Myocardial Infarction Causes Increased Expression But Decreased Activity of the Myocardial Na<sup>+</sup>—Ca<sup>2+</sup> Exchanger in the Rabbit

Quinn, F. Russell; Currie, Susan; Duncan, A. M.; Miller, S.; Sayeed, Rana; Cobbe, Stuart M.; Smith, Godfrey L.

doi:10.1113/jphysiol.2003.050716

Cited by 60 publications

(48 citation statements)

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“…5 In a rabbit model of myocardial infarction, ENDO cells exhibited greater NCX expression and function than EPI cells in both control and failing hearts. 6 In humans, Northern blot analysis showed no difference in NCX mRNA levels between EPI and ENDO in both normal and failing hearts, but the authors noted large interindividual variability of NCX mRNA levels. 7 Furthermore, Northern blotting is a less-robust mRNA quantification method than real-time quantitative PCR.…”

Section: Discussionmentioning

confidence: 98%

Transmural Heterogeneity of Na ⁺ –Ca ²⁺ Exchange

Xiong

Tian

DiSilvestre

et al. 2005

Circulation Research

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Spatial electrical heterogeneity has a profound effect on normal cardiac electrophysiology and genesis of cardiac arrhythmias in diseased hearts. The Na ؉ -Ca 2؉ exchanger (NCX) is a key linker, through Ca 2؉ signaling, between contractility and arrhythmias. Here we characterize the differential transmural expression of NCX in normal and rapid pacing-induced failing canine hearts. Significant transmural heterogeneity of NCX was present in normal hearts, as NCX current density measured at ؉80 mV was significantly (P<0.05) greater in epicardial (EPI) (5.49 pA/pF) than mid-myocardial (MID) (2.84 pA/pF) and endocardial (ENDO) (2.21 pA/pF) cells. Interestingly, heart failure caused a selective increase in NCX current density (P<0.05) limited to ENDO (by 202%) and MID (by 76%) but not EPI myocytes (P‫؍‬not significant). The differences in functional expression were associated with changes in both mRNA and protein levels. The normal EPI layer exhibited the greatest NCX mRNA and protein levels compared with MID and ENDO layers, whereas the ENDO layer underwent the most pronounced increase in mRNA (by 185%) and protein (by 207%) levels in heart failure. The transmural NCX gradient, from EPI (greatest) to ENDO (least), is disrupted in heart failure. A selective upregulation of NCX expression in MID and ENDO in heart failure markedly redirects the orientation of the transmural functional gradient of NCX and may lead to enhanced vulnerability to cardiac arrhythmias. S udden death is prevalent in patients with heart failure (HF). 1 Abnormalities in functional expression of calcium-handling proteins are prominent in HF and constitute a crucial link between arrhythmias and decreased contraction. The Na ϩ -Ca 2ϩ exchanger (NCX) plays important roles in both contractile dysfunction and arrhythmogenesis in HF. 2 Prolongation of action potential duration (APD) is a hallmark of failing myocytes, which is arrhythmogenic and contributes to the increased incidence of sudden death in patients with HF. More importantly, transmural dispersion of repolarization (TDR) has a crucial role in arrhythmogenesis. 1 In failing hearts, downregulation of K ϩ currents and upregulation of NCX have been reported (see review by Tomaselli and Zipes 1 ). The transmural homogenenous downregulation of K ϩ currents 3 does not suffice to account for the exaggerated TDR characteristic of HF. We characterized the differential transmural expression of NCX in control and failing hearts. The alterations in transmural NCX heterogeneity in failing hearts highlight a potential substrate for the production of lethal arrhythmias in HF. Materials and MethodsReal-time quantitative RT-PCR, Western blotting, and whole-cell patch clamp were used to measure the NCX mRNA, immunoreactive protein levels, and current, respectively. An expanded Materials and Methods can be found in the online data supplement available at http://circres.ahajournals.org. Figure 1A illustrates representative traces of Ni 2ϩ -sensitive current in a normal MID cell. To confirm that the Ni 2ϩ -se...

