Secreted Frizzled Protein 3 Is A Novel Cardioprotective Mechanism Unique to the Clinically Relevant 4th Window of Ischemic Preconditioning

Most studies on ischemic preconditioning (IPC) use one or two ischemic stimuli, before examining cardioprotection. In order to better simulate the clinical situation, we examined, in pigs, the effects of 6 episodes of 10 min coronary artery occlusion (CAO) 12 hours apart, followed by 60 min CAO. We named this model the 4th window of IPC. In order to determine the novel mechanisms mediating cardioprotection in the 4th window, gene analysis was examined in 4th window IPC cardiac tissue, 60 min after the last episode of 10 min CAO. Secreted Frizzled Related Protein 3 (sFRP3) was the most significantly upregulated gene that was unique to the 4th window, i.e., not found in the 1st, 2nd or 3rd window IPC. To study the effects of sFRP3 on cardioprotection, sFRP3 was injected in the hearts of WT mice. In the CAO/CAR model (30 min CAO followed by 24 hour CAR), infarct size was less, p<0.01, after sFRP3 injection (14±1.7%) compared to vehicle injection (48±1.6%). sFRP3 injection also protected the development of heart failure following permanent CAO for 2 wks. Left ventricular ejection fraction was significantly improved, p<0.05, at 2 weeks after CAO with sFRP3 (53±5%) compared with vehicle (36±2%), and was accompanied by significant, p<0.01, reductions in myocardial fibrosis (53±4%), myocyte size (17±3%), apoptosis (100%) and mortality (56%). Thus, sFRP3, unique to the clinically relevant 4th window IPC model, is a novel mechanism mediating ischemic cardioprotection.

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A novel nomogram to predict perioperative acute kidney injury following isolated coronary artery bypass grafting surgery with impaired left ventricular ejection fraction

BMC Cardiovascular Disorders ◽

10.1186/s12872-020-01799-1 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Hongyuan Lin ◽

Jianfeng Hou ◽

Hanwei Tang ◽

Kai Chen ◽

Hansong Sun ◽

...

Keyword(s):

Coronary Artery ◽

Artery Bypass ◽

Kidney Injury ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

The Novel ◽

Net Benefit ◽

Ventricular Ejection Fraction ◽

Derivation Cohort ◽

Postoperative Aki

Abstract Background and objective Heart failure (HF) is a global health issue, and coronary artery bypass graft (CABG) is one of the most effective surgical treatments for HF with coronary artery disease. Unfortunately, the incidence of postoperative acute kidney injury (AKI) is high in HF patients following CABG, and there are few tools to predict AKI after CABG surgery for such patients. The aim of this study is to establish a nomogram to predict the incidence of AKI after CABG in patients with impaired left ventricular ejection fraction (LVEF). Methods From 2012 to 2017, Clinical information of 1208 consecutive patients who had LVEF< 50% and underwent isolated CABG was collected to establish a derivation cohort. A novel nomogram was developed using the logistic regression model to predict postoperative AKI among these patients. According to the same inclusion criteria and the same period, we extracted the data of patients from 6 other large cardiac centers in China (n = 540) from the China Heart Failure Surgery Registry (China-HFSR) database for external validation of the new model. The nomogram was compared with 3 other available models predicting renal failure after cardiac surgery in terms of calibration, discrimination and net benefit. Results In the derivation cohort (n = 1208), 90 (7.45%) patients were diagnosed with postoperative AKI. The nomogram included 7 independent risk factors: female, increased preoperative creatinine(> 2 mg/dL), LVEF< 35%, previous myocardial infarction (MI), hypertension, cardiopulmonary bypass(CPB) used and perioperative blood transfusion. The area under the receiver operating characteristic curve (AUC) was 0.738, higher than the other 3 models. By comparing calibration curves and decision curve analyses (DCA) with other models, the novel nomogram showed better calibration and greater net benefit. Among the 540 patients in the validation cohort, 104 (19.3%) had postoperative AKI, and the novel nomogram performed better with respect to calibration, discrimination and net benefit. Conclusions The novel nomogram is a reliable model to predict postoperative AKI following isolated CABG for patients with impaired LVEF.

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Bioenergetic and Functional Consequences of Bone Marrow–Derived Multipotent Progenitor Cell Transplantation in Hearts With Postinfarction Left Ventricular Remodeling

Circulation ◽

10.1161/circulationaha.106.659730 ◽

2007 ◽

Vol 115 (14) ◽

pp. 1866-1875 ◽

Cited By ~ 195

Author(s):

Lepeng Zeng ◽

Qingsong Hu ◽

Xiaohong Wang ◽

Abdul Mansoor ◽

Joseph Lee ◽

...

Keyword(s):

Myocardial Infarction ◽

Ejection Fraction ◽

Cell Transplantation ◽

Cyclosporine A ◽

Artery Occlusion ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Infarct Zone ◽

Ventricular Ejection Fraction ◽

Left Anterior Descending Artery

Background— The present study examined whether transplantation of adherent bone marrow–derived stem cells, termed pMultistem, induces neovascularization and cardiomyocyte regeneration that stabilizes bioenergetic and contractile function in the infarct zone and border zone (BZ) after coronary artery occlusion. Methods and Results— Permanent left anterior descending artery occlusion in swine caused left ventricular remodeling with a decrease of ejection fraction from 55±5.6% to 30±5.4% (magnetic resonance imaging). Four weeks after left anterior descending artery occlusion, BZ myocardium demonstrated profound bioenergetic abnormalities, with a marked decrease in subendocardial phosphocreatine/ATP ( 31 P magnetic resonance spectroscopy; 1.06±0.30 in infarcted hearts [n=9] versus 1.90±0.15 in normal hearts [n=8; P <0.01]). This abnormality was significantly improved by transplantation of allogeneic pMultistem cells (subendocardial phosphocreatine/ATP to 1.34±0.29; n=7; P <0.05). The BZ protein expression of creatine kinase–mt and creatine kinase–m isoforms was significantly reduced in infarcted hearts but recovered significantly in response to cell transplantation. MRI demonstrated that the infarct zone systolic thickening fraction improved significantly from systolic “bulging” in untreated animals with myocardial infarction to active thickening (19.7±9.8%, P <0.01), whereas the left ventricular ejection fraction improved to 42.0±6.5% ( P <0.05 versus myocardial infarction). Only 0.35±0.05% donor cells could be detected 4 weeks after left anterior descending artery ligation, independent of cell transplantation with or without immunosuppression with cyclosporine A (with cyclosporine A, n=6; no cyclosporine A, n=7). The fraction of grafted cells that acquired an endothelial or cardiomyocyte phenotype was 3% and ≈2%, respectively. Patchy spared myocytes in the infarct zone were found only in pMultistem transplanted hearts. Vascular density was significantly higher in both BZ and infarct zone of cell-treated hearts than in untreated myocardial infarction hearts ( P <0.05). Conclusions— Thus, allogeneic pMultistem improved BZ energetics, regional contractile performance, and global left ventricular ejection fraction. These improvements may have resulted from paracrine effects that include increased vascular density in the BZ and spared myocytes in the infarct zone.

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Prognostic value of biomarkers in chronic heart failure with preserved left ventricular ejection fraction

Terapevticheskii arkhiv ◽

10.17116/terarkh2016889102-105 ◽

2016 ◽

Vol 88 (9) ◽

pp. 102-105 ◽

Cited By ~ 1

Author(s):

T A Nikiforova ◽

D Yu Shchekochikhin ◽

F Yu Kopylov ◽

A L Syrkin

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Left Ventricular Ejection Fraction ◽

Ejection Fraction ◽

Prognostic Value ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

The Novel ◽

Preserved Ejection Fraction ◽

Ventricular Ejection Fraction

The paper reviews major biomarkers for determining the prognosis in patients with chronic heart failure and preserved ejection fraction. It also considers cystatin C, one of the novel and probably the most practically important biomarkers.

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Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism: first demonstration of remote ischemic perconditioning

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00617.2006 ◽

2007 ◽

Vol 292 (4) ◽

pp. H1883-H1890 ◽

Cited By ~ 183

Author(s):

M. R. Schmidt ◽

M. Smerup ◽

I. E. Konstantinov ◽

M. Shimizu ◽

J. Li ◽

...

Keyword(s):

Myocardial Infarction ◽

Coronary Artery ◽

Ischemic Preconditioning ◽

Limb Ischemia ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Left Ventricular ◽

Force Frequency ◽

Stroke Work ◽

Dependent Mechanism

Remote ischemic preconditioning reduces myocardial infarction (MI) in animal models. We tested the hypothesis that the systemic protection thus induced is effective when ischemic preconditioning is administered during ischemia (PerC) and before reperfusion and examined the role of the K+-dependent ATP (KATP) channel. Twenty 20-kg pigs were randomized (10 in each group) to 40 min of left anterior descending coronary artery occlusion with 120 min of reperfusion. PerC consisted of four 5-min cycles of lower limb ischemia by tourniquet during left anterior descending coronary artery occlusion. Left ventricular (LV) function was assessed by a conductance catheter and extent of infarction by tetrazolium staining. The extent of MI was significantly reduced by PerC (60.4 ± 14.3 vs. 38.3 ± 15.4%, P = 0.004) and associated with improved functional indexes. The increase in the time constant of diastolic relaxation was significantly attenuated by PerC compared with control in ischemia and reperfusion ( P = 0.01 and 0.04, respectively). At 120 min of reperfusion, preload-recruitable stroke work declined 38 ± 6% and 3 ± 5% in control and PerC, respectively ( P = 0.001). The force-frequency relation was significantly depressed at 120 min of reperfusion in both groups, but optimal heart rate was significantly lower in the control group ( P = 0.04). There were fewer malignant arrhythmias with PerC during reperfusion ( P = 0.02). These protective effects of PerC were abolished by glibenclamide. Intermittent limb ischemia during myocardial ischemia reduces MI, preserves global systolic and diastolic function, and protects against arrhythmia during the reperfusion phase through a KATPchannel-dependent mechanism. Understanding this process may have important therapeutic implications for a range of ischemia-reperfusion syndromes.

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Functional Significance of Collateral Circulation in Patients with Total Coronary Occlusion

Asian Cardiovascular and Thoracic Annals ◽

10.1177/021849239300100404 ◽

1993 ◽

Vol 1 (4) ◽

pp. 156-162

Author(s):

Ha Jong Won ◽

Cho Seung Yun ◽

Jang Yang Soo ◽

Chung Nam Sik ◽

Shim Won Hewn ◽

...

Keyword(s):

Myocardial Infarction ◽

Collateral Circulation ◽

Coronary Occlusion ◽

Artery Occlusion ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction ◽

Segmental Wall Motion ◽

Group 2 ◽

Group 1

Functional significance of collateral circulation was evaluated in 125 patients with total coronary occlusion. Patients were classified into 2 groups: group 1, patients without myocardial infarction; and group 2, patients with a first transmural myocardial infarction occurring within 3 months of symptom onset. There was a higher prevalence of well-developed collaterals and multivessel disease in patients without myocardial infarction than in those with myocardial infarction. The left ventricular ejection fraction, left ventricular enddiastolic pressure, and segmental wall motion scores were significantly better in group 1 than group 2. Despite total coronary occlusion, 61% of group 1 had a normal resting electrocardiogram; however, 96% of patients who underwent treadmill tests proved positive. The proportions of well-developed collaterals in 3 groups, divided according to the internal between onset of myocardial infarction and angiography (within 1 day of operation, 2 to 14 days, or 15 days to 3 months), were 13%, 54%, and 60%. There were no significant differences in left ventricular ejection fraction, segmental wall motion score, and left ventricular enddiastolic pressure in myocardial infarction patients with poorly developed collaterals and well-developed collaterals. The degree of collateral development is higher in myocardial infarction with right coronary artery occlusion compared with that of left anterior descending artery occlusion, without regarding the dominancy or length. Collateral circulation can prevent myocardial ischemia and present myocardial function in a significant number of patients without infarction; however, it does not provide protection against exercise-induced myocardial ischemia in the majority of patients from group 1. Although well-developed collaterals are not usually present within 1 day after myocardial infarction, they are generally present after 2 weeks. Collateral vessels in patients with myocardial infarction have no beneficial effects on preserving myocardial function.

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Remote ischemic preconditioning in patients undergoing coronary bypass grafting following acute coronary syndrome without ST elevation

Vojnosanitetski pregled ◽

10.2298/vsp180414179m ◽

2020 ◽

Vol 77 (10) ◽

pp. 1017-1023

Author(s):

Miroslav Milicic ◽

Ivan Soldatovic ◽

Dusko Nezic ◽

Miomir Jovic ◽

Vera Maravic-Stojkovic ◽

...

Keyword(s):

Acute Coronary Syndrome ◽

Ischemic Preconditioning ◽

Coronary Bypass ◽

Left Ventricular ◽

Remote Ischemic Preconditioning ◽

Left Ventricular Ejection ◽

Hemodynamic Parameters ◽

Ventricular Ejection Fraction ◽

Coronary Syndrome ◽

Significant Difference

Background/Aim. A protection of heart and other organs from ischemic-reperfusion injuries can be provided by remote ischemic preconditioning (RIPC) by brief episodes of ischemia and reperfusion in distant tissues. The aim of this study was to assess effects of RIPC on early outcomes in patients underwent coronary bypass surgery (CABG) following acute coronary syndrome without persistent ST segment elevation (NSTEMI ACS). Methods. This trial included 42 patients randomized into two groups: the group 1 received RIPC and the group 2 was without RIPC (control group). Pre-, intra- and postoperative parameters were compared but primary endpoint was myocardial injury reflected as value of troponin I measured preoperatively and 1, 6, 12, 24, 48 and 72 h postoperatively. The secondary endpoints were hemodynamic parameters, blood loss, intensive care unit stay, mortality etc. Results. The groups 1 and 2 were similar in preoperative characteristics including age, New York Heart Association (NYHA) class, EuroSCORE II, left ventricular ejection fraction. The only significant difference between groups was for triple vessel coronary disease with dominance in the RIPC group [20 (100%) vs. 17 (77.3%), p = 0.049]. Cardiopulmonary bypass time [mean (? standard deviation): 83.0 (22.9) vs. 67.0 (17.4) minutes, p = 0.015], cross clamp time [57.9 (15.4) vs. 44.3 (14.3) minutes, p = 0.005] and number of conduits [median (25?75th percentile): 23.5(3?4) vs. 3(2?3), p = 0.002] were different. Other intra- and postoperative variables did not differ between groups. There were no differences in C reactive protein levels and postoperative hemodynamic parameters. Average troponin values in all time points revealed no significant differences between groups (p0h = 0.740, p1h = 0.212, p6h = 0.504, p12h = 0.597, p24h = 0.562, p48h = 0.465 and p72h = 0.715, respectively). Furthermore, there were no significant differences in adverse events, hospital stay and mortality between groups. Conclusion. Treatment with RIPC during CABG following NSTEMI ACS did not provide better myocardial protection and hemodynamics characteristics but further larger randomized studies are needed t. prove its real value.

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Cardioprotection of ischemic preconditioning in rats involves upregulating adiponectin

Journal of Molecular Endocrinology ◽

10.1530/jme-16-0163 ◽

2017 ◽

Vol 58 (4) ◽

pp. 155-165 ◽

Cited By ~ 3

Author(s):

Hui Wang ◽

Wenjing Wu ◽

Jun Duan ◽

Ming Ma ◽

Wei Kong ◽

...

Keyword(s):

Ischemic Preconditioning ◽

Myocardial Injury ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Protective Effects ◽

Adult Rats ◽

Male Adult ◽

Ventricular Ejection Fraction ◽

Protein Levels ◽

Ampk Phosphorylation

It has been reported that ischemic preconditioning (IPC) and adiponectin (APN) are cardioprotective in many cardiovascular disorders. However, whether APN mediates the effect of IPC on myocardial injury has not been elucidated. This study was conducted to investigate whether IPC affects myocardial ischemic injury by increasing APN expression. Male adult rats with cardiac knockdowns of APN and its receptors via intramyocardial small-interfering RNA injection were subjected to IPC and then myocardial infarction (MI) at 24 h after IPC. Globular APN (gAd) was injected at 10 min before MI. APN mRNA and protein levels in myocardium as well as the plasma APN concentration were markedly high at 6 and 12 h after IPC. IPC ameliorated myocardial injury as evidenced by improved cardiac functions and a reduced infarct size. Compared with the control MI group, rats in the IPC + MI group had elevated levels of left ventricular ejection fraction and fractional shortening and a smaller MI size (P < 0.05). However, the aforementioned protective effects were ameliorated in the absence of APN and APN receptors, followed by the inhibition of AMP-activated protein kinase (AMPK) phosphorylation, but reversed by gAd treatment in wild-type rats, and AMPK phosphorylation increased (P < 0.05). Overall, our results suggest that the cardioprotective effects of IPC are partially due to upregulation of APN and provide a further insight into IPC-mediated signaling effects.

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Sevoflurane Reduces Myocardial Infarct Size and Decreases the Time Threshold for Ischemic Preconditioning in Dogs

Anesthesiology ◽

10.1097/00000542-199911000-00037 ◽

1999 ◽

Vol 91 (5) ◽

pp. 1437-1437 ◽

Cited By ~ 108

Author(s):

Wolfgang G. Toller ◽

Judy R. Kersten ◽

Paul S. Pagel ◽

Douglas A. Hettrick ◽

David C. Warltier

Keyword(s):

Coronary Artery ◽

Infarct Size ◽

Ischemic Preconditioning ◽

Myocardial Infarct ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Left Ventricular ◽

Myocardial Infarct Size ◽

Myocardial Ischemia And Reperfusion ◽

Time Threshold

Background Recent evidence indicates that volatile anesthetics exert protective effects during myocardial ischemia and reperfusion. The authors tested the hypothesis that sevoflurane decreases myocardial infarct size by activating adenosine triphosphate-sensitive potassium (K(ATP)) channels and reduces the time threshold of ischemic preconditioning necessary to protect against infarction. Methods Barbiturate-anesthetized dogs (n = 75) were instrumented for measurement of aortic and left ventricular pressures and maximum rate of increase of left ventricular pressure and were subjected to a 60-min left anterior descending (LAD) coronary artery occlusion followed by 3-h reperfusion. In four separate groups, dogs received vehicle or the K(ATP) channel antagonist glyburide (0.1 mg/kg intravenously), and 1 minimum alveolar concentration sevoflurane (administered until immediately before coronary artery occlusion) in the presence or absence of glyburide. In three additional experimental groups, sevoflurane was discontinued 30 min (memory) before the 60-min LAD occlusion or a 2-min LAD occlusion as an ischemic preconditioning stimulus was used with or without subsequent sevoflurane (with memory) pretreatment. Regional myocardial perfusion and infarct size were measured with radioactive microspheres and triphenyltetrazolium staining, respectively. Results Vehicle (23 +/- 1% of the area at risk; mean +/- SEM) and glyburide (23 +/- 2%) alone produced equivalent effects on myocardial infarct size. Sevoflurane significantly (P < 0.05) decreased infarct size (13 +/- 2%). This beneficial effect was abolished by glyburide (21 +/- 3%). Neither the 2-min LAD occlusion nor sevoflurane followed by 30 min of memory were protective alone, but together, sevoflurane enhanced the effects of the brief ischemic stimulus and profoundly reduced infarct size (9 +/- 2%). Conclusion Sevoflurane reduces myocardial infarct size by activating K(ATP) channels and reduces the time threshold for ischemic preconditioning independent of hemodynamic effects in vivo.

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Effect of Ischemic Preconditioning and Postconditioning on Exosome-Rich Fraction microRNA Levels, in Relation with Electrophysiological Parameters and Ventricular Arrhythmia in Experimental Closed-Chest Reperfused Myocardial Infarction

International Journal of Molecular Sciences ◽

10.3390/ijms20092140 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2140 ◽

Cited By ~ 9

Author(s):

Andreas Spannbauer ◽

Denise Traxler ◽

Dominika Lukovic ◽

Katrin Zlabinger ◽

Johannes Winkler ◽

...

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Ischemic Preconditioning ◽

Cardiac Mri ◽

Left Ventricular ◽

Cardiac Conduction ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction ◽

St Elevation ◽

Antiarrhythmic Effects

We investigated the antiarrhythmic effects of ischemic preconditioning (IPC) and postconditioning (PostC) by intracardiac electrocardiogram (ECG) and measured circulating microRNAs (miRs) that are related to cardiac conduction. Domestic pigs underwent 90-min. percutaneous occlusion of the mid left anterior coronary artery, followed by reperfusion. The animals were divided into three groups: acute myocardial infarction (AMI, n = 7), ischemic preconditioning-acute myocardial infarction (IPC-AMI) (n = 9), or AMI-PostC (n = 5). IPC was induced by three 5-min. episodes of repetitive ischemia/reperfusion cycles (rI/R) before AMI. PostC was induced by six 30-s rI/R immediately after induction of reperfusion 90 min after occlusion. Before the angiographic procedure, a NOGA endocardial mapping catheter was placed again the distal anterior ventricular endocardium to record the intracardiac electrogram (R-amplitude, ST-Elevation, ST-area under the curve (AUC), QRS width, and corrected QT time (QTc)) during the entire procedure. An arrhythmia score was calculated. Cardiac MRI was performed after one-month. IPC led to significantly lower ST-elevation, heart rate, and arrhythmia score during ischemia. PostC induced a rapid recovery of R-amplitude, decrease in QTc, and lower arrhythmia score during reperfusion. Slightly higher levels of miR-26 and miR-133 were observed in AMI compared to groups IPC-AMI and AMI-PostC. Significantly lower levels of miR-1, miR-208, and miR-328 were measured in the AMI-PostC group as compared to animals in group AMI and IPC-AMI. The arrhythmia score was not significantly associated with miRNA plasma levels. Cardiac MRI showed significantly smaller infarct size in the IPC-AMI group when compared to the AMI and AMI-PostC groups. Thus, IPC led to better left ventricular ejection fraction at one-month and it exerted antiarrhythmic effects during ischemia, whereas PostC exhibited antiarrhythmic properties after reperfusion, with significant downregulaton of ischemia-related miRNAs.

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