Reperfused hemorrhagic myocardial infarction in rats

Background Intramyocardial hemorrhage following reperfusion is strongly associated with major adverse cardiovascular events in myocardial infarction (MI) patients; yet the mechanisms contributing to these outcomes are not well understood. Large animal models have been used to investigate intramyocardial hemorrhage, but they are exorbitantly expensive and difficult to use for mechanistic studies. In contrast, rat models are widely used to investigate mechanistic aspects of cardiovascular physiology, but a rat model that consistently recapitulates the characteristics of an hemorrhagic MI does not exist. To bridge this gap, we investigated the physiological conditions of MI that would create intramyocardial hemorrhage in rats so that a reliable model of hemorrhagic MI would become available for basic research. Methods & results Sprague-Dawley rats underwent either a 90-minute (90-min) ischemia and then reperfusion (I/R) (n = 22) or 30-minute (30-min) I/R (n = 18) of the left anterior descending coronary artery. Sham rats (n = 12) were used as controls. 90-min I/R consistently yielded hemorrhagic MI, while 30-min I/R consistently yielded non-hemorrhagic MI. Twenty-four hours post-reperfusion, ex-vivo late-gadolinium-enhancement (LGE) and T2* cardiac MRI performed on excised hearts from 90-min I/R rats revealed colocalization of iron deposits within the scarred tissue; however, in 30-min I/R rats scar was evident on LGE but no evidence of iron was found on T2* CMR. Histological studies verified tissue damage (H&E) detected on LGE and the presence of iron (Perl’s stain) observed on T2*-CMR. At week 4 post-reperfusion, gene and protein expression of proinflammatory markers (TNF-α, IL-1β and MMP-9) were increased in the 90-min I/R group when compared to 30-min I/R groups. Further, transmission electron microscopy performed on 90-min I/R myocardium that were positive for iron on T2* CMR and Perl’s stain showed accumulation of granular iron particles within the phagosomes. Conclusion Ischemic time prior to reperfusion is a critical factor in determining whether a MI is hemorrhagic or non-hemorrhagic in rats. Specifically, a period of 90-min of ischemia prior to reperfusion can produce rat models of hemorrhagic MI, while 30-minutes of ischemia prior to reperfusion can ensure that the MIs are non-hemorrhagic. Hemorrhagic MIs in rats result in marked increase in iron deposition, proinflammatory burden and adverse left—ventricular remodeling compared to rats with non-hemorrhagic MIs.

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Reducing Cardiac Injury during ST-Elevation Myocardial Infarction: A Reasoned Approach to a Multitarget Therapeutic Strategy

Journal of Clinical Medicine ◽

10.3390/jcm10132968 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2968

Author(s):

Alessandro Bellis ◽

Giuseppe Di Gioia ◽

Ciro Mauro ◽

Costantino Mancusi ◽

Emanuele Barbato ◽

...

Keyword(s):

Myocardial Infarction ◽

Reperfusion Injury ◽

Therapeutic Strategy ◽

Ventricular Remodeling ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

St Elevation Myocardial Infarction ◽

Ischemic Time ◽

St Elevation

The significant reduction in ‘ischemic time’ through capillary diffusion of primary percutaneous intervention (pPCI) has rendered myocardial-ischemia reperfusion injury (MIRI) prevention a major issue in order to improve the prognosis of ST elevation myocardial infarction (STEMI) patients. In fact, while the ischemic damage increases with the severity and the duration of blood flow reduction, reperfusion injury reaches its maximum with a moderate amount of ischemic injury. MIRI leads to the development of post-STEMI left ventricular remodeling (post-STEMI LVR), thereby increasing the risk of arrhythmias and heart failure. Single pharmacological and mechanical interventions have shown some benefits, but have not satisfactorily reduced mortality. Therefore, a multitarget therapeutic strategy is needed, but no univocal indications have come from the clinical trials performed so far. On the basis of the results of the consistent clinical studies analyzed in this review, we try to design a randomized clinical trial aimed at evaluating the effects of a reasoned multitarget therapeutic strategy on the prevention of post-STEMI LVR. In fact, we believe that the correct timing of pharmacological and mechanical intervention application, according to their specific ability to interfere with survival pathways, may significantly reduce the incidence of post-STEMI LVR and thus improve patient prognosis.

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Delivery of a matrix metalloproteinase-responsive hydrogel releasing TIMP-3 after myocardial infarction: effects on left ventricular remodeling

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00076.2018 ◽

2018 ◽

Vol 315 (4) ◽

pp. H814-H825 ◽

Cited By ~ 13

Author(s):

Brendan P. Purcell ◽

Shayne C. Barlow ◽

Paige E. Perreault ◽

Lisa Freeburg ◽

Heather Doviak ◽

...

