Late sodium current contributes to diastolic cell Ca2+ accumulation in chronic heart failure

Undrovinas, Nidas A.; Maltsev, Victor A.; Belardinelli, Luiz; Sabbah, Hani N.; Undrovinas, A. I.

doi:10.1007/s12576-010-0092-0

Cited by 80 publications

(99 citation statements)

References 58 publications

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“…doubling) with respect to the basic HF increase, APD is prolonged 22% and no change at all in this current leads to a shortening of the APD 90 by 10% with respect to basic HF conditions. This result is in agreement with experimental recordings in failing human myocytes, where I NaL has a crucial role in APD [19]. Similarly, the downregulation of Na + /K + pump in HF has a relevant effect on APD 90 shortening, and further reduction of the current leads to a decrease of 22% with respect to HF APD 90 value, which is in agreement with experimental observations [37].…”

Section: Effects Of I Nal On Human Apsupporting

confidence: 91%

“…The formulation of the I NaL model and its introduction in the GPB model was essential to draw our conclusions. Previous formulations have been proposed to model the behavior of I NaL for different animal species using the Hodgkin-Huxley or Markov formalisms [19,20,30,46,58,59]. Noble and colleagues [59] in 1998 formulated the I NaL for guinea pig by adding to their AP model a Na + current with reduced conductance and slow inactivation.…”

Section: Important Role Of I Nal During Heart Failure and Clinical Immentioning

confidence: 99%

“…Noble and colleagues [59] in 1998 formulated the I NaL for guinea pig by adding to their AP model a Na + current with reduced conductance and slow inactivation. Similarly, other Hodgkin-Huxley formulations have been proposed for rabbit [20] and dog [19,46]. To avoid the complexity of Markov models for I NaL [30], we adapted the Hodgkin-Huxley mathematical description of Hund et al [46] to human data, as we did in a previous work using ten Tusscher et al AP model [48].…”

Section: Important Role Of I Nal During Heart Failure and Clinical Immentioning

confidence: 99%

“…Major changes in intracellular and sarcoplasmic reticulum (SR) Ca 2+ homeostasis are also associated with HF in several animal species, included human [9,[11][12][13]. In myocytes from failing hearts [Na + ] i concentration and Ca 2+ handling are closely linked; [Na + ] i is increased in failing ventricular myocytes from human and other animal species [3,4,9,14] and a prominent increase of the human late Na + current (I NaL ) has also been documented [15,16], and has been proposed as a therapeutic target [17][18][19]. Experimental studies have shown that the I NaL is involved in the generation of EADs in myocytes [17,18] and life-threatening arrhythmias, such as torsade de pointes (TdP) [20], especially under conditions of reduced repolarization reserve in several animal species [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

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Influence of heart failure on nucleolar organization and protein expression in human hearts

Roselló‐Lletí¹,

Rivera²,

Cortés³

et al. 2012

Biochemical and Biophysical Research Communications

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Heart failure constitutes a major public health problem worldwide. The electrophysiological remodeling of failing hearts sets the stage for malignant arrhythmias, in which the role of the late Na + current (I NaL ) is relevant and is currently under investigation. In this study we examined the role of I NaL in the electrophysiological phenotype of ventricular myocytes, and its proarrhythmic effects in the failing heart. A model for cellular heart failure was proposed using a modified version of Grandi et al. model for human ventricular action potential that incorporates the formulation of I NaL . A sensitivity analysis of the model was performed and simulations of the pathological electrical activity of the cell were conducted. The proposed model for the human I NaL and the electrophysiological remodeling of myocytes from failing hearts accurately reproduce experimental observations. The sensitivity analysis of the modulation of electrophysiological parameters of myocytes from failing hearts due to ion channels remodeling, revealed a role for I NaL in the prolongation of action potential duration (APD), triangulation of the shape of the AP, and changes in Ca 2+ transient. A mechanistic investigation of intracellular Na + accumulation and APD shortening with increasing frequency of stimulation of failing myocytes revealed a role for the Na + / K + pump, the Na + /Ca 2+ exchanger and I NaL . The results of the simulations also showed that in failing myocytes, the enhancement of I NaL increased the reverse rate-dependent APD prolongation and the probability of initiating early afterdepolarizations. The electrophysiological remodeling of failing hearts and especially the enhancement of the I NaL prolong APD and alter Ca 2+ transient facilitating the development of early afterdepolarizations. An enhanced I NaL appears to be an important contributor to the electrophysiological phenotype and to the dysregulation of [Ca 2+ ] i homeostasis of failing myocytes.

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Section: Effects Of I Nal On Human Apsupporting

confidence: 91%

Section: Important Role Of I Nal During Heart Failure and Clinical Immentioning

confidence: 99%

Section: Important Role Of I Nal During Heart Failure and Clinical Immentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Influence of heart failure on nucleolar organization and protein expression in human hearts

Roselló‐Lletí¹,

Rivera²,

Cortés³

et al. 2012

Biochemical and Biophysical Research Communications

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“…The prolongation of the AP has important implications in the excitation contraction-coupling of old cardiomyocytes. (8,13,22,31,38,(41)(42)(43)(44)48).…”

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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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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Late sodium current contributes to diastolic cell Ca2+ accumulation in chronic heart failure

Cited by 80 publications

References 58 publications

Influence of heart failure on nucleolar organization and protein expression in human hearts

Influence of heart failure on nucleolar organization and protein expression in human hearts

Myocyte repolarization modulates myocardial function in aging dogs

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

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