Atrioventricular Node Dysfunction and Ion Channel Transcriptome in Pulmonary Hypertension

Abstract

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.

Structural and functional remodeling of the atrioventricular node with aging in rats: The role of hyperpolarization-activated cyclic nucleotide–gated and ryanodine 2 channels

“…Electrophysiological experiments were carried out on the AVN preparations in a tissue bath with oxygenated Tyrode's solution. 12 The spontaneous sinus node (SN) cycle length (SCL), paced AH interval, WBCL, AVNERP, and AVN functional refractory period (AVFRP) were measured using bipolar electrodes. Measurements were then repeated with cesium (2 mM, specific for I f ) and ryanodine (2 μM, specific for RyR).…”

Isolated heart model demonstrates evidence of contractile and diastolic dysfunction in right ventricles from rats with sugen/hypoxia-induced pulmonary hypertension

“…; Temple et al. ). Of note, all these studies have been performed in the monocrotaline model of PAH, a model which only incompletely recapitulates the human PAH phenotype (Stenmark et al.…”

“…Modification of the preparation for studies of the RV is technically more challenging, and the Langendorff technique has only rarely been used for studies of RV function. Published studies used the preparation in order to study RV contractile or electrophysiological function (Nagendran et al 2007(Nagendran et al , 2013Handoko et al 2009;Piao et al 2010;Umar et al 2012;Temple et al 2016). Of note, all these studies have been performed in the monocrotaline model of PAH, a model which only incompletely recapitulates the human PAH phenotype (Stenmark et al 2009;Maarman et al 2013).…”

“…; Temple et al. ). These models allow for the detailed study of RV contractile and diastolic function independent of changes in the pulmonary vasculature.…”

“…While several treatment strategies have been shown to improve RV function in PAH, many of these interventions concomitantly target the pulmonary vasculature, making it challenging to differentiate their pulmonary vascular effects from their potential effects on intrinsic RV function (Vonk-Noordegraaf et al 2013. In order to circumvent this problem, isolated heart models have been used (Nagendran et al 2007(Nagendran et al , 2013Handoko et al 2009;Piao et al 2010;Umar et al 2012;Temple et al 2016). These models allow for the detailed study of RV contractile and diastolic function independent of changes in the pulmonary vasculature.…”