Using Big Data Approaches to Map Myocardial Infarction Signatures

Myocardial Infarction (MI) results in a loss of cardiomyocytes, which stimulates a wound healing response to form scar tissue in the heart. Mapping inflammatory and extracellular matrix (ECM) gene changes after MI will help us to understand the temporal evolution in profiles. Using the Mouse Heart Attack Research Tool (mHART), a comprehensive database of previous MI studies in wild-type C57/BL6J mice, we retrospectively analyzed gene array data that included 84 inflammatory genes (n=91 mice) and 84 ECM genes (n=109 mice) at time 0 (no MI) and MI day (D)1, 3, 5, 7, and 28. Temporal evolution was assessed by ANOVA, and unpaired t-test was used to compare consecutive days. Ingenuity Pathway Analysis was used for data visualization and to identify pathways enriched at specific MI days. Overall, we saw three major shifts in wound healing after MI. The first was an early robust inflammation at D1 and D3, shifting to resolution of inflammation by D5 and D7, and leading to establishment of a neo-homeostasis by MI D28. The major genes represented at MI D1 were IL1b, IL1a, and IFNg; at D3 were inhibition of IL13, IL4, and C3; at D5 were activation of TGFb1, IFNg, and TNF; at D7 were inhibition of TNF, IL17Ra and IL36A; and at D28 inhibition of IFNg, CCR5, and CCR2. The transition from D0 to MI D1 showed maximum activation of the inflammatory response, with the primary pathways induced being activation and adhesion of neutrophils, cellular movement, and recruitment of antigen presenting cells. The signaling pathways induced during the shift from MI D5 to D7 included inhibition of cellular infiltration of myeloid cells and inhibition of chemotaxis of monocytes. Pathways induced from MI D7 to D28 indicated a shift to the new homeostasis indicated by further inhibition of cellular movement and inhibition of growth of blood vessels. In summary, our evaluation revealed a steady shift in signaling from early inflammation to resolution and repair over the course of MI.https://digitalcommons.unmc.edu/surp2021/1003/thumbnail.jp

Combining experimental and mathematical modeling to reveal mechanisms of macrophage-dependent left ventricular remodeling

<p>Abstract</p> <p>Background</p> <p>Progressive remodeling of the left ventricle (LV) following myocardial infarction (MI) can lead to congestive heart failure, but the underlying initiation factors remain poorly defined. The objective of this study, accordingly, was to determine the key factors and elucidate the regulatory mechanisms of LV remodeling using integrated computational and experimental approaches.</p> <p>Results</p> <p>By examining the extracellular matrix (ECM) gene expression and plasma analyte levels in C57/BL6J mice LV post-MI and ECM gene responses to transforming growth factor (TGF-β₁) in cultured cardiac fibroblasts, we found that key factors in LV remodeling included macrophages, fibroblasts, transforming growth factor-β₁, matrix metalloproteinase-9 (MMP-9), and specific collagen subtypes. We established a mathematical model to study LV remodeling post-MI by quantifying the dynamic balance between ECM construction and destruction. The mathematical model incorporated the key factors and demonstrated that TGF-β₁stimuli and MMP-9 interventions with different strengths and intervention times lead to different LV remodeling outcomes. The predictions of the mathematical model fell within the range of experimental measurements for these interventions, providing validation for the model.</p> <p>Conclusions</p> <p>In conclusion, our results demonstrated that the balance between ECM synthesis and degradation, controlled by interactions of specific key factors, determines the LV remodeling outcomes. Our mathematical model, based on the balance between ECM construction and destruction, provides a useful tool for studying the regulatory mechanisms and for predicting LV remodeling outcomes.</p

Neutrophil Signaling During Myocardial Infarction Wound Repair

Neutrophils are key effector cells of the innate immune system, serving as a first line of defense in the response to injury and playing essential roles in the wound healing process. Following myocardial infarction (MI), neutrophils infiltrate into the infarct region to propagate inflammation and begin the initial phase of cardiac wound repair. Pro-inflammatory neutrophils release proteases to degrade extracellular matrix (ECM), a necessary step for the removal of necrotic myocytes as a prelude for scar formation. Neutrophils transition their phenotype over time to regulate MI inflammation resolution and stabilize scar formation. Neutrophils contribute to the evolution from inflammation to resolution and scar formation by serving anti-inflammatory and repair functions. As anti-inflammatory cells, neutrophils contribute ECM proteins during scar formation, in particular fibronectin, galectin-3, and vimentin. The diverse and polarizing functions that contribute to MI wound repair make this innate immune cell a viable target to improve MI outcomes. Thus, understanding the signaling involved in neutrophil physiology in the context of MI may help to identify novel therapeutic targets

Piglet cardiopulmonary bypass induces intestinal dysbiosis and barrier dysfunction associated with systemic inflammation

The intestinal microbiome is essential to human health and homeostasis, and is implicated in the pathophysiology of disease, including congenital heart disease and cardiac surgery. Improving the microbiome and reducing inflammatory metabolites may reduce systemic inflammation following cardiac surgery with cardiopulmonary bypass (CPB) to expedite recovery postoperatively. Limited research exists in this area and identifying animal models that can replicate changes in the human intestinal microbiome after CPB is necessary. We used a piglet model of CPB with two groups, CPB (n=5) and a control group with mechanical ventilation (n=7), to evaluate changes to the microbiome, intestinal barrier dysfunction and intestinal metabolites with inflammation after CPB. We identified significant changes to the microbiome, barrier dysfunction, intestinal short-chain fatty acids and eicosanoids, and elevated cytokines in the CPB/deep hypothermic circulatory arrest group compared to the control group at just 4 h after intervention. This piglet model of CPB replicates known human changes to intestinal flora and metabolite profiles, and can be used to evaluate gut interventions aimed at reducing downstream inflammation after cardiac surgery with CPB