Cardiac contractility modulation attenuates structural and electrical remodeling in a chronic heart failure rabbit model

Ning, Bin; Zhang, Feifei; Hao, Qian; Li, Yingxiao; Li, Rong; Dang, Yi

doi:10.1177/0300060520962910

Cited by 13 publications

(9 citation statements)

References 34 publications

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“…These changes in ion channel proteins are similar to those in other disease states. Kv4.3 proteins have been verified to be downregulated in failing hearts (38,42), while the expression levels of Kv4.2 and KChIP2 proteins decreased in the myocardial tissues of type 2 diabetic rats compared with nondiabetic controls (43). BB536, a bifidobacterium longum strain, was then used to treat CKD rats; we found that BB536 could reduce IS levels in serum and heart tissue of CKD rats, and it reversed the decreased Kv4.2, Kv4.3, and KChIP2 proteins.…”

Section: Discussionmentioning

confidence: 99%

Indoxyl sulfate reduces Ito,f by activating ROS/MAPK and NF-κB signaling pathways

Yang¹,

Zhang²,

Zhou³

2022

JCI Insight

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There is a high prevalence of ventricular arrhythmias related to sudden cardiac death in patients with chronic kidney disease (CKD). To explored the possible mechanism of CKD-related ventricular arrhythmias, a CKD rat model was created, and indoxyl sulfate (IS) was further used in vivo and in vitro. This project used the following methods: patch clamp, electrocardiogram, and some molecular biology experimental techniques. IS was found to be significantly elevated in the serum of CKD rats. Interestingly, the expression levels of the fast transient outward potassium current–related (I to,f -related) proteins (Kv4.2, Kv4.3, and KChIP2) in the heart of CKD rats and rats treated with IS decreased. IS dose-dependently reduced I to,f density, accompanied by the decreases in Kv4.2, Kv4.3, and KChIP2 proteins in vitro. IS also prolonged the action potential duration and QT interval, and paroxysmal ventricular tachycardia could be induced by IS. In-depth studies have shown that ROS/p38MAPK, ROS–p44/42 MAPK, and NF-κB signaling pathways play key roles in the reduction of I to,f density and I to,f -related proteins caused by IS. These data suggest that IS reduces I to,f -related proteins and I to,f density by activating ROS/MAPK and NF-κB signaling pathways, and the action potential duration and QT interval are subsequently prolonged, which contributes to increasing the susceptibility to arrhythmia in CKD.

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Section: Discussionmentioning

confidence: 99%

Indoxyl sulfate reduces Ito,f by activating ROS/MAPK and NF-κB signaling pathways

Yang¹,

Zhang²,

Zhou³

2022

JCI Insight

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“…To the best of our knowledge the effects of CCM stimulation on human QT interval remains unknown. However, one publication demonstrated CCM‐induced attenuation of prolonged QTc interval in a rabbit HF model in vivo (Ning et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Acute effects of cardiac contractility modulation on human induced pluripotent stem cell–derived cardiomyocytes

Feaster

Casciola

Narkar

et al. 2021

Physiological Reports

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Cardiac contractility modulation (CCM) is an intracardiac therapy whereby nonexcitatory electrical simulations are delivered during the absolute refractory period of the cardiac cycle. We previously evaluated the effects of CCM in isolated adult rabbit ventricular cardiomyocytes and found a transient increase in calcium and contractility. In the present study, we sought to extend these results to human cardiomyocytes using human induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs) to develop a robust model to evaluate CCM in vitro. HiPSC‐CMs (iCell Cardiomyocytes2, Fujifilm Cellular Dynamic, Inc.) were studied in monolayer format plated on flexible substrate. Contractility, calcium handling, and electrophysiology were evaluated by fluorescence‐ and video‐based analysis (CellOPTIQ, Clyde Biosciences). CCM pulses were applied using an A‐M Systems 4100 pulse generator. Robust hiPSC‐CMs response was observed at 14 V/cm (64 mA) for pacing and 28 V/cm (128 mA, phase amplitude) for CCM. Under these conditions, hiPSC‐CMs displayed enhanced contractile properties including increased contraction amplitude and faster contraction kinetics. Likewise, calcium transient amplitude increased, and calcium kinetics were faster. Furthermore, electrophysiological properties were altered resulting in shortened action potential duration (APD). The observed effects subsided when the CCM stimulation was stopped. CCM‐induced increase in hiPSC‐CMs contractility was significantly more pronounced when extracellular calcium concentration was lowered from 2 mM to 0.5 mM. This study provides a comprehensive characterization of CCM effects on hiPSC‐CMs. These data represent the first study of CCM in hiPSC‐CMs and provide an in vitro model to assess physiologically relevant mechanisms and evaluate safety and effectiveness of future cardiac electrophysiology medical devices.

