Response In Myocardial Infarction Research Articles

Exploring Shared Biomarkers of Myocardial Infarction and Alzheimer's Disease via Single-Cell/Nucleus Sequencing and Bioinformatics Analysis.

Patients are at increased risk of dementia, including Alzheimer's disease (AD), after myocardial infarction (MI), but the biological link between MI and AD is unclear. To understand the association between the pathogenesis of MI and AD and identify common biomarkers of both diseases. Using public databases, we identified common biomarkers of MI and AD. Least absolute shrinkage and selection operator (LASSO) regression and protein-protein interaction (PPI) network were performed to further screen hub biomarkers. Functional enrichment analyses were performed on the hub biomarkers. Single-cell/nucleus analysis was utilized to further analyze the hub biomarkers at the cellular level in carotid atherosclerosis and AD datasets. Motif enrichment analysis was used to screen key transcription factors. 26 common differentially expressed genes were screened between MI and AD. Function enrichment analyses showed that these differentially expressed genes were mainly associated with inflammatory pathways. A key gene, Regulator of G-protein Signaling 1 (RGS1), was obtained by LASSO regression and PPI network. RGS1 was confirmed to mainly express in macrophages and microglia according to single-cell/nucleus analysis. The difference in expression of RGS1 in macrophages and microglia between disease groups and controls was statistically significant (p < 0.0001). The expression of RGS1 in the disease groups was upregulated with the differentiation of macrophages and microglia. RelA was a key transcription factor regulating RGS1. Macrophages and microglia are involved in the inflammatory response of MI and AD. RGS1 may be a key biomarker in this process.

Analysis of C-reactive protein and lactoferrin levels in patients with myocardial infarction with chronic obstructive pulmonary disease depending on presence of complications

Purpose. To analyze the levels of C-reactive protein (CRP) and lactoferrin (LF) in patients with myocardial infarction (MI) with chronic obstructive pulmonary disease (COPD) depending on the presence of acute MI complications.Materials and methods. In total were examined 325 patients with MI: 195 patients with acute MI + COPD and 130 MI patients without COPD and 110 healthy somatic subjects. Complications of acute MI were observed in 84 (43.1 %) MI + COPD patients and in 32 (24.6 %) MI patients without COPD.Results of the study. The level of inflammatory markers we studied was elevated in all observation groups relative to controls. In MI + COPD patients and in MI patients without COPD the level of highly sensitive CRP was statistically significantly higher in the presence of acute period complications. LF levels did not depend on the presence of complications in any of the observation groups.Conclusions. Increased inflammatory markers in MI patients without COPD and in MI + COPD groups indicate the significance of the inflammatory component in the pathogenesis of MI. In patients with MI + COPD the severity of systemic inflammation is maximal. CRP is informative as an indicator of inflammatory response in MI. The highest CRP level was observed in patients with complicated MI.

Monocyte response in myocardial infarction in patients with type 2 diabetes

Aim. To reveal the features of monocyte response in myocardial infarction (MI) in pa­­tients with type 2 diabetes (T2D).Material and methods. The study included 121 patients with MI and T2D as follows: 76 — with target glycated hemoglobin (HbA1c), 45 — with elevated HbA1c values. In addition to the standard examination, all patients underwent a blood test for HbA1c on day 1 of MI, while on days 1, 3, 5, and 12±1, monocyte subpopulations were assessed by flow cytometry.Results. Patients with target HbA1c were older than patients with elevated HbA1c levels. In the group with target HbA1c, the number of CD16(+) monocytes on the 1st day of MI was significantly higher: 61,38 (39,2; 100,08) cells/µl vs 35,7 (28,98; 40,33) cells/µl, p=0,03; on the 3rd day of MI, the number of "intermediate" CD14(+)CD16(+) monocytes was higher: 74,82 (71,78; 83,2) cells/µl vs 25,90 (14,04; 57,12) cells/µl, p=0,03, while the CD16(-) to CD16(+) monocyte ratio on the 3rd day of MI was lower: 8,32 (6 ,87; 10,03) vs 10,81 (8,90; 21,10), p=0,04. At the same time, in the group of patients with target HbA1c values, the level of CD16(+) monocytes on the 3rd day of MI was significantly higher in patients aged &lt;71 years compared with patients ≥71 years: 104,55 (63,64; 149,7) cells/µl vs 55,20 (36,92; 76,59) cells/µl, p=0,03.Conclusion. In patients with T2D and target HbA1c values, compared with patients with elevated HbA1c, the inflammatory response in MI is associated with higher levels of CD16(+) monocytes on days 1 and 3 of MI, which is more typical for people aged &lt;71 years.

