Limiting sarcolemmal Na+entry during resuscitation from ventricular fibrillation prevents excess mitochondrial Ca2+accumulation and attenuates myocardial injury

2007 ◽  
Vol 103 (1) ◽  
pp. 55-65 ◽  
Author(s):  
Sufen Wang ◽  
Jeejabai Radhakrishnan ◽  
Iyad M. Ayoub ◽  
Julieta D. Kolarova ◽  
Domenico M. Taglieri ◽  
...  
Keyword(s):  
Ventricular Fibrillation ◽  
Chest Compression ◽  
Myocardial Injury ◽  
Troponin I ◽  
Myocardial Dysfunction ◽  
Aortic Pressure ◽  
Left Ventricular ◽  
Ischemia And Reperfusion ◽  
Reverse Mode ◽  
Ventricular Compliance

Background: intracellular Na+accumulation during ischemia and reperfusion leads to cytosolic Ca2+overload through reverse-mode operation of the sarcolemmal Na+-Ca2+exchanger. Cytosolic Ca2+accumulation promotes mitochondrial Ca2+(Ca2+m) overload, leading to mitochondrial injury. We investigated whether limiting sarcolemmal Na+entry during resuscitation from ventricular fibrillation (VF) attenuates Ca2+moverload and lessens myocardial dysfunction in a rat model of VF and closed-chest resuscitation. Methods: hearts were harvested from 10 groups of 6 rats each representing baseline, 15 min of untreated VF, 15 min of VF with chest compression given for the last 5 min (VF/CC), and 60 min postresuscitation (PR). VF/CC and PR included four groups each randomized to receive before starting chest compression the new NHE-1 inhibitor AVE4454B (1.0 mg/kg), the Na+channel blocker lidocaine (5.0 mg/kg), their combination, or vehicle control. The left ventricle was processed for intracellular Na+and Ca2+mmeasurements. Results: limiting sarcolemmal Na+entry attenuated cytosolic Na+increase during VF/CC and the PR phase and prevented Ca2+moverload yielding levels that corresponded to 77% and 71% of control hearts at VF/CC and PR, without differences among specific Na+-limiting interventions. Limiting sarcolemmal Na+entry attenuated reductions in left ventricular compliance during VF and prompted higher mean aortic pressure (110 ± 7 vs. 95 ± 11 mmHg, P < 0.001) and higher cardiac work index (159 ± 34 vs. 126 ± 29 g·m·min−1·kg−1, P < 0.05) with lesser increases in circulating cardiac troponin I at 60 min PR. Conclusions: Na+-limiting interventions prevented excess Ca2+maccumulation induced by ischemia and reperfusion and ameliorated myocardial injury and dysfunction.

Abstract 87: Cyclosporin A does not Prevent Myocardial Dysfunction after Resuscitation from Cardiac Arrest in Rats

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Iyad M Ayoub ◽  
Jeejabai Radhakrishnan ◽  
Raúl J Gazmuri
Keyword(s):  
Cardiac Arrest ◽  
Cyclosporin A ◽  
Chest Compression ◽  
Rat Model ◽  
Mitochondrial Permeability Transition ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
List Type ◽  
Ischemia And Reperfusion ◽  
Biphasic Waveform

Objective: We have previously reported in a rat model of VF and closed-chest resuscitation that cytochrome c is released into the bloodstream after resuscitation from cardiac arrest attaining plasma levels inversely proportional to survival. Recent evidence indicates that release of cytochrome c during ischemia and reperfusion may be a manifestation of prolonged opening of the mitochondrial permeability transition pore (mPTP). In this study, we investigated whether cyclosporin A (CsA, an inhibitor of mPTP opening) can prevent post-resuscitation (PR) myocardial dysfunction and improve survival. Methods: VF was electrically induced and left untreated for 10 mins. Resuscitation was attempted by 8 mins of chest compression followed by biphasic waveform defibrillation. Rats were randomized to received a bolus CsA (10 mg/kg) five minutes before inducing VF (n=6), immediately before starting chest compression (n=6), or to receive vehicle control before inducing VF (n=3) or before starting chest compression (n=3). CsA-treated (n=12) and vehicle-treated (n=6) rats were pooled for this analysis after noticing no differences between subgroups. Resuscitated rats were monitored for up to 6 hours. Results: All rats were successfully resuscitated. Treatment with CsA did not improve PR myocardial function (Table ). Survival time was comparable between CsA-treated (321±67 mins) and vehicle-treated (331±67 mins) rats. Conclusions: In our rat model of VF and resuscitation, CsA failed to prevent PR myocardial dysfunction and improve survival. These data contrast with numerous studies demonstrating a protective effect in isolated heart models of ischemia and reperfusion. Two possible explanations are the mPTP does not open in this unique setting of cardiac arrest and resuscitation, and the optimal in vivo dose of CsA needs to be determined as the protective effects of CsA are dose dependent. Hemodynamic and Left Ventricular Function

scholarly journals The role of neurohormonal blockers in the primary prevention of acute-, early-, and late-onset anthracycline-induced cardiotoxicity

2020 ◽  
Vol 72 (1) ◽  
Author(s):  
Ahmed Ayuna ◽  
Nik Abidin
Keyword(s):  
Primary Prevention ◽  
Myocardial Injury ◽  
Troponin I ◽  
Late Onset ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Main Body ◽  
Converting Enzyme Inhibitors ◽  
Ventricular Ejection Fraction

Abstract Background Anthracycline-induced cardiotoxicity has been classified based on its onset into acute, early, and late. It may have a significant burden on the quality and quantity of life of those exposed to this class of medication. Currently, there are several ongoing debates on the role of different measures in the primary prevention of cardiotoxicity in cancer survivors. Our article aims to focus on the role of neurohormonal blockers in the primary prevention of anthracycline-induced cardiotoxicity, whether it is acute, early, or late onset. Main body of the abstract PubMed and Google Scholar database were searched for the relevant articles; we reviewed and appraised 15 RCTs, and we found that angiotensin-converting enzyme inhibitors (ACEI) and B-blockers were the most commonly used agents. Angiotensin II receptor blockers (ARBs) and mineralocorticoid receptor antagonists (MRAs) were used in a few other trials. The follow-up period was on the range of 1–156 weeks (mode 26 weeks). Left ventricular ejection fraction (LVEF), left ventricular diameters, and diastolic function were assessed by either echocardiogram or occasionally by cardiac magnetic resonance imaging (MRI). The occurrence of myocardial injury was assessed by troponin I. It was obvious that neurohormonal blockers reduced the occurrence of LVEF and myocardial injury in 14/15 RCTs. Short conclusion Beta-blockers, especially carvedilol and ACEI, especially enalapril, should be considered for the primary prevention of acute- and early-onset cardiotoxicity. ARB and MRA are suitable alternatives when patients are intolerant to ACE-I and B-blockers. We recommend further studies to explore and establish the role of neurohormonal blockers in the primary prevention of the acute-, early-, and late-onset cardiotoxicity.

Abstract 1712: The P2Y 12 Antagonist Cangrelor and the GP IIb/IIIa Blocker Abciximab Reduce Platelet-Mediated Myocardial Injury After Ischemia and Reperfusion

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Jose A Barrabes ◽  
Javier Inserte ◽  
Maribel Mirabet ◽  
Adoracion Quiroga ◽  
Victor Hernando ◽  
...  
Keyword(s):  
Myocardial Injury ◽  
Myocardial Damage ◽  
Left Ventricular ◽  
Myocardial Salvage ◽  
Ischemia And Reperfusion ◽  
Activated Platelets ◽  
Rat Hearts ◽  
Developed Pressure ◽  
Enddiastolic Pressure ◽  
Isolated Rat

Objective: Platelets activated during experimental acute myocardial infarction (AMI) contribute to myocardial injury. We aimed to investigate whether platelets from patients with AMI increase myocardial damage after transient ischemia in isolated rat hearts and the modification of this effect by the P2Y 12 receptor antagonist cangrelor and the GPIIb/IIIa receptor blocker abciximab. Methods: Platelets were obtained from 9 AMI patients (7 thrombolyzed, all on aspirin) within 24 h after symptom onset. Incubation with 100 μM cangrelor or 50 μg/ml abciximab resulted, respectively, in 78 ± 4 and 90 ± 2% inhibition of aggregation (optical aggregometry). Isolated rat hearts (four simultaneous experiments per patient) were subjected to 40 min of global ischemia and 60 min of reperfusion. Hearts received no additional intervention (Control) or were infused during the 5 min prior to ischemia with platelets (22.5x10 6 /min), either untreated or treated with cangrelor or abciximab. Results: P-selectin expression (flow cytometry) in isolated platelets before infusion was 31 ± 3% (P = NS between groups). Platelets augmented myocardial injury, as demonstrated by worse left ventricular developed pressure (LVDevP), higher left ventricular enddiastolic pressure (LVEDP) and coronary resistance, and greater LDH release and infarct size (TTC staining), and both cangrelor and abciximab greatly attenuated these effects (Table ). Conclusions: Activated platelets from patients with AMI increase myocardial injury after ischemia and reperfusion, and cangrelor and abciximab attenuate this effect. The results support the notion that very early antiplatelet treatment may increase myocardial salvage by direct effects on the microcirculation in these patients.