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“…In a canine HFrEF model, CCM therapy reduced left ventricular filling pressure due to the improvement of ventricular compliance and relaxation and improved diastolic Ca ++ physiology [ 29 ]. In a rabbit HFrEF model, CCM therapy reduced cardiac expression of connective tissue growth factor and galectin-3 (a pro-fibrotic marker involved in myocardial structural remodeling) with a reduction of myocardial fibrosis [ 11 ]. These effects of CCM therapy observed in animal models may explain the improvement in diastolic function and GLS observed in this study, as well as a reduction of the E/e’ ratio and of the NT-proBNP plasma levels both expression of left ventricular filling pressure.…”

Section: Discussionmentioning

confidence: 99%

“…Although the gold standard for quantification of MEE is cardiac catheterization (bilateral and of the coronary sinus) [ 3 ], recently, an echocardiographic approach has been proposed, enabling more extensive clinical applications [ 4 , 5 ]. Cardiac contractility modulation (CCM) is an innovative therapy for the treatment of patients with HF [ 6 ] that through delivery, via an implantable device (Optimizer Smart ® , Impulse Dynamics, Marlton, NJ, USA), of high-energy biphasic non-excitatory impulses during the absolute refractory period of the cardiomyocytes results in improved calcium handling [ 7 ], reverses titin downregulation and fetal gene expression [ 8 , 9 ] and reduces adrenergic tone and myocardial fibrosis [ 10 , 11 ]. These effects on failing myocardium biology result in an improvement of quality of life and functional capacity [ 12 ], reduction of hospitalizations [ 13 ], and a biventricular reverse remodeling [ 14 , 15 ] in patients with HFrEF.…”

Section: Introductionmentioning

confidence: 99%

The Effects of Device-Based Cardiac Contractility Modulation Therapy on Left Ventricle Global Longitudinal Strain and Myocardial Mechano-Energetic Efficiency in Patients with Heart Failure with Reduced Ejection Fraction

Masarone

Kittleson

Vivo

et al. 2022

JCM

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Background: Virtually all patients with heart failure with reduced ejection fraction have a reduction of myocardial mechano-energetic efficiency (MEE). Cardiac contractility modulation (CCM) is a novel therapy for the treatment of patients with HFrEF, in whom it improves the quality of life and functional capacity, reduces hospitalizations, and induces biventricular reverse remodeling. However, the effects of CCM on MEE and global longitudinal strain (GLS) are still unknown; therefore, this study aims to evaluate whether CCM therapy can improve the MEE of patients with HFrEF. Methods: We enrolled 25 patients with HFrEF who received an Optimizer Smart implant (the device that develops CCM therapy) between January 2018 and January 2021. Clinical and echocardiographic evaluations were performed in all patients 24 h before and six months after CCM therapy. Results: At six months, follow-up patients who underwent CCM therapy showed an increase of left ventricular ejection fraction (30.8 ± 7.1 vs. 36.1 ± 6.9%; p = 0.032) as well a rise of GLS 10.3 ± 2.7 vs. −12.9 ± 4.2; p = 0.018), of MEE (32.2 ± 10.1 vs. 38.6 ± 7.6 mL/s; p = 0.013) and of MEE index (18.4 ± 6.3 vs. 24.3 ± 6.7 mL/s/g; p = 0.022). Conclusions: CCM therapy increased left ventricular performance, improving left ventricular ejection fraction, GLS, as well as MEE and MEEi.

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Cardiac contractility modulation attenuates structural and electrical remodeling in a chronic heart failure rabbit model

Cited by 13 publications

References 34 publications

Indoxyl sulfate reduces Ito,f by activating ROS/MAPK and NF-κB signaling pathways

Indoxyl sulfate reduces Ito,f by activating ROS/MAPK and NF-κB signaling pathways

Acute effects of cardiac contractility modulation on human induced pluripotent stem cell–derived cardiomyocytes

The Effects of Device-Based Cardiac Contractility Modulation Therapy on Left Ventricle Global Longitudinal Strain and Myocardial Mechano-Energetic Efficiency in Patients with Heart Failure with Reduced Ejection Fraction

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