Keyword(s):

Myocardial Infarction ◽

Matrix Metalloproteinases ◽

Ventricular Remodeling ◽

Left Ventricular ◽

Large Animal Model ◽

Left Ventricular Geometry ◽

Relative Reduction ◽

Large Animal ◽

Early Reperfusion ◽

Localized Delivery

Although improvements in timing and approach for early reperfusion with acute coronary syndromes have occurred, myocardial injury culminating in a myocardial infarction (MI) remains a common event. Although a multifactorial process, an imbalance between the induction of proteolytic pathways, such as matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of metalloproteinase (TIMPs), has been shown to contribute to this process. In the present study, a full-length TIMP-3 recombinant protein (rTIMP-3) was encapsulated in a specifically formulated hyaluronic acid (HA)-based hydrogel that contained MMP-cleavable peptide cross-links, which influenced the rate of rTIMP-3 release from the HA gel. The effects of localized delivery of this MMP-sensitive HA gel (HAMMPS) alone and containing rTIMP-3 (HAMMPS/rTIMP-3) were examined in terms of the natural history of post-MI remodeling. Pigs were randomized to one of the following three different groups: MI and saline injection (MI/saline group, 100-μl injection at nine injection sites, n = 7), MI and HAMMPS injection (MI/HAMMPS group; 100-μl injection at nine injection sites, n = 7), and MI and HAMMPS/rTIMP-3 injection (MI/HAMMPS/rTIMP-3 group; 20-μg/100-μl injection at nine injection sites, n = 7). Left ventricular (LV) echocardiography was serially performed up to 28 days post-MI. LV dilation, as measured by end-diastolic volume, and the degree of MI wall thinning were reduced by ~50% in the HAMMPS/rTIMP-3 group ( P < 0.05). Furthermore, indexes of heart failure progression post-MI, such as LV filling pressures and left atrial size, were also attenuated to the greatest degree in the HAMMPS/rTIMP-3 group. At 28 days post-MI, HAMMPS/rTIMP-3 caused a relative reduction in the transcriptional profile for myofibroblasts as well as profibrotic pathways, which was confirmed by subsequent histochemistry. In conclusion, these findings suggest that localized delivery of a MMP-sensitive biomaterial that releases a recombinant TIMP holds promise as a means to interrupt adverse post-MI remodeling. NEW & NOTEWORTHY The present study targeted a myocardial matrix proteolytic system, matrix metalloproteinases (MMPs), through the use of a recombinant tissue inhibitor of MMPs incorporated into a MMP-sensitive hydrogel, which was regionally injected using a large animal model of myocardial infarction. Left ventricular geometry and function and indexes of myocardial remodeling were improved with this approach and support the advancement of localized therapeutic strategies that specifically target the myocardial matrix.

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Comparative Analysis of Methods to Induce Myocardial Infarction in a Closed-Chest Rabbit Model

BioMed Research International ◽

10.1155/2015/893051 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 6

Author(s):

Marc-Antoine Isorni ◽

Amaury Casanova ◽

Julie Piquet ◽

Valérie Bellamy ◽

Charly Pignon ◽

...

Keyword(s):

Myocardial Infarction ◽

Animal Models ◽

Rabbit Model ◽

Left Ventricular ◽

Balloon Occlusion ◽

Gelatin Sponge ◽

Large Animal ◽

Alcohol Injection ◽

Closed Chest ◽

Large Animal Models

Objective.To develop a rabbit model of closed-chest catheter-induced myocardial infarction.Background.Limitations of rodent and large animal models justify the search for clinically relevant alternatives.Methods.Microcatheterization of the heart was performed in 47 anesthetized 3-4 kg New Zealand rabbits to test five techniques of myocardial ischemia: free coils (n=4), interlocking coils (n=4), thrombogenic gelatin sponge (n=4), balloon occlusion (n=4), and alcohol injection (n=8). In order to limit ventricular fibrillation, an antiarrhythmic protocol was implemented, with beta-blockers/amiodarone before and xylocaine infusion during the procedure. Clinical, angiographic, and echographic data were gathered. End points included demonstration of vessel occlusion (TIMI flow grades 0 and 1 on the angiogram), impairment of left ventricular function at 2 weeks after procedure (by echocardiography), and pathologically confirmed myocardial infarction.Results.The best arterial access was determined to be through the right carotid artery. The internal mammary guiding catheter 4-Fr was selected as the optimal device for selective intracoronary injection. Free coils deployed prematurely and tended to prolapse into the aorta. Interlocking coils did not deploy completely and failed to provide reliable results. Gelatin sponge was difficult to handle, adhered to the catheter, and could not be clearly visualized by fluoroscopy. Balloon occlusion yielded inconsistent results. Alcohol injection was the most efficient and reproducible method for inducing myocardial infarction (4 out of 6 animals), the extent of which could be fine-tuned by using a coaxial balloon catheter as a microcatheter (0.52 mm) to achieve a superselective injection of 0.2 mL of alcohol. This approach resulted in a 20% decrease in LVEF and infarcted myocardium was confirmed histologically.Conclusions.By following a stepwise approach, a minimally invasive, effective, and reproducible rabbit model of catheter-induced myocardial infarction has been developed which addresses the limitations of rodent experiments while avoiding the logistical and cost issues associated with large animal models.

