Increased late sodium current in myocytes from a canine heart failure model and from failing human heart

Valdivia, Carmen R.; Chu, William W.; Pu, Jielin; Foell, Jason D.; Haworth, Robert A.; Wolff, Matthew R.; Kamp, Timothy J.; Makielski, Jonathan C.

doi:10.1016/j.yjmcc.2004.12.012

Cited by 398 publications

(301 citation statements)

References 36 publications

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“…I Na reduction is well established in HF,4, 5, 6 but the possibility that sodium channel density and/or function is differentially remodeled within the various subcellular compartments (microdomains) of failing cardiomyocytes has not been previously addressed. Sodium channel clusters in various cardiomyocyte microdomains exhibit distinct current amplitudes and gating properties 9.…”

Section: Discussionmentioning

confidence: 99%

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Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

Rivaud

Agullo‐Pascual

Lin

et al. 2017

JAHA

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BackgroundCardiac sodium channel (NaV1.5) dysfunction contributes to arrhythmogenesis during pathophysiological conditions. Nav1.5 localizes to distinct subcellular microdomains within the cardiomyocyte, where it associates with region‐specific proteins, yielding complexes whose function is location specific. We herein investigated sodium channel remodeling within distinct cardiomyocyte microdomains during heart failure.Methods and ResultsMice were subjected to 6 weeks of transverse aortic constriction (TAC; n=32) to induce heart failure. Sham–operated on mice were used as controls (n=20). TAC led to reduced left ventricular ejection fraction, QRS prolongation, increased heart mass, and upregulation of prohypertrophic genes. Whole‐cell sodium current (INa) density was decreased by 30% in TAC versus sham–operated on cardiomyocytes. On macropatch analysis, INa in TAC cardiomyocytes was reduced by 50% at the lateral membrane (LM) and by 40% at the intercalated disc. Electron microscopy and scanning ion conductance microscopy revealed remodeling of the intercalated disc (replacement of [inter‐]plicate regions by large foldings) and LM (less identifiable T tubules and reduced Z‐groove ratios). Using scanning ion conductance microscopy, cell‐attached recordings in LM subdomains revealed decreased INa and increased late openings specifically at the crest of TAC cardiomyocytes, but not in groove/T tubules. Failing cardiomyocytes displayed a denser, but more stable, microtubule network (demonstrated by increased α‐tubulin and Glu‐tubulin expression). Superresolution microscopy showed reduced average NaV1.5 cluster size at the LM of TAC cells, in line with reduced INa.ConclusionsHeart failure induces structural remodeling of the intercalated disc, LM, and microtubule network in cardiomyocytes. These adaptations are accompanied by alterations in NaV1.5 clustering and INa within distinct subcellular microdomains of failing cardiomyocytes.

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Section: Discussionmentioning

confidence: 99%

“…In failing hearts, reduced sodium current (I Na ) contributes to slowed conduction 4, 5, 6. Na V 1.5 is the major pore‐forming protein of the cardiac sodium channel and is responsible for the fast entry of sodium ions into cardiomyocytes, thereby underlying the upstroke of the action potential and mediating cardiac conduction.…”

mentioning

confidence: 99%

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

Rivaud

Agullo‐Pascual

Lin

et al. 2017

JAHA

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“…The underlying mechanisms for elevated [Na + ] i are incompletely understood, but may involve a decrease in Na + /K + -ATPase activity [58,156,169,172,175,206], enhanced Na + /H + -exchanger (NHE) activity [2,6,40,142], or an increase in a tetrodotoxin-sensitive persistent (late) I Na [58,121,[203][204][205]. During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,210,212].…”