Retracted: Muscone Inhibits the Excessive Inflammatory Response in Myocardial Infarction by Targeting TREM-1.

[This retracts the article DOI: 10.1155/2022/9112479.].

Muscone Inhibits the Excessive Inflammatory Response in Myocardial Infarction by Targeting TREM-1.

The inhibitory effect of muscone on the hyperinflammatory response after myocardial ischemia reperfusion injury (MIRI) was investigated, and the target and signal pathways of muscone were explored. The levels of inflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor alpha were detected through qRT-PCR and ELISA. The expression levels of p38 and NF-κB signaling pathway-related proteins were detected through Western blot. TREM-1 siRNA was transfected into macrophages in vitro. The rat model of myocardial ischemia was established and used in studying the inhibitory effect of muscone on the inflammatory response and its protective effect muscone on myocardial apoptosis. The expression of TREM-1 was upregulated during myocardial ischemia. Knocking down TREM-1 decreased the increase in inflammatory cytokines in the supernatant of macrophages induced by rmHMGB1 (1 μg/mL) and rmHSP60 (1 mol/mL). In addition, knocking down TREM-1 decreased p38 and NF-κB signaling activation. Muscone can protect myocardial cells by inhibiting the expression of TREM-1 and the inflammatory response after myocardial infarction. Further study showed that muscone inhibited the production of DAM-triggered (damage-associated molecular pattern trigger) inflammatory cytokines. In addition, muscone inhibited the activation of p38 and NF-κB signals under DAM-induced conditions. Muscone and TREM-1 gene knockout reduced cell apoptosis and provided protection against MIRI by inhibiting p38 and NF-κB signaling activation. Mechanism studies showed that muscone inhibited the production and release of inflammatory cytokines by inhibiting TREM-1, and thereby reducing the inflammatory response and providing protection against MIRI.

The ceRNA Crosstalk between mRNAs and lncRNAs in Diabetes Myocardial Infarction

Competitive endogenous RNA regulation suggests an intricate network of all transcriptional RNAs that have the function of repressing miRNA function and regulating mRNA expression. Today, the specific ceRNA regulatory mechanisms of lncRNA–miRNA–mRNA in patients who have diabetes mellitus (DM) and myocardial infarction (MI) are still unknown. Two data sets, GSE34198 and GSE112690, were rooted in the Gene Expression Omnibus database to search for changes of lncRNA, miRNA, and mRNA in MI patients with diabetes. Weighted gene correlation network analysis (WGCNA) was used to identify the modules related to the development of diabetes in patients with MI. Target genes of miRNAs were predicted using miRWalk, TargetScan, mirDB, RNA22, and miRanda. Then, functional and enrichment analyses were performed to build the lncRNA–miRNA–mRNA interaction network. We built ceRNA regulatory networks with three lncRNAs, two miRNAs, and nine mRNAs. Differentially expressed genes enriched in biological process, including neutrophil activation, refer to immune response and positive system of defense feedback. Besides, there is significant enrichment in molecular function of calcium toll−like receptor binding, icosanoid binding, RAGE receptor binding, and arachidonic acid binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis enriched differentially expressed genes (DEGs) in pathways that were well known in MI, indicating inflammation and immune response. Pathways associated with diabetes were also significantly enriched. We confirmed significantly altered lncRNA, miRNA, and mRNA in MI patients with diabetes, which might serve as biomarkers for the progress and development of diabetic cardiovascular diseases. We constructed a ceRNA regulatory network of lncRNA–miRNA–mRNA, which will enable us to understand the novel molecular mechanisms included in the initiation, progression, and interaction between DM and MI, laying the foundation for clinical diagnosis and treatment.

Disparities in Awareness of Myocardial Infarction and Stroke Symptoms and Response Among United States- and Foreign-Born Adults in the National Health Interview Survey.

