RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism

Wang, Yue Yi; Mesirca, Pietro; Marqués-Sulé, Elena; Zahradníková, Alexandra; Villejoubert, Olivier; D’Ocón, Pilar; Ruiz, Cristina; Domingo, Diana; Zorio, Esther; Mangoni, Matteo E.; Benitah, Jean-Pierre; Gómez, Ana M.

doi:10.1172/jci.insight.91872

Cited by 27 publications

(37 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Data from both isolated sinoatrial nodal (SAN) cells and mouse models of CaMKII inhibition have demonstrated a role for CaMKII activity in the heart rate response to β-adrenergic stimulation but not the maintenance of the basal heart rate 35 . CPVT patients display baseline bradycardia 36 possibly from alternations in the Ca 2+ clock within pacemaker cells through negative regulation of the L-type Ca 2+ channel 37 . Therefore it is reasonable to hypothesize that CaMKII inhibition with AIP in Ryr2 R176Q/+ animals restores the Ca 2+ clock within the sinoatrial node, leading to the recovery of a normal isoproterenol response.…”

Section: Discussionmentioning

confidence: 99%

Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia by Inhibition of Ca ²⁺ /Calmodulin-Dependent Kinase II

et al. 2019

View full text Add to dashboard Cite

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited cardiac arrhythmia characterized by adrenergically triggered arrhythmias, is inadequately treated by current standard of care. Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), an adrenergically activated kinase that contributes to arrhythmogenesis in heart disease models, is a candidate therapeutic target in CPVT. However, translation of CaMKII inhibition has been limited by the need for selective CaMKII inhibition in cardiomyocytes. Here we tested the hypothesis that CaMKII inhibition using a cardiomyocyte-targeted gene therapy strategy would suppress arrhythmia in CPVT mouse models. Methods:We developed AAV9-GFP-AIP, an adeno-associated viral vector in which a potent CaMKII inhibitory peptide (AIP), is fused to GFP and expressed from a cardiomyocyte selective promoter. The vector was delivered systemically. Arrhythmia burden was evaluated using invasive electrophysiology testing in adult mice. AIP was also tested on induced pluripotent stem cells (iPSC) derived from CPVT patients with different disease-causing mutations to determine the effectiveness of our proposed therapy on human iPSC-derived cardiomyocytes (iPSC-CMs) and different pathogenic genotypes.Results: AAV9-GFP-AIP was robustly expressed in the heart without significant expression in extra-cardiac tissues, including the brain. Administration of AAV9-GFP-AIP to neonatal mice with a known CPVT mutation (RYR2 R176Q/+ ) effectively suppressed ventricular arrhythmias induced by either β-adrenergic stimulation or programmed ventricular pacing, without significant proarrhythmic effect. Intravascular delivery of AAV9-GFP-AIP to adolescent mice transduced ~50% of cardiomyocytes and was effective in suppressing arrhythmia in CPVT mice. iPSC-CMs derived from two different CPVT patients with different pathogenic mutations demonstrated

show abstract

Section: Discussionmentioning

confidence: 99%

Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia by Inhibition of Ca ²⁺ /Calmodulin-Dependent Kinase II

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Ventricular myocytes were isolated from C57Bl/6 or homozygous RyR2 R420Q knock‐in male mice, aged between 3 and 11 months (Wang et al . 2017 ) following an established protocol (Louch et al . 2011 ).…”

Section: Methodsmentioning

confidence: 99%

“…Ventricular myocytes were isolated from C57Bl/6 or homozygous RyR2 R420Q knock in male mice, aged between 3 and 11 months (Wang et al, 2017) following an established protocol (Louch et al, 2011). Adult mice were euthanized by cervical dislocation and the hearts were excised, cannulated and retrogradely perfused on a Langendorff system.…”

Section: Animals and Cardiac Myocytes Isolationmentioning

confidence: 99%

Local recovery of cardiac calcium‐induced calcium release interrogated by ultra‐effective, two‐photon uncaging of calcium

Janíček

Agarwal

Gómez

et al. 2021

The Journal of Physiology

View full text Add to dashboard Cite

In cardiac myocytes, subcellular local calcium release signals, calcium sparks, are recruited to form each cellular calcium transient and activate the contractile machinery  Abnormal timing of spark recovery after their termination may contribute to arrhythmias  We developed a method to interrogate recovery of calcium spark trigger probabilities and their amplitude over time using two photon photolysis of a new ultra-effective caged calcium compound  The findings confirm the utility of the technique to define an elevated sensitivity of the calcium release mechanism in-situ and to follow hastened recovery of spark trigger probabilities in a mouse model of an inherited cardiac arrhythmia, which was used for validation  Analogous methods are likely to be applicable to investigate other microscopic subcellular signaling systems in a variety of cell types

show abstract

“…Hearts from anaesthetized db/db (n = 8) and db/+ (n = 9) mice were quickly excised and placed in Tyrode solution (140 mmol/L NaCl, 5.4 mmol/L KCl, 1 mmol/L MgCl 2 , 1.8 mmol/L CaCl 2 , 5.5 mmol/L glucose and 5 mmol/L of 4‐(2‐hydroxyethyl)‐1‐piperazineethanesulfonic acid (HEPES)) at 37°C, pH 7.4, and a constant oxygenation with 100% O 2 . The SAN and surrounding right atrial tissue was identified and pinned to the bottom of a custom‐made optical chamber, as previously detailed . The endocardial side of the preparation was facing upwards.…”

Section: Methodsmentioning

confidence: 99%

Aberrant sinus node firing during β‐adrenergic stimulation leads to cardiac arrhythmias in diabetic mice

et al. 2020

View full text Add to dashboard Cite

Aim: Cardiovascular complications, including cardiac arrhythmias, result in high morbidity and mortality in patients with type-2 diabetes mellitus (T2DM). Clinical and experimental data suggest electrophysiological impairment of the natural pacemaker of the diabetic heart. The present study examined sinoatrial node (SAN) arrhythmias in a mouse model of T2DM and physiologically probed their underlying cause. Methods: Electrocardiograms were obtained from conscious diabetic db/db and lean control db/+ mice. In vivo SAN function was probed through pharmacological autonomic modulation with isoprenaline, atropine and carbachol. Blood pressure stability and heart rate variability (HRV) were evaluated. Intrinsic SAN function was evaluated through ex vivo imaging of spontaneous Ca 2+ transients in isolated SAN preparations. Results: While lean control mice showed constant RR intervals during isoprenaline challenge, the diabetic mice experienced SAN arrhythmias with large RR fluctuations in a dose-dependent manner. These arrhythmias were completely abolished by atropine pre-treatment, while carbachol pretreatment significantly increased SAN arrhythmia frequency in the diabetic mice. Blood pressure and HRV were comparable in db/db and db/+ mice, suggesting that neither augmented baroreceptor feedback nor autonomic neuropathy is a likely arrhythmia mechanism. Cycle length response to isoprenaline was comparable in isolated SAN preparations from db/db and db/+ mice; however, Ca 2+ spark frequency was significantly increased in db/db mice compared to db/+ at baseline and after isoprenaline. Conclusion: Our results demonstrate a dysfunction of cardiac pacemaking in an animal model of T2DM upon challenge with a β-adrenergic agonist. Ex vivo, higher Ca 2+ spark frequency is present in diabetic mice, which may be directly linked to in vivo arrhythmias. K E Y W O R D Sautonomic nervous system, baroreflex, calcium, electrophysiology, isoprenaline, type-2 diabetes

show abstract

RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism

Cited by 27 publications

References 55 publications

Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia by Inhibition of Ca ²⁺ /Calmodulin-Dependent Kinase II

Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia by Inhibition of Ca ²⁺ /Calmodulin-Dependent Kinase II

Local recovery of cardiac calcium‐induced calcium release interrogated by ultra‐effective, two‐photon uncaging of calcium

Aberrant sinus node firing during β‐adrenergic stimulation leads to cardiac arrhythmias in diabetic mice

Contact Info

Product

Resources

About

RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism

Cited by 27 publications

References 55 publications

Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia by Inhibition of Ca 2+ /Calmodulin-Dependent Kinase II

Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia by Inhibition of Ca 2+ /Calmodulin-Dependent Kinase II

Local recovery of cardiac calcium‐induced calcium release interrogated by ultra‐effective, two‐photon uncaging of calcium

Aberrant sinus node firing during β‐adrenergic stimulation leads to cardiac arrhythmias in diabetic mice

Contact Info

Product

Resources

About

Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia by Inhibition of Ca ²⁺ /Calmodulin-Dependent Kinase II

Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia by Inhibition of Ca ²⁺ /Calmodulin-Dependent Kinase II