Abstract 117: TWEAK (Tumor Necrosis Factor-Like Weak Inducer of Apoptosis) Impedes Healing After Myocardial Infarction in Mice

Introduction: TNF-related weak inducer of apoptosis (TWEAK) triggers multiple cellular responses involved in left ventricular remodelling after myocardial infarction (MI), including cytokine production, inflammation, and wound healing. We therefore hypothesized that TWEAK-Fn14 interactions improve wound healing after experimental MI. Methods/Results: We investigated the effects of exogenous TWEAK by applying (1) cross-linked TWEAK - activating the classical NF-kB-signalling pathway, (2) TWEAK and (3) human serum albumin-tagged (HSA)-TWEAK - both activating the alternative NFkB-signalling pathway, or (4) placebo after the induction of experimental MI. Treatment with TWEAK and HSA-TWEAK surprisingly resulted in significantly higher mortality after MI (survival, placebo vs. TWEAK vs. HSA-TWEAK, 66.7 (10 of 15) vs. 14.3 (4 of 26) vs. 7.1 % (1 of 19)) due to cardiac ruptures in the TWEAK- and HSA-TWEAK groups. Ruptures were not related to changes in cardiac architecture since left ventricular dimensions as measured by echocardiography were identical between HSA-TWEAK and the placebo group three days after MI, a time point where cardiac ruptures had not taken place yet. We rule out direct remodelling defects, since MMP9 mRNA expression and proteolytic activity (gelatine zymography), and collagen1α1 mRNA expression were not altered between the groups. HSA-TWEAK induced an exaggerated inflammatory response: Infiltration of neutrophils into the border zone was significantly increased as assessed by immunohistochemistry (placebo vs. HSA-TWEAK, 297.91 vs. 455.75 neutrophils/ mm2, p < 0.001). FACS-Analysis showed a significant up-regulation of CD45+-cells in the infarcted area (CD45+-cells, placebo vs. HSA-TWEAK, 4.52 vs. 9.38 %, p < 0.05). This was associated with the up-regulation of genes important for the recruitment (MIP2, MCP-1 and MCP-5) and differentiation (IL5, IL12 and IFN-γ) of leukocytes (pg/ml, placebo vs. HSA-TWEAK: p < 0.05: MIP2, 1.41 vs. 7.83; IL5, 4.13 vs. 18.75; p < 0.001: MCP-1, N.D. vs. 28.72; MCP-5, N.D. vs. 7.36; IL12, 2.07 vs. 44.51; IFN-γ, N.D. vs. 7.47). Conclusion: Treatment with TWEAK reduces survival after experimental MI due to left ventricular rupture. This may be mediated by an exaggerated inflammatory response.

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Abstract 814: Atorvastatin Attenuates Oxidative Stress And Improves Neuronal Nitric Oxide Synthase In The Brain Stem Of Heart Failure Mice

Circulation ◽

10.1161/circ.116.suppl_16.ii_157-d ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Joseph Francis ◽