BackgroundAtherosclerotic cardiovascular disease, defined as nonfatal myocardial infarction (MI), coronary heart disease death, or fatal or nonfatal stroke, is the leading cause of death in the United States. MI and stroke symptom awareness and response reduce delays in hospitalization and mortality.Methods and ResultsWe analyzed cross‐sectional data from the 2014 and 2017 National Health Interview Surveys on US‐ and foreign‐born adults from 9 regions of birth (Europe, South America, Mexico/Central America/Caribbean, Russia, Africa, Middle East, Indian subcontinent, Asia, and Southeast Asia). The outcomes were recommended MI and stroke knowledge, defined as knowing all 5 symptoms of MI or stroke, respectively, and choosing “call 9‐1‐1” as the best response. We included 63 059 participants, with a mean age 49.4 years; 54.1% were women, and 38.5% had a high school education or less. Recommended MI and stroke knowledge were highest in US‐born people. In both 2014 and 2017, MI knowledge was lowest in individuals born in Asia (23.9%±2.5% and 32.1%±3.3%, respectively), and stroke knowledge lowest for the Indian subcontinent (44.4%±2.4% and 46.0%±3.2%, respectively). Among foreign‐born adults, people from Russia and Europe had the highest prevalence of recommended MI knowledge in 2014 (37.4%±5.4%) and 2017 (43.5%±2.5%), respectively, and recommended stroke knowledge was highest in people from Europe (61.0%±2.6% and 67.2%±2.5%). Improvement in knowledge was not significant in all groups between 2014 and 2017.ConclusionsThese findings suggest a disparity in MI and stroke symptom awareness and response among immigrants in the United States. Culturally tailored public health education and health literacy initiatives are needed to help reduce these disparities in awareness.

Monocytic and lymphocytic inflammatory reaction during myocardial infarction complicated with acute heart failure in patients with type 2 diabetes mellitus

Background. The processes of inflammation and repair in the area of myocardial infarction (MI) are carried out and regulated by various populations of immune cells, including monocytes, lymphocytes, and NK-cells. The success of myocardial recovery after infarction and the risk of developing acute heart failure (AHF) depend on their adequate interaction. The presence of type 2 diabetes mellitus (T2DM), in which chronic low-gradient inflammation occurs, can affect the monocytic and lymphocytic response in MI, which may contribute to the development of AHF.Objective. to assess the features of monocytic and lymphocytic responses in patients with MI T2DM complicated by the development of AHF.Design and methods. The study included 121 patients with MI T2DM (38 of them with AHF). The control group included 59 patients without diabetes mellitus (including 13 patients with AHF). For all patients within 1 day, on days 3, 5 and 12 of MI, the total number of monocytes and lymphocytes, the monocytes-to-lymphocytes ratio (MLR), subpopulations of monocytes and T-lymphocytes with NK cells (T&amp;NK-cells) were determined by flow cytometry.Results. In patients with T2DM, the number of monocytes of different subpopulations did not differ depending on the development of AHF. In patients without T2DM with MI, complicated by AHF, compared with patients without AHF, on day 3, the number of CD14(+)CD16(-)monocytes was higher: 1018 (824; 1144) vs 593 (557; 677) cells/μL, p &lt;0,01, and on days 3 and 5, the number of CD16(+) T&amp;NK-cells was lower: 122 (95; 275) cells/μL and 307 (220; 406) cells/μL, respectively (p = 0,03); (117 (61; 228) and 437 (408; 545) cells/μL, respectively, p &lt; 0,01. On the 12th day of MI in patients with T2DM and AHF lymphocytes and CD16(+)T&amp;NK-cells counts were lower in comparison with patients without AHF: 1856 (1245; 1975) cells/μL and 2294 (1827; 2625) cells/μL, respectively, p = 0,04; 268 (128; 315) cells/μL and 344 (226 ; 499) cells/ μL, respectively, p = 0,04.Conclusion. In patients with T2DM, the development of AHF is associated with a low number of lymphocytes in the absence of a pronounced monocytic response. In non-diabetic patients, the development of AHF is associated with an increase in CD16(-)monocytes and a lower number of CD16 (+) T&amp;NК-cells.

