scholarly journals Inhibition of N-type calcium channels in cardiac sympathetic neurons attenuates ventricular arrhythmogenesis in heart failure

2020 ◽  
Author(s):  
Dongze Zhang ◽  
Huiyin Tu ◽  
Chaojun Wang ◽  
Liang Cao ◽  
Wenfeng Hu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Coronary Artery ◽  
Ventricular Arrhythmias ◽  
Sympathetic Neurons ◽  
Coronary Artery Ligation ◽  
Channel Blockers ◽  
Artery Ligation ◽  
Cell Excitability ◽  
Ventricular Arrhythmogenesis

Abstract Aims Cardiac sympathetic overactivation is an important trigger of ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic post-ganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF. Methods and results Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time polymerase chain reaction and western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry electrocardiogram recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of ventricular tachycardia/ventricular fibrillation but also improved CHF-induced heterogeneity of ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to ventricular arrhythmias in anaesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and ventricular arrhythmogenesis in CHF rats. Conclusions Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and ventricular arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal ventricular arrhythmias in CHF.

scholarly journals Sufentanil–medetomidine anaesthesia compared with fentanyl/fluanisone–midazolam is associated with fewer ventricular arrhythmias and death during experimental myocardial infarction in rats and limits infarct size following reperfusion

2017 ◽  
Vol 52 (3) ◽  
pp. 271-279 ◽  
Author(s):  
Ellis N ter Horst ◽  
Paul A J Krijnen ◽  
Paul Flecknell ◽  
Klaas W Meyer ◽  
Klaas Kramer ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Rate ◽  
Coronary Artery ◽  
Infarct Size ◽  
Ventricular Arrhythmias ◽  
Anaesthetic Agent ◽  
Therapeutic Interventions ◽  
Coronary Artery Ligation ◽  
Artery Ligation

To improve infarct healing following myocardial infarction in humans, therapeutic interventions can be applied during the inflammatory response. Animal models are widely used to study this process. However, induction of MI in rodents is associated with high mortality due to ventricular fibrillation (VF) during coronary artery ligation. The anaesthetic agent used during the procedure appears to influence the frequency of this complication. In this retrospective study, the effect on ventricular arrhythmia incidence during ligation and infarct size following in vivo reperfusion of two anaesthetic regimens, sufentanil–medetomidine (SM) and fentanyl/fluanisone–midazolam (FFM) was evaluated in rats. Anaesthetics were administered subcutaneously using fentanyl/fluanisone (0.5 mL/kg) with midazolam (5 mg/kg) (FFM group, n = 48) or sufentanil (0.05 mg/kg) with medetomidine (0.15 mg/kg) (SM group, n = 47). The coronary artery was ligated for 40 min to induce MI. Heart rate and ventricular arrhythmias were recorded during ligation, and infarct size was measured via histochemistry after three days of reperfusion. In the SM group, heart rate and VF incidence were lower throughout the experiment compared with the FFM group (6% versus 30%) ( P < 0.01). Fatal VF did not occur in the SM group whereas this occurred in 25% of the animals in the FFM group. Additionally, after three days of reperfusion, the infarcted area following SM anaesthesia was less than half as large as that following FFM anaesthesia (8.5 ± 6.4% versus 20.7 ± 5.6%) ( P < 0.01). Therefore, to minimize the possibility of complications related to VF and acute death arising during ligation, SM anaesthesia is recommended for experimental MI in rats.

Suppression of ventricular arrhythmias resulting from acute coronary artery ligation in rat by imipramine

1990 ◽  
Vol 42 (5) ◽  
pp. 360-362
Author(s):  
Samiha A. M. El-Mahdy ◽  
A. A. Alhaider ◽  
Afaf A. Mahgoub ◽  
Abdulwahab M. Bashandy
Keyword(s):  
Coronary Artery ◽  
Ventricular Arrhythmias ◽  
Coronary Artery Ligation ◽  
Artery Ligation

An antibody to leukocyte integrins attenuates coronary vascular injury due to ischemia and reperfusion in dogs

1997 ◽  
Vol 272 (2) ◽  
pp. H618-H624 ◽  
Author(s):  
L. D. Horwitz ◽  
D. Kaufman ◽  
Y. Kong
Keyword(s):  
Coronary Artery ◽  
Leukocyte Adhesion ◽  
Microvascular Permeability ◽  
Coronary Artery Ligation ◽  
Ischemia And Reperfusion ◽  
Artery Ligation ◽  
Isotope Technique ◽  
Coronary Ischemia

