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Natural IgM Blockade Limits Infarct Expansion and Left Ventricular Dysfunction in a Swine Myocardial Infarct Model.

ABSTRACT: Acute coronary syndrome is the leading cause of mortality worldwide. However, treatment of acute coronary occlusion inevitably results in ischemia-reperfusion injury. Circulating natural IgM has been shown to play a significant role in mouse models of ischemia-reperfusion injury. A highly conserved self-antigen, nonmuscle myosin heavy chain II, has been identified as a target of pathogenic IgM. We hypothesized that a monoclonal antibody (m21G6) directed against nonmuscle myosin heavy chain II may inhibit IgM binding and reduce injury in a preclinical model of myocardial infarction. Thus, our objective was to evaluate the efficacy of intravenous m21G6 treatment in limiting infarct expansion, troponin release, and left ventricular dysfunction in a swine myocardial infarction model.Massachusetts General Hospital miniature swine underwent occlusion of the midleft anterior descending coronary artery for 60 minutes, followed by 1 hour, 5-day, or 21-day reperfusion. Specificity and localization of m21G6 to injured myocardium were confirmed using fluorescently labeled m21G6. Treatment with m21G6 before reperfusion resulted in a 49% reduction in infarct size (P<0.005) and a 61% reduction in troponin-T levels (P<0.05) in comparison with saline controls at 5-day reperfusion. Furthermore, m21G6-treated animals recovered 85.4% of their baseline left ventricular function as measured by 2-dimensional transthoracic echocardiography in contrast to 67.1% in controls at 21-day reperfusion (P<0.05).Treatment with m21G6 significantly reduced infarct size and troponin-T release, and led to marked preservation of cardiac function in our study. Overall, these findings suggest that pathogenic IgM blockade represents a valid therapeutic strategy in mitigating myocardial ischemia-reperfusion injury.

SUBMITTER: Sihag S

PROVIDER: S-EPMC4687758 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Natural IgM Blockade Limits Infarct Expansion and Left Ventricular Dysfunction in a Swine Myocardial Infarct Model.

Sihag Smita S Haas Michael S MS Kim Karen M KM Guerrero J Luis JL Beaudoin Jonathan J Alicot Elisabeth M EM Schuerpf Franziska F Gottschall James D JD Puro Robyn J RJ Madsen Joren C JC Sachs David H DH Newman Walter W Carroll Michael C MC Allan James S JS

Circulation. Cardiovascular interventions 20160101 1

<h4>Background</h4>Acute coronary syndrome is the leading cause of mortality worldwide. However, treatment of acute coronary occlusion inevitably results in ischemia-reperfusion injury. Circulating natural IgM has been shown to play a significant role in mouse models of ischemia-reperfusion injury. A highly conserved self-antigen, nonmuscle myosin heavy chain II, has been identified as a target of pathogenic IgM. We hypothesized that a monoclonal antibody (m21G6) directed against nonmuscle myosi ...[more]

PMID: 26671971

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Project description:PurposeTo quantitatively evaluate the dynamic changes of extracellular volume (ECV) and native T1 in hypertensive swine over time using histologic findings as standard of reference.Materials and methodsEighteen hypertensive (hypertension group) and six healthy (control group) swine aged 6-12 months were studied. Both groups underwent cardiac MRI, including pre- and postcontrast T1 mapping and late gadolinium enhancement (LGE) imaging at three time points: baseline, 1 month, and 3 months after hypertensive model induction. The left ventricular function, strain, and strain rate were also calculated using the cine images. Animals were killed after the last MRI examination. Histopathologic examination of the heart was performed later. Analysis of the relationship between strain, ECV, and native T1 was carried out by Pearson correlation and linear regression models.ResultsThe mean systolic and diastolic pressure increased from 111 mg Hg and 68 mm Hg to 160 mm Hg and 97 mm Hg, respectively, over 3 months during developing hypertension (P = .03, .02, respectively). There was no LGE detected at any of three imaging times. The ECV and native T1 value of myocardium in the hypertension group increased over 3 months (ECV, increased from 21.5% ± 4.4 to 27.3% ± 5.4; native T1, increased from a mean of 1056 msec ± 32 [standard deviation] to 1218 msec ± 66; all P < .001). The collagen volume fraction (CVF) was calculated and correlated with ECV (r = 0.63, P = .01) and native T1 (r = 0.80, P < .001). In addition, ECV was associated with longitudinal diastolic strain rate (r =-.34, P = .04). Native T1 was associated with radial strain (r = -0.62, P < .001) as well as circumferential strain (r = 0.57, P < .001).ConclusionNative T1 and ECV correlated significantly with the CVF, indicating that early myocardial interstitial fibrosis exists in hypertensive heart disease. As hypertension progresses, the values of ECV fraction and T1 native increase. Supplemental material is available for this article. © RSNA, 2020.

Project description:Cell therapy for myocardial infarction (MI) may be limited by poor cell survival and lack of transdifferentiation. We report a novel technique of implanting whole autologous myocardial tissue from preserved myocardial regions into infarcted regions.Fourteen rats were used to optimize cardiomyotissue size with peritoneal wall implantation (300 ?m identified as optimal size). Thirty-nine pigs were used to investigate cardiomyotissue implantation in MI induced by left anterior descending balloon occlusion (10 animals died; male-to-female transplantation for tracking with in situ hybridization for Y chromosome, n=4 [2 donors and 2 MI animals]; acute MI implantation cohort at 1 hour, n=13; and healed MI implantation at 2 weeks, n=12). Assessment included echocardiography, magnetic resonance imaging, hemodynamics, triphenyltetrazolium chloride staining, and histological and molecular analyses. Tracking studies demonstrated viable implants with donor cells interspersed in the adjacent myocardium with gap junctions and desmosomes. In the acute MI cohort, treated animals compared with controls had improved perfusion by magnetic resonance imaging (1.2±0.01 versus 0.86±0.05; P<0.01), decreased MI size (magnetic resonance imaging: left ventricle, 2.2±0.5% versus 5.4±1.5%, P=0.04; triphenyltetrazolium chloride: anterior wall, 10.3±4.6% versus 28.9±5.8%, P<0.03), and improved contractility (dP/dt, 1235±215 versus 817±817; P<0.05). In the healed MI cohort, treated animals had less decline in ejection fraction between 2 and 4 week assessment (-3±4% versus -13±-4%; P<0.05), less decline in ±dP/dt, and smaller MI (triphenyltetrazolium chloride, 21±11% versus 3±8%; P=0.006) than control animals. Infarcts in the treated animals contained more mdr-1(+) cells and fewer c-kit(+) cells with a trend for decreased expression of matrix metalloproteinase-2 and increased expression of tissue inhibitor of metalloproteinase-2.Autologous cardiomyotissue implanted in an MI area remains viable, exhibits electromechanical coupling, decreases infarct size, and improves left ventricular function.

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Natural IgM Blockade Limits Infarct Expansion and Left Ventricular Dysfunction in a Swine Myocardial Infarct Model.

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Natural IgM Blockade Limits Infarct Expansion and Left Ventricular Dysfunction in a Swine Myocardial Infarct Model.

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