from ultralow to high explains the dual pathway electrophysiology of the AV node, the presence of 2 nodal extensions, longitudinal dissociation in the penetrating bundle, and, most importantly, how the AV node maintains slow conduction between the atria and the ventricles. It is shown that the complex patterning of connexins is the consequence of the embryonic development of the cardiac conduction system. Finally, it is argued that connexin dysregulation may be responsible for AV node dysfunction.

BackgroundMacitentan is a new endothelin receptor antagonist that is used to treat pulmonary arterial hypertension in humans. Treatment of established pulmonary hypertension with macitentan was studied using the monocrotaline model of pulmonary hypertension.MethodsThree groups of rats were created (n = 12): control (CON: macitentan only), monocrotaline (MCT: monocrotaline only) and macitentan (MACI: macitentan and monocrotaline). Monocrotaline (60 mg/kg) was injected in the MCT and MACI groups on day 0; volume matched saline was injected in the CON groups. Macitentan therapy (30 mg/kg/day) was commenced on day 11 in the CON and MACI groups. Serial echocardiography and ECGs were performed. The rats were sacrificed if they showed clinical deterioration.ResultsThe MCT and MACI rats showed signs of pulmonary hypertension by day 7 (maximum pulmonary velocity, CON 1.15 ± 0.15 m/s vs MCT 1.04 ± 0.10 m/s vs MACI 0.99 ± 0.18 m/s; p < 0.05). Both the MCT and MACI groups developed pulmonary hypertension, but this was less severe in the MACI group (day 21 pulmonary artery acceleration time, MCT 17.55 ± 1.56 ms vs MACI 22.55 ± 1.00 ms; pulmonary artery deceleration, MCT 34.72 ± 3.72 m/s2 vs MACI 17.30 ± 1.89 m/s2; p < 0.05). Right ventricular hypertrophy and QT interval increases were more pronounced in MCT than MACI (right ventricle wall thickness, MCT 0.13 ± 0.1 cm vs MACI 0.10 ± 0.1 cm; QT interval, MCT 85 ± 13 ms vs MACI 71 ± 14 ms; p < 0.05). Survival benefit was not seen in the MACI group (p = 0.50).ConclusionsMacitentan treatment improves haemodynamic parameters in established pulmonary hypertension. Further research is required to see if earlier introduction of macitentan has greater effects.

P ulmonary hypertension (PHT) is a disease characterized by raised pulmonary vascular resistance. It has a poor prognosis typically resulting in progressive right ventricular failure and death. The incidence of arrhythmias in patients with PHT is high.1-3 All forms of supraventricular tachycardia are more common in PHT with studies suggesting an incidence of ≈3% per year and a prevalence of supraventricular arrhythmia of ≈12%.3 Atrial flutter, atrial fibrillation, and atrioventricular (AV) nodal reentrant tachycardia are common. 3,4 There is evidence of AV node dysfunction in PHT with a 14% incidence of first-degree heart block, a mean PR interval of 180±50 ms (mean±SD), and 2% of patients requiring a pacemaker for high-degree heart block on initial screening of PHT patients. 1This can be compared with an incidence of first-degree heart block of 2.1% and mean PR interval of 160±22 ms (mean±SD) for men and 153±22 ms (mean±SD) for women in the general population.5 Sleep apnea causes PHT 6 and is associated with heart block (heart block during sleep has been described in ≤10% of patients with obstructive sleep apnea).7 Despite the evidence of a high burden of arrhythmias in patients with PHT, including dysfunction of the AV node, there are limited experimental data looking at the mechanisms of arrhythmia © 2016 American Heart Association, Inc. Original ArticleBackground-Heart block is associated with pulmonary hypertension, and the aim of the study was to test the hypothesis that the heart block is the result of a change in the ion channel transcriptome of the atrioventricular (AV) node. Methods and Results-The most commonly used animal model of pulmonary hypertension, the monocrotaline-injected rat, was used. The functional consequences of monocrotaline injection were determined by echocardiography, ECG recording, and electrophysiological experiments on the Langendorff-perfused heart and isolated AV node. The ion channel transcriptome was measured by quantitative PCR, and biophysically detailed computer modeling was used to explore the changes observed. After monocrotaline injection, echocardiography revealed the pattern of pulmonary artery blood flow characteristic of pulmonary hypertension and right-sided hypertrophy and failure; the Langendorff-perfused heart and isolated AV node revealed dysfunction of the AV node (eg, 50% incidence of heart block in isolated AV node); and quantitative PCR revealed a widespread downregulation of ion channel and related genes in the AV node (eg, >50% downregulation of Ca v 1.2/3 and HCN1/2/4 channels). Computer modeling predicted that the changes in the transcriptome if translated into protein and function would result in heart block. Conclusions-Pulmonary hypertension results in a derangement of the ion channel transcriptome in the AV node, and this is the likely cause of AV node dysfunction in this disease. (Circ Arrhythm Electrophysiol. 2016;9:e003432.