scholarly journals Acute stimulation of the soluble guanylate cyclase does not impact on left ventricular capacitance in normal and hypertrophied porcine hearts in vivo

2018 ◽  
Vol 315 (3) ◽  
pp. H669-H680 ◽  
Author(s):  
Alessio Alogna ◽  
Michael Schwarzl ◽  
Martin Manninger ◽  
Nazha Hamdani ◽  
Birgit Zirngast ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Diastolic Pressure ◽  
Aortic Pressure ◽  
Left Ventricular ◽  
Concentric Hypertrophy ◽  
Ventricular Compliance ◽  
Left Ventricular Compliance ◽  
Stimulation Of

Experimental data indicate that stimulation of the nitric oxide-soluble guanylate cyclase(sGC)-cGMP-PKG pathway can increase left ventricular (LV) capacitance via phosphorylation of the myofilamental protein titin. We aimed to test whether acute pharmacological sGC stimulation with BAY 41-8543 would increase LV capacitance via titin phosphorylation in healthy and deoxycorticosteroneacetate (DOCA)-induced hypertensive pigs. Nine healthy Landrace pigs and 7 pigs with DOCA-induced hypertension and LV concentric hypertrophy were acutely instrumented to measure LV end-diastolic pressure-volume relationships (EDPVRs) at baseline and during intravenous infusion of BAY 41-8543 (1 and 3 μg·kg−1·min−1 for 30 min, respectively). Separately, in seven healthy and six DOCA pigs, transmural LV biopsies were harvested from the beating heart to measure titin phosphorylation during BAY 41-8543 infusion. LV EDPVRs before and during BAY 41-8543 infusion were superimposable in both healthy and DOCA-treated pigs, whereas mean aortic pressure decreased by 20–30 mmHg in both groups. Myocardial titin phosphorylation was unchanged in healthy pigs, but total and site-specific (Pro-Glu-Val-Lys and N2-Bus domains) titin phosphorylation was increased in DOCA-treated pigs. Bicoronary nitroglycerin infusion in healthy pigs ( n = 5) induced a rightward shift of the LV EDPVR, demonstrating the responsiveness of the pathway in this model. Acute systemic sGC stimulation with the sGC stimulator BAY 41-8543 did not recruit an LV preload reserve in both healthy and hypertrophied LV porcine myocardium, although it increased titin phosphorylation in the latter group. Thus, increased titin phosphorylation is not indicative of increased in vivo LV capacitance. NEW & NOTEWORTHY We demonstrate that acute pharmacological stimulation of soluble guanylate cyclase does not increase left ventricular compliance in normal and hypertrophied porcine hearts. Effects of long-term soluble guanylate cyclase stimulation with oral compounds in disease conditions associated with lowered myocardial cGMP levels, i.e., heart failure with preserved ejection fraction, remain to be investigated.

Electrophysiologic properties and ventricular fibrillation in normal and myopathic hearts

1999 ◽  
Vol 77 (7) ◽  
pp. 510-519 ◽  
Author(s):  
Katherine M Kavanagh ◽  
Patricia A Guerrero ◽  
Bodh I Jugdutt ◽  
Francis X Witkowski ◽  
Jeffrey E Saffitz
Keyword(s):  
Ventricular Fibrillation ◽  
Myocardial Dysfunction ◽  
Myocardial Cell ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Control Group ◽  
Functional Abnormality ◽  
Ventricular Ejection Fraction ◽  
Anisotropic Properties

