scholarly journals Excess ischemic tachyarrhythmias trigger protection against myocardial infarction in hypertensive rats

2021 ◽  
Vol 135 (17) ◽  
pp. 2143-2163
Author(s):  
Jan Neckář ◽  
Petra Alánová ◽  
Veronika Olejníčková ◽  
František Papoušek ◽  
Lucie Hejnová ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
In Vivo Model ◽  
Acute Ischemia ◽  
Myocardial Salvage ◽  
Ventricular Tachyarrhythmias ◽  
Hypertensive Rats ◽  
Transgenic Expression ◽  
Remote Ischemic Perconditioning

Abstract Increased level of C-reactive protein (CRP) is a risk factor for cardiovascular diseases, including myocardial infarction and hypertension. Here, we analyzed the effects of CRP overexpression on cardiac susceptibility to ischemia/reperfusion (I/R) injury in adult spontaneously hypertensive rats (SHR) expressing human CRP transgene (SHR-CRP). Using an in vivo model of coronary artery occlusion, we found that transgenic expression of CRP predisposed SHR-CRP to repeated and prolonged ventricular tachyarrhythmias. Excessive ischemic arrhythmias in SHR-CRP led to a significant reduction in infarct size (IS) compared with SHR. The proarrhythmic phenotype in SHR-CRP was associated with altered heart and plasma eicosanoids, myocardial composition of fatty acids (FAs) in phospholipids, and autonomic nervous system imbalance before ischemia. To explain unexpected IS-limiting effect in SHR-CRP, we performed metabolomic analysis of plasma before and after ischemia. We also determined cardiac ischemic tolerance in hearts subjected to remote ischemic perconditioning (RIPer) and in hearts ex vivo. Acute ischemia in SHR-CRP markedly increased plasma levels of multiple potent cardioprotective molecules that could reduce IS at reperfusion. RIPer provided IS-limiting effect in SHR that was comparable with myocardial infarction observed in naïve SHR-CRP. In hearts ex vivo, IS did not differ between the strains, suggesting that extra-cardiac factors play a crucial role in protection. Our study shows that transgenic expression of human CRP predisposes SHR-CRP to excess ischemic ventricular tachyarrhythmias associated with a drop of pump function that triggers myocardial salvage against lethal I/R injury likely mediated by protective substances released to blood from hypoxic organs and tissue at reperfusion.

scholarly journals Modification of Cardiac Progenitor Cell-Derived Exosomes by miR-322 Provides Protection against Myocardial Infarction through Nox2-Dependent Angiogenesis

Antioxidants ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 18 ◽  
Author(s):  
Seock-Won Youn ◽  
Yang Li ◽  
Young-Mee Kim ◽  
Varadarajan Sudhahar ◽  
Kareem Abdelsaid ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ischemia Reperfusion Injury ◽  
Capillary Tube ◽  
Ischemia Reperfusion ◽  
Direct Injection ◽  
Cardiac Injury ◽  
Tube Formation ◽  
Acute Ischemia ◽  
Paracrine Effects ◽  
Border Zones

Myocardial infarction (MI) is the primary cause of cardiovascular mortality, and therapeutic strategies to prevent or mitigate the consequences of MI are a high priority. Cardiac progenitor cells (CPCs) have been used to treat cardiac injury post-MI, and despite poor engraftment, they have been shown to inhibit apoptosis and to promote angiogenesis through poorly understood paracrine effects. We previously reported that the direct injection of exosomes derived from CPCs (CPCexo) into mouse hearts provides protection against apoptosis in a model of acute ischemia/reperfusion injury. Moreover, we and others have reported that reactive oxygen species (ROS) derived from NADPH oxidase (NOX) can enhance angiogenesis in endothelial cells (ECs). Here we examined whether bioengineered CPCexo transfected with a pro-angiogenic miR-322 (CPCexo-322) can improve therapeutic efficacy in a mouse model of MI as compared to CPCexo. Systemic administration of CPCexo-322 in mice after ischemic injury provided greater protection post-MI than control CPCexo, in part, through enhanced angiogenesis in the border zones of infarcted hearts. Mechanistically, the treatment of cultured human ECs with CPCexo-322 resulted in a greater angiogenic response, as determined by increased EC migration and capillary tube formation via increased Nox2-derived ROS. Our study reveals that the engineering of CPCexo via microRNA (miR) programing can enhance angiogenesis, and this may be an effective therapeutic strategy for the treatment of ischemic cardiovascular diseases.

A Model of Blood Component–Heart Interaction in Cardiac Ischemia–Reperfusion Injury using a Langendorff-Based Ex Vivo Assay

2019 ◽  
Vol 25 (2) ◽  
pp. 164-173 ◽  
Author(s):  
Johanna M. Muessig ◽  
Sema Kaya ◽  
Luise Moellhoff ◽  
Johanna Noelle ◽  
Leonie Hidalgo Pareja ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricular Function ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Cardiac Ischemia ◽  
Transfer Model ◽  
Blood Components ◽  
The Impact ◽  
Human Rbcs

Introduction: Myocardial infarction is one of the leading causes of morbidity and mortality worldwide. Cellular interactions of red blood cells (RBCs) and platelets with endothelial cells and cardiomyocytes play a crucial role in cardiac ischemia/reperfusion (I/R) injury. However, addressing the specific impact of such cell-to-cell interactions in commonly employed in vivo models of cardiac I/R injury is challenging due to overlap of neuronal, hormonal, and immunological pathways. This study aimed to refine a Langendorff-based ex vivo transfer model to evaluate the impact of specific blood components on cardiac I/R injury. Material and methods: Murine whole blood, defined murine blood components (RBCs, platelet-rich plasma [PRP], and platelet-poor plasma [PPP], respectively) as well as human RBCs were loaded to the coronary system of isolated murine hearts in a Langendorff system before initiating global ischemia for 40 minutes. Following 60 minutes of reperfusion with Krebs Henseleit Buffer, left ventricular function and coronary flow were assessed. Infarct size was determined by specific histological staining following 120 minutes of reperfusion. Results: Loading of murine whole blood to the coronary system of isolated murine hearts at the beginning of 40 minutes of global ischemia improved left ventricular function after 60 minutes of reperfusion and reduced the infarct size in comparison to buffer-treated controls. Similarly, isolated murine RBCs, PRP, and PPP mediated a protective effect in the cardiac I/R model. Furthermore, human RBCs showed a comparable protective capacity as murine RBCs. Conclusion: This Langendorff-based transfer model of cardiac I/R injury is a feasible, time-, and cost-effective model to evaluate the impact of blood components on myocardial infarction. The presented method facilitates loading of blood components of genetically modified mice to murine hearts of a different mouse strain, thus complementing time- and cost-intensive chimeric models and contributing to the development of novel targeted therapies.

Pleiotropic preconditioning-like cardioprotective effects of hypolipidemic drugs in acute ischemia–reperfusion in normal and hypertensive rats

2015 ◽  
Vol 93 (7) ◽  
pp. 495-503 ◽  
Author(s):  
Táňa Ravingerová ◽  
Veronika Ledvényiová-Farkašová ◽  
Miroslav Ferko ◽  
Monika Barteková ◽  
Iveta Bernátová ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Single Gene ◽  
Cardiac Response ◽  
Acute Ischemia ◽  
Peroxisome Proliferator ◽  
Hypertensive Rats ◽  
Cardioprotective Effects ◽  
Peroxisome Proliferator Activated Receptors ◽  
Hypolipidemic Drugs

Although pleiotropy, which is defined as multiple effects derived from a single gene, was recognized many years ago, and considerable progress has since been achieved in this field, it is not very clear how much this feature of a drug is clinically relevant. During the last decade, beneficial pleiotropic effects from hypolipidemic drugs (as in, effects that are different from the primary ones) have been associated with reduction of cardiovascular risk. As with statins, the agonists of peroxisome proliferator-activated receptors (PPARs), niacin and fibrates, have been suggested to exhibit pleiotropic activity that could significantly modify the outcome of a cardiovascular ailment. This review examines findings demonstrating the impacts of treatment with hypolipidemic drugs on cardiac response to ischemia in a setting of acute ischemia–reperfusion, in relation to PPAR activation. Specifically, it addresses the issue of susceptibility to ischemia, with particular regard to the preconditioning-like cardioprotection conferred by hypolipidemic drugs, as well as the potential molecular mechanisms behind this cardioprotection. Finally, the involvement of PPAR activation in the mechanisms of non-metabolic cardioprotective effects from hypolipidemic drugs, and their effects on normal and pathologically altered myocardium (in the hearts of hypertensive rats) is also discussed.

Vinpocetine modulates metabolic activity and function during retinal ischemia

2015 ◽  
Vol 308 (9) ◽  
pp. C737-C749 ◽  
Author(s):  
Lisa Nivison-Smith ◽  
Brendan J. O'Brien ◽  
Mai Truong ◽  
Cindy X. Guo ◽  
Michael Kalloniatis ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Müller Cells ◽  
Retinal Ischemia ◽  
Retinal Function ◽  
Metabolic Effects ◽  
In Vivo Model ◽  
Muller Cells ◽  
Metabolic Demand ◽  
Lactate Dehydrogenase Activity

Vinpocetine protects against a range of degenerative conditions and insults of the central nervous system via multiple modes of action. Little is known, however, of its effects on metabolism. This may be highly relevant, as vinpocetine is highly protective against ischemia, a process that inhibits normal metabolic function. This study uses the ischemic retina as a model to characterize vinpocetine's effects on metabolism. Vinpocetine reduced the metabolic demand of the retina following ex vivo hypoxia and ischemia to normal levels based on lactate dehydrogenase activity. Vinpocetine delivered similar effects in an in vivo model of retinal ischemia-reperfusion, possibly through increasing glucose availability. Vinpocetine's effects on glucose also appeared to improve glutamate homeostasis in ischemic Müller cells. Other actions of vinpocetine following ischemia-reperfusion, such as reduced cell death and improved retinal function, were possibly a combination of the drug's actions on metabolism and other retinal pathways. Vinpocetine's metabolic effects appeared independent of its other known actions in ischemia, as it recovered retinal function in a separate metabolic model where the glutamate-to-glutamine metabolic pathway was inhibited in Müller cells. The results of this study indicate that vinpocetine mediates ischemic damage partly through altered metabolism and has potential beneficial effects as a treatment for ischemia of neuronal tissues.

scholarly journals Clinical translation of myocardial conditioning

2018 ◽  
Vol 314 (6) ◽  
pp. H1225-H1252 ◽  
Author(s):  
Hans Erik Bøtker ◽  
Thomas Ravn Lassen ◽  
Nichlas Riise Jespersen
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Blood Flow ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Acute Ischemia ◽  
Remote Ischemic Conditioning ◽  
Ischemic Conditioning ◽  
Flow Restriction

Rapid admission and acute interventional treatment combined with modern antithrombotic pharmacologic therapy have improved outcomes in patients with ST elevation myocardial infarction. The next major target to further advance outcomes needs to address ischemia-reperfusion injury, which may contribute significantly to the final infarct size and hence mortality and postinfarction heart failure. Mechanical conditioning strategies including local and remote ischemic pre-, per-, and postconditioning have demonstrated consistent cardioprotective capacities in experimental models of acute ischemia-reperfusion injury. Their translation to the clinical scenario has been challenging. At present, the most promising mechanical protection strategy of the heart seems to be remote ischemic conditioning, which increases myocardial salvage beyond acute reperfusion therapy. An additional aspect that has gained recent focus is the potential of extended conditioning strategies to improve physical rehabilitation not only after an acute ischemia-reperfusion event such as acute myocardial infarction and cardiac surgery but also in patients with heart failure. Experimental and preliminary clinical evidence suggests that remote ischemic conditioning may modify cardiac remodeling and additionally enhance skeletal muscle strength therapy to prevent muscle waste, known as an inherent component of a postoperative period and in heart failure. Blood flow restriction exercise and enhanced external counterpulsation may represent cardioprotective corollaries. Combined with exercise, remote ischemic conditioning or, alternatively, blood flow restriction exercise may be of aid in optimizing physical rehabilitation in populations that are not able to perform exercise practice at intensity levels required to promote optimal outcomes.

Speckle tracking imaging improves in vivo assessment of EPO-induced myocardial salvage early after ischemia-reperfusion in rats

2010 ◽  
Vol 298 (6) ◽  
pp. H1679-H1686 ◽  
Author(s):  
Frederic Treguer ◽  
Erwan Donal ◽  
Sophie Tamareille ◽  
Nehmat Ghaboura ◽  
Geneviève Derumeaux ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Rat Model ◽  
Speckle Tracking ◽  
Ischemia Reperfusion ◽  
Control Group ◽  
Myocardial Salvage ◽  
Speckle Tracking Imaging ◽  
Triphenyltetrazolium Chloride ◽  
Conventional Echocardiography

A noninvasive assessment of infarct size and transmural extension of myocardial infarction (TEMI) is fundamental in experimental models of ischemia-reperfusion. Conventional echocardiography parameters are limited in this purpose. This study was designed to examine whether speckle tracking imaging can be used in a rat model of ischemia-reperfusion to accurately detect the reduction of infarct size and TEMI induced by erythropoietin (EPO) as early as 24 h after reperfusion. Rats were randomly assigned to one of three groups: myocardial infarction (MI)-control group, 45 min ischemia followed by 24 h of reperfusion; MI-EPO group, similar surgery with a single bolus of EPO administered at the onset of reperfusion; and sham-operated group. Short-axis two-dimensional echocardiography was performed after reperfusion. Global radial (GSr) and circumferential (GScir) strains were compared with infarct size and TEMI assessed after triphenyltetrazolium chloride staining. As a result, ejection fraction, shortening fraction, GSr, and GScir significantly correlated to infarct size, whereas only GSr and GScir significantly correlated to TEMI. EPO significantly decreased infarct size (30.8 ± 3.5 vs. 56.2 ± 5.7% in MI-control, P < 0.001) and TEMI (0.37 ± 0.05 vs. 0.77 ± 0.05 in MI-control, P < 0.001). None of the conventional echocardiography parameters was significantly different between the MI-EPO and MI-control groups, whereas GSr was significantly higher in the MI-EPO group (29.1 ± 4.7 vs. 16.4 ± 3.3% in MI-control; P < 0.05). Furthermore, GScir and GSr appeared to be the best parameters to identify a TEMI >0.75 24 h after reperfusion. In conclusion, these findings demonstrate the usefulness of speckle tracking imaging in the early evaluation of a cardioprotective strategy in a rat model of ischemia-reperfusion.

Abstract 217: Use of Magnetic Resonance Imaging Method For Quantification Of Myocardial Salvage In A Rat Model Of Ischemia-reperfusion Injury.

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Stuart M Grieve ◽  
Jawad Mazhar ◽  
Fraser Callaghan ◽  
Cindy Y Kok ◽  
Ravinay Bhindi ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Observer Variation ◽  
Myocardial Salvage ◽  
Imaging Method ◽  
Signal Loss ◽  
Current Standard ◽  
Area At Risk ◽  
Myocardial Area

Introduction: Quantification of myocardial “area-at-risk” (AAR) and infarct (MI) zone is critical for assessing novel therapies targeting myocardial ischemia-reperfusion (IR) injury. The current standard method involves perfusion with Evan’s Blue (EB), staining with TTC and manual slicing and analysis. We have developed an MRI method for quantifying MI and AAR in whole hearts which provides superior 3D resolution to the standard approach. Methods: Rats were given an IR injury, recovered for 24 hours then infused with Gd-DTPA via the tail vein. The coronary artery was then religated, and a solution containing both iron oxide microparticles and EB was infused. For comparison, hearts were then harvested and transversally sectioned for TTC staining. Some hearts were kept intact for MRI only analysis. Ex-vivo MRI T2* and T1 images were acquired on a 9.4T magnet. The AAR (red) was quantified by comparing the T2* signal loss in perfused regions (blue) and high T1-signal in infarcted zones (white) from Gd-DTPA retention. Results: MRI and EB/TTC measures on the same slice for both AAR and MI were highly correlated (r=0.92-0.94;p<0.05). 3D MRI acquisition and analysis of whole hearts reduced intra-observer variability, and automated segmentation and analysis further reduced inter-observer variation. Conclusion: This novel MRI technique allows precise assessment of infarct and AAR zones and is highly suited to automation of both analysis and acquisition. This method could remove the need for tissue slicing, and via a centralised MRI facility, could permit 3D digital analysis of hearts at high anatomical resolution, accessible for all laboratories already performing IR experiments.

scholarly journals Role of Androgens in Sex Differences in Cardiac Damage During Myocardial Infarction

Endocrinology ◽  
2014 ◽  
Vol 155 (2) ◽  
pp. 568-575 ◽  
Author(s):  
Thi Y. L. Le ◽  
Anthony W. Ashton ◽  
Mahidi Mardini ◽  
Peter G. Stanton ◽  
John W. Funder ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Sex Differences ◽  
Androgen Receptor ◽  
Sex Steroids ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
B Cell Lymphoma ◽  
Male Rats ◽  
Cardiac Damage

Age-specific incidence of ischemic heart disease in men is higher than in women, although women die more frequently without previous symptoms; the molecular mechanism(s) are poorly understood. Most studies focus on protection by estrogen, with less attention on androgen receptor-mediated androgen actions. Our aim was to determine the role of androgens in the sex differences in cardiac damage during myocardial infarction. Mature age-matched male and female Sprague Dawley rats, intact or surgically gonadectomized (Gx), received testosterone (T) or 17β-estradiol (E2) via subdermal SILASTIC (Dow Corning Corp.) implants; a subset of male rats received dihydrotestosterone. After 21 days, animals were anesthetized, and hearts were excised and subjected to ex vivo regional ischemia-reperfusion (I-R). Hearts from intact males had larger infarcts than those from females following I-R; Gx produced the opposite effect, confirming a role for sex steroids. In Gx males, androgens (dihydrotestosterone, T) and E2 aggravated I-R-induced cardiac damage, whereas in Gx females, T had no effect and E2 reduced infarct area. Increased circulating T levels up-regulated androgen receptor and receptor for advanced glycation end products, which resulted in enhanced apoptosis aggravating cardiac damage in both males and females. In conclusion, our study demonstrates, for the first time, that sex steroids regulate autophagy during myocardial infarction and shows that a novel mechanism of action for androgens during I-R is down-regulation of antiapoptotic protein Bcl-xL (B cell lymphoma-extra large), a key controller for cross talk between autophagy and apoptosis, shifting the balance toward apoptosis and leading to aggravated cardiac damage.

scholarly journals Melatonin Prevents Early but Not Delayed Ventricular Fibrillation in the Experimental Porcine Model of Acute Ischemia

2020 ◽  
Vol 22 (1) ◽  
pp. 328
Author(s):  
Alena S. Tsvetkova ◽  
Olesya G. Bernikova ◽  
Natalya J. Mikhaleva ◽  
Darya S. Khramova ◽  
Alexey O. Ovechkin ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ventricular Fibrillation ◽  
Porcine Model ◽  
Ex Vivo ◽  
Interventricular Septum ◽  
Left Ventricular ◽  
Acute Ischemia ◽  
Dispersion Of Repolarization ◽  
Intramyocardial Electrograms ◽  
Antiarrhythmic Effects

Antiarrhythmic effects of melatonin have been demonstrated ex vivo and in rodent models, but its action in a clinically relevant large mammalian model remains largely unknown. Objectives of the present study were to evaluate electrophysiological and antiarrhythmic effects of melatonin in a porcine model of acute myocardial infarction. Myocardial ischemia was induced by 40-min coronary occlusion in 25 anesthetized pigs. After ischemia onset, 12 animals received melatonin (4 mg/kg). 48 intramyocardial electrograms were recorded from left ventricular wall and interventricular septum (IVS). In each lead, activation time (AT) and repolarization time (RT) were determined. During ischemia, ATs and dispersion of repolarization (DOR = RTmax − RTmin) increased reaching maximal values by 3–5 and 20–25 min, respectively. Ventricular fibrillation (VF) incidence demonstrated no relations to redox state markers and was associated with increased DOR and delayed ATs (specifically, in an IVS base, an area adjacent to the ischemic zone) (p = 0.031). Melatonin prevented AT increase in the IVS base, (p < 0.001) precluding development of early VF (1–5 min, p = 0.016). VF occurrence in the delayed phase (17–40 min) where DOR was maximal was not modified by melatonin. Thus, melatonin-related enhancement of activation prevented development of early VF in the myocardial infarction model.

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