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

2018 ◽  
Vol 315 (4) ◽  
pp. H814-H825 ◽  
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.

Bioengineering Quantification of Left Ventricular Remodeling Following Myocardial Infarction

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.

scholarly journals Regional Changes in Myocardial Strain Predict Ventricular Remodelling after Myocardial Infarction in a Large Animal Model

2021 ◽  
Author(s):  
Doyin S. Mansell ◽  
Vito D. Bruno ◽  
Eva Sammut ◽  
Amedeo Chiribiri ◽  
Tom Johnson ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Circumferential Strain ◽  
Myocardial Strain ◽  
Left Ventricular ◽  
Large Animal Model ◽  
Large Animal ◽  
Strain Rates ◽  
Ventricular Remodelling ◽  
Early Predictors ◽  
Over Time

Abstract To identify early predictors of late left ventricular remodelling (LVR) post-myocardial infarction (MI) and related molecular signatures, a porcine model of closed-chest balloon MI was used. LVR was assessed by cardiac magnetic resonance imaging (CMRI) at baseline, 12–48 hours (acute), and 5–6 weeks (chronic) post-MI. Changes in myocardial strain and strain rates were derived from CMRI data. Tissue proteomics was compared between infarcted and non-infarcted territories. Peak values of left ventricular (LV) apical circumferential strain (ACS) changed over time together with peak global circumferential strain (GCS) while peak GLS epicardial strains or strain rates did not change over time. LVR post-MI enhanced abundance of 39 proteins in infarcted LV territories,21 of which correlated with LV equatorial circumferential strain rate (ECSR). The strongest associations were observed for D-3-phosphoglycerate dehydrogenase (D-3PGDH), cysteine and glycine-rich protein-2 (CG-RP-2), and secreted frizzled-related protein 1 (sFRP1). Results indicate that early changes in regional peak ACS predict late LV remodelling and LVR post-MI is associated with augmented levels of D-3PGDH and sFRP1, which show the strongest association with peak ECSR. These findings might help to prevent LVR post-MI by influencing/directing LV unloading strategies or by pharmacological control of tissue levels of D-3PGDH and sFRP1.

scholarly journals Acute regional changes in myocardial strain may predict ventricular remodelling after myocardial infarction in a large animal model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
D. S. Mansell ◽  
V. D. Bruno ◽  
E. Sammut ◽  
A. Chiribiri ◽  
T. Johnson ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Circumferential Strain ◽  
Myocardial Strain ◽  
Left Ventricular ◽  
Large Animal Model ◽  
Large Animal ◽  
Strain Rates ◽  
Ventricular Remodelling ◽  
Tissue Levels ◽  
Over Time

AbstractTo identify predictors of left ventricular remodelling (LVR) post-myocardial infarction (MI) and related molecular signatures, a porcine model of closed-chest balloon MI was used along with serial cardiac magnetic resonance imaging (CMRI) up to 5–6 weeks post-MI. Changes in myocardial strain and strain rates were derived from CMRI data. Tissue proteomics was compared between infarcted and non-infarcted territories. Peak values of left ventricular (LV) apical circumferential strain (ACS) changed over time together with peak global circumferential strain (GCS) while peak GLS epicardial strains or strain rates did not change over time. Early LVR post-MI enhanced abundance of 39 proteins in infarcted LV territories, 21 of which correlated with LV equatorial circumferential strain rate. The strongest associations were observed for D-3-phosphoglycerate dehydrogenase (D-3PGDH), cysteine and glycine-rich protein-2, and secreted frizzled-related protein 1 (sFRP1). This study shows that early changes in regional peak ACS persist at 5–6 weeks post-MI, when early LVR is observed along with increased tissue levels of D-3PGDH and sFRP1. More studies are needed to ascertain if the observed increase in tissue levels of D-3PGDH and sFRP1 might be casually involved in the pathogenesis of adverse LV remodelling.

Novel intracoronary supersaturated oxygen treatment for anterior myocardial infarction

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.

scholarly journals Reperfused hemorrhagic myocardial infarction in rats

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243207
Author(s):  
Anand R. Nair ◽  
Eric A. Johnson ◽  
Hsin-Jung Yang ◽  
Ivan Cokic ◽  
Joseph Francis ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ventricular Remodeling ◽  
Ex Vivo ◽  
Left Ventricular ◽  
Major Adverse Cardiovascular Events ◽  
Large Animal ◽  
Ischemic Time ◽  
Rat Models ◽  
Large Animal Models ◽  
Gene And Protein Expression

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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