Intrinsic Electrical Remodeling Underlies Atrioventricular Block in Athletes
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Intrinsic Electrical Remodeling Underlies Atrioventricular Block in Athletes. / Mesirca, Pietro; Nakao, Shu; Nissen, Sarah Dalgas; Forte, Gabriella; Anderson, Cali; Trussell, Tariq; Li, Jue; Cox, Charlotte; Zi, Min; Logantha, Sunil; Yaar, Sana; Cartensen, Helena; Bidaud, Isabelle; Stuart, Luke; Soattin, Luca; Morris, Gwilym M.; Da Costa Martins, Paula A.; Cartwright, Elizabeth J.; Oceandy, Delvac; Mangoni, Matteo E.; Jespersen, Thomas; Buhl, Rikke; Dobrzynski, Halina; Boyett, Mark R.; D'Souza, Alicia.
In: Circulation Research, Vol. 129, No. 1, 2021, p. E1-E20.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Intrinsic Electrical Remodeling Underlies Atrioventricular Block in Athletes
AU - Mesirca, Pietro
AU - Nakao, Shu
AU - Nissen, Sarah Dalgas
AU - Forte, Gabriella
AU - Anderson, Cali
AU - Trussell, Tariq
AU - Li, Jue
AU - Cox, Charlotte
AU - Zi, Min
AU - Logantha, Sunil
AU - Yaar, Sana
AU - Cartensen, Helena
AU - Bidaud, Isabelle
AU - Stuart, Luke
AU - Soattin, Luca
AU - Morris, Gwilym M.
AU - Da Costa Martins, Paula A.
AU - Cartwright, Elizabeth J.
AU - Oceandy, Delvac
AU - Mangoni, Matteo E.
AU - Jespersen, Thomas
AU - Buhl, Rikke
AU - Dobrzynski, Halina
AU - Boyett, Mark R.
AU - D'Souza, Alicia
N1 - Publisher Copyright: © 2021 Lippincott Williams and Wilkins. All rights reserved.
PY - 2021
Y1 - 2021
N2 - Rationale: Athletes present with atrioventricular node dysfunction manifesting as atrioventricular block. This can necessitate electronic pacemaker implantation, known to be more frequent in athletes with a long training history. Objective: Atrioventricular block in athletes is attributed to high vagal tone. Here, we investigated the alternative hypothesis that electrical remodeling of the atrioventricular node is responsible. Methods and Results: Radiotelemetry ECG data and atrioventricular node biopsies were collected in sedentary and trained Standardbred racehorses, a large-animal model of the athlete's heart. Trained horses presented with longer PR intervals (that persisted under complete autonomic block) versus sedentary horses, concomitant with reduced expression of key ion channels involved in atrioventricular node conduction: L-type Ca2+channel subunit CaV1.2 and HCN4 (hyperpolarization-activated cyclic nucleotide-gated channel 4). Atrioventricular node electrophysiology was explored further in mice; prolongation of the PR interval (in vivo and ex vivo), Wenckebach cycle length, and atrioventricular node refractory period were observed in mice trained by swimming versus sedentary mice. Transcriptional profiling in laser-capture microdissected atrioventricular node revealed striking reduction in pacemaking ion channels in trained mice, translating into protein downregulation of CaV1.2 and HCN4. Correspondingly, patch-clamp recordings in isolated atrioventricular node myocytes demonstrated a training-induced reduction in ICa,Land Ifdensity that likely contributed to the observed lower frequency of action potential firing in trained cohorts. MicroRNA (miR) profiling and in vitro studies revealed miR-211-5p and miR-432 as direct regulators of CaV1.2 and HCN4. In vivo miRs suppression or detraining restored training-induced PR prolongation and ion channel remodeling. Conclusions: Training-induced atrioventricular node dysfunction is underscored by likely miR-mediated transcriptional remodeling that translates into reduced current density of key ionic currents involved in impulse generation and conduction. We conclude that electrical remodeling is a key mechanism underlying atrioventricular block in athletes.
AB - Rationale: Athletes present with atrioventricular node dysfunction manifesting as atrioventricular block. This can necessitate electronic pacemaker implantation, known to be more frequent in athletes with a long training history. Objective: Atrioventricular block in athletes is attributed to high vagal tone. Here, we investigated the alternative hypothesis that electrical remodeling of the atrioventricular node is responsible. Methods and Results: Radiotelemetry ECG data and atrioventricular node biopsies were collected in sedentary and trained Standardbred racehorses, a large-animal model of the athlete's heart. Trained horses presented with longer PR intervals (that persisted under complete autonomic block) versus sedentary horses, concomitant with reduced expression of key ion channels involved in atrioventricular node conduction: L-type Ca2+channel subunit CaV1.2 and HCN4 (hyperpolarization-activated cyclic nucleotide-gated channel 4). Atrioventricular node electrophysiology was explored further in mice; prolongation of the PR interval (in vivo and ex vivo), Wenckebach cycle length, and atrioventricular node refractory period were observed in mice trained by swimming versus sedentary mice. Transcriptional profiling in laser-capture microdissected atrioventricular node revealed striking reduction in pacemaking ion channels in trained mice, translating into protein downregulation of CaV1.2 and HCN4. Correspondingly, patch-clamp recordings in isolated atrioventricular node myocytes demonstrated a training-induced reduction in ICa,Land Ifdensity that likely contributed to the observed lower frequency of action potential firing in trained cohorts. MicroRNA (miR) profiling and in vitro studies revealed miR-211-5p and miR-432 as direct regulators of CaV1.2 and HCN4. In vivo miRs suppression or detraining restored training-induced PR prolongation and ion channel remodeling. Conclusions: Training-induced atrioventricular node dysfunction is underscored by likely miR-mediated transcriptional remodeling that translates into reduced current density of key ionic currents involved in impulse generation and conduction. We conclude that electrical remodeling is a key mechanism underlying atrioventricular block in athletes.
KW - atrioventricular block
KW - cardiac electrophysiology
KW - exercise
KW - ion channels
KW - microRNAs
U2 - 10.1161/CIRCRESAHA.119.316386
DO - 10.1161/CIRCRESAHA.119.316386
M3 - Journal article
C2 - 33849278
AN - SCOPUS:85108363022
VL - 129
SP - E1-E20
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 1
ER -
ID: 273642702