C-X-C motif chemokine 16, modulated by microRNA-545, aggravates myocardial damage and affects the inflammatory responses in myocardial infarction

BackgroundMyocardial infarction (MI), a common type of coronary heart disease, is the major cause of morbidity and mortality around the world. Chemokine-mediated inflammatory cell infiltration and local inflammatory damage response are recent research hotspots. Hence, we attempted to examine the role of C-X-C motif chemokine 16 (CXCL16) as a potential candidate in MI.MethodsHuman cardiomyocytes were treated with hypoxia/reoxygenation (H/R) to establish an in vitro cell model. GEO database provided the clinical data of MI patients and GSEA verified the relationship of chemokine and MI. CCK-8 and flow cytometry analyses were used to measure cell viability and apoptosis. Bioinformatics analysis and luciferase reporter assay were conducted to determine the correlation between CXCL16 and miR-545. qRT-PCR and western blot assays were performed to investigate the expression level of the indicated genes. The activity of lactate dehydrogenase (LDH) and the levels of TNF-α, IL-6, IL-1β, and IL-10 were explored using ELISA assay.ResultsCXCL16 was increased in MI. CXCL16 knockdown can reverse the inhibitory effect of H/R treatment on cell viability, while overexpression of CXCL16 showed the opposite trend. MiR-545 directly targeted CXCL16 and negatively regulated CXCL16 levels. MiR-545 promoted cell proliferation and inhibited apoptosis in the MI cell model, which attenuated the CXCL16-induced injury on cardiomyocytes.ConclusionThese findings demonstrated that CXCL16 aggravated MI damage through being directly targeted by miR-545 and mediating inflammatory responses, thereby providing potential therapeutic targets for MI therapy.

MST1-Hippo pathway regulates inflammation response following myocardial infarction through inhibiting HO-1 signaling pathway

Context: Mammalian STE20-like protein kinases 1 (MST1) has been found to be associated with cardiomyocyte damage following acute myocardial infarction.Aim: The aim of our study is to explore the influence of MST1 in inflammation response following myocardial infarction.Methods: Cardiomyocyte cell line was used in vitro with hypoxia treatment to establish myocardial infarction model. ELISA, qPCR, Western blots, and siRNA technology were used to analyze the role of MST1 in inflammation response following myocardial infarction.Results: The transcription and expression of MST1 was significantly elevated following myocardial infarction. Loss of MST1 attenuated the levels of inflammation response and thus contributed to the survival of cardiomyocyte in vitro. Mechanistically, MST1 deletion reversed the activity of heme oxygenase-1 (HO-1) and thus reduced hypoxia-mediated cardiomyocyte death.Conclusions: Altogether, in this study, we found that MST1-Hippo pathway is activated in myocardial infarction and contributes to the inflammation response in cardiomyocytes through inhibiting the HO-1 signaling pathway. This finding would provide a potential target to reverse cardiomyocyte viability and reduce inflammation response in myocardial infarction.

Heat-Shock Protein 27 (HSPB1) Is Upregulated and Phosphorylated in Human Platelets during ST-Elevation Myocardial Infarction.

Heat-shock proteins are a family of proteins which are upregulated in response to stress stimuli including inflammation, oxidative stress, or ischemia. Protective functions of heat-shock proteins have been studied in vascular disease models, and malfunction of heat-shock proteins is associated with vascular disease development. Heat-shock proteins however have not been investigated in human platelets during acute myocardial infarction ex vivo. Using two-dimensional electrophoresis and immunoblotting, we observed that heat-shock protein 27 (HSPB1) levels and phosphorylation are significantly increased in platelets of twelve patients with myocardial infarction compared to patients with nonischemic chest pain (6.4 ± 1.0-fold versus 1.0 ± 0.9-fold and 5.9 ± 1.8-fold versus 1.0 ± 0.8-fold; p < 0.05). HSP27 (HSPB1) showed a distinct and characteristic intracellular translocation from the cytoskeletal fraction into the membrane fraction of platelets during acute myocardial infarction that did not occur in the control group. In this study, we could demonstrate for the first time that HSP27 (HSPB1) is upregulated and phosphorylated in human platelets during myocardial infarction on a cellular level ex vivo with a characteristic intracellular translocation pattern. This HSP27 (HSPB1) phenotype in platelets could thus represent a measurable stress response in myocardial infarction and potentially other acute ischemic events.

P6349Inflammation mitigation improves post-infarction functional recovery of the heart

Abstract Aim The in vitro evaluation of the cardiac functional effects of TNF-α antagonist administration in rats after isoproterenol induced myocardial infarction. Material and methods Myocardial infarction was reproduced using a proven model based on isoproterenol i/p administration in rats in 2 consecutive days in a similar dose, 150 mg/kg. In another group the animals after isoproterenol induced myocardial infarction (series IMI) have received daily TNF-α antagonist, a specific monoclonal antibody (ma-TNF-α) i/p in dose of 50 mg/kg during 8 days (series IMI+ma-TNF-α). In both series the animals were sacrificed after 10 days from the 1st injection and their isolated hearts ware perfused with Krebs solution according to Langendorff and Neely-Rovetto models. Results The most remarkable traits of left ventricle dysfunction in IMI in comparison to control were following: (1) diminution of cardiac output (CO), systolic pressure (SP) and +dP/dT max by respectively 28,7 and 34,7 and 23,3%; (2) negative inotropic effect to action of endothelin-1 manifested by decrease of SP and aortic jet during stimulation up to 13,9%; (3) increased cardiac arrhythmogenic activity in response to calcium overload; (4) increasing by 45,2% of ischemia induced contracture as well as decreasing by 37,5% of SP during reperfusion. The ma-TNF-α administration in post-infarction period led to noticeable benefits such as: significant enhancement of SP and CO respectively by 17,3 and 18,6% as well as positive inotropic effect developing to ET-1 action as well as significant increase of time regarding the appearance of ventricular extrasystole and ventricular tachyarrhythmia by respectively 12,9 and 11,7% as well as perceptible improvement of ischemia-reperfusion syndrome. Conclusion A sustained inflammation inhibition by ma-TNF-α administration in post-infarction period improves tangibly the cardiac functioning that proves the role of inflammatory response in myocardial infarction induced functional and structural myocardial remodeling and underlines the inflammation as a therapeutic target.

Plasma CXCL1 levels and TRAF3IP2 variants in patients with myocardial infarction.

IL-17A plays an important role in inflammatory responses in myocardial infarction (MI). IL-17A signals through its receptor, for which, Act1 (TRAF3IP2) functions as a key upstream adaptor in the pathway. To compare frequencies of functional polymorphisms of TRAF3IP2 (rs13210247, rs33980500) between patients with MI and healthy controls. The selected SNPs were studied in 201 Iranian MI patients and 201 healthy blood donors from Fars Province by PCR-RFLP in association with clinicopathologic criteria of patients. CXCL1 plasma levels in 126 MI patients and 50 normal subjects were measured by ELISA. A significant increase in the mutant (T) allele of TRAF3IP2 rs33980500 in patients with diastolic dysfunction of the heart (P=.01) was observed. The highest correlation, however, was observed between the TRAF3IP2 rs33980500 TT genotype and T allele with left main coronary artery stenosis (P=.01, P<.001; OR=31.03). T allele of TRAF3IP2 rs33980500 was also associated with female gender, family history of cardiovascular disease, and mechanical complications of heart (P=.04, P=.02, and P=.01, respectively). Moreover, TRAF3IP2 rs13210247 (G) correlated with mechanical complications of the heart (P=.01). A significant increase in the plasma levels of CXCL1 chemokine in patients (P=.0006) associated with TT genotype of TRAF3IP2 (rs33980500) was observed (P=.04). The gene variants of Act1 adaptor are associated with correlates of poor outcome in patients with MI and plasma CXCL1 levels.

Sestrin2 Suppresses Classically Activated Macrophages-Mediated Inflammatory Response in Myocardial Infarction through Inhibition of mTORC1 Signaling.

Myocardial infarction (MI) triggers an intense inflammatory response that is essential for dead tissue clearance but also detrimental to cardiac repair. Macrophages are active and critical players in the inflammatory response after MI. Understanding the molecular mechanisms by which macrophage-mediated inflammatory response is regulated is important for designing new therapeutic interventions for MI. In the current study, we examined the role of Sestrin2, which is a stress-inducible protein that regulate metabolic homeostasis, in the regulation of inflammatory response of cardiac macrophages after MI. We found that cardiac macrophages upregulated Sestrin2 expression in a mouse MI model. Using a lentiviral transduction system to overexpress Sestrin2 in polarized M1 and M2 macrophages, we revealed that Sestrin2 predominantly functioned on M1 rather than M2 macrophages. Sestrin2 overexpression suppressed inflammatory response of M1 macrophages both in vitro and in vivo. Furthermore, in the mouse MI model with selective depletion of endogenous macrophages and adoptive transfer of exogenous Sestrin2-overexpressing macrophages, the anti-inflammatory and repair-promoting effect of Sestrin2-overexpressing macrophages was demonstrated. Furthermore, Sestrin2 significantly inhibited mTORC1 signaling in M1 macrophages. Taken together, our study indicates the importance of Sestrin2 for suppression of M1 macrophage-mediated cardiac inflammation after MI.

