Late sodium current in failing heart: Friend or foe?

Maltsev, Victor A.; Undrovinas, A. I.

doi:10.1016/j.pbiomolbio.2007.07.010

Cited by 89 publications

(92 citation statements)

References 130 publications

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“…Increased expression of Na v 1.5 is expected to lead to an increase in I Na density, as is the increased expression of Na v β1 (Na v β1 increases I Na density when expressed with Na v 1.5; Nerbonne & Kass, 2005). An increase in I Na density could help explain the increase in APD with age, because the late Na + current (I Na,L ) can affect APD (Maltsev & Undrovinas, 2008). However, in canine right atrium, I Na density does not change with age (Baba et al 2006), and the AP upstroke velocity is reported to decrease with age in rat right atrium (Cavoto et al 1974).…”

Section: Age-dependent Increase In Apdmentioning

confidence: 99%

Ageing-dependent remodelling of ion channel and Ca²⁺clock genes underlying sino-atrial node pacemaking

Tellez

Mączewski

Yanni

et al. 2011

Experimental Physiology

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The function of the sino-atrial node (SAN), the pacemaker of the heart, is known to decline with age, resulting in pacemaker disease in the elderly. The aim of the study was to investigate the effects of ageing on the SAN by characterizing electrophysiological changes and determining whether changes in gene expression are involved. In young and old rats, SAN function was characterized in the anaesthetized animal, isolated heart and isolated right atrium using ECG and action potential recordings; gene expression was characterized using quantitative PCR. The SAN function declined with age as follows: the intrinsic heart rate declined by 18 ± 3%; the corrected SAN recovery time increased by 43 ± 13%; and the SAN action potential duration increased by 11 ± 3% (at 75% repolarization). Gene expression in the SAN changed considerably with age, e.g. there was an age-dependent decrease in the Ca 2+ clock gene, RYR2, and changes in many ion channels (e.g. increases in Na v 1.5, Na v β1 and Ca v 1.2 and decreases in K v 1.5 and HCN1). In conclusion, with age, there are changes in the expression of ion channel and Ca 2+clock genes in the SAN, and the changes may provide a partial explanation for the age-dependent decline in pacemaker function.

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Section: Age-dependent Increase In Apdmentioning

confidence: 99%

Ageing-dependent remodelling of ion channel and Ca²⁺clock genes underlying sino-atrial node pacemaking

Tellez

Mączewski

Yanni

et al. 2011

Experimental Physiology

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“…A recent study has shown that SCN1B gene silencing caused increased I NaP as a result of increased expression of SCN5A in the SCN1B-null mice (14) . The biophysical properties of I NaP recorded in the SCB1-null mice, however, have not been fully examined, which makes it difficult to compare them with well-known properties of the slowly inactivating I NaL reported in a variety of species including humans, dogs, guinea pig, rabbit, and rat (26). To explain the augmented I NaP in SCN1B-null mice, Lopez-Santiago et al (14) suggest a transcriptional regulation mechanism.…”

Section: Molecular Mechanisms Of I Nal Modulation By Na V ␤ 1 and Na mentioning

confidence: 99%

“…5 and 6), 2) decrease beat-to-beat APD variability, and 3) improvement of Ca 2ϩ handling and contractility (22,25,41,42,44). Accordingly, I NaL has emerged as a novel target for cardioprotection to treat the failing heart (24,26,34). The fact that I NaT is decreased but I NaL is increased in HF (21,23,25,42,45,48) suggests that not all NaCh must be equally targeted.…”

Section: Physiological Significancementioning

confidence: 99%

Post-transcriptional silencing of SCN1B and SCN2B genes modulates late sodium current in cardiac myocytes from normal dogs and dogs with chronic heart failure

