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Hypernatremia and intercalated disc edema synergistically exacerbate long-QT syndrome type 3 phenotype

American journal of physiology. Heart and circulatory physiology, 2021-12, Vol.321 (6), p.H1042-H1055 [Peer Reviewed Journal]

Copyright American Physiological Society Dec 2021 ;Copyright © 2021 the American Physiological Society. 2021 American Physiological Society ;ISSN: 0363-6135 ;EISSN: 1522-1539 ;DOI: 10.1152/ajpheart.00366.2021 ;PMID: 34623182

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Title:
Hypernatremia and intercalated disc edema synergistically exacerbate long-QT syndrome type 3 phenotype
Author: Wu, Xiaobo ; Hoeker, Gregory S ; Blair, Grace A ; King, D Ryan ; Gourdie, Robert G ; Weinberg, Seth H ; Poelzing, Steven
Subjects: Action potential ; Action Potentials ; Animals ; Arrhythmia ; Cnidarian Venoms ; Computer applications ; Computer Simulation ; Depletion ; Disease Models, Animal ; Edema ; Edema, Cardiac - complications ; Edema, Cardiac - metabolism ; Edema, Cardiac - pathology ; Edema, Cardiac - physiopathology ; Genotype & phenotype ; Guinea Pigs ; Heart ; Heart Rate ; Hypernatremia ; Hypernatremia - blood ; Hypernatremia - complications ; Hypernatremia - physiopathology ; Isolated Heart Preparation ; Long QT Syndrome - chemically induced ; Long QT Syndrome - metabolism ; Long QT Syndrome - physiopathology ; Male ; Mannitol ; Models, Cardiovascular ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - pathology ; NAV1.5 Voltage-Gated Sodium Channel - metabolism ; Patients ; Phenotypes ; Prolongation ; Sodium ; Sodium - blood ; Sodium channels (voltage-gated) ; Synergistic effect ; Toxins ; Ventricle
Is Part Of: American journal of physiology. Heart and circulatory physiology, 2021-12, Vol.321 (6), p.H1042-H1055
Description: Cardiac voltage-gated sodium channel gain-of-function prolongs repolarization in the long-QT syndrome type 3 (LQT3). Previous studies suggest that narrowing the perinexus within the intercalated disc, leading to rapid sodium depletion, attenuates LQT3-associated action potential duration (APD) prolongation. However, it remains unknown whether extracellular sodium concentration modulates APD prolongation during sodium channel gain-of-function. We hypothesized that elevated extracellular sodium concentration and widened perinexus synergistically prolong APD in LQT3. LQT3 was induced with sea anemone toxin (ATXII) in Langendorff-perfused guinea pig hearts ( = 34). Sodium concentration was increased from 145 to 160 mM. Perinexal expansion was induced with mannitol or the sodium channel β1-subunit adhesion domain antagonist (βadp1). Epicardial ventricular action potentials were optically mapped. Individual and combined effects of varying clefts and sodium concentrations were simulated in a computational model. With ATXII, both mannitol and βadp1 significantly widened the perinexus and prolonged APD, respectively. The elevated sodium concentration alone significantly prolonged APD as well. Importantly, the combination of elevated sodium concentration and perinexal widening synergistically prolonged APD. Computational modeling results were consistent with animal experiments. Concurrently elevating extracellular sodium and increasing intercalated disc edema prolongs repolarization more than the individual interventions alone in LQT3. This synergistic effect suggests an important clinical implication that hypernatremia in the presence of cardiac edema can markedly increase LQT3-associated APD prolongation. Therefore, to our knowledge, this is the first study to provide evidence of a tractable and effective strategy to mitigate LQT3 phenotype by means of managing sodium levels and preventing cardiac edema in patients. This is the first study to demonstrate that the long-QT syndrome type 3 (LQT3) phenotype can be exacerbated or concealed by regulating extracellular sodium concentrations and/or the intercalated disc separation. The animal experiments and computational modeling in the current study reveal a critically important clinical implication: sodium dysregulation in the presence of edema within the intercalated disc can markedly increase the risk of arrhythmia in LQT3. These findings strongly suggest that maintaining extracellular sodium within normal physiological limits may be an effective and inexpensive therapeutic option for patients with congenital or acquired sodium channel gain-of-function diseases.
Publisher: United States: American Physiological Society
Language: English
Identifier: ISSN: 0363-6135
EISSN: 1522-1539
DOI: 10.1152/ajpheart.00366.2021
PMID: 34623182
Source: GFMER Free Medical Journals
MEDLINE
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Hypernatremia and intercalated disc edema synergistically exacerbate long-QT syndrome type 3 phenotype

Copyright American Physiological Society Dec 2021 ;Copyright © 2021 the American Physiological Society. 2021 American Physiological Society ;ISSN: 0363-6135 ;EISSN: 1522-1539 ;DOI: 10.1152/ajpheart.00366.2021 ;PMID: 34623182

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