LCZ696 Therapy Reduces Ventricular Tachyarrhythmia Inducibility in a Myocardial Infarction-Induced Heart Failure Rat Model

Chang, Po Cheng; Lin, Shien‐Fong; Chu, Yen-Chang; Wo, Hung Ta; Lee, Hui Ling; Huang, Yhu-Chering; Wen, Ming; Chou, Chung Chuan

doi:10.1155/2019/6032631

Cited by 33 publications

(31 citation statements)

References 26 publications

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“…Activation of STAT1 has been demonstrated to induce cardiomyocyte apoptosis following ischemia/reperfusion injury by enhancing the expression of pro-apoptotic proteins, which suggests that STAT1 plays a key role in the pathology of MI ( 68 – 70 ). AKT3 is involved in cardiomyocyte cell death ( 71 ). In rats, the expression of AKT3 is decreased in the spinal cord following myocardial ischemia-reperfusion injury ( 72 ).…”

Section: Discussionmentioning

confidence: 99%

Uncovering potential differentially expressed miRNAs and targeted mRNAs in myocardial infarction based on integrating analysis

Wang¹,

Cao²

2020

Mol Med Rep

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Myocardial infarction (Mi) is one of the leading causes of death globally. The aim of the present study was to find valuable micrornas (mirnas/mirs) and target mrnas in order to contribute to our understanding of the pathology of Mi. mirna and mrna data were downloaded for differential expression analysis. Then, a regulatory network between mirnas and mrnas was established, followed by function annotation of target mrnas. Thirdly, prognosis and diagnostic analysis of differentially methylated target mrnas were performed. Finally, an in vitro experiment was used to validate the expression of selected mirnas and target mrnas. a total of 19 differentially expressed mirnas and 1,007 differentially expressed mRNAs were identified. Several regulatory interaction pairs between mirna and mrnas were identified, such as hsa-mir-142-2p-long-chain-fattyacid-coa ligase 1 (acSl1), hsa-mir-15a-3p-nicotinamide phosphoribosyltransferase (naMPT), hsa-mir-33b-5p-regulator of G-protein signaling 2 (rGS2), hsa-mir-17-3p-Jun dimerization protein 2 (JdP2), hsa-mir-24-1-5p-aquaporin-9 (aQP9) and hsa-mir-34a-5p-STaT1/aKT3. of note, it was demonstrated that acSl1, naMPT, rGS2, JdP2, aQP9, STaT1 and aKT3 had diagnostic and prognostic values for patients with Mi. in addition, STaT1 was involved in the 'chemokine signaling pathway' and 'Jak-STaT signaling pathway'. aKT3 was involved in both the 'MaPK signaling pathway' and 'T cell receptor signaling pathway'. reverse transcription-quantitative Pcr validation of hsa-mir-142-3p, hsa-mir-15a-3p, hsa-mir-33b-5p, acSl1, naMPT, rGS2 and JdP2 expression was consistent with the bioinformatics analysis. In conclusion, the identified miRNAs and mRNAs may be involved in the pathology of Mi.

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Section: Discussionmentioning

confidence: 99%

Uncovering potential differentially expressed miRNAs and targeted mRNAs in myocardial infarction based on integrating analysis

Wang¹,

Cao²

2020

Mol Med Rep

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“…While the underlying mechanism of sacubitril/valsartan remains unclear, the activated NP system promotes left ventricular reverse remodeling and reduced myocardial fibrosis, which may prevent the development of fatal arrhythmias [22]. Moreover, sacubitril/valsartan reduced the inducibility of ventricular arrhythmia and restored the expression of downregulated potassium channels in an experimental model of myocardial infarction in rats [23]. These results identify possible mechanisms associated with the reduced sudden cardiac death observed in the sacubitril/valsartan treatment groups.…”

Section: Results From Randomized Controlled Trials Of Angiotensin Recmentioning

confidence: 73%

Angiotensin receptor-neprilysin inhibitor for the treatment of heart failure: a review of recent evidence

Choi

Shin

2020

Korean J Intern Med

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Heart failure (HF) is a growing health concern in aging societies worldwide. Sacubitril/valsartan is changing the real-world treatment in the whole spectrum of HF. The beginning was the PARADIGM-HF trial published in 2014, which demonstrated the beneficial effects of inhibiting natriuretic peptide breakdown in combination with hindering the renin-angiotensin system in HF patients with a reduced ejection fraction. Subsequent large-scale randomized trials have evaluated angiotensin receptor-neprilysin inhibitor in HF patients with acute decompensation or with preserved ejection fraction. The post hoc analyses are being conducted as well. This review summarizes the recent evidence of sacubitril/ valsartan regarding patient-centered outcomes, based on randomized controlled trials and their associated studies.

