Sacubitril/Valsartan Therapy Ameliorates Ventricular Tachyarrhythmia Inducibility in a Rabbit Myocardial Infarction Model

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

doi:10.1016/j.cardfail.2020.03.007

Cited by 31 publications

(27 citation statements)

References 28 publications

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“…Sacubitril/valsartan also reduced the inducibility of ventricular arrhythmias in SHRs in association with improved cardiac function and reduced electrical and structural remodeling, including normalization of action potential duration (APD) [50]. In the setting of chronic MI and HF, sacubitril/valsartan-treated rabbits also consistently displayed shorter APD, faster conduction velocity and reduced ventricular arrhythmia inducibility [51,52]. Similarly, in rats with MI-induced HF, sacubitril/valsartan attenuated the HF-induced ventricular ERP prolongation through transcriptional regulation of cardiac potassium channels [53], while in rats with ischemic cardiomyopathy, ARNI lowered ventricular arrhythmia inducibility, attenuated sympathetic neural remodeling, reversed myocardial fibrosis and increased connexin-43 expression [54].…”

Section: Preclinical Studies Investigating the Electrophysiological Consequences Of Arnimentioning

confidence: 93%

“…By contrast, in HF, sacubitril/valsartan appears to reduce APD/ERP by increasing I Kr and I Ks through transcriptional regulation of KCNH2, KCNE1 and KCNE2 [53], potentially reducing the likelihood of proarrhythmic EADs. Moreover, it may suppress cellular determinants of ectopic activity via the downregulation of RyR2, NCX1 and CaMKII phosphorylation [51], although further studies are required to confirm the exact mechanisms and therapeutic efficacy. Finally, sacubitril/valsartan improves conduction velocity [51], which may also contribute to the reduced VF inducibility in HF.…”

Section: Potential Mechanisms Through Which Arni Modulate Cardiac Arrhythmiasmentioning

confidence: 99%

“…Moreover, it may suppress cellular determinants of ectopic activity via the downregulation of RyR2, NCX1 and CaMKII phosphorylation [51], although further studies are required to confirm the exact mechanisms and therapeutic efficacy. Finally, sacubitril/valsartan improves conduction velocity [51], which may also contribute to the reduced VF inducibility in HF. Although the abovementioned molecular mechanisms of ARNI are plausible potential contributors to the observed in vivo antiarrhythmic effects, there is at present no conclusive mechanism underlying ARNI-mediated arrhythmia suppression in patients.…”

Section: Potential Mechanisms Through Which Arni Modulate Cardiac Arrhythmiasmentioning

confidence: 99%

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Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and Cardiac Arrhythmias

Sutanto

Dobrev

Heijman

2021

IJMS

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The renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiovascular health and disease. Short-term RAAS activation controls water and salt retention and causes vasoconstriction, which are beneficial for maintaining cardiac output in low blood pressure and early stage heart failure. However, prolonged RAAS activation is detrimental, leading to structural remodeling and cardiac dysfunction. Natriuretic peptides (NPs) are activated to counterbalance the effect of RAAS and sympathetic nervous system by facilitating water and salt excretion and causing vasodilation. Neprilysin is a major NP-degrading enzyme that degrades multiple vaso-modulatory substances. Although the inhibition of neprilysin alone is not sufficient to counterbalance RAAS activation in cardiovascular diseases (e.g., hypertension and heart failure), a combination of angiotensin receptor blocker and neprilysin inhibitor (ARNI) was highly effective in several clinical trials and may modulate the risk of atrial and ventricular arrhythmias. This review summarizes the possible link between ARNI and cardiac arrhythmias and discusses potential underlying mechanisms, providing novel insights about the therapeutic role and safety profile of ARNI in the cardiovascular system.

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Section: Preclinical Studies Investigating the Electrophysiological Consequences Of Arnimentioning

confidence: 93%

Section: Potential Mechanisms Through Which Arni Modulate Cardiac Arrhythmiasmentioning

confidence: 99%

Section: Potential Mechanisms Through Which Arni Modulate Cardiac Arrhythmiasmentioning

confidence: 99%

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Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and Cardiac Arrhythmias

Sutanto

Dobrev

Heijman

2021

IJMS

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“…Animal models have shown that ARNI modulates natriuretic peptides thereby decreasing subsequent myocardial stiffness and remodeling, sparing of LVEF and mechanics, and decreasing LV dilation and fibrosis (44). In rat models with coronary artery ligation and secondary reduced LVEF, compared with enalapril therapy, sacubitril/valsartan modified CaMKII-p expression, upregulated expression of potassium channels, attenuated post-MI LV dysfunction and electrophysiologic remodeling reducing ventricular arrhythmia inducibility (45,46). PARADISE-MI (Prospective ARNI vs.…”

Section: Coronary Artery Disease (Cad)mentioning

confidence: 99%

Narrative review in the current role of angiotensin receptor-neprilysin inhibitors