Mishra

Undrovinas

Maltsev

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Mishra S, Undrovinas NA, Maltsev VA, Reznikov V, Sabbah HN, Undrovinas A. Post-transcriptional silencing of SCN1B and SCN2B genes modulates late sodium current in cardiac myocytes from normal dogs and dogs with chronic heart failure. Am J Physiol Heart Circ Physiol 301: H1596 -H1605, 2011. First published June 24, 2011 doi:10.1152/ajpheart.00948.2009.-The emerging paradigm for Na ϩ current in heart failure (HF) is that its transient component (INaT) responsible for the action potential (AP) upstroke is decreased, whereas the late component (INaL) involved in AP plateau is augmented. Here we tested whether Nav␤1-and Nav␤2-subunits can modulate INaL parameters in normal and failing ventricular cardiomyocytes (VCMs). Chronic HF was produced in nine dogs by multiple sequential coronary artery microembolizations, and six dogs served as a control. INa and APs were measured by the whole cell and perforated patch-clamp in freshly isolated and cultured VCMs, respectively. INaL was augmented with slower decay in HF VCMs compared with normal heart VCMs, and these properties remained unchanged within 5 days of culture. Posttranscriptional silencing SCN1B and SCN2B were achieved by virally delivered short interfering RNA (siRNA) specific to Nav␤1 and Nav␤2. The delivery and efficiency of siRNA were evaluated by green fluorescent protein expression, by the real-time RT-PCR, and Western blots, respectively. Five days after infection, the levels of mRNA and protein for Nav␤1 and Nav␤2 were reduced by Ͼ80%, but mRNA and protein of Nav1.5, as well as INaT, remained unchanged in HF VCMs. Nav␤1-siRNA reduced INaL density and accelerated INaL two-exponential decay, whereas Nav␤2-siRNA produced an opposite effect in VCMs from both normal and failing hearts. Physiological importance of the discovered INaL modulation to affect AP shape and duration was illustrated both experimentally and by numerical simulations of a VCM excitationcontraction coupling model. We conclude that in myocytes of normal and failing dog hearts Nav␤1 and Nav␤2 exhibit oppositely directed modulation of INaL. action potential; in silico simulation THE EMERGING PARADIGM FOR Na ϩ current (I Na ) in chronic heart failure (HF) is that its transient component (I NaT ) responsible for the action potential (AP) upstroke and excitation propagation is decreased, whereas the late component (I NaL ) involved in AP plateau is augmented (21,23,25,42,45,48). Molecular mechanisms of these HF-related I Na alterations are still understudied. Numerous studies indicate a possible role of Na v ␤ auxiliary subunits to modulate Na ϩ channel (NaCh) expression and function (27), but implications of Na v ␤ in I NaL modulation have not been studied in detail, especially in HF. Our previous studies in a canine chronic HF model showed that the protein level of the main NaCh isoform expressed in the heart, Na v 1.5, underlying I NaL (18), is reduced but remains unchanged for Na v ␤ 1 -and Na v ␤ 2 -subunits, making these ␤-subunits relatively upregulated (48). Thus an intriguing possibility...

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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%

“…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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Late sodium current in failing heart: Friend or foe?

Cited by 89 publications

References 130 publications

Ageing-dependent remodelling of ion channel and Ca²⁺clock genes underlying sino-atrial node pacemaking

Ageing-dependent remodelling of ion channel and Ca²⁺clock genes underlying sino-atrial node pacemaking

Post-transcriptional silencing of SCN1B and SCN2B genes modulates late sodium current in cardiac myocytes from normal dogs and dogs with chronic heart failure

Myocyte repolarization modulates myocardial function in aging dogs

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Late sodium current in failing heart: Friend or foe?

Cited by 89 publications

References 130 publications

Ageing-dependent remodelling of ion channel and Ca2+clock genes underlying sino-atrial node pacemaking

Ageing-dependent remodelling of ion channel and Ca2+clock genes underlying sino-atrial node pacemaking

Post-transcriptional silencing of SCN1B and SCN2B genes modulates late sodium current in cardiac myocytes from normal dogs and dogs with chronic heart failure

Myocyte repolarization modulates myocardial function in aging dogs

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Ageing-dependent remodelling of ion channel and Ca²⁺clock genes underlying sino-atrial node pacemaking

Ageing-dependent remodelling of ion channel and Ca²⁺clock genes underlying sino-atrial node pacemaking