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Section: Discussionmentioning

confidence: 98%

Transmural Heterogeneity of Na ⁺ –Ca ²⁺ Exchange

Xiong

Tian

DiSilvestre

et al. 2005

Circulation Research

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“…This is an obvious departure from previously published studies of HF in human patients21 or animal studies, of which large animal models utilizing dogs or rabbits have been thought to provide the most clinically useful replacements 11. Nonetheless, although large animal models present with important similarities to humans, for example, with respect to excitation contraction coupling and contractile mechanisms, they also differ with respect to aetiology and have been reported to differ in aspects of cardiac function and response to injury;52, 53, 54 see also the review by Hasenfuss 11…”

Section: Discussionmentioning

confidence: 99%

Human cardiomyocyte calcium handling and transverse tubules in mid‐stage of post‐myocardial‐infarction heart failure

et al. 2018

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AimsCellular processes in the heart rely mainly on studies from experimental animal models or explanted hearts from patients with terminal end‐stage heart failure (HF). To address this limitation, we provide data on excitation contraction coupling, cardiomyocyte contraction and relaxation, and Ca2+ handling in post‐myocardial‐infarction (MI) patients at mid‐stage of HF.Methods and resultsNine MI patients and eight control patients without MI (non‐MI) were included. Biopsies were taken from the left ventricular myocardium and processed for further measurements with epifluorescence and confocal microscopy. Cardiomyocyte function was progressively impaired in MI cardiomyocytes compared with non‐MI cardiomyocytes when increasing electrical stimulation towards frequencies that simulate heart rates during physical activity (2 Hz); at 3 Hz, we observed almost total breakdown of function in MI. Concurrently, we observed impaired Ca2+ handling with more spontaneous Ca2+ release events, increased diastolic Ca2+, lower Ca2+ amplitude, and prolonged time to diastolic Ca2+ removal in MI (P < 0.01). Significantly reduced transverse‐tubule density (−35%, P < 0.01) and sarcoplasmic reticulum Ca2+ adenosine triphosphatase 2a (SERCA2a) function (−26%, P < 0.01) in MI cardiomyocytes may explain the findings. Reduced protein phosphorylation of phospholamban (PLB) serine‐16 and threonine‐17 in MI provides further mechanisms to the reduced function.ConclusionsDepressed cardiomyocyte contraction and relaxation were associated with impaired intracellular Ca2+ handling due to impaired SERCA2a activity caused by a combination of alteration in the PLB/SERCA2a ratio and chronic dephosphorylation of PLB as well as loss of transverse tubules, which disrupts normal intracellular Ca2+ homeostasis and handling. This is the first study that presents these mechanisms from viable and intact cardiomyocytes isolated from the left ventricle of human hearts at mid‐stage of post‐MI HF.

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“…During experiments, the cells were superfused with NT solution at 37°C. The degree of detubulation was assessed by a custom-written macro using ImageJ (29), which calculates the relative area stained for t-tubules from the fluorescent signal through the midsection of the z-series stack (28).…”

Section: Methodsmentioning

confidence: 99%

Effects of clenbuterol on contractility and Ca²⁺ homeostasis of isolated rat ventricular myocytes

Siedlecka

Arora²,

Kolettis³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Myocardial Infarction Causes Increased Expression But Decreased Activity of the Myocardial Na⁺—Ca²⁺ Exchanger in the Rabbit

Abstract: Journal of Physiologyventricle in rabbit heart 8-9 weeks after an experimentally induced apical infarct, and compares these values with equivalent measurements from sham-operated (sham) hearts.

Cited by 60 publications

References 48 publications

Transmural Heterogeneity of Na ⁺ –Ca ²⁺ Exchange

Transmural Heterogeneity of Na ⁺ –Ca ²⁺ Exchange

Human cardiomyocyte calcium handling and transverse tubules in mid‐stage of post‐myocardial‐infarction heart failure

Effects of clenbuterol on contractility and Ca²⁺ homeostasis of isolated rat ventricular myocytes

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Myocardial Infarction Causes Increased Expression But Decreased Activity of the Myocardial Na+—Ca2+ Exchanger in the Rabbit

Abstract: Journal of Physiologyventricle in rabbit heart 8-9 weeks after an experimentally induced apical infarct, and compares these values with equivalent measurements from sham-operated (sham) hearts.

Cited by 60 publications

References 48 publications

Transmural Heterogeneity of Na + –Ca 2+ Exchange

Transmural Heterogeneity of Na + –Ca 2+ Exchange

Human cardiomyocyte calcium handling and transverse tubules in mid‐stage of post‐myocardial‐infarction heart failure

Effects of clenbuterol on contractility and Ca2+ homeostasis of isolated rat ventricular myocytes

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Myocardial Infarction Causes Increased Expression But Decreased Activity of the Myocardial Na⁺—Ca²⁺ Exchanger in the Rabbit

Transmural Heterogeneity of Na ⁺ –Ca ²⁺ Exchange

Transmural Heterogeneity of Na ⁺ –Ca ²⁺ Exchange

Effects of clenbuterol on contractility and Ca²⁺ homeostasis of isolated rat ventricular myocytes