Rodríguez¹,

Cu²,

Siddiqui³

2021

Ann Transl Med

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Heart failure (HF) accounts for a tremendous burden on health care systems and the society.Since the landmark PARADIGM-HF trial, sacubitril/valsartan, the first in the class of angiotensin receptor neprilysin inhibitor (ARNI) showed superiority to enalapril in patients with HF with reduced ejection fraction (HFrEF). We performed a narrative literature review, hand-searched the reference lists of included articles and relevant reviews. Inhibition of neprilysin increases bradykinin, natriuretic peptides and adrenomedullin levels counteract the neurohormal activation that leads to sodium retention, vasoconstriction, and cardiac remodeling. In PARADIGM-HF the primary outcome of CV death or HF hospitalization was reduced 20% in the ARNI group (HR 0.80, P<0.001) similar to mortality due to cardiovascular cause (HR 0.80, P<0.001) in patients with HFrEF, rendering a number needed to treat of 21 patients. This effect was consistent across subgroups. The safety of starting ARNI inpatient once the acute decompensation of HF is stabilized was demonstrated in PIONEER-HF trial. With willingness-topay thresholds commonly acceptable in the United States, sacubitril/valsartan is likely to be cost effective, which might not be in other health systems. Although its safety has been reassured in some clinical trials, common side effects are hypotension, worsening kidney function, hyperkalemia and angioedema. In HFpEF (PARAGON-HF), sacubitril/valsartan showed decrease in the level of the cardiac biomarkers, with improve functional NYHA and decrease in hospitalizations, predominately in women and patients with borderline ejection fraction. Some ongoing studies aim to demonstrate the effects of ARNI in acute coronary syndrome, stable ischemic heart disease, advanced HF, mitral regurgitation, aortic impedance and pulmonary hypertension. In conclusion, sacubitril/valsartan has proven to be an effective addition to the HFrEF arsenal, with safety comparable to current standard of care. In HFpEF, it improves quality of life, particularly in women and in patients with borderline ejection fraction, with no effect on mortality.

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“…used a rabbit MI and HF model to demonstrate SAC/VAL could preserve heart systolic function and avert MI-induced electrophysiologic remodeling by reducing phosphorylated expression calmodulin-dependent protein kinase II (p-CaMKII) [19]. Vaskova et al showed that downregulation of miR-181a exosomes could also be one of the mechanisms by which SAC/VAL improves cardiac function and reduces myocardial brosis in rats with chronic MI [20].…”

Section: Introductionmentioning

confidence: 99%

Sacubitril/valsartan Decreased Atrial Fibrillation Susceptibility by Inhibiting Angiotensin II-induced Atrial Fibrosis through p-Smad2/3, p-JNK, and p-p38 Signaling Pathways

Zhang

et al. 2020

Preprint

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Background: Sacubitril/valsartan (SAC/VAL), combined inhibitors of angiotensin receptor (AT-R) and neprilysin receptor, prevents Angiotensin Ⅱ (AngⅡ) from binding AT1-R and blocks degradation of natriuretic peptides. Despite its efficacy in reducing ventricular fibrosis and preserving cardiac functions, which has been extensively demonstrated in myocardial infarction or pressure overload models, few studies have been conducted to determine whether SAC/VAL could attenuate atrial fibrosis and decrease atrial fibrillation (AF) susceptibility. Methods: Sprague-Dawley rats were divided into three groups after implantation of an osmotic pump preloaded with AngⅡ and received corn oil, VAL, or SAC/VAL treatment for 28 days. Electrophysiological study was performed to determine inducibility and duration of AF. Echocardiography was performed before and 28 days after osmotic mini-pump implantation to evaluate cardiac functions. Enzyme-linked immunosorbent assay was perfomed to detect the serum concentration of atrial natriuretic peptide (ANP), N-terminal pro-brain natriuretic peptide (NT-proBNP) and AngⅡ. Masson staining was performed to determine the extent of interstitial fibrosis. Immunohistochemical, and immunofluorescence staining as well as transwell and MTT assay were also performed. Western blot analysis was perfomed to figure out how SAC/VAL exerts its anti-fibrosis effects in atriums.Results: After 28 days of AngⅡ stimulation, rats in SAC/VAL group exhibited reduced reduced extent of atrial fibrosis, inhibited proliferation, migration, and differentiation of atrial fibroblasts and decreased susceptibility to atrial fibrillation. We further found that SAC/VAL exerted its effect on AngⅡ-induced atrial fibrosis by inhibiting the p-Smad2/3, p-JNK, and p-p38 MAPK signaling pathways in vivo. Conclusions: Our study provided experimental evidence for the inhibition of atrial fibrosis and reduced susceptibility to AF by SAC/VAL. These results emphasize the importance of SAC/VAL in the prevention of AngⅡ-induced atrial fibrosis and may help to enrich the options for atrial fibrillation pharmacotherapy.

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Sacubitril/Valsartan Therapy Ameliorates Ventricular Tachyarrhythmia Inducibility in a Rabbit Myocardial Infarction Model

Cited by 31 publications

References 28 publications

Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and Cardiac Arrhythmias

Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and Cardiac Arrhythmias

Narrative review in the current role of angiotensin receptor-neprilysin inhibitors

Sacubitril/valsartan Decreased Atrial Fibrillation Susceptibility by Inhibiting Angiotensin II-induced Atrial Fibrosis through p-Smad2/3, p-JNK, and p-p38 Signaling Pathways

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