Abstract 120: Pericytes Contribute To Myofibroblast Expansion And Vascular Maturation In The Infarcted Heart

Infarct healing is dependent on recruitment of inflammatory leukocytes and subsequent activation of myofibroblasts (MF) and neovessel formation, ultimately resulting in formation of a highly vascularized collagen-enriched scar. Though the heart has an abundant population of periendothelial pericytes, its role in wound healing upon myocardial infarction (MI) has not been studied. We hypothesized that in the infarcted myocardium, pericytes may become activated, contributing to inflammatory, fibrotic and angiogenic responses. We used pericyte/fibroblast reporter mice (NG2 DsRed ;PDGFRα GFP ), lineage tracing studies and in vitro approaches to study the fate and role of pericytes in the infarcted myocardium. In normal hearts, NG2+/PDGFRα- pericytes and PDGFRα+/NG2- fibroblasts had distinct transcriptomic profiles. Pericytes expressed mural genes like Acta2 , Pdgfrb and low amounts of extracellular matrix (ECM) genes, whereas fibroblasts synthesized collagens, Timp2/3 and matricellular genes. 7 days post-MI, expansion of the NG2+ population in the infarct zone was associated with emergence of non-mural NG2+/αSMA+ cells with MF characteristics. FACS-sorted NG2+/PDGFRα- cells from 7-day infarcts expressed higher levels of collagens when compared to NG2+/PDGFRα- cells from normal hearts. Infarct pericytes had high integrin and MMP14 expression, reflecting an activated migratory phenotype. Lineage tracing using NG2CreER TM ;Rosa tdTomato ;PDGFRα GFP mice showed that 5.7%±1.04 of PDGFRα+ fibroblasts and 10.49%±2.73 of infarct MFs were derived from NG2+ lineage. Pericyte-derived fibroblasts exhibited higher ECM gene synthesis, in comparison to fibroblasts from non-pericyte origin, while pericyte-derived mural cells showed accentuated inflammatory cytokine gene expression. Immunostaining showed pericytes actively contribute to vascular maturation, forming a mural cell coat enwrapping infarct neovessels. In vitro, TGFβ induced integrins, collagens and MMPs in human pericytes, similar to the changes observed in infarct pericytes. Taken together, our evidences show that after MI, pericytes become activated and contribute to repair by undergoing conversion to a subset of myofibroblasts and by coating infarct neovessels.

Epicardial Surface Area of Infarction

Background: Microvascular obstruction (MO) is a pathophysiologic complication of acute myocardial infarction that portends poor prognosis; however, it is transient and disappears with infarct healing. Much remains unknown regarding its pathophysiology and whether there are predictors of MO that could function as stable surrogates. We tested for clinical and cardiovascular magnetic resonance predictors of MO to gain insight into its pathophysiology and to find a stable surrogate. Methods: Three hundred two consecutive patients from 2 centers underwent cardiovascular magnetic resonance within 2 weeks of first acute myocardial infarction. Three measures of infarct morphology: infarct size, transmurality, and a new index—the epicardial surface area (EpiSA) of full-thickness infarction—were quantified on delayed-enhancement cardiovascular magnetic resonance. Results: Considering all clinical characteristics, only measures of infarct morphology were independent predictors of MO. EpiSA was the strongest predictor of MO and provided incremental predictive value beyond that of infarct size and transmurality ( P <0.0001). In patients with 3-month follow-up cardiovascular magnetic resonance (n=81), EpiSA extent remained stable while MO disappeared, and EpiSA was a predictor of adverse ventricular remodeling. After 20 months of follow-up, 11 died and 1 had heart transplantation. Patients with an EpiSA larger than the median value (≥6%) had worse outcome than those with less than the median value (adverse events: 6.4% versus 1.9%, P =0.045). Conclusions: The EpiSA of infarction is a novel index of infarct morphology which accurately predicts MO during the first 2 weeks of MI, but unlike MO, does not disappear with infarct healing. This index has potential as a stable surrogate of the presence of acute MO and may be useful as a predictor of adverse remodeling and outcome which is less dependent on the time window of patient assessment.

High sensitivity C-reactive protein is associated with worse infarct healing after revascularized ST-elevation myocardial infarction

Background The inflammatory response due to myocardial tissue injury in the setting of acute ST-elevation myocardial infarction (STEMI) is essential for proper local infarct healing. However, an excessive inflammatory response may aggravate myocardial damage and hampers infarct healing processes. The present study aimed to investigate the association of systemic inflammatory biomarkers with infarct size (IS) dynamics post-STEMI, using cardiac magnetic resonance (CMR) imaging. Methods This prospective observational study included 245 STEMI patients treated with primary percutaneous coronary intervention (pPCI). Peