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

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

Modulating Cardiac Remodeling After Myocardial Infarction

Cardiac remodeling after myocardial infarction (MI) is indicated by infarct wall thinning, reduced ejection fraction, and dilation of the left ventricle (LV). Inflammation presides in the early days of MI as a key event in cardiac wound healing. Infiltration of inflammatory cells, predominantly neutrophils and macrophages, is stimulated by ischemic cardiomyocytes that secrete inflammatory cues. This dissertation focused on identifying factors that influence cardiac remodeling after MI. S100A9 is a neutrophil-derived factor identified that exacerbated infarct wall thinning and cardiac dilation by increasing neutrophil and macrophage infiltration. Similarly, murinoglobulin 1 (Mug1) and galectin (Lgals)3 were macrophage-derived factors identified that regulate neutrophil degranulation and correlate with infarct wall thickness. Matrix metalloproteinase (MMP)-12 was released by both neutrophils and macrophages after MI and mapping the MMP-12 signalome revealed that MMP-12 induced neutrophil apoptosis. In my current project, I identified 5 plasma markers of adverse cardiac remodeling after MI in a retrospective study at MI D3: apolipoprotein A1 (ApoA1), interleukin (IL)17E, immunoglobulin (Ig)A, haptoglobin, and tissue inhibitor of matrix metalloproteinases (TIMP)-1. ApoA1, IL-17E, IgA, and TIMP1 in the plasma mirrored cardiac dysfunction after MI in a prospective study at MI D7. In conclusion, this thesis identified prominent modulators that influenced cardiac remodeling after MI

Mapping geographical inequalities in access to drinking water and sanitation facilities in low-income and middle-income countries, 2000–17

Abstract Background: Universal access to safe drinking water and sanitation facilities is an essential human right, recognised in the Sustainable Development Goals as crucial for preventing disease and improving human wellbeing. Comprehensive, high-resolution estimates are important to inform progress towards achieving this goal. We aimed to produce high-resolution geospatial estimates of access to drinking water and sanitation facilities. Methods: We used a Bayesian geostatistical model and data from 600 sources across more than 88 low-income and middle-income countries (LMICs) to estimate access to drinking water and sanitation facilities on continuous continent-wide surfaces from 2000 to 2017, and aggregated results to policy-relevant administrative units. We estimated mutually exclusive and collectively exhaustive subcategories of facilities for drinking water (piped water on or off premises, other improved facilities, unimproved, and surface water) and sanitation facilities (septic or sewer sanitation, other improved, unimproved, and open defecation) with use of ordinal regression. We also estimated the number of diarrhoeal deaths in children younger than 5 years attributed to unsafe facilities and estimated deaths that were averted by increased access to safe facilities in 2017, and analysed geographical inequality in access within LMICs. Findings: Across LMICs, access to both piped water and improved water overall increased between 2000 and 2017, with progress varying spatially. For piped water, the safest water facility type, access increased from 40·0% (95% uncertainty interval [UI] 39·4–40·7) to 50·3% (50·0–50·5), but was lowest in sub-Saharan Africa, where access to piped water was mostly concentrated in urban centres. Access to both sewer or septic sanitation and improved sanitation overall also increased across all LMICs during the study period. For sewer or septic sanitation, access was 46·3% (95% UI 46·1–46·5) in 2017, compared with 28·7% (28·5–29·0) in 2000. Although some units improved access to the safest drinking water or sanitation facilities since 2000, a large absolute number of people continued to not have access in several units with high access to such facilities (>80%) in 2017. More than 253 000 people did not have access to sewer or septic sanitation facilities in the city of Harare, Zimbabwe, despite 88·6% (95% UI 87·2–89·7) access overall. Many units were able to transition from the least safe facilities in 2000 to safe facilities by 2017; for units in which populations primarily practised open defecation in 2000, 686 (95% UI 664–711) of the 1830 (1797–1863) units transitioned to the use of improved sanitation. Geographical disparities in access to improved water across units decreased in 76·1% (95% UI 71·6–80·7) of countries from 2000 to 2017, and in 53·9% (50·6–59·6) of countries for access to improved sanitation, but remained evident subnationally in most countries in 2017. Interpretation: Our estimates, combined with geospatial trends in diarrhoeal burden, identify where efforts to increase access to safe drinking water and sanitation facilities are most needed. By highlighting areas with successful approaches or in need of targeted interventions, our estimates can enable precision public health to effectively progress towards universal access to safe water and sanitation