Short-Long Heart Rate Variation Increases Dispersion of Action Potential Duration in Long QT Type 2 Transgenic Rabbit Model

Kim, Tae Yun; Jeng, Paul; Hwang, Jung Min; Pfeiffer, Zachary A.; Patel, Divyang; Cooper, Leon N.; Kossidas, Konstantinos; Centracchio, Jason; Peng, Xuwen; Koren, Gideon; Qu, Zhilin; Choi, Bum Rak

doi:10.1038/s41598-019-51230-9

Cited by 7 publications

(4 citation statements)

References 64 publications

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“…This is often associated with an increased T peak –T end interval and U-wave amplitude, and even with ventricular ectopy in LQTS patients 79 and experimental models. In one study on LQT2 transgenic rabbits, 80 short–long variation of the rate increased APD dispersion. Importantly, Sauer et al recently demonstrated a link between an increased T peak –T end interval and diastolic dysfunction in unselected (non-LQTS) patients referred for exercise echocardiography.…”

Section: Mechanical Pertubations In the Congenital Long-qt Syndromementioning

confidence: 99%

Electromechanical reciprocity and arrhythmogenesis in long-QT syndrome and beyond

Odening

Linde

Ackerman

et al. 2022

European Heart Journal

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An abundance of literature describes physiological and pathological determinants of cardiac performance, building on the principles of excitation–contraction coupling. However, the mutual influencing of excitation–contraction and mechano-electrical feedback in the beating heart, here designated ‘electromechanical reciprocity’, remains poorly recognized clinically, despite the awareness that external and cardiac-internal mechanical stimuli can trigger electrical responses and arrhythmia. This review focuses on electromechanical reciprocity in the long-QT syndrome (LQTS), historically considered a purely electrical disease, but now appreciated as paradigmatic for the understanding of mechano-electrical contributions to arrhythmogenesis in this and other cardiac conditions. Electromechanical dispersion in LQTS is characterized by heterogeneously prolonged ventricular repolarization, besides altered contraction duration and relaxation. Mechanical alterations may deviate from what would be expected from global and regional repolarization abnormalities. Pathological repolarization prolongation outlasts mechanical systole in patients with LQTS, yielding a negative electromechanical window (EMW), which is most pronounced in symptomatic patients. The electromechanical window is a superior and independent arrhythmia-risk predictor compared with the heart rate-corrected QT. A negative EMW implies that the ventricle is deformed—by volume loading during the rapid filling phase—when repolarization is still ongoing. This creates a ‘sensitized’ electromechanical substrate, in which inadvertent electrical or mechanical stimuli such as local after-depolarizations, after-contractions, or dyssynchrony can trigger abnormal impulses. Increased sympathetic-nerve activity and pause-dependent potentiation further exaggerate electromechanical heterogeneities, promoting arrhythmogenesis. Unraveling electromechanical reciprocity advances the understanding of arrhythmia formation in various conditions. Real-time image integration of cardiac electrophysiology and mechanics offers new opportunities to address challenges in arrhythmia management.

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Section: Mechanical Pertubations In the Congenital Long-qt Syndromementioning

confidence: 99%

Electromechanical reciprocity and arrhythmogenesis in long-QT syndrome and beyond

Odening

Linde

Ackerman

et al. 2022

European Heart Journal

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“…It is possible that the prolongation of QT and QTc intervals may be contributed mostly by prolonged APDs from left ventricle. Therefore, the discrepant effects of CKD on APDs between right and left ventricle may increase interventricular dispersion of APDs, which could increase the genesis of micro‐reentry circuits . Moreover, prolonged QT interval may result in ventricular arrhythmia due to triggered activity of EAD, and we found more EADs in our CKD mice.…”