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Novel intracoronary supersaturated oxygen treatment for anterior myocardial infarction

Future Cardiology ◽

10.2217/fca-2020-0133 ◽

2021 ◽

Author(s):

Carmen Wheeler ◽

Federico De Puy ◽

Richard Schatz

Keyword(s):

Myocardial Infarction ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Significant Proportion ◽

Left Ventricular ◽

Major Adverse Cardiovascular Events ◽

Early Reperfusion ◽

St Segment Elevation ◽

Segment Elevation Myocardial Infarction ◽

St Segment

Primary percutaneous coronary intervention (PCI) is now the recommended reperfusion technique for patients with acute ST-segment elevation myocardial infarction. However, despite early reperfusion in the majority of patients, PCI does not achieve effective myocardial reperfusion in a significant proportion of patients due to the prevalence of coronary microvascular obstruction. The amount of infarcted myocardium has been considered to be a reliable indicator of major adverse cardiovascular events and resultant adverse left ventricular remodeling. The purpose of this paper is to review the clinical benefits of supersaturated oxygen therapy following PCI for ST-segment elevation myocardial infarction.

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Clofibrate Treatment Decreases Inflammation and Reverses Myocardial Infarction-Induced Remodelation in a Rodent Experimental Model

Molecules ◽

10.3390/molecules24020270 ◽

2019 ◽

Vol 24 (2) ◽

pp. 270 ◽

Cited By ~ 4

Author(s):

Luz Ibarra-Lara ◽

María Sánchez-Aguilar ◽

Elizabeth Soria-Castro ◽

Jesús Vargas-Barrón ◽

Francisco Roldán ◽

...

Keyword(s):

Myocardial Infarction ◽

Coronary Artery ◽

Cardiac Remodeling ◽

Ventricular Remodeling ◽

Ex Vivo ◽

Left Ventricular ◽

Coronary Artery Ligation ◽

Cardiac Damage ◽

Artery Ligation ◽

Apoptotic Proteins

Myocardial infarction (MI) initiates an inflammatory response that promotes both beneficial and deleterious effects. The early response helps the myocardium to remove damaged tissue; however, a prolonged later response brings cardiac remodeling characterized by functional, metabolic, and structural pathological changes. Current pharmacological treatments have failed to reverse ischemic-induced cardiac damage. Therefore, our aim was to study if clofibrate treatment was capable of decreasing inflammation and apoptosis, and reverse ventricular remodeling and MI-induced functional damage. Male Wistar rats were assigned to (1) Sham coronary artery ligation (Sham) or (2) Coronary artery ligation (MI). Seven days post-MI, animals were further divided to receive vehicle (V) or clofibrate (100 mg/kg, C) for 7 days. The expression of IL-6, TNF-α, and inflammatory related molecules ICAM-1, VCAM-1, MMP-2 and -9, nuclear NF-kB, and iNOS, were elevated in MI-V. These inflammatory biomarkers decreased in MI-C. Also, apoptotic proteins (Bax and pBad) were elevated in MI-V, while clofibrate augmented anti-apoptotic proteins (Bcl-2 and 14-3-3ε). Clofibrate also protected MI-induced changes in ultra-structure. The ex vivo evaluation of myocardial functioning showed that left ventricular pressure and mechanical work decreased in infarcted rats; clofibrate treatment raised those parameters to control values. Echocardiogram showed that clofibrate partially reduced LV dilation. In conclusion, clofibrate decreases cardiac remodeling, decreases inflammatory molecules, and partly preserves myocardial diameters.