Li Yu ◽

Anuradha Guggilam ◽

Srinivas Sriramula ◽

Irving H Zucker

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Myocardial Infarction ◽

Heart Failure ◽

Brain Stem ◽

Mrna Expression ◽

Natriuretic Peptide ◽

Left Ventricular ◽

Neuronal Nos ◽

The Brain

3-Hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to reduce the incidence of myocardial infarction independent of their lipid-lowering effects. Nitric oxide (NO) in the central nervous system contributes to cardiovascular regulatory mechanisms. Imbalance between nitric oxide (NO) and superoxide anion (O 2 . − ) in the brain may contribute to enhanced sympathetic drive in heart failure (HF). This study was done to determine whether treatment with atorvastatin (ATS) ameliorates the imbalance between NO and O 2 . − production in the brain stem and contributes to improvement of left ventricular (LV) function. Methods and Results: Myocardial infarction (MI) was induced by ligation of the left coronary artery or sham surgery. Subsequently, mice were treated with ATS (10 μg/kg) (MI + ATS), or vehicle (MI + V). After 5 weeks, echocardiography revealed left ventricular dilatation in MI mice. Realtime RT-PCR indicated an increase in the mRNA expression of the LV hypertrophy markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Neuronal NOS (nNOS) and endothelial NOS (eNOS) mRNA expression were significantly reduced, while that of NAD(P)H oxidase subunit (gp91phox) expression was elevated in the brain stem of MI mice. Compared with sham-operated mice, ATS-treated mice showed reduced cardiac dilatation, decreased ANP and BNP in the LV. ATS also reduced gp91phox expression and increased nNOS mRNA expression in the brain stem, while no changes in eNOS and iNOS were observed. Conclusion: These findings suggest that ATS reduces oxidative stress and increases neuronal NOS in the brain stem, and improves left ventricular function in heart failure.

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Abstract 5393: Increased C-Reactive Protein Expression Exacerbates Left Ventricular Dysfunction and Remodeling after Myocardial Infarction

Circulation ◽

10.1161/circ.118.suppl_18.s_541-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Toshiyuki Takahashi ◽

Toshihisa Anzai ◽

Hidehiro Kaneko ◽

Atsushi Anzai ◽

Yoshinori Mano ◽

...

Keyword(s):

Myocardial Infarction ◽

Angiotensin Ii ◽

Left Ventricular ◽

Receptor Expression ◽

Border Zone ◽

Histological Evaluation ◽

Control Group ◽

C Reactive Protein ◽

Reactive Protein ◽

Lv Remodeling

We have previously reported that elevated serum C-reactive protein (CRP) level after acute myocardial infarction (MI) is associated with adverse outcomes including cardiac rupture, left ventricular (LV) remodeling and cardiac death. Recent experimental studies have shown that CRP per se has some biological properties including proinflammatory and proapoptotic effects, suggesting a pathogenetic role of CRP in the remodeling process after MI. We tested the hypothesis that increased CRP expression would exacerbate adverse LV remodeling after MI through some deleterious effects of CRP. Transgenic mice with human CRP expression (CRP-Tg) and their nontransgenic littermates (Control) underwent proximal ligation of the left coronary artery. Despite increased serum CRP level and cardiac CRP expression in CRP-Tg mice, there was no difference in phenotype between CRP-Tg and control mice before MI. Mortality at five weeks after MI was not different between groups (CRP-Tg: 49%, n=35; Control: 38%, n=40, P =0.28). Five weeks after MI, echocardiography showed that CRP-Tg mice had more LV dilation (LVEDD, CRP-Tg: 5.8 ± 0.1 mm, n=14; Control: 5.2 ± 0.1 mm, n=17, P =0.002) and worse LV function (EF, CRP-Tg: 13 ± 2%, n=14; Control: 19 ± 1%, n=17, P =0.01). Hemodynamic studies indicated that LV +dP/dt (CRP-Tg: 2,947 ± 480 mmHg/s, n=9; Control: 3,788 ± 656 mmHg/s, n=10, P =0.02) and -dP/dt (CRP-Tg: −2,230 ± 48 mmHg/s, n=9; Control: −2,890 ± 161 mmHg/s, n=10, P =0.003) were lower in the CRP-Tg group than in the Control group, although infarct size was comparable. Histological evaluation at one week after MI showed a higher rate of apoptosis in the border zone of infarcted hearts from CRP-Tg mice (CRP-Tg: 1,434 ± 322 per 10 5 nuclei; Control: 596 ± 112 per 10 5 nuclei, n=6 for each, P =0.03). Quantitative RT-PCR showed that angiotensin II type 1a receptor and interleukin-6 were upregulated in viable LV samples from CRP-Tg mice compared with controls. Increased CRP expression exacerbates LV dysfunction and remodeling after MI, associated with increased apoptotic rates, increased angiotensin II receptor expression and exaggerated inflammatory response.