The Innate Immune Response in Myocardial Infarction, Repair, and Regeneration.

Following myocardial infarction (MI), resident innate immune cells such as macrophages, innate lymphoid cells, and mast cells rapidly coordinate their function to contain inflammation by removing dying cells and promoting cardiomyocyte replenishment. To sustain local tissue repair functions, hematopoietic progenitors are mobilized from the bone marrow to the spleen to generate subsequent myeloid cells such as monocytes and neutrophils, which are rapidly recruited at the site of MI. A finely tuned balance between local adaptation and recruitment controls the overall outcome of the cardiac tissue regeneration versus repair and scar formation.In this chapter, the (potential) roles of the innate immune system residing in the heart are discussed in the context of recent findings about macrophage ontogeny and their homeostasis with circulating monocytes during cardiac tissue growth and after myocardial infarction. Their interactions with other members of the innate immune system are also discussed with a particular emphasis on the potential involvement of mast cells and innate lymphoid cells during MI, largely underestimated until recently. Understanding the development and the functions of the different protagonists responding to MI as well as their potential cross talk could help design new strategies for regenerative medicine intervention.

Nrf-2–HO-1–HMGB1 axis: An important therapeutic approach for protection against myocardial ischemia and reperfusion injury

Myocardial reperfusion therapy is the optimal therapeutic strategy for acute myocardial infarction to preserve myocardial viability and function by reversing myocardial ischemia and reducing the infarct size [ [1] Takemura G. Nakagawa M. Kanamori H. et al. Benefits of reperfusion beyond infarction size limitation. Cardiovasc Res. 2009; 83: 269-276 Crossref PubMed Scopus (43) Google Scholar ]. However, the subsequent ischemia and reperfusion (I/R) injury may attenuate the therapeutic benefit [ [1] Takemura G. Nakagawa M. Kanamori H. et al. Benefits of reperfusion beyond infarction size limitation. Cardiovasc Res. 2009; 83: 269-276 Crossref PubMed Scopus (43) Google Scholar ]. Although reperfusion therapy is essential for the survival of ischemic tissue, reperfusion itself may cause additional cellular injury by causing local myocardial inflammation, accompanying with apoptosis, which could result in myocardial cell damage [ [2] Frangoginis N.G. Smith C.W. Entman M.L. The inflammatory response in myocardial infarction. Cardiovasc Res. 2002; 53: 31-47 Crossref PubMed Scopus (1704) Google Scholar ].

NLRP3 Inflammasome as a Novel Player in Myocardial Infarction

Inflammasomes are multiple protein complexes that serve as molecular platforms to activate caspase-1 and regulate maturation of a potent proinflammatory cytokine, interleukin (IL)-1β, as well as proinflammatory cell death, pyroptosis. Although several types of inflammasomes have been reported so far, recent investigations indicate that the NLRP3 inflammasome recognizes non-microbial danger signals and leads to sterile inflammatory responses in various disease conditions. Sterile inflammatory responses are also implicated in the development of myocardial infarction (MI). In particular, IL-1β is an early and prominent mediator of inflammatory responses in MI, suggesting the pathophysiologic role of NLRP3 inflammasomes in MI. This review highlights the current state of knowledge regarding the role of NLRP3 inflammasomes in MI.