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“…25 In addition to remodelling of ventricular hypertrophy, ion channels play an essential role in modulating the cardiac action potential for electrical conduction throughout the hypertrophic heart. 26 In respect of systolic HF rat model, Chang et al 9 observed that LCZ696 could up-regulate expression of K + channel proteins, including KCNH2, KCNE1, and KCNE 2, which caused shortened APD and ameliorated ventricle arrhythmogeneity of myocardial infarction-related HF. In contrast, in the SHR group, we observed up-regulation of tissue expression of small-conductance Ca 2+ -activated K + (SK and K Ca 2).…”

Section: Discussionmentioning

confidence: 99%

“…SV is a first‐in‐class medicine that has been proven to minimize the risk of non‐sustained and sustained ventricular tachycardia in HFrEF patients 7,8 . Previous studies have shown that LCZ696 improves systolic function, electrophysiological benefits, and down‐regulation of sodium and potassium channel protein expression, which are important contributors to systolic dysfunction‐related ventricular arrhythmia 9,10 . On the other hand, the rate of sudden cardiac death (SCD) is 0.3 per 100 patient‐years in hypertensive patients without cardiovascular diease 11 .…”

Section: Introductionmentioning

confidence: 99%

Reverse electromechanical modelling of diastolic dysfunction in spontaneous hypertensive rat after sacubitril/valsartan therapy

et al. 2020

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Aims Hypertension is a significant risk for the development of left ventricular hypertrophy, diastolic dysfunction, followed by heart failure and sudden cardiac death. While therapy with sacubitril/valsartan (SV) reduces the risk of sudden cardiac death in patients with heart failure and systolic dysfunction, the effect on those with diastolic dysfunction remains unclear. We hypothesized that, in the animal model of hypertensive heart disease, treatment with SV reduces the susceptibility to ventricular arrhythmia. Methods and results Young adult female spontaneous hypertensive rats (SHRs) were randomly separated into three groups, which were SHRs, SHRs treated with valsartan, and SHRs treated with SV. In addition, the age-matched and weight-matched Wistar Kyoto rats were considered as controls, and there were 12 rats in each group. In vivo ventricular tachyarrhythmia induction and in vitro optical mapping were used to measure the inducibility of ventricular arrhythmias and to characterize the dynamic properties of electrical propagation. The level of small-conductance Ca 2+-activated potassium channel type 2 (KCNN2) was analysed in cardiac tissue. Compared with SHR with left ventricular hypertrophy, treatment with SV significantly improved cardiac geometry (relative wall thickness, 0.68 ± 0.11 vs. 0.76 ± 0.13, P < 0.05) and diastolic dysfunction (isovolumetric relaxation time, 59.4 ± 3.2 vs. 70.5 ± 4.2 ms, P < 0.05; deceleration time of mitral E wave, 46 ± 4.8 vs. 42 ± 3.8, P < 0.05). The incidence of induced ventricular arrhythmia was significantly reduced in SHR treated with SV compared with SHR (ventricular tachycardia, 1.14 ± 0.32 vs. 2.91 ± 0.5 episodes per 10 stimuli, P < 0.001; ventricular fibrillation, 1.72 ± 0.31 vs. 5.81 ± 0.42 episodes per 10 stimuli, P < 0.001). The prolonged action potential duration (APD) and increase of the maximum slope of APD restitution were observed in SHR, while the treatment of SV improved the arrhythmogeneity (APD, 37.12 ± 6.18 vs. 92.41 ± 10.71 ms at 250 ms pacing cycle length, P < 0.001; max slope 0.29 ± 0.01 vs. 1.48 ± 0.04, P < 0.001). These effects were strongly associated with down-regulation of KCNN2 (0.38 ± 0.07 vs. 0.74 ± 0.12 ng/ml, P < 0.001). The treatment of SV also decreased the level of N-terminal pro-B-type natriuretic peptide, cardiac bridging integrator-1, and intramyocardial fibrosis of SHR. Conclusions In conclusion, synergistic blockade of the neprilysin and the renin-angiotensin system by SV in SHRs results in KCNN2-associated electrical remodelling in ventricle, which stabilizes electrical dynamics and attenuates arrhythmogenesis.

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LCZ696 Therapy Reduces Ventricular Tachyarrhythmia Inducibility in a Myocardial Infarction-Induced Heart Failure Rat Model

Cited by 33 publications

References 26 publications

Uncovering potential differentially expressed miRNAs and targeted mRNAs in myocardial infarction based on integrating analysis

Uncovering potential differentially expressed miRNAs and targeted mRNAs in myocardial infarction based on integrating analysis

Angiotensin receptor-neprilysin inhibitor for the treatment of heart failure: a review of recent evidence

Reverse electromechanical modelling of diastolic dysfunction in spontaneous hypertensive rat after sacubitril/valsartan therapy

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