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New Imaging-derived Biomarkers Based on Tridimensional CTA/MRI Hybrid Models for Complex Assessment of Myocardial Viability after Myocardial Infarction – the HYBRIDHEART Study

Journal of Interdisciplinary Medicine ◽

10.2478/jim-2018-0009 ◽

2018 ◽

Vol 3 (1) ◽

pp. 16-20

Author(s):

Alexandra Stănescu ◽

Imre Benedek ◽

Mirabela Morariu ◽

Mihaela Rațiu ◽

Ramona Zavate ◽

...

Keyword(s):

Myocardial Infarction ◽

Myocardial Viability ◽

Hybrid Imaging ◽

Imaging Techniques ◽

Left Ventricular ◽

Major Adverse Cardiovascular Events ◽

Ischemic Time ◽

Complex Evaluation ◽

Secondary Objective ◽

Magnetic Resonance Imaging Mri

Abstract Hybrid imaging represents a combination of two different imaging techniques resulting in a single image that contains all the information provided by the two investigations. Hybrid imaging tends to improve the accuracy of the diagnosis in many diseases. Coronary computed tomography angiography (CCTA) has unquestionable abilities in highlighting coronary artery diseases (CAD). Cardiac magnetic resonance imaging (MRI) also has a powerful predictive role in assessing the functionality of the myocardial tissue. The aim of the study is to develop new imaging markers for a complex evaluation of myocardial viability (MV) after an acute myocardial infarction (AMI), using hybrid technology. Material and methods: This study will enroll 100 patients at one month after an AMI. CCTA, MRI, 3D echocardiography, and blood tests will be performed in all patients. All the acquisitions will be processed using a supercomputer, and MV and other parameters will be assessed on hybrid images. A secondary objective will be to correlate the level of inflammatory markers with the outcome of patients, left ventricular function, ischemic time, and the rate of major adverse cardiovascular events.

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Optimized Treatment of ST-Elevation Myocardial Infarction

Circulation Research ◽

10.1161/circresaha.119.315344 ◽

2019 ◽

Vol 125 (2) ◽

pp. 245-258 ◽

Cited By ~ 33

Author(s):

Giampaolo Niccoli ◽

Rocco A. Montone ◽

Borja Ibanez ◽

Holger Thiele ◽

Filippo Crea ◽

...

Keyword(s):

Myocardial Infarction ◽

Infarct Size ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Coronary Intervention ◽

Left Ventricular ◽

Major Adverse Cardiovascular Events ◽

St Segment Elevation ◽

St Segment ◽

Percutaneous Coronary

Primary percutaneous coronary intervention is nowadays the preferred reperfusion strategy for patients with acute ST-segment–elevation myocardial infarction, aiming at restoring epicardial infarct-related artery patency and achieving microvascular reperfusion as early as possible, thus limiting the extent of irreversibly injured myocardium. Yet, in a sizeable proportion of patients, primary percutaneous coronary intervention does not achieve effective myocardial reperfusion due to the occurrence of coronary microvascular obstruction (MVO). The amount of infarcted myocardium, the so-called infarct size, has long been known to be an independent predictor for major adverse cardiovascular events and adverse left ventricular remodeling after myocardial infarction. Previous cardioprotection studies were mainly aimed at protecting cardiomyocytes and reducing infarct size. However, several clinical and preclinical studies have reported that the presence and extent of MVO represent another important independent predictor of adverse left ventricular remodeling, and recent evidences support the notion that MVO may be more predictive of major adverse cardiovascular events than infarct size itself. Although timely and complete reperfusion is the most effective way of limiting myocardial injury and subsequent ventricular remodeling, the translation of effective therapeutic strategies into improved clinical outcomes has been largely disappointing. Of importance, despite the presence of a large number of studies focused on infarct size, only few cardioprotection studies addressed MVO as a therapeutic target. In this review, we provide a detailed summary of MVO including underlying causes, diagnostic techniques, and current therapeutic approaches. Furthermore, we discuss the hypothesis that simultaneously addressing infarct size and MVO may help to translate cardioprotective strategies into improved clinical outcome following ST-segment–elevation myocardial infarction.