Ischemia and reperfusion cause coronary vascular and myocardial injury, which may be due to leukocyte-mediated processes. Antileukocyte measures have reduced injury after brief reperfusion periods of 1-3 h, but there has been little information on whether benefits are apparent after longer periods of reperfusion. We examined the effect of pretreatment with a monoclonal antibody (R15.7) to the CD18 family of leukocyte adhesion molecules (beta2-integrins) in dogs exposed to regional coronary ischemia for 1 h of left anterior descending coronary artery ligation and then reperfused for 48 h. Coronary microvascular permeability was assessed in vivo by measurement of protein leak index (PLI), using a double-isotope technique with autologous radiolabeled transferrin and erythrocytes. Vasorelaxation was measured in vitro with preconstricted epicardial coronary artery rings subjected to increasing concentrations of the endothelium-dependent vasodilators bradykinin (BK) and ADP and the endothelium-independent vasodilator nitroprusside. At 48 h of reperfusion in untreated dogs there were substantial increases in PLI in the previously ischemic regions, indicative of increased extravascular transferrin. These abnormalities were decreased, but not abolished, in the dogs treated with R15.7. Relaxation of rings from the ischemic/reperfused artery to BK and ADP were blunted in the untreated dogs. R15.7 resulted in improvement in some, but not all, indexes of relaxation in response to BK and ADP. Relaxation to nitroprusside was normal in ischemic/reperfused coronary rings from both treated and untreated dogs. Therefore, after 1 h of regional coronary ischemia and 48 h of reperfusion, coronary endothelial injury, which was manifested by increased coronary microvascular permeability and abnormalities in coronary endothelium-dependent relaxation, was reduced by pretreatment with the anti-CD18 integrin antibody R15.7.

scholarly journals Integrative System Biology Analyses Identify Seven MicroRNAs to Predict Heart Failure

2019 ◽  
Vol 5 (1) ◽  
pp. 22 ◽  
Author(s):  
Henri Charrier ◽  
Marie Cuvelliez ◽  
Emilie Dubois-Deruy ◽  
Paul Mulder ◽  
Vincent Richard ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systems Biology ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Mirna Signature ◽  
Artery Ligation ◽  
Proteomic Data

Heart failure (HF) has several etiologies including myocardial infarction (MI) and left ventricular remodeling (LVR), but its progression remains difficult to predict in clinical practice. Systems biology analyses of LVR after MI provide molecular insights into this event such as modulation of microRNA (miRNA) that could be used as a signature of HF progression. To define a miRNA signature of LVR after MI, we use 2 systems biology approaches, integrating either proteomic data generated from LV of post-MI rat induced by left coronary artery ligation or multi-omics data (proteins and non-coding RNAs) generated from plasma of post-MI patients from the REVE-2 study. The first approach predicted that 13 miRNAs and 3 of these miRNAs would be validated to be associated with LVR in vivo: miR-21-5p, miR-23a-3p and miR-222-3p. The second approach predicted that 24 miRNAs among 1310 molecules and 6 of these miRNAs would be selected to be associated with LVR in silico: miR-17-5p, miR-21-5p, miR-26b-5p, miR-222-3p, miR-335-5p and miR-375. We identified a signature of 7 microRNAs associated with LVR after MI that support the interest of integrative systems biology analyses to define a miRNA signature of HF progression.

scholarly journals Changes in myofilament proteins, but not Ca2+ regulation, are associated with a high-fat diet-induced improvement in contractile function in heart failure

2011 ◽  
Vol 301 (4) ◽  
pp. H1438-H1446 ◽  
Author(s):  
Y. Cheng ◽  
W. Li ◽  
T. A. McElfresh ◽  
X. Chen ◽  
J. M. Berthiaume ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein Expression ◽  
Contractile Function ◽  
Left Ventricular ◽  
Contractile Properties ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Cell Shortening ◽  
Regulatory Properties

Pathological conditions such as diabetes, insulin resistance, and obesity are characterized by elevated plasma and myocardial lipid levels and have been reported to exacerbate the progression of heart failure (HF). Alterations in cardiomyocyte Ca2+ regulatory properties and myofilament proteins have also been implicated in contractile dysfunction in HF. However, our prior studies reported that high saturated fat (SAT) feeding improves in vivo myocardial contractile function, thereby exerting a cardioprotective effect in HF. Therefore, we hypothesized that SAT feeding improves contractile function by altering Ca2+ regulatory properties and myofilament protein expression in HF. Male Wistar rats underwent coronary artery ligation (HF) or sham surgery (SH) and were fed normal chow (SHNC and HFNC groups) or a SAT diet (SHSAT and HFSAT groups) for 8 wk. Contractile properties were measured in vivo [echocardiography and left ventricular (LV) cannulation] and in isolated LV cardiomyocytes. In vivo measures of contractility (peak LV +dP/d t and −dP/d t) were depressed in the HFNC versus SHNC group but improved in the HFSAT group. Isolated cardiomyocytes from both HF groups were hypertrophied and had decreased percent cell shortening and a prolonged time to half-decay of the Ca2+ transient versus the SH group; however, SAT feeding reduced in vivo myocyte hypertrophy in the HFSAT group only. The peak velocity of cell shortening was reduced in the HFNC group but not the HFSAT group and was positively correlated with in vivo contractile function (peak LV +dP/d t). The HFNC group demonstrated a myosin heavy chain (MHC) isoform switch from fast MHC-α to slow MHC-β, which was prevented in the HFSAT group. Alterations in Ca2+ transients, L-type Ca2+ currents, and protein expression of sarco(endo)plasmic reticulum Ca2+-ATPase and phosphorylated phospholamban could not account for the changes in the in vivo contractile properties. In conclusion, the cardioprotective effects associated with SAT feeding in HF may occur at the level of the isolated cardiomyocyte, specifically involving changes in myofilament function but not sarcoplasmic reticulum Ca2+ regulatory properties.

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