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Late Na(+) current and protracted electrical recovery are critical determinants of the aging myopathy.

ABSTRACT: The aging myopathy manifests itself with diastolic dysfunction and preserved ejection fraction. We raised the possibility that, in a mouse model of physiological aging, defects in electromechanical properties of cardiomyocytes are important determinants of the diastolic characteristics of the myocardium, independently from changes in structural composition of the muscle and collagen framework. Here we show that an increase in the late Na(+) current (INaL) in aging cardiomyocytes prolongs the action potential (AP) and influences temporal kinetics of Ca(2+) cycling and contractility. These alterations increase force development and passive tension. Inhibition of INaL shortens the AP and corrects dynamics of Ca(2+) transient, cell contraction and relaxation. Similarly, repolarization and diastolic tension of the senescent myocardium are partly restored. Thus, INaL offers inotropic support, but negatively interferes with cellular and ventricular compliance, providing a new perspective of the biology of myocardial aging and the aetiology of the defective cardiac performance in the elderly.

SUBMITTER: Signore S

PROVIDER: S-EPMC4638135 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Late Na(+) current and protracted electrical recovery are critical determinants of the aging myopathy.

Signore Sergio S Sorrentino Andrea A Borghetti Giulia G Cannata Antonio A Meo Marianna M Zhou Yu Y Kannappan Ramaswamy R Pasqualini Francesco F O'Malley Heather H Sundman Mark M Tsigkas Nikolaos N Zhang Eric E Arranto Christian C Mangiaracina Chiara C Isobe Kazuya K Sena Brena F BF Kim Junghyun J Goichberg Polina P Nahrendorf Matthias M Isom Lori L LL Leri Annarosa A Anversa Piero P Rota Marcello M

Nature communications 20151106

The aging myopathy manifests itself with diastolic dysfunction and preserved ejection fraction. We raised the possibility that, in a mouse model of physiological aging, defects in electromechanical properties of cardiomyocytes are important determinants of the diastolic characteristics of the myocardium, independently from changes in structural composition of the muscle and collagen framework. Here we show that an increase in the late Na(+) current (INaL) in aging cardiomyocytes prolongs the act ...[more]

PMID: 26541940

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Project description:ObjectivesPatients who survive critical illness navigate arduous and disparate recovery pathways that include referrals and participation in community-based rehabilitation services. Examining rehabilitation pathways during recovery is crucial to understanding the relationship on patient-centered outcomes. Furthermore, an understanding of social determinants of health (SDOH) in relation to outcomes and rehabilitation use will help ensure equitable access for future care. Therefore, there is a need to define and understand patient care pathways, specifically rehabilitation after discharge, through a SDOH lens after surviving a critical illness to improve long-term outcomes.Data sourcesMEDLINE, PubMed, Web of Science Core Collection (Clarivate), the CINAHL, and the Physiotherapy Evidence Database.Study selection and data extractionA systematic review of the literature was completed examining literature from inception to March 2024. Articles were included if post-hospital rehabilitation utilization was reported in adult patients who survived critical illness. Discharge disposition was examined as a proxy for rehabilitation pathways. Patients were grouped by patient diagnosis for grouped analysis and reporting of data. Two independent researchers reviewed manuscripts for inclusion and data were extracted by one reviewer using Covidence. Both reviewers used the Newcastle-Ottawa Scale to assess risk of bias.Data synthesisOf 72 articles included, only four articles reported detailed rehabilitation utilization. The majority of the studies included were cohort studies (91.7%) with most articles using a retrospective design (56.9%). The most common patient population was acute respiratory diagnoses (51.4%). Most patients were discharged directly home from the hospital (75.4%). Race/ethnicity was the most frequently reported SDOH (43.1%) followed by insurance status (13.9%) and education (13.9%).ConclusionsThe small number of articles describing rehabilitative utilization allows for limited understanding of rehabilitation pathways following critical illness. The reporting of detailed rehabilitation utilization and SDOH are limited in the literature but may play a vital role in the recovery and outcomes of survivors of critical illness.

Project description:BackgroundRapid delayed rectifier K+ current (IKr) and late Na+ current (INaL) significantly shape the cardiac action potential (AP). Changes in their magnitudes can cause either long or short QT syndromes associated with malignant ventricular arrhythmias and sudden cardiac death.MethodsPhysiological self AP-clamp was used to measure INaL and IKr during the AP in rabbit and porcine ventricular cardiomyocytes to test our hypothesis that the balance between IKr and INaL affects repolarization stability in health and disease conditions.ResultsWe found comparable amount of net charge carried by IKr and INaL during the physiological AP, suggesting that outward K+ current via IKr and inward Na+ current via INaL are in balance during physiological repolarization. Remarkably, IKr and INaL integrals in each control myocyte were highly correlated in both healthy rabbit and pig myocytes, despite high overall cell-to-cell variability. This close correlation was lost in heart failure myocytes from both species. Pretreatment with E-4031 to block IKr (mimicking long QT syndrome 2) or with sea anemone toxin II to impair Na+ channel inactivation (mimicking long QT syndrome 3) prolonged AP duration (APD); however, using GS-967 to inhibit INaL sufficiently restored APD to control in both cases. Importantly, INaL inhibition significantly reduced the beat-to-beat and short-term variabilities of APD. Moreover, INaL inhibition also restored APD and repolarization stability in heart failure. Conversely, pretreatment with GS-967 shortened APD (mimicking short QT syndrome), and E-4031 reverted APD shortening. Furthermore, the amplitude of AP alternans occurring at high pacing frequency was decreased by INaL inhibition, increased by IKr inhibition, and restored by combined INaL and IKr inhibitions.ConclusionsOur data demonstrate that IKr and INaL are counterbalancing currents during the physiological ventricular AP and their integrals covary in individual myocytes. Targeting these ionic currents to normalize their balance may have significant therapeutic potential in heart diseases with repolarization abnormalities. Visual Overview: A visual overview is available for this article.

Dataset Information

Late Na(+) current and protracted electrical recovery are critical determinants of the aging myopathy.

Publications

Late Na(+) current and protracted electrical recovery are critical determinants of the aging myopathy.

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