Intracellular Dyssynchrony of Diastolic Cytosolic [Ca
            <sup>2+</sup>
            ] Decay in Ventricular Cardiomyocytes in Cardiac Remodeling and Human Heart Failure

Hohendanner, Felix; Ljubojevic, Senka; Macquaide, Niall; Sacherer, Michael; Sedej, Simon; Biesmans, Liesbeth; Wakula, Paulina; Platzer, Dieter; Sokolow, Sophie; Herchuelz, André; Antoons, Gudrun; Sipido, Karin R.; Pieske, Burkert; Heinzel, Frank R.

doi:10.1161/circresaha.113.300895

Cited by 50 publications

(58 citation statements)

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“…Fluorescence staining results revealed that the overall mitochondrial mass increased in the nonischemic HF group, consistent with previous reports (Figure 9A) 11, 12. Moreover, phosphorylation of MCU protein was significantly enhanced from 0.30±0.04 to 1.45±0.46 with nonischemic HF.…”

Section: Resultssupporting

confidence: 91%

“…After depolarizations are thought to involve alterations in Ca 2+ handling 6, 12. Mitochondria are known to sequester Ca 2+ and are altered in cardiomyopathy 12.…”

Section: Discussionmentioning

confidence: 99%

“…Ca 2+ /calmodulin‐dependent protein kinase II activity is elevated in HF and positively correlates with enhanced mitochondria Ca 2+ uptake 10. Mitochondrial numbers and area are increased in HF 11, 12. Reactive oxygen species are increased in HF, and oxidation of the MCU Cys‐97 residue can increase MCU activity 13.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Xie

Song

Liu

et al. 2018

JAHA

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BackgroundHeart failure (HF) is associated with increased arrhythmia risk and triggered activity. Abnormal Ca2+ handling is thought to underlie triggered activity, and mitochondria participate in Ca2+ homeostasis.Methods and ResultsA model of nonischemic HF was induced in C57BL/6 mice by hypertension. Computer simulations were performed using a mouse ventricular myocyte model of HF. Isoproterenol‐induced premature ventricular contractions and ventricular fibrillation were more prevalent in nonischemic HF mice than sham controls. Isolated myopathic myocytes showed decreased cytoplasmic Ca2+ transients, increased mitochondrial Ca2+ transients, and increased action potential duration at 90% repolarization. The alteration of action potential duration at 90% repolarization was consistent with in vivo corrected QT prolongation and could be explained by augmented L‐type Ca2+ currents, increased Na+‐Ca2+ exchange currents, and decreased total K+ currents. Of myopathic ventricular myocytes, 66% showed early afterdepolarizations (EADs) compared with 17% of sham myocytes (P<0.05). Intracellular application of 1 μmol/L Ru360, a mitochondrial Ca2+ uniporter–specific antagonist, could reduce mitochondrial Ca2+ transients, decrease action potential duration at 90% repolarization, and ameliorate EADs. Furthermore, genetic knockdown of mitochondrial Ca2+ uniporters inhibited mitochondrial Ca2+ uptake, reduced Na+‐Ca2+ exchange currents, decreased action potential duration at 90% repolarization, suppressed EADs, and reduced ventricular fibrillation in nonischemic HF mice. Computer simulations showed that EADs promoted by HF remodeling could be abolished by blocking either the mitochondrial Ca2+ uniporter or the L‐type Ca2+ current, consistent with the experimental observations.ConclusionsMitochondrial Ca2+ handling plays an important role in EADs seen with nonischemic cardiomyopathy and may represent a therapeutic target to reduce arrhythmic risk in this condition.

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Section: Resultssupporting

confidence: 91%

“…After depolarizations are thought to involve alterations in Ca 2+ handling 6, 12. Mitochondria are known to sequester Ca 2+ and are altered in cardiomyopathy 12.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Xie

Song

Liu

et al. 2018

JAHA

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“…2+ Decay (p 527) 49 Heart cells clear up their cytoplasmic calcium somewhat dyssynchronously, say Hohendanner et al, and this dyssynchrony gets worse in failing hearts.…”

Section: Dyssynchrony In Cytosolic Camentioning

confidence: 99%

Circulation Research “In This Issue” Anthology

Williams¹

2014

Circulation Research

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“…Dyssynchronous diastolic Ca 2+ decay within individual cardiomyocytes contributes to dyssynchronous intracellular sarcomere relengthening. It is conceivable that the subcellular synchrony of cytosolic Ca 2+ decay and sarcomere relengthening determine the efficacy of cardiomyocyte relaxation [10]. The SERCA is the main mediator of Ca 2+ decay.…”

Section: Introductionmentioning

confidence: 99%

Effect of Valsartan on Sarcoplasmic Reticulum Ca2+-ATPase Pump of the Left Ventricular Myocardium in Rats with Heart Failure with Preserved Ejection Fraction

et al. 2016

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Objectives: The aim was to investigate the effects of valsartan on the sarcoplasmic reticulum Ca²⁺-ATPase pump (SERCA) and L-type Ca²⁺ channel current (I_CaL) of the left ventricular myocardium in rats with heart failure with preserved ejection fraction. Methods: The 30-week-old male spontaneously hypertensive rats (SHRs) are randomly divided into the non-Valsartan and Valsartan groups, and the 30-week-old male Wistar-Kyoto rats served as control rats. The expression of SERCA is measured by Western blot. The I_CaL is measured by whole-cell patch clamp. The left ventricular end-diastolic pressure and left ventricular relaxation time constant quantity are measured at the same time. Results: The left ventricular end-diastolic pressure is much higher in SHRs compared with that in control rats (p < 0.01). The left ventricular relaxation time constant quantity is markedly extended in SHRs compared with control rats (p < 0.01). Valsartan cannot increase the expression of SERCA nor decrease the density of I_CaL compared with the non-Valsartan group (p > 0.05). Conclusions: Valsartan has no effect on SERCA and I_CaL of the left ventricular myocardium in rats with heart failure with preserved ejection fraction.

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Intracellular Dyssynchrony of Diastolic Cytosolic [Ca ²⁺ ] Decay in Ventricular Cardiomyocytes in Cardiac Remodeling and Human Heart Failure

Cited by 50 publications

References 50 publications

Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Circulation Research “In This Issue” Anthology

Effect of Valsartan on Sarcoplasmic Reticulum Ca2+-ATPase Pump of the Left Ventricular Myocardium in Rats with Heart Failure with Preserved Ejection Fraction

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Intracellular Dyssynchrony of Diastolic Cytosolic [Ca 2+ ] Decay in Ventricular Cardiomyocytes in Cardiac Remodeling and Human Heart Failure

Cited by 50 publications

References 50 publications

Mitochondrial Ca 2+ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Mitochondrial Ca 2+ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Circulation Research “In This Issue” Anthology

Effect of Valsartan on Sarcoplasmic Reticulum Ca2+-ATPase Pump of the Left Ventricular Myocardium in Rats with Heart Failure with Preserved Ejection Fraction

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Intracellular Dyssynchrony of Diastolic Cytosolic [Ca ²⁺ ] Decay in Ventricular Cardiomyocytes in Cardiac Remodeling and Human Heart Failure

Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy