Abstract 13725: Oxidative Stress Accelerates Senescence and Reduces Life Span but Does Not Alter Cardioprotection in Mice Over-expressing H11kinase/hsp22

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Didier Morin ◽  
Romain Long ◽  
Lydie Laure ◽  
Christophe Depre ◽  
Stephen F Vatner ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Infarct Size ◽  
Life Span ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Left Ventricular Cavity ◽  
Ventricular Ejection Fraction

H11 kinase/Hsp22 (H11K) is a small heat shock protein which provides powerful cardioprotection, i.e., reduction by 80% of infarct size expressed as a fraction of area at risk following 45 min coronary occlusion/4 hr reperfusion when over-expressed in a cardiac-specific transgenic (TG) mouse model. The goal of this investigation was to determine if these protective mechanisms would also enhance longevity and be effective in protecting from age-related myocardial dysfunction. Surprisingly, TG mice showed a reduction of 48% in their mean life span as compared to wild type (WT). The mechanism of premature death was most likely cardiac as left ventricular ejection fraction was reduced in one year old TG mice (49% vs 74% in WT, p<0.01), left ventricular cavity was dilated and cardiac hypertrophy was increased by 58%, all compatible with severe dilated cardiomyopathy. At the molecular level, hearts from TG mice showed a significant increase in reactive oxygen species, oxidized/reduced glutathione ratio, NADPH and xanthine oxidase activities, Nox2 expression associated with an increase in p16, p19 mRNA, β-galactosidase positive cells and telomerase activity. Subgroups of WT and TG mice were also treated with the antioxidant tempol (100 mg/kg/d) from weaning to their sacrifice. Chronic tempol treatment abolished oxidative stress, reduced cardiac hypertrophy, extended life span (+31%) and prevented aging markers (p16, p19 mRNA, β-galactosidase positive cells) in TG mice. The marked reduction in infarct size with ischemia/reperfusion noted above, observed in 10-12 weeks old mice, remained unchanged after tempol in TG mice and was not abolished with aging. Thus, this is the first demonstration that the mechanisms mediating reduced longevity such as increased oxidative stress do not reduce cardioprotection in H11K TG mice, and conversely, the mechanisms mediating powerful cardioprotection against ischemic stress are ineffective in maintaining normal cardiac function with aging.

Recombinant Soluble P-Selectin Glycoprotein Ligand-Ig (rPSGL-Ig) Attenuates Infarct Size and Myeloperoxidase Activity in a Canine Model of Ischemia-Reperfusion

2002 ◽  
Vol 88 (07) ◽  
pp. 149-154 ◽  
Author(s):  
Xiaorong Zhou ◽  
Zhongmin Zhou ◽  
Khaldoun Tarakji ◽  
Jian Qin ◽  
Marta Sitges ◽  
...  
Keyword(s):  
Infarct Size ◽  
Myocardial Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Balloon Occlusion ◽  
Left Ventricular Ejection ◽  
Myeloperoxidase Activity ◽  
Ventricular Ejection Fraction ◽  
Occlusion Time ◽  
Soluble P

SummaryThe role of P-selectin in the process of reperfusion injury was evaluated using a recombinant soluble P-selectin glycoprotein ligand-Ig (rPSGL-Ig) in a canine coronary artery balloon occlusion model. rPSGL-Ig (1 mg/kg) or saline was given as an intravenous bolus 15 min before balloon deflation. Balloon occlusion time was 90 min followed by either 120 min or 7 days reperfusion. Infarct size was significantly reduced in the treatment group when expressed either as percentage of the area at risk or as absolute infarct size. Histological analysis showed that extensive myocardial injury and neutrophil infiltration were reduced by rPSGL-Ig. Myeloperoxidase activity (MPO) was significantly reduced in the risk area in the rPSGL-Ig group. Left ventricular ejection fraction was significantly less impaired during the first 24 h after reperfusion in the rPSGL-Ig group, although there was no difference by 7-day follow-up. Thus, administration of rPSGL-Ig decreases myocardial injury and inflammatory response for at least 7 days after reperfusion of ischemic myocardium.

Cardiac overexpression of A1-adenosine receptor protects intact mice against myocardial infarction

2002 ◽  
Vol 282 (3) ◽  
pp. H949-H955 ◽  
Author(s):  
Zequan Yang ◽  
Rachael J. Cerniway ◽  
Anne M. Byford ◽  
Stuart S. Berr ◽  
Brent A. French ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
At Risk ◽  
Infarct Size ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Blue Staining ◽  
Ventricular Ejection Fraction ◽  
High Level

Previous studies have shown that high-level (300-fold normal) cardiac overexpression of A1-adenosine receptors (A1-ARs) in transgenic (TG) mice protects isolated hearts against ischemia-reperfusion injury. However, this high level of overexpression is associated with bradycardia and increased incidence of arrhythmia during ischemia in intact mice, which interfered with studies to determine whether this line of TG mice might also be protected against myocardial infarction (MI) in vivo. For these studies, we therefore selected a line of TG mice that overexpresses the A1-AR at more moderate levels (30-fold normal), which affords cardioprotection in the isolated heart while minimizing bradycardia and arrhythmia during ischemia in intact mice. Wild-type (WT; n = 10) and moderate-level A1-AR TG ( n = 10) mice underwent 45 min of left anterior descending coronary artery occlusion, followed by 24-h reperfusion. Infarct size and region at risk were determined by triphenyltetrazolium chloride and phthalo blue staining, respectively. Infarct size (% region at risk) in WT mice was 52 ± 3%, whereas overexpression of A1-ARs in the TG mice markedly reduced infarct size to 31 ± 3% ( P < 0.05). Furthermore, contractile function (left ventricular ejection fraction) as determined by cardiac magnetic resonance imaging 24 h after MI was better preserved in TG vs. WT mice. Cardiac overexpression of A1-ARs reduces infarct size by 40% and preserves cardiac function in intact mice after MI.

scholarly journals Qiliqiangxin Protects Against Cardiac Ischemia-Reperfusion Injury via Activation of the mTOR Pathway

2015 ◽  
Vol 37 (2) ◽  
pp. 454-464 ◽  
Author(s):  
Yonglan Zhou ◽  
Hongyi Fang ◽  
Shenghui Lin ◽  
Shutong Shen ◽  
Lichan Tao ◽  
...  
Keyword(s):  
Infarct Size ◽  
Western Blotting ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Mtor Pathway ◽  
Cardiac Ischemia ◽  
Left Ventricular Ejection ◽  
Protective Effects ◽  
Mtor Inhibition ◽  
Ventricular Ejection Fraction

Background/Aims: Qiliqiangxin (QL) has been used for the treatment of chronic heart failure in China. Accumulating evidence suggests QL's cardio-protective effects on continuous myocardial ischemia. However, it is unclear whether QL has beneficial effects on cardiac ischemia-reperfusion (I/R) injury. Methods: A mouse model of cardiac I/R was established by ligation of the left anterior descending coronary artery for 45 minutes followed by reperfusion. The mice were treated with QL for three days before surgery and continually after I/R. Triphenyltetrazolium chloride staining, echocardiography and Masson's trichrome staining were used to determine infarct size, cardiac function, and fibrosis, respectively. Expression levels of phospho-mTOR (Ser2448), mTOR, phospho-4EBP (Ser65), 4EBP, phospho-Akt (Ser473) and Akt were detected by Western blotting. Results: At 1 day after I/R, QL treatment significantly reduced the infarct size of mice exposed to I/R. At 7 days after I/R, mortality was reduced in QL treated animals in comparison with the control group. In addition, QL treated mice showed increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) at 1 and 7 days after I/R. In agreement, Masson's trichrome staining demonstrated that interstitial fibrosis was less pronounced in QL treated mice compared with controls, suggesting that adverse left ventricular remodeling is attenuated in QL treated mice. Moreover, western blotting analysis demonstrated that QL activated the mTOR pathway, while mTOR inhibition via Rapamycin abolished the protective effects of QL against I/R injury. Conclusion: This study suggests that QL attenuates the progression of cardiac remodeling after I/R likely via mTOR activation. This represents a new application for QL in the prevention of I/R injury.

Colchicine for Left Ventricular Infarct Size Reduction in Acute Myocardial Infarction: A Phase II, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Study Protocol – The COVERT-MI Study

Cardiology ◽  
2021 ◽  
pp. 1-10
Author(s):  
Didier Bresson ◽  
François Roubille ◽  
Cyril Prieur ◽  
Loic Biere ◽  
Fabrice Ivanes ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Phase Ii ◽  
Myocardial Injury ◽  
Ventricular Remodeling ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Controlled Study ◽  
Ventricular Ejection Fraction

Inflammatory processes have been identified as key mediators of ischemia-reperfusion injury in ST-segment elevation myocardial infarction (STEMI). They add damage to the myocardium and are associated with clinical adverse events (heart failure and cardiovascular death) and poor myocardial recovery. Colchicine is a well-known alkaloid with potent anti-inflammatory properties. In a proof-of-concept phase II trial, colchicine has been associated with a significant 50% reduction of infarct size (assessed by creatine kinase levels) in comparison to placebo in acute STEMI patients referred for primary percutaneous coronary intervention (PPCI). The Colchicine in STEMI Patients Study (COVERT-MI) is an ongoing confirmative prospective, multicenter, randomized, double-blind trial testing whether a short course oral treatment with colchicine versus placebo decreases myocardial injury in patients presenting with STEMI referred for PPCI. Adult patients, with a first STEMI episode and an initial TIMI flow ≤1, referred for PPCI, will be randomized (<i>n</i> = 194) in a 1:1 ratio to receive an oral bolus of colchicine of 2 mg followed by 0.5 mg b.i.d. treatment during 5 days or matching placebo. The primary endpoint will be the reduction in infarct size as assessed by cardiac magnetic resonance at 5 ± 2 days between both groups. The main secondary endpoints will be tested between groups in hierarchical order with left ventricular ejection fraction at 5 days, microvascular obstruction presence at 5 days, and absolute adverse left ventricular remodeling between 5 days and 3 months. This academic study is being financed by a grant from the French Ministry of Health (PHRCN-16-0357). Results from this study will contribute to a better understanding of the complex pathophysiology underlying myocardial injury after STEMI. The present study describes the rationale, design, and methods of the trial.

Implication of anti-angiogenic VEGF-A165b in angiogenesis and systolic function after reperfused myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
V Marcos Garces ◽  
C Rios-Navarro ◽  
L Hueso ◽  
A Diaz ◽  
C Bonanad ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Adjuvant Therapy ◽  
Ejection Fraction ◽  
Infarct Size ◽  
Systolic Function ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Funding Source ◽  
Coronary Reperfusion ◽  
Ventricular Ejection Fraction

Abstract Background Angiogenesis participates in re-establishing microcirculation after myocardial infarction (MI). Purpose In this study, we aim to further understand the role of the anti-angiogenic isoform vascular endothelial growth factor (VEGF)-A165b after MI and explore its potential as a co-adjuvant therapy to coronary reperfusion. Methods Two mice MI models were formed: 1) permanent coronary ligation (non-reperfused MI), 2) transient 45-min coronary occlusion followed by reperfusion (reperfused MI); in both models, animals underwent echocardiography before euthanasia at day 21 after MI induction. Serum and myocardial VEGF-A165b levels were determined. In both experimental MI models, functional and structural implication of VEGF-A165b blockade was assessed. In a cohort of 104 ST-segment elevation MI patients, circulating VEGF-A165b levels were correlated with cardiovascular magnetic resonance-derived left ventricular ejection fraction at 6-months and with the occurrence of adverse events (death, heart failure and/or re-infarction). Results In both models, circulating and myocardial VEGF-A165b presence was increased 21 days after MI induction. Serum VEGF-A165b levels inversely correlated with systolic function evaluated by echocardiography. VEGF-A165b blockage increased capillary density, reduced infarct size, and enhanced left ventricular function in reperfused, but not in non-reperfused MI experiments. In patients, higher VEGF-A165b levels correlated with depressed ejection fraction and worse outcomes. Conclusions In experimental and clinical studies, higher serum VEGF-A165b levels associates with a worse systolic function. Its blockage enhances neoangiogenesis, reduces infarct size, and increases ejection fraction in reperfused, but not in non-reperfused MI experiments. Therefore, VEGF-A165b neutralization represents a potential co-adjuvant therapy to coronary reperfusion. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This study was funded by “Instituto de Salud Carlos III” and “Fondos Europeos de Desarrollo Regional FEDER” (Exp. PIE15/00013, PI17/01836, PI18/00209 and CIBERCV16/11/00486).

Breathing nitric oxide plus hydrogen gas reduces ischemia-reperfusion injury and nitrotyrosine production in murine heart

2013 ◽  
Vol 305 (4) ◽  
pp. H542-H550 ◽  
Author(s):  
Toshihiro Shinbo ◽  
Kenichi Kokubo ◽  
Yuri Sato ◽  
Shintaro Hagiri ◽  
Ryuji Hataishi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Function ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Left Ventricular ◽  
Hydrogen Gas ◽  
Coronary Artery Ligation

Inhaled nitric oxide (NO) has been reported to decrease the infarct size in cardiac ischemia-reperfusion (I/R) injury. However, reactive nitrogen species (RNS) produced by NO cause myocardial dysfunction and injury. Because H2 is reported to eliminate peroxynitrite, it was expected to reduce the adverse effects of NO. In mice, left anterior descending coronary artery ligation for 60 min followed by reperfusion was performed with inhaled NO [80 parts per million (ppm)], H2 (2%), or NO + H2, starting 5 min before reperfusion for 35 min. After 24 h, left ventricular function, infarct size, and area at risk (AAR) were assessed. Oxidative stress associated with reactive oxygen species (ROS) was evaluated by staining for 8-hydroxy-2′-deoxyguanosine and 4-hydroxy-2-nonenal, that associated with RNS by staining for nitrotyrosine, and neutrophil infiltration by staining for granulocyte receptor-1. The infarct size/AAR decreased with breathing NO or H2 alone. NO inhalation plus H2 reduced the infarct size/AAR, with significant interaction between the two, reducing ROS and neutrophil infiltration, and improved the cardiac function to normal levels. Although nitrotyrosine staining was prominent after NO inhalation alone, it was eliminated after breathing a mixture of H2 with NO. Preconditioning with NO significantly reduced the infarct size/AAR, but not preconditioning with H2. In conclusion, breathing NO + H2 during I/R reduced the infarct size and maintained cardiac function, and reduced the generation of myocardial nitrotyrosine associated with NO inhalation. Administration of NO + H2 gases for inhalation may be useful for planned coronary interventions or for the treatment of I/R injury.

scholarly journals Temporal Course of Plasma Trimethylamine N-Oxide (TMAO) Levels in ST-Elevation Myocardial Infarction

2021 ◽  
Vol 10 (23) ◽  
pp. 5677
Author(s):  
Mohammad A. Almesned ◽  
Femke M. Prins ◽  
Erik Lipšic ◽  
Margery A. Connelly ◽  
Erwin Garcia ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Renal Function ◽  
Infarct Size ◽  
Impaired Renal Function ◽  
Left Ventricular ◽  
St Elevation Myocardial Infarction ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Temporal Course ◽  
St Elevation

The gut metabolite trimethylamine N-oxide (TMAO) at admission has a prognostic value in ST-elevation myocardial infarction (STEMI) patients. However, its sequential changes and relationship with long-term infarct-related outcomes after primary percutaneous coronary intervention (PCI) remain elusive. We delineated the temporal course of TMAO and its relationship with infarct size and left ventricular ejection fraction (LVEF) post-PCI, adjusting for the estimated glomerular filtration rate (eGFR). We measured TMAO levels at admission, 24 h and 4 months post-PCI in 379 STEMI patients. Infarct size and LVEF were determined by cardiac magnetic resonance 4 months after PCI. TMAO levels decreased from admission (4.13 ± 4.37 μM) to 24 h (3.41 ± 5.84 μM, p = 0.001) and increased from 24 h to 4 months (3.70 ± 3.86 μM, p = 0.026). Higher TMAO values at 24 h were correlated to smaller infarct sizes (rho = −0.16, p = 0.024). Larger declines between admission and 4 months suggestively correlated with smaller infarct size, and larger TMAO increases between 24 h and 4 months were associated with larger infarct size (rho = −0.19, p = 0.008 and rho = −0.18, p = 0.019, respectively). Upon eGFR stratification using 90 mL/min/1.73 m2 as a cut-off, significant associations between TMAO and infarct size were only noted in subjects with impaired renal function. In conclusion, TMAO levels in post-PCI STEMI patients are prone to fluctuations, and these fluctuations could be prognostic for infarct size, particularly in patients with impaired renal function.

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.

Sign in / Sign up

Export Citation Format

Share Document