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Myocardial infarction remodeling that progresses to heart failure: a signaling misunderstanding

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00131.2018 ◽

2018 ◽

Vol 315 (1) ◽

pp. H71-H79 ◽

Cited By ~ 16

Author(s):

Alan J. Mouton ◽

Osvaldo J. Rivera ◽

Merry L. Lindsey

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Wound Healing ◽

Current Knowledge ◽

Healing Process ◽

Cell Types ◽

Left Ventricular ◽

Wound Healing Process ◽

The Status ◽

The Right

After myocardial infarction, remodeling of the left ventricle involves a wound-healing orchestra involving a variety of cell types. In order for wound healing to be optimal, appropriate communication must occur; these cells all need to come in at the right time, be activated at the right time in the right amount, and know when to exit at the right time. When this occurs, a new homeostasis is obtained within the infarct, such that infarct scar size and quality are sufficient to maintain left ventricular size and shape. The ideal scenario does not always occur in reality. Often, miscommunication can occur between infarct and remote spaces, across the temporal wound-healing spectrum, and across organs. When miscommunication occurs, adverse remodeling can progress to heart failure. This review discusses current knowledge gaps and recent development of the roles of inflammation and the extracellular matrix in myocardial infarction remodeling. In particular, the macrophage is one cell type that provides direct and indirect regulation of both the inflammatory and scar-forming responses. We summarize current research efforts focused on identifying biomarker indicators that reflect the status of each component of the wound-healing process to better predict outcomes.

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Retracted: Tanshinone IIA prevents left ventricular remodelling via the TLR 4/MyD88/ NF ‐κB signalling pathway in rats with myocardial infarction

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.13557 ◽

2018 ◽

Vol 22 (6) ◽

pp. 3058-3072 ◽

Cited By ~ 19

Author(s):

Dong‐Mei Wu ◽

Yong‐Jian Wang ◽

Xin‐Rui Han ◽

Xin Wen ◽

Lei Li ◽

...

Keyword(s):

Myocardial Infarction ◽

Left Ventricular ◽

Signalling Pathway ◽

Tanshinone Iia ◽

Ventricular Remodelling ◽

Left Ventricular Remodelling

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Increased C-reactive protein expression exacerbates left ventricular dysfunction and remodeling after myocardial infarction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00001.2010 ◽

2010 ◽

Vol 299 (6) ◽

pp. H1795-H1804 ◽

Cited By ~ 24

Author(s):

Toshiyuki Takahashi ◽

Toshihisa Anzai ◽

Hidehiro Kaneko ◽

Yoshinori Mano ◽

Atsushi Anzai ◽

...

Keyword(s):

Myocardial Infarction ◽

Left Ventricular ◽

Macrophage Infiltration ◽

Border Zone ◽

Histological Evaluation ◽

Coronary Artery Ligation ◽

Apparent Difference ◽

C Reactive Protein ◽

Reactive Protein ◽

Lv Remodeling

We previously reported serum C-reactive protein (CRP) elevation after acute myocardial infarction (MI) to be associated with adverse outcomes including cardiac rupture, left ventricular (LV) remodeling, and cardiac death. Experimental studies have indicated that CRP per se has various biological actions including proinflammatory and proapoptotic effects, suggesting a pathogenic role of CRP in the post-MI remodeling process. We tested the hypothesis that increased CRP expression would exacerbate adverse LV remodeling after MI via deleterious effects of CRP. Transgenic mice with human CRP expression (CRP-Tg) and their transgene-negative littermates (control) underwent left coronary artery ligation. There was no apparent difference in phenotypic features between CRP-Tg and control mice before MI. Although mortality and infarct size were similar in the two groups, CRP-Tg mice showed more LV dilation and worse LV function with more prominent cardiomyocyte hypertrophy and fibrosis in the noninfarcted regions after MI than controls. Histological evaluation conducted 1 wk post-MI revealed a higher rate of apoptosis and more macrophage infiltration in the border zones of infarcted hearts from CRP-Tg mice in relation to increased monocyte chemotactic protein (MCP)-1 expression and matrix metalloproteinase (MMP)-9 activity. Increased CRP expression exacerbates LV dysfunction and promotes adverse LV remodeling after MI in mice. The deleterious effect of CRP on post-MI LV remodeling may be associated with increased apoptotic rates, macrophage infiltration, MCP-1 expression, and MMP-9 activity in the border zone.