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Evolution of scar structure, mechanics, and ventricular function after myocardial infarction in the rat

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00495.2009 ◽

2010 ◽

Vol 298 (1) ◽

pp. H221-H228 ◽

Cited By ~ 114

Author(s):

Gregory M. Fomovsky ◽

Jeffrey W. Holmes

Keyword(s):

Myocardial Infarction ◽

Mechanical Properties ◽

Ventricular Function ◽

Heart Function ◽

Systolic Pressure ◽

Left Ventricular ◽

Collagen Content ◽

Lv Function ◽

Large Animal ◽

Large Animal Models

The mechanical properties of the healing scar are an important determinant of heart function following myocardial infarction. Yet the relationship between scar structure, scar mechanics, and ventricular function remains poorly understood, in part because no published study has tracked all of these factors simultaneously in any animal model. We therefore studied the temporal evolution of scar structure, scar mechanics, and left ventricular (LV) function in large anterior myocardial infarcts in rats. At 1, 2, 3, and 6 wk after left anterior descending coronary ligation, we examined LV function using sonomicrometry, infarct mechanical properties using biaxial mechanical testing, infarct structure using polarized light microscopy, and scar collagen content and cross-linking using biochemical assays. Healing infarcts in the rat were structurally and mechanically isotropic at all time points. Collagen content increased with time and was the primary determinant of scar mechanical properties. The presence of healing infarcts influenced systolic LV function through a rightward shift of the end-systolic pressure-volume relationship (ESPVR) that depended on infarct size, infarct collagen content, and LV dilation. We conclude that in sharp contrast to previous reports in large animal models, healing infarcts are structurally and mechanically isotropic in the standard rat model of myocardial infarction. On the basis of the regional strain patterns we observed in healing rat infarcts in this study and in healing pig infarcts in previous studies, we hypothesize that the local pattern of stretching determines collagen alignment in healing myocardial infarct scars.

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Bioengineering Quantification of Left Ventricular Remodeling Following Myocardial Infarction

ASME 2009 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2009-206779 ◽

2009 ◽

Author(s):

Changfu Wu ◽

Won-Bae Chang ◽

Marc Gibber ◽

P. Griffith Bartley ◽

Zhongjun J. Wu

Keyword(s):

Myocardial Infarction ◽

Cardiac Remodeling ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Left Ventricular ◽

Large Animal Model ◽

Western World ◽

Large Animal ◽

Lv Remodeling ◽

Geometric Changes

Myocardial infarction (MI)-induced heart failure is the prevailing cause of morbidity and mortality in the western world. It is the sequela of the deleterious left ventricular (LV) remodeling process. So far, the mechanisms of the cardiac remodeling process are not completely understood. A clinically relevant large animal model is an essential vehicle for studying the mechanisms of cardiac remodeling. In our laboratory, we have developed a reproducible ovine model of post-infarct chronic cardiac remodeling. Throughout the study period of an animal, the functional and geometric changes of the LV were monitored by echocardiographic and bioengineering means.

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High-resolution imaging of murine myocardial infarction with delayed-enhancement cine micro-CT

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01307.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. H3172-H3178 ◽

Cited By ~ 47

Author(s):

Matthias Nahrendorf ◽

Cristian Badea ◽

Laurence W. Hedlund ◽

Jose-Luiz Figueiredo ◽

David E. Sosnovik ◽

...

Keyword(s):

Myocardial Infarction ◽

Infarct Size ◽

Ventricular Remodeling ◽

Ex Vivo ◽

Myocardial Infarct ◽

Left Ventricular ◽

Delayed Enhancement ◽

Constant Infusion ◽

Mouse Heart ◽

Myocardial Infarct Size

The objective of this study was to determine the feasibility of delayed-enhancement micro-computed tomography (μCT) imaging to quantify myocardial infarct size in experimental mouse models. A total of 20 mice were imaged 5 or 35 days after surgical ligation of the left coronary artery or sham surgery ( n = 6 or 7 per group). We utilized a prototype μCT that covers a three-dimensional (3D) volume with an isotropic spatial resolution of 100 μm. A series of image acquisitions were started after a 200 μl bolus of a high-molecular-weight blood pool CT agent to outline the ventricles. CT imaging was continuously performed over 60 min, while an intravenous constant infusion with iopamidol 370 was started at a dosage of 1 ml/h. Thirty minutes after the initiation of this infusion, signal intensity in Hounsfield units was significantly higher in the infarct than in the remote, uninjured myocardium. Cardiac morphology and motion were visualized with excellent contrast and in fine detail. In vivo CT determination of infarct size at the midventricular level was in good agreement with ex vivo staining with triphenyltetrazolium chloride [5 days post-myocardial infarction (MI): r2 = 0.86, P < 0.01; 35 days post-MI: r2 = 0.92, P < 0.01]. In addition, we detected significant left ventricular remodeling consisting of left ventricular dilation and decreased ejection fraction. 3D cine μCT reliably and rapidly quantifies infarct size and assesses murine anatomy and physiology after coronary ligation, despite the small size and fast movement of the mouse heart. This efficient imaging tool is a valuable addition to the current phenotyping armamentarium and will allow rapid testing of novel drugs and cell-based interventions in murine models.

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