This study tests the hypothesis that moderate myocardial dysfunction is associated with altered myocardial anisotropic properties and structurally altered ventricular fibrillation (VF). Mongrel dogs were randomized to either a control group or a group that was rapidly paced at 250 beats/min until the left ventricular ejection fraction was [Formula: see text] 40%. Changes in anisotropic properties and the electrical characteristics of VF associated with the development of moderate myocardial dysfunction were assessed by microminiature epicardial mapping studies. In vivo conduction, refractory periods, and repolarization times were prolonged in both longitudinal and transverse directions in myopathic animals versus controls. VF was different in myopathic versus control animals. There were significantly more conducted deflections during VF in normal hearts compared with myopathic hearts. Propagated deflection-to-deflection intervals during VF were significantly longer in myopathic hearts compared with controls (125.5 ± 49.06 versus 103.4 ± 32.9 ms, p = 0.009). There were no abnormalities in cell size, cell shape, or the number of intercellular gap junctions and there was no detectable change in the expression of the gap junction proteins Cx43 and Cx45. Moderate myocardial dysfunction is associated with significant electrophysiological abnormalities in the absence of changes in myocardial cell morphology or intercellular connections, suggesting a functional abnormality in cell-to-cell communication.Key words: cardiomyopathy, anisotropy, fibrillation, defibrillation.

Abstract 17250: Serum vs. Imaging Biomarkers of Myocardial Injury in Duchenne Muscular Dystrophy: Findings from the E-SCAR DMD Trial

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Subha V Raman ◽  
Kan N Hor ◽  
Wojciech Mazur ◽  
Nancy Halnon ◽  
Tam Tran ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Myocardial Injury ◽  
Troponin I ◽  
Left Ventricular ◽  
Serum Biomarkers ◽  
Left Ventricular Ejection ◽  
Imaging Biomarkers ◽  
Mineralocorticoid Receptor Antagonist ◽  
Lge Cmr

Introduction: Cardiomyopathy has become a leading cause of death in Duchenne muscular dystrophy (DMD). We previously showed that early mineralocorticoid receptor antagonist therapy reduces myocardial damage in a preclinical model of DMD. The Eplerenone for Subclinical Cardiomyopathy in DMD (E-SCAR DMD, NCT01521546) is a multicenter randomized placebo-controlled clinical trial evaluating eplerenone in boys with preserved left ventricular ejection fraction (LVEF) and evident myocardial injury by late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Hypothesis: To better define biomarkers of early disease, we hypothesized that LGE has greater sensitivity vs. serum biomarkers for myocardial injury in DMD cardiomyopathy. Methods: Boys with DMD age ≥ 7 years were enrolled across 3 centers. LGE-CMR images were acquired using comparable techniques across 3T scanners, and core laboratory LGE quantification was performed blinded to laboratory findings as a percentage of LV mass using software based on the full-width half-maximum technique. Troponin-I, creatine kinase (CK) and CK isoenzymes were measured from blood samples obtained at the time of CMR examination using standardized clinical assays. Results: 42 boys age 16 ± 7 years had preserved LVEF (57 ± 6%), and LGE-positive regions averaged 5.0 ± 2.6% of LV myocardium. While 100% had evident myocardial injury by LGE, 43% had measurable CK-MB and only 18% had detectable troponin-I in serum (Figure). %LGE was higher (5.4 ± 2.7 vs. 3.3 ± 1.8%, p<0.05) and LVEF was lower (55.4 ± 4.9 vs. 59.0 ± 7.1%, p < 0.01) in boys with detectable vs. those with undetectable troponin-I, whereas detectable CK-MB did not predict higher %LGE or lower LVEF. Conclusion: DMD patients with abnormal myocardium by LGE-CMR may have no detectable abnormalities by serum biomarkers, underscoring the importance of myocardial injury imaging in identifying patients with subclinical cardiomyopathy who may benefit from early treatment.

Improved myocardial performance induced by dofibrate during reperfusion after acute myocardial infarction

1988 ◽  
Vol 66 (12) ◽  
pp. 1518-1523 ◽  
Author(s):  
M. Renuka Prasad ◽  
Ronald Clement ◽  
Hajime Otani ◽  
Randall Jones ◽  
Dipak K. Das ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Myocardial Injury ◽  
Left Ventricular ◽  
Ischemia And Reperfusion ◽  
Cardioplegic Arrest ◽  
Beneficial Effects ◽  
Hypolipidemic Drug ◽  
And Control ◽  
Experimental Pigs

The increase of cellular fatty acids appears to be one of the causes of the myocardial injury during ischemia and reperfusion. This study was designed to examine whether a hypolipidemic drug such as clofibrate can reduce the myocardial injury during ischemia and reperfusion. Clofibrate was fed to experimental pigs for 9 days. Isolated in situ hearts from both experimental and control pigs were subjected to 60 min of regional ischemia induced by occluding the left anterior descending coronary artery, followed by 60 min of global ischemia by hypothermic cardioplegic arrest and 60 min of reperfusion. The clofibrate feeding resulted in the better cardiac performance as judged by increased coronary blood flow, improved left ventricular function, and reduced myocardial injury as judged by creatine kinase release. Although the clofibrate-fed animals contained higher levels of thiobarbituric reactive materials, the free fatty acid levels of plasma and myocardium were much lower compared with control animals. The clofibrate feeding was also associated with increased peroxisomal catalase and (β-oxidation of fatty acids. These results suggest that decreased levels of free fatty acids in the plasma and the myocardium and increased catalase activity induced by antilipolytic therapy appear to provide beneficial effects to the myocardium during ischemia and reperfusion.

Interleukin-27 attenuates myocardial injury after ischemia-reperfusion through down-regulation of inflammatory response

2021 ◽  
Vol 9 (1) ◽  
pp. 62-75
Author(s):  
Mai HN ◽  
Lee YS
Keyword(s):  
Inflammatory Response ◽  
Ventricular Function ◽  
Myocardial Injury ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Left Ventricular ◽  
Mice Model ◽  
Down Regulation ◽  
Stat Pathway

The proinflammatory cytokines may mediate myocardial dysfunction associated with myocardial injury and inflammatory response is an important process during the pathogenesis of myocardial I/R injury. IL-27, this cytokine is mainly produced by cells of myeloid origin such as monocytes, macrophages, dendritic cells, and microglial cells, in response to stimuli acting through Toll-like receptors. The objective of present study is to assess whether IL-27 can improve ventricular function after myocardial ischemia by down-regulation of inflammatory response. The results demonstrated that the IL-27 markedly attenuated Left Ventricular Function (LVF) in mice model, and reduced plasma level of cTn-I as marker of cardiac injury. Moreover, the IL-27 was associated with up-regulation in both chemokine and cytokines expression following I/R, through down-regulation of activation of JAK/STAT pathway.

β-Adrenergic receptors desensitization is not involved in exercise-induced cardiac fatigue: NADPH oxidase-induced oxidative stress as a new trigger

2011 ◽  
Vol 111 (5) ◽  
pp. 1242-1248 ◽  
Author(s):  
Damien Vitiello ◽  
Julien Boissière ◽  
Grégory Doucende ◽  
Sandrine Gayrard ◽  
Anne Polge ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Troponin I ◽  
Ex Vivo ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
Strenuous Exercise ◽  
Lv Dysfunction ◽  
Cardiac Fatigue

Prolonged strenuous exercise (PSE) induces transient left ventricular (LV) dysfunction. Previous studies suggest that β-adrenergic pathway desensitization could be involved in this phenomenon, but it remains to be confirmed. Moreover, other underlying mechanisms involving oxidative stress have been recently proposed. The present study aimed to evaluate the involvement of both the β-adrenergic pathway and NADPH oxidase (Nox) enzyme-induced oxidative stress in myocardial dysfunction in rats following PSE. Rats were divided into 4 groups: controls (Ctrl), 4-h exercised on treadmill (PSE), and 2 groups in which Nox enzyme was inhibited with apocynin treatment (Ctrl APO and PSE APO, respectively). We evaluated cardiac function in vivo and ex vivo during basal conditions and isoproterenol stress. GSH/GSSG ratio, cardiac troponin I (cTnI) release, and lipid peroxidation (MDA) were evaluated. PSE induced a decrease in LV developed pressure, intrinsic myocardial contractility, and relaxation associated with an increase in plasma cTnI release. Our in vivo and ex vivo results demonstrated no differences in myocardial response to isoproterenol and of effective dose 50 between control and PSE rats. Interestingly, the LV dysfunction was reversed by apocynin treatment. Moreover, apocynin prevented cellular oxidation [GSH/GSSG ratio: PSE APO rats vs. PSE rats in arbitrary units (au): 1.98 ± 0.07 vs. 1.35 ± 0.10; P < 0.001]. However, no differences in MDA were observed between groups. These data suggest that myocardial dysfunction observed after PSE was not due to β-adrenergic receptor desensitization but could be due to a signaling oxidative stress from the Nox enzyme.

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