Section: Pathophysiological Aspects Defects In Ec Coupling In Chronicmentioning

confidence: 99%

“…These defects, potentially aggravated by L-type Ca 2+ channel dysfunction [41,71,81,86,113,131,146,184] or t-tubular derangement [32,86,115,145,184] [17,81,113,115,146,184]. Decreased SR Ca 2+ -ATPase activity is partly compensated by increased expression and activity of the NCX [16,65,93,146,178,190] The underlying mechanisms for elevated [Na + ] i are incompletely understood, but may involve a decrease in Na + /K + -ATPase activity [58,156,169,172,175,206], enhanced Na + /H + -exchanger (NHE) activity [2,6,40,142], or an increase in a tetrodotoxin-sensitive persistent (late) I Na [58,121,[203][204][205]. During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,…”

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confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

213

180

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Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, P i , and Ca 2+ . However, the kinetics of mitochondrial Ca 2+ -uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca 2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca 2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca 2+ microdomain could explain seemingly controversial results on mitochondrial Ca 2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca 2+ uptake facilitated by microdomains may shape cytosolic Ca 2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca 2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. Keywords calcium; sodium; microdomain; heart failure; adenosine triphosphate; adenosine diphosphate; respiration; tricarboxylic acid cycle Physiological aspectsThe most important function of the heart is to pump blood to supply the body with oxygen and substrates. In order to adapt cardiac output to the constantly changing demand of blood supply, the heart utilizes three major mechanisms to increase cardiac output: the force-frequency relationship (the Bowditch effect or Treppe; [22]), the Frank-Starling mechanism (sarcomere length-dependent activation of contractile force) [66,149,164], and sympathetic activation [28]. All of these mechanisms increase and accelerate myocardial force generation, and at the same time increase cellular energy demand. By these mechanisms, cardiac output during exertion can be increased more than five-fold compared to resting conditions. © Steinkopff Verlag 2007Correspondence to: Christoph Maack. NIH Public Access Excitation-contraction couplingOf fundamental importance for cardiac contraction and relaxation are the processes of excitation-contraction (EC) coupling (Fig. 1). During the action potential (AP), voltage-gated Na + -channels are activated, and the inward Na + -current (I Na ) induces a rapid depolarization of the cell membrane, facilitating voltage-dependent opening of L-type Ca 2+ -channels (I Ca,L ). The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process te...

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“…In this study, we carried out the first steps in characterizing the domestic dog (Canis familiaris) as a model for investigation of the relationship between low body temperature and obesity. Dogs are common laboratory subjects and have been successfully used as models for human social cognition, 13 human aging, 14 human epididymal function, 15 human heart failure 16 and many other processes. Importantly, we have previously shown that body temperature is inversely correlated with body size in lean dogs.…”

Section: Introductionmentioning

confidence: 99%

Association between obesity and reduced body temperature in dogs

et al. 2010

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Background: Industrialized nations are currently experiencing an obesity epidemic, the causes of which are not fully known. One possible mechanism of enhanced energy efficiency that has received almost no attention is a reduction in the metabolic cost of homeothermy, which could be achieved by a modest lowering of body core temperature. We evaluated the potential of this obesity-inducing mechanism in a canine model of the metabolic syndrome. Methods: We compared the rectal temperature of lean dogs and obese dogs by (a) conducting cross-sectional measurements in 287 dogs of many breeds varying greatly in body size, (b) conducting longitudinal measurements in individual dogs over 7-10 years and (c) tracking rectal temperature of lean and obese dogs at 3-h intervals for 48 consecutive hours in the laboratory. Results: We found that larger dogs have lower rectal temperatures than smaller dogs and that, for the same body mass, obese dogs have lower rectal temperatures than lean dogs. The results were consistent in the cross-sectional, longitudinal and aroundthe-clock measurements. Conclusion: These findings document an association between obesity and reduced body temperature in dogs and support the hypothesis that obesity in this and other species of homeotherms may result from an increase in metabolic efficiency achieved by a regulated lowering of body temperature.

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Increased late sodium current in myocytes from a canine heart failure model and from failing human heart

Cited by 398 publications

References 36 publications

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

Sodium Channel Remodeling in Subcellular Microdomains of Murine Failing Cardiomyocytes

Excitation-contraction coupling and mitochondrial energetics

Association between obesity and reduced body temperature in dogs

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