Section: Discussionmentioning

confidence: 68%

Cardiac calcium dysregulation in mice with chronic kidney disease

Chin

Tsai

et al. 2020

J Cellular Molecular Medi

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Cardiovascular complications are leading causes of morbidity and mortality in patients with chronic kidney disease (CKD). CKD significantly affects cardiac calcium (Ca2+) regulation, but the underlying mechanisms are not clear. The present study investigated the modulation of Ca2+ homeostasis in CKD mice. Echocardiography revealed impaired fractional shortening (FS) and stroke volume (SV) in CKD mice. Electrocardiography showed that CKD mice exhibited longer QT interval, corrected QT (QTc) prolongation, faster spontaneous activities, shorter action potential duration (APD) and increased ventricle arrhythmogenesis, and ranolazine (10 µmol/L) blocked these effects. Conventional microelectrodes and the Fluo‐3 fluorometric ratio techniques indicated that CKD ventricular cardiomyocytes exhibited higher Ca2+ decay time, Ca2+ sparks, and Ca2+ leakage but lower [Ca2+]i transients and sarcoplasmic reticulum Ca2+ contents. The CaMKII inhibitor KN93 and ranolazine (RAN; late sodium current inhibitor) reversed the deterioration in Ca2+ handling. Western blots revealed that CKD ventricles exhibited higher phosphorylated RyR2 and CaMKII and reduced phosphorylated SERCA2 and SERCA2 and the ratio of PLB‐Thr17 to PLB. In conclusions, the modulation of CaMKII, PLB and late Na+ current in CKD significantly altered cardiac Ca2+ regulation and electrophysiological characteristics. These findings may apply on future clinical therapies.

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“…Young and aged hearts were prepared as described previously ( Liu et al, 2018 ; Kim et al, 2019 ). Hearts were stained with the voltage-sensitive dye di-4-ANEPPS, and ECG and perfusion pressure were constantly monitored (PowerLab, ADInstruments, Sydney, Australia).…”

Section: Methodsmentioning

confidence: 99%

Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart

Baggett,

Murphy,

Sengun

et al. 2023

eLife

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Progressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhythmias. This process is well studied in young animals, but little is known about pro-arrhythmic changes in aged animals. Senescent cells accumulate with age and accelerate age-associated diseases. Senescent cells interfere with cardiac function and outcome post-MI with age, but studies have not been performed in larger animals, and the mechanisms are unknown. Specifically, age-associated changes in timecourse of senescence and related changes in inflammation and fibrosis are not well understood. Additionally, the cellular and systemic role of senescence and its inflammatory milieu in influencing arrhythmogenesis with age is not clear, particularly in large animal models with cardiac electrophysiology more similar to humans than previously studied animal models. Here, we investigated the role of senescence in regulating inflammation, fibrosis, and arrhythmogenesis in young and aged infarcted rabbits. Aged rabbits exhibited increased peri-procedural mortality and arrhythmogenic electrophysiological remodeling at the infarct border zone (IBZ) compared to young rabbits. Studies of the aged infarct zone revealed persistent myofibroblast senescence and increased inflammatory signaling over a twelve-week timecourse. Senescent IBZ myofibroblasts in aged rabbits appear to be coupled to myocytes, and our computational modeling showed that senescent myofibroblast-cardiomyocyte coupling prolongs action potential duration (APD) and facilitates conduction block permissive of arrhythmias. Aged infarcted human ventricles show levels of senescence consistent with aged rabbits, and senescent myofibroblasts also couple to IBZ myocytes. Our findings suggest that therapeutic interventions targeting senescent cells may mitigate arrhythmias post-MI with age.

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Short-Long Heart Rate Variation Increases Dispersion of Action Potential Duration in Long QT Type 2 Transgenic Rabbit Model

Cited by 7 publications

References 64 publications

Electromechanical reciprocity and arrhythmogenesis in long-QT syndrome and beyond

Electromechanical reciprocity and arrhythmogenesis in long-QT syndrome and beyond

Cardiac calcium dysregulation in mice with chronic kidney disease

Myofibroblast senescence promotes arrhythmogenic remodeling in the aged infarcted rabbit heart

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