The Triggering of Myocardial Infarction by Fine Particles Is Enhanced When Particles Are Enriched in Secondary Species

Previous studies have reported an increased risk of myocardial infarction (MI) associated with acute increases in PM concentration. Recently, we reported that MI/fine particle (PM2.5) associations may be limited to transmural infarctions. In this study, we retained data on hospital discharges with a primary diagnosis of acute myocardial infarction (using International Classification of Diseases ninth Revision [ICD-9] codes), for those admitted January 1, 2004 to December 31, 2006, who were ≥ 18 years of age, and were residents of New Jersey at the time of their MI. We excluded MI with a diagnosis of a previous MI and MI coded as a subendocardial infarction, leaving n = 1563 transmural infarctions available for analysis. We coupled these health data with PM2.5 species concentrations predicted by the Community Multiscale Air Quality chemical transport model, ambient PM2.5 concentrations, and used the same case-crossover methods to evaluate whether the relative odds of transmural MI associated with increased PM2.5 concentration is modified by the PM2.5 composition/mixture (i.e., mass fractions of sulfate, nitrate, elemental carbon, organic carbon, and ammonium). We found the largest relative odds estimates on the days with the highest tertile of sulfate mass fraction (OR = 1.13; 95% CI = 1.00, 1.27), nitrate mass fraction (OR = 1.18; 95% CI = 0.98, 1.35), and ammonium mass fraction (OR = 1.13; 95% CI = 1.00 1.28), and the lowest tertile of EC mass fraction (OR = 1.17; 95% CI = 1.03, 1.34). Air pollution mixtures on these days were enhanced in pollutants formed through atmospheric chemistry (i.e., secondary PM2.5) and depleted in primary pollutants (e.g., EC). When mixtures were laden with secondary PM species (sulfate, nitrate, and/or organics), we observed larger relative odds of myocardial infarction associated with increased PM2.5 concentrations. Further work is needed to confirm these findings and examine which secondary PM2.5 component(s) is/are responsible for an acute MI response.

Analysis of a gene co-expression network establishes robust association between Col5a2 and ischemic heart disease

BackgroundThis study aims to expand knowledge of the complex process of myocardial infarction (MI) through the application of a systems-based approach.MethodsWe generated a gene co-expression network from microarray data originating from a mouse model of MI. We characterized it on the basis of connectivity patterns and independent biological information. The potential clinical novelty and relevance of top predictions were assessed in the context of disease classification models. Models were validated using independent gene expression data from mouse and human samples.ResultsThe gene co-expression network consisted of 178 genes and 7298 associations. The network was dissected into statistically and biologically meaningful communities of highly interconnected and co-expressed genes. Among the most significant communities, one was distinctly associated with molecular events underlying heart repair after MI (P < 0.05). Col5a2, a gene previously not specifically linked to MI response but responsible for the classic type of Ehlers-Danlos syndrome, was found to have many and strong co-expression associations within this community (11 connections with ρ > 0.85). To validate the potential clinical application of this discovery, we tested its disease discriminatory capacity on independently generated MI datasets from mice and humans. High classification accuracy and concordance was achieved across these evaluations with areas under the receiving operating characteristic curve above 0.8.ConclusionNetwork-based approaches can enable the discovery of clinically-interesting predictive insights that are accurate and robust. Col5a2 shows predictive potential in MI, and in principle may represent a novel candidate marker for the identification and treatment of ischemic cardiovascular disease.

Investigation of Hypoxia-Induced Myocardial Injury Dynamics in a Tissue Interface Mimicking Microfluidic Device

Myocardial infarction is a major cause of morbidity and mortality worldwide. However, the methodological development of a spatiotemporally controllable investigation of the damage events in myocardial infarction remains challengeable. In the present study, we describe a micropillar array-aided tissue interface mimicking microfluidic device for the dynamic study of hypoxia-induced myocardial injury in a microenvironment-controllable manner. The mass distribution in the device was visually characterized, calculated, and systematically evaluated using the micropillar-assisted biomimetic interface, physiologically relevant flows, and multitype transportation. The fluidic microenvironment in the specifically functional chamber for cell positioning and analysis was successfully constructed with high fluidic relevance to the myocardial tissue. We also performed a microenvironment-controlled microfluidic cultivation of myocardial cells with high viability and regular structure integration. Using the well-established culture device with a tissue-mimicking microenvironment, a further on-chip investigation of hypoxia-induced myocardial injury was carried out and the varying apoptotic responses of myocardial cells were temporally monitored and measured. The results show that the hypoxia directionally resulted in observable cell shrinkage, disintegration of the cytoskeleton, loss of mitochondrial membrane potential, and obvious activation of caspase-3, which indicates its significant apoptosis effect on myocardial cells. We believe this microfluidic device can be suitable for temporal investigations of cell activities and responses in myocardial infarction. It is also potentially valuable to the microcontrol development of tissue-simulated studies of multiple clinical organ/tissue disease dynamics.