Systemic mesenchymal stem cell-derived exosomes reduce myocardial infarct size: characterization with MRI in a porcine model

Abstract Background Mesenchymal stem cells (MSCs) have been shown to exert cardiac protection and repair via their secretome with the active component(s) identified as exosomes. Purpose To determine whether MSC-derived exosomes administered systemically by the convenient method of intravenous (IV) bolus injection reduce infarct size and improve cardiac function in an established porcine model of myocardial infarction (MI). Methods A total of 20 pigs underwent experimental MI by permanent ligation of the left circumflex coronary artery (LCX). Ten pigs (exosome treated) received twice daily IV injection of exosomes (1000ug protein equivalent) for 7 days. The remaining 10 pigs received vehicle control injections. Cardiac structure and function were measured by MRI which was performed at baseline (pre-MI) and repeated on days 7 and 28 post-MI. Infarct size was also confirmed post-mortem. Blood samples were drawn over first 7 days for measurement of hs Troponin T. The study followed the principles of laboratory animal care and was approved by our institution's IACUC. Results All LCX ligations resulted in permanent ischaemia with MI as evidenced by pallor of the myocardium, ECG changes including ST segment elevation and increases in plasma hs Troponin T. Exosomes administered IV for 7 days resulted in clear reduction (30–40%) of infarct size measured at both 7 (p<0.05) and 28 days (p<0.01) post-MI, despite near identical release of hs Troponin T. Together with reduced infarct size, exosome treatment reduced transmurality and lessened wall thinning (p<0.01) in the infarct zone. Exosome treated pigs showed relative preservation of LV function with significant amelioration of falls in fractional wall thickening (p<0.01) compared with control. However, global measures of LV function were less protected by exosome treatment. It is possible that greater preservation of global LV function may have been attenuated by increased cardiac fibrosis, as T1 values showed significant increase in the exosome pigs compared to control particularly in the infarct related segments. Conclusion Taken together, our results show clear effects of IV exosomes administered over 7 days to reduce infarct size with relatively preserved cardiac function compared to control treated infarct pigs. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): STaR Award (AM Richards), National Medical Research Council, Singapore. IAF-ICP, National Research Foundation, Singapore (RC Lai and SK Lim).

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Evolution of left ventricular function after Wharton's jelly mesenchymal stem cells transcoronary administration: 5-year follow up in a pilot cohort of CIRCULATE-AMI Randomized Trial

European Heart Journal ◽

10.1093/ehjci/ehaa946.1719 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

E Kwiecien ◽

L Drabik ◽

A Mazurek ◽

M Sikorska ◽

L Czyz ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Infarct Size ◽

Troponin T ◽

Left Ventricular ◽

Lv Function ◽

Funding Source ◽

Double Blind ◽

Wharton's Jelly

Abstract Introduction CIRCULATE-Acute Myocardial Infarction is a double-blind controlled trial randomizing (RCT) in 105 consecutive patients with their first, large AMI (cMRI-LVEF ≤45% and/or cMRI-infarct size ≥10% of LV) with successful infarct-related artery (IRA) primary percutaneous coronary intervention (pPCI) to transcoronary administration of Wharton's Jelly Mesenchymal Stem Cells (WJMSCs) vs. placebo (2:1). The pilot study cohort (PSC) preceded the RCT. Aim To evaluate WJMSCs long-term safety, and evolution of left-ventricular (LV) function in CIRCULATE-AMI PSC. Material and methods 30 000 000 WJMSCs (50% labelled with 99mTc-exametazime) were administered via IRA in a ten-patient PCS (age 32–65 years, peak hs-Troponin T 17.3±9.1ng/mL and peak CK-MB 533±89U/L, cMRI-LVEF 40.3±2.7% and infarct size 20.1±2.8%) at ≈5–7 days after AMI using a cell delivery-dedicated, coronary-non-occlusive method. Other treatments were per guidelines. WJMSCs showed an unprecedented high myocardial uptake (30.2±5.3%; 95% CI 26.9–33.5%), corresponding to ≈9×10 000 000 cells retention in the infarct zone – in absence of epicardial flow or myocardial perfusion impairment (TIMI-3 in all; cTFC 45±8 vs. 44±9, p=0.51) or any hs-Troponin T elevation. Five-year follow up included cardiac Magnetic Resonance Imaging (cMRI) (at baseline, 1 year and 3 years) and detailed echocardiography (echo) at baseline, 1 year, 3 years and 5 years. Results By 5 years, one patient died from a new, non-index territory AMI. There were no other cardiovascular events and MACCE that might be related to WJMSCs transplantation. On echo (Fig), there was an increase in left ventricular ejection fraction (LVEF) between WJMSCs administration point and 1 year (37.7±2.9% vs. 48.3±2.5%, p=0.002) that was sustained at 3 years (47.2±2.6%, p=0.005 vs. baseline) and at 5 years: (44.7±3.2%, p=0.039 vs. baseline). LVEF reached a peak at 1 year after the AMI and WJMSCs transfer (Fig). cMRI data (obtained up to 3 years; 1 year 41.9±2.6% vs. 51.0±3.3%, p<0.01; 3 years 52.2±4.0%, p<0.01 vs. baseline) were consistent with the echo LVEF assessment. Conclusions 5-year follow up in CIRCULATE-AMI PSC indicates that WJMSC transcoronary application is safe and may be associated with an LVEF improvement. The magnitude of LV increase appears to peak at 1 year, suggesting a potential role for repeated WJMSCs administration(s). Currently running double-blind RCT will provide placebo-controlled insights into the WJMSCs effect(s) on changes in LV function, remodelling, scar reduction and clinical outcomes. Echo-LVEF evolution Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): STRATEGMED 265761 “CIRCULATE” National Centre for Research and Development/Poland/ZDS/00564 Jagiellonian University Medical College

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Therapeutic Effect of Local Injection of VX765 Sodium Alginate Nanogel on Myocardial Infarction

10.21203/rs.3.rs-850289/v1 ◽

2021 ◽

Author(s):

Qingxin Tian ◽

Jianlong Liu ◽

Qin Chen ◽

Mingxiao Zhang

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Infarct Size ◽

Sodium Alginate ◽

Cardiac Fibrosis ◽

Myocardial Infarct ◽

Morphological Observation ◽

Myocardial Infarct Size ◽

Sprague Dawley

Abstract Objectives: To determine the effect of polyethyleneimine/sodium alginate composite nano-gel (AG/PEI-VX765NGs) coated with VX765 on cardiac function in rats with myocardial infarction (MI). Methods: VX765-polyethyleneimine nano-microspheres (PEI-VX765 NP) were encapsulated by sodium alginate (AG) nanogel (NGs) to construct AG/PEI-VX765 NGs. The morphological observation was performed under scanning electron microscope (SEM). The viability was evaluated by using CCK-8 assay in vitro. Then, 24 male SPF Sprague-Dawley rats were randomly divided into 4 groups: Sham, MI, PEI-VX765NP, and AG/PEI-VX765NGs. After 28 days, rats in each group were subjected to assessment of cardiac function by echocardiography. The myocardial infarct size was evaluated by TTC test, and the differences in cardiac fibrosis and cardiomyocyte apoptosis between groups were analyzed by histological methods. Results: The prepared NGs shows a porous structure, while PEI-VX765 NP is uniformly distributed in the AG NGs samples. AG/PEI-VX765 NGs with a concentration of VX765 (range: 0-1000 μM) displayed no significant toxicity to cells. Meanwhile, we observed a relatively more persistent release of VX765 from AG/PEI-VX765 NGs compared with PEI-VX765. LVIDs and LVIDd in both PEI-VX765 and AG/PEI-VX765NGs groups were significantly smaller than those in MI group, while ejection fraction (EF) and short-axis shortening rate (FS) were markedly increased in the above-mentioned two groups. Compared with MI group, PEI-VX765 and AG/PEI-VX765NGs groups exhibited a significant reduction in the infarct size, degree of fibrosis, and the rate of TUNEL positive cells. Conclusion: AG/PEI-VX765NGs can significantly improve the cardiac function of rats with MI.

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Cardioprotection with esmolol-based cardioplegia for non-infarcted and infarcted rat hearts

European Journal of Cardio-Thoracic Surgery ◽

10.1093/ejcts/ezab117 ◽

2021 ◽

Author(s):

Alexander B Veitinger ◽

Audrey Komguem ◽

Lena Assling-Simon ◽

Martina Heep ◽

Julia Schipke ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Infarct Size ◽

Myocardial Infarct ◽

Lactate Production ◽

Left Ventricular ◽

Myocardial Infarct Size ◽

Cardioplegic Arrest ◽

Blood Cardioplegia ◽

Rat Hearts

Abstract OBJECTIVES Esmolol-based cardioplegic arrest offers better cardioprotection than crystalloid cardioplegia but has been compared experimentally with blood cardioplegia only once. We investigated the influence of esmolol crystalloid cardioplegia (ECCP), esmolol blood cardioplegia (EBCP) and Calafiore blood cardioplegia (Cala) on cardiac function, metabolism and infarct size in non-infarcted and infarcted isolated rat hearts. METHODS Two studies were performed: (i) the hearts were subjected to a 90-min cardioplegic arrest with ECCP, EBCP or Cala and (ii) a regional myocardial infarction was created 30 min before a 90-min cardioplegic arrest. Left ventricular peak developed pressure (LVpdP), velocity of contractility (dLVP/dtmax), velocity of relaxation over time (dLVP/dtmin), heart rate and coronary flow were recorded. In addition, the metabolic parameters were analysed. The infarct size was determined by planimetry, and the myocardial damage was determined by electron microscopy. RESULTS In non-infarcted hearts, cardiac function was better preserved with ECCP than with EBCP or Cala relative to baseline values (LVpdP: 100 ± 28% vs 86 ± 11% vs 57 ± 7%; P = 0.002). Infarcted hearts showed similar haemodynamic recovery for ECCP, EBCP and Cala (LVpdP: 85 ± 46% vs 89 ± 55% vs 56 ± 26%; P = 0.30). The lactate production with EBCP was lower than with ECCP (0.6 ± 0.7 vs 1.4 ± 0.5 μmol/min; P = 0.017). The myocardial infarct size and (ECCP vs EBCP vs Cala: 16 ± 7% vs 15 ± 9% vs 24 ± 13%; P = 0.21) the ultrastructural preservation was similar in all groups. CONCLUSIONS In non-infarcted rat hearts, esmolol-based cardioplegia, particularly ECCP, offers better myocardial protection than Calafiore. After an acute myocardial infarction, cardioprotection with esmolol-based cardioplegia is similar to that with Calafiore.

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Systemic Mesenchymal Stem Cell-Derived Exosomes Reduce Myocardial Infarct Size: Characterization With MRI in a Porcine Model

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2020.601990 ◽

2020 ◽

Vol 7 ◽

Author(s):

Christopher J. Charles ◽

Renee R. Li ◽

Teresa Yeung ◽

Stephane M. Ibraham Mazlan ◽

Ruenn Chai Lai ◽

...

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Infarct Size ◽

Porcine Model ◽

Myocardial Infarct ◽

Myocardial Infarct Size ◽

Size Characterization

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SGLT2 inhibitors reduce infarct size in reperfused ischemic heart and improve cardiac function during ischemic episodes in preclinical models

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2020.165770 ◽

2020 ◽

Vol 1866 (7) ◽

pp. 165770 ◽

Cited By ~ 6

Author(s):

Ioanna Andreadou ◽

Robert M. Bell ◽

Hans Erik Bøtker ◽

Coert J. Zuurbier

Keyword(s):

Cardiac Function ◽

Infarct Size ◽

Sglt2 Inhibitors ◽

Ischemic Heart ◽

Preclinical Models ◽

Reduce Infarct Size

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Late preconditioning enhances recovery of myocardial function after infarction in conscious rabbits

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.5.h2372 ◽

2000 ◽

Vol 279 (5) ◽

pp. H2372-H2381 ◽

Cited By ~ 6

Author(s):

Hitoshi Takano ◽

Xian-Liang Tang ◽

Eitaro Kodani ◽

Roberto Bolli

Keyword(s):

Myocardial Infarction ◽

Infarct Size ◽

Left Ventricular ◽

Nitric Oxide Donor ◽

Lv Function ◽

Wall Thickening ◽

Triphenyltetrazolium Chloride ◽

Independent Evidence ◽

Late Preconditioning ◽

Conscious Rabbits

It is unknown whether late preconditioning (PC) enhances the recovery of left ventricular (LV) function after a myocardial infarction. Thus 25 conscious rabbits were subjected to a 30-min coronary occlusion followed by 28 days of reperfusion after PC 24 h earlier with either ischemia or nitric oxide donor administration [ S-nitroso- N-acetylpenicillamine (SNAP)]. The recovery of wall thickening (WTh) after reperfusion was significantly improved in the ischemic PC and SNAP PC groups compared with controls, both at rest and during dobutamine stress. Interestingly, neither ischemia- nor SNAP-induced late PC attenuated myocardial stunning from day 1 through day 14. Infarct size was smaller in the ischemic PC and SNAP PC groups compared with controls. In all groups, WTh at 28 days was positively and linearly related to the percentage of viable tissue in the region underlying the ultrasonic crystal ( r = 0.90), indicating that the improvement in LV function after both ischemia-induced and NO donor-induced late PC can be fully explained by the reduction in infarct size; a separate effect of late PC on LV remodeling or LV contractility need not be invoked. In conclusion, in conscious rabbits late PC, induced either by ischemia or pharmacologically, not only limits infarct size but also enhances the recovery of LV function after myocardial infarction. This finding has important clinical implications and provides triphenyltetrazolium chloride-independent evidence that late PC limits myocellular death after sustained ischemia.

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Glycolipid RC-552 induces delayed preconditioning-like effect via iNOS-dependent pathway in mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.277.6.h2418 ◽

1999 ◽

Vol 277 (6) ◽

pp. H2418-H2424 ◽

Cited By ~ 11

Author(s):

Lei Xi ◽

Fadi Salloum ◽

Demet Tekin ◽

Novlet C. Jarrett ◽

Rakesh C. Kukreja

Keyword(s):

Infarct Size ◽

Knockout Mice ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Myocardial Infarct Size ◽

Perfused Heart ◽

Reduce Infarct Size ◽

Monophosphoryl Lipid A ◽

Dependent Pathway ◽

Delayed Cardioprotection

We recently demonstrated that monophosphoryl lipid A (MLA)-induced delayed cardioprotection is mediated by inducible nitric oxide synthase (iNOS) in mice. In the present study, we determined whether RC-552, a novel synthetic glycolipid related in chemical structure to MLA, could afford similar protection. Adult mice were pretreated with vehicle or RC-552 (350 μg/kg ip, n = 7 mice/group) 24 h before global ischemia and reperfusion in a Langendorff isolated, perfused heart model. A group of RC-552-treated mice received S-methylisothiourea (SMT), a selective inhibitor of iNOS (3 mg/kg ip), 30 min before heart perfusion. Myocardial infarct size was significantly reduced from 19.2 ± 2.0% in vehicle to 8.2 ± 2.9% in RC-552 group ( P < 0.05). Treatment with SMT abolished RC-552-induced reduction in infarct size (20.0 ± 3.9%). In addition, RC-552 failed to reduce infarct size in isolated hearts from iNOS knockout mice (27.1 ± 2.8%) compared with that in hearts from control knockout mice without drug treatment (22.9 ± 5.4%). Acute buffer perfusion with RC-552 (0.1, 1.0, or 2.5 μg/ml) for 8 min immediately before ischemia-reperfusion did not reduce infarct size significantly. We concluded that RC-552 induces delayed cardioprotection via an iNOS-dependent pathway.

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