ORCID Profile
0000-0002-8892-3373
Current Organisation
Centre National de la Recherche Scientifique
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Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.PBIOMOLBIO.2021.06.008
Abstract: The funny current, I
Publisher: Oxford University Press (OUP)
Date: 12-2000
DOI: 10.1016/S0008-6363(00)00182-6
Abstract: The L-type Ca(2+) current (I(Ca,L)) contributes to the generation and modulation of the pacemaker action potential (AP). We investigated facilitation of I(Ca,L) in sino-atrial cells. Facilitation was studied in regularly-beating cells isolated enzymatically from young albino rabbits (0.8-1 kg). We used the whole-cell patch-cl technique to vary the frequency of the test depolarizations evoked at -10 mV or the conditioning diastolic membrane potential prior to the test pulse. High frequencies (range 0.2-3.5 Hz) slowed the decay kinetics of I(Ca,L) evoked from a holding potential (HP) of -80 mV in 68% of cells resulting in a larger Ca(2+) influx during the test pulse. The amount of facilitation increased progressively between 0.2 and 3.0 Hz. When the frequency was changed from 0.1 to 1 Hz, the averaged increase in the time integral of I(Ca,L) was 27+/-7% (n=22). Application of conditioning voltages between -80 and -50 mV induced similar facilitation of I(Ca,L) in 73% of cells. The maximal increase of Ca(2+) entry occurred between -60 and -50 mV, and was on average 38+/-14% for conditioning prepulses of 5 s in duration (n=15). Numerical simulations of the pacemaker activity showed that facilitation of I(Ca,L) promotes stability of sino-atrial rate by enhancing Ca(2+) entry, thus establishing a negative feedback control against excessive heart rate slowing. Facilitation of I(Ca,L) is present in rabbit sino-atrial cells. The underlying mechanism reflects modulation of I(Ca,L) decay kinetics by diastolic membrane potential and frequency of depolarization. This phenomenon may provide an important regulatory mechanism of sino-atrial automaticity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-06-2021
DOI: 10.1161/CIRCRESAHA.119.316386
Abstract: 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. 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. 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 Ca 2+ channel subunit Ca V 1.2 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 Ca V 1.2 and HCN4. Correspondingly, patch-cl recordings in isolated atrioventricular node myocytes demonstrated a training-induced reduction in I Ca, L and I f density 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 Ca V 1.2 and HCN4. In vivo miRs suppression or detraining restored training-induced PR prolongation and ion channel remodeling. 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.
Location: No location found
Location: France
No related grants have been discovered for Matteo Mangoni.