The Late Na+ Current - Origin and Pathophysiological Relevance

Zaza, Antonio; Rocchetti, Marcella

doi:10.1007/s10557-012-6430-0

Cited by 44 publications

(38 citation statements)

References 64 publications

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“…The reduced repolarization reserve of old cardiomyocytes may have enhanced the function of the late Na ϩ current (I NaL ), which is operative in the plateau and repolarization phases of the AP. The prolonged repolarization may have sustained Na ϩ influx via I NaL , a factor that may contribute to the slower electrical recovery in old cells, with important implication on intracellular ionic homeostasis (3,22,54,55).…”

Section: Physiological Aging Alters Ventricular Performancementioning

confidence: 99%

Myocyte repolarization modulates myocardial function in aging dogs

Sorrentino

Signore

Qanud

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Studies of myocardial aging are complex and the mechanisms involved in the deterioration of ventricular performance and decreased functional reserve of the old heart remain to be properly defined. We have studied a colony of beagle dogs from 3 to 14 yr of age kept under a highly regulated environment to define the effects of aging on the myocardium. Ventricular, myocardial, and myocyte function, together with anatomical and structural properties of the organ and cardiomyocytes, were evaluated. Ventricular hypertrophy was not observed with aging and the structural composition of the myocardium was modestly affected. Alterations in the myocyte compartment were identified in aged dogs, and these factors negatively interfere with the contractile reserve typical of the young heart. The duration of the action potential is prolonged in old cardiomyocytes contributing to the slower electrical recovery of the myocardium. Also, the remodeled repolarization of cardiomyocytes with aging provides inotropic support to the senescent muscle but compromises its contractile reserve, rendering the old heart ineffective under conditions of high hemodynamic demand. The defects in the electrical and mechanical properties of cardiomyocytes with aging suggest that this cell population is an important determinant of the cardiac senescent phenotype. Collectively, the delayed electrical repolarization of aging cardiomyocytes may be viewed as a critical variable of the aging myopathy and its propensity to evolve into ventricular decompensation under stressful conditions. aging; myocardium; contractile reserve NEW & NOTEWORTHYWe have investigated the effects of aging on the heart using a genetically uniform large animal model, maintained under highly regulated conditions. Our results indicate that the myocyte compartment undergoes physiological alterations with age that negatively interfere with ventricular function.STUDIES OF MYOCARDIAL AGING in humans are complex, as it is difficult to separate the effects of time from genetic, ethnic, lifestyle, and environmental factors, which may modify physiological cardiac aging. Additionally, the incidence of cardiovascular diseases increases with age (24) and intervening pathologies may change the natural temporal evolution of the organ. Therefore, the mechanisms involved in the age-related deterioration of ventricular performance and decreased functional reserve of the old heart (9, 12, 17, 18, 39) remain to be properly defined.The general belief has been that abnormalities in ventricular compliance with age occur as a result of collagen deposition and diffuse interstitial fibrosis, which, together with cardiomyocyte loss, lead to depressed systolic and diastolic function (17,18,26,39). Additionally, myocardial hypertrophy has been proposed as a critical variable of the senescent myopathy (5), in spite of the lack of organ hypertrophy in older humans (25). Current understanding of the pathophysiology of the aging myopathy and the mechanisms involved in the increased incidence of heart failure and ...

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Section: Physiological Aging Alters Ventricular Performancementioning

confidence: 99%

Myocyte repolarization modulates myocardial function in aging dogs

Sorrentino

Signore

Qanud

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…When INa,L is measured by self action potential clamp method, the magnitude of the current is comparable with that of major potassium currents making it a cardinal player in shaping AP [20]. 3. The identity of sustained plateau sodium current: one current with multiple mechanisms?…”

Section: Brief Historical Remarks On Cardiac Late Sodium Currentmentioning

confidence: 99%

“…This flip-flop between active and inactive states can provide a steady-state current if membrane potential is held within this sensitive voltage range. When identity of INa,L is discussed in the literature, the flip-flopping of the Na channel in the window region is usually the first mechanism used to explain the origin of sustained plateau sodium current [1][2][3][4]. The window mechanism seems like a plausible resolution to seemingly incompatible rapid inactivation of the sodium channels seen in voltage clamp experiments under rectangular command steps and the remarkably persistent sodium current during a several hundred milliseconds long AP plateau.…”

Section: Window Currentsmentioning

confidence: 99%

“…In spite of the small magnitude of plateau sodium current, there is a consensus that the contribution of the sustained component provides a significant fraction (30-50%) of the total sodium entry [3,6]. It is well documented that INa,L facilitation results in increase of cytosolic sodium concentration and it's specific inhibition can prevent sodium accumulation in cardiac myocytes [121][122][123].…”

Section: Nal and Calcium Homeostasis Of Cardiac Cellsmentioning

confidence: 99%

“…In the same time, inhibition of the currents was demonstrated to prevent or reduce arrhythmic activity in multiple pathologic models. Exponentially increasing number of research publications and comprehensive reviews [1][2][3][4][5][6] published in the last few years indicate the great expectation on INa,L as a new, potential therapeutic target. At the present, one of the greatest limiting factors that delay the progress of the field is the lack of specific INa,L inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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An Emerging Antiarrhythmic Target: Late Sodium Current

Bányász

Szentandrássy²,

Magyar³

et al. 2014

CPD

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The cardiac late sodium current (INa,L) has been in the focus of research in the last decade. The first reports on the sustained component of voltage activated sodium current dates back to the early seventies, but early observations interpreted this tiny current as a product of a few channels that fail to inactivate having neither physiologic nor pathologic implications. INa,L has emerged recently as a potentially major arrhythmogenic mechanism in various heart diseases attracting the attention of both clinicians and researchers. Research activity on INa,L has exponentially increased since Ranolazine, an FDA-approved antianginal drug was shown to successfully suppress cardiac arrhythmias by inhibiting INa,L. This review aims to conclude a series of papers concerned with physiology and regulation of cardiac late sodium current. Focusing on some recent development of the field we discuss here critical evidences implicating INa,L as a potential target for treating myocardial dysfunction and cardiac arrhythmias.

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The late sodium current in heart failure: pathophysiology and clinical relevance

Horváth

Bers

2014

ESC Heart Failure

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Large and growing body of data suggest that an increased late sodium current (I Na,late ) can have a significant pathophysiological role in heart failure and other heart diseases. The first goal of this article is to describe how I Na,late functions under physiological circumstances. The second goal is to show the wide range of cellular mechanisms that can increase I Na,late in cardiac disease, and also to describe how the up-regulated I Na,late contributes to the pathophysiology of heart failure. The final section of the article discusses the possible use of I Na,late -modifying drugs in heart failure, on the basis of experimental and preclinical data.

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The Late Na+ Current - Origin and Pathophysiological Relevance

Cited by 44 publications

References 64 publications

Myocyte repolarization modulates myocardial function in aging dogs

Myocyte repolarization modulates myocardial function in aging dogs

An Emerging Antiarrhythmic Target: Late Sodium Current

The late sodium current in heart failure: pathophysiology and clinical relevance

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