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Monitoring of Bone Marrow Cell Homing in the Infarcted Human Myocardium by PET.

Blood ◽

10.1182/blood.v104.11.2696.2696 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2696-2696 ◽

Cited By ~ 1

Author(s):

Bernd Hertenstein ◽

Kai C. Wollert ◽

Michael Hofmann ◽

Gerd P. Meyer ◽

Lubomir Arseniev ◽

...

Keyword(s):

Myocardial Infarction ◽

Bone Marrow ◽

Tissue Distribution ◽

Cell Function ◽

Left Ventricular ◽

Border Zone ◽

Early Event ◽

Cell Transfer ◽

Therapeutic Application ◽

Cell Homing

Abstract Intracoronary transfer of autologous bone marrow cells (BMCs) has been shown to promote recovery of left ventricular (LV) systolic function in patients with acute myocardial infarction. (BOOST Trial; Wollert et al. Lancet, 2004, 364 141-8). Although the mechanisms of this effect remain to be established, homing of BMCs to the infarcted LV is probably a crucial early event. We determined BMC tissue distribution after therapeutic application in nine patients with a first ST-elevation myocardial infarction, who had undergone stenting of the infarct-related artery (all male; median age 43 ys; range 36 – 66). The study was approved by the local ethics committee and all patients provided written informed consent. Time from symptom onset to percutaneous coronary intervention (PCI) was 8 h (3–27) and median maximum CK level was 1767 U/l. Cells were harvested from the posterior iliac crest during short anesthesia with etomidate and midazolam and subjected to 4% gelatine polysuccinate sedimentation to obtain a preparation of unfractionated BMCs. 2.5 ± 0,7 x 108 unfractionated BMCs (10% of the harvested cell number) were radiolabeled with 100 MBq 2′-[18F]-fluoro-deoxyglucose (FDG) and infused into the infarct-related coronary artery (i.c., n=3 patients) or injected via an antecubital vein (i.v., n=3 patients). In 3 additional patients, CD34pos cells were immunomagnetically enriched from unfractionated BMCs (Clinimacs, Miltenyi, Germany), labeled with FDG, and infused i.c. Cell transfer was performed 8±2 days after stenting. Following application of FDG labelled cells all patients received 20 ± 6 x 108 non-labeled BMCs i.c. (i.e. the cell dosage that improved cell function in the BOOST trial). More than 98% of the total radioactivity infused was cell-bound. Cell viability after FDG-labeling was 95±2%. Sixty minutes after cell transfer, all patients underwent 3D-positron emission tomography imaging. After i.c. transfer, 3.4±1.4% of FDG-labeled unfractionated BMCs were detected in the infarcted LV; the remaining activity was found primarily in the liver and spleen. After i.v. transfer, only background activity was detectable in the infarcted LV. After i.c. transfer of FDG-labeled CD34-enriched cells, 25±13% of the total activity was detectable in the infarcted LV. Unfractionated BMCs engrafted in the infarct center and border zone, CD34pos cell homing was more pronounced in the border zone. FDG-labeling can be used to monitor myocardial homing and tissue distribution of BMCs after therapeutic application. I.c. transfer is superior to i.v. application in terms of BMC homing in the the infarcted LV. CD34-enriched cells display a 7-fold higher retention in the infarcted LV as compared to unfractionated BMCs.

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