Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function, and prevents sudden arrhythmic death in failing hearts
Sudden cardiac death (SCD) from ventricular tachycardia/fibrillation (VT/VF) is a leading cause of death, but current therapies are limited. Despite extensive research on drugs targeting sarcolemmal ion channels, none have proven sufficiently effective for preventing SCD. Sarcoplasmic ryanodine rece...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/88638 |
| _version_ | 1797396936482881536 |
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| author | Pooja Joshi Shanea Estes Deeptankar DeMazumder Bjorn C Knollmann Swati Dey |
| author_facet | Pooja Joshi Shanea Estes Deeptankar DeMazumder Bjorn C Knollmann Swati Dey |
| author_sort | Pooja Joshi |
| collection | DOAJ |
| description | Sudden cardiac death (SCD) from ventricular tachycardia/fibrillation (VT/VF) is a leading cause of death, but current therapies are limited. Despite extensive research on drugs targeting sarcolemmal ion channels, none have proven sufficiently effective for preventing SCD. Sarcoplasmic ryanodine receptor 2 (RyR2) Ca2+ release channels, the downstream effectors of sarcolemmal ion channels, are underexplored in this context. Recent evidence implicates reactive oxygen species (ROS)-mediated oxidation and hyperactivity of RyR2s in the pathophysiology of SCD. We tested the hypothesis that RyR2 inhibition of failing arrhythmogenic hearts reduces sarcoplasmic Ca2+ leak and repolarization lability, mitigates VT/VF/SCD and improves contractile function. We used a guinea pig model that replicates key clinical aspects of human nonischemic HF, such as a prolonged QT interval, a high prevalence of spontaneous arrhythmic SCD, and profound Ca2+ leak via a hyperactive RyR2. HF animals were randomized to receive dantrolene (DS) or placebo in early or chronic HF. We assessed the incidence of VT/VF and SCD (primary outcome), ECG heart rate and QT variability, echocardiographic left ventricular (LV) structure and function, immunohistochemical LV fibrosis, and sarcoplasmic RyR2 oxidation. DS treatment prevented VT/VF and SCD by decreasing dispersion of repolarization and ventricular arrhythmias. Compared to placebo, DS lowered resting heart rate, preserved chronotropic competency during transient β-adrenergic challenge, and improved heart rate variability and cardiac function. Inhibition of RyR2 hyperactivity with dantrolene mitigates the vicious cycle of sarcoplasmic Ca2+ leak-induced increases in diastolic Ca2+ and ROS-mediated RyR2 oxidation, thereby reducing repolarization lability and protecting against VT/VF/SCD. Moreover, the consequent increase in sarcoplasmic Ca2+ load improves contractile function. These potentially life-saving effects of RyR2 inhibition warrant further investigation, such as clinical studies of repurposing dantrolene as a potential new therapy for heart failure and/or SCD. |
| first_indexed | 2024-03-09T01:02:52Z |
| format | Article |
| id | doaj.art-7ab20141589e45118ed66b0577d066e3 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-09T01:02:52Z |
| publishDate | 2023-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7ab20141589e45118ed66b0577d066e32023-12-11T15:30:41ZengeLife Sciences Publications LtdeLife2050-084X2023-12-011210.7554/eLife.88638Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function, and prevents sudden arrhythmic death in failing heartsPooja Joshi0https://orcid.org/0000-0002-1415-1251Shanea Estes1Deeptankar DeMazumder2Bjorn C Knollmann3Swati Dey4https://orcid.org/0000-0003-4692-6848Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United StatesDivision of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United StatesSection of Cardiac Electrophysiology, Division of Cardiology, Department of Internal Medicine, Veterans Affairs Pittsburgh Health System, Pittsburgh, United States; Section of Cardiac Electrophysiology, Division of Cardiology, Department of Internal Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, United States; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, United States; McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United StatesDivision of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United StatesDivision of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, United StatesSudden cardiac death (SCD) from ventricular tachycardia/fibrillation (VT/VF) is a leading cause of death, but current therapies are limited. Despite extensive research on drugs targeting sarcolemmal ion channels, none have proven sufficiently effective for preventing SCD. Sarcoplasmic ryanodine receptor 2 (RyR2) Ca2+ release channels, the downstream effectors of sarcolemmal ion channels, are underexplored in this context. Recent evidence implicates reactive oxygen species (ROS)-mediated oxidation and hyperactivity of RyR2s in the pathophysiology of SCD. We tested the hypothesis that RyR2 inhibition of failing arrhythmogenic hearts reduces sarcoplasmic Ca2+ leak and repolarization lability, mitigates VT/VF/SCD and improves contractile function. We used a guinea pig model that replicates key clinical aspects of human nonischemic HF, such as a prolonged QT interval, a high prevalence of spontaneous arrhythmic SCD, and profound Ca2+ leak via a hyperactive RyR2. HF animals were randomized to receive dantrolene (DS) or placebo in early or chronic HF. We assessed the incidence of VT/VF and SCD (primary outcome), ECG heart rate and QT variability, echocardiographic left ventricular (LV) structure and function, immunohistochemical LV fibrosis, and sarcoplasmic RyR2 oxidation. DS treatment prevented VT/VF and SCD by decreasing dispersion of repolarization and ventricular arrhythmias. Compared to placebo, DS lowered resting heart rate, preserved chronotropic competency during transient β-adrenergic challenge, and improved heart rate variability and cardiac function. Inhibition of RyR2 hyperactivity with dantrolene mitigates the vicious cycle of sarcoplasmic Ca2+ leak-induced increases in diastolic Ca2+ and ROS-mediated RyR2 oxidation, thereby reducing repolarization lability and protecting against VT/VF/SCD. Moreover, the consequent increase in sarcoplasmic Ca2+ load improves contractile function. These potentially life-saving effects of RyR2 inhibition warrant further investigation, such as clinical studies of repurposing dantrolene as a potential new therapy for heart failure and/or SCD.https://elifesciences.org/articles/88638guinea pigcavia porcellusmurine |
| spellingShingle | Pooja Joshi Shanea Estes Deeptankar DeMazumder Bjorn C Knollmann Swati Dey Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function, and prevents sudden arrhythmic death in failing hearts eLife guinea pig cavia porcellus murine |
| title | Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function, and prevents sudden arrhythmic death in failing hearts |
| title_full | Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function, and prevents sudden arrhythmic death in failing hearts |
| title_fullStr | Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function, and prevents sudden arrhythmic death in failing hearts |
| title_full_unstemmed | Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function, and prevents sudden arrhythmic death in failing hearts |
| title_short | Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function, and prevents sudden arrhythmic death in failing hearts |
| title_sort | ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization improves contractile function and prevents sudden arrhythmic death in failing hearts |
| topic | guinea pig cavia porcellus murine |
| url | https://elifesciences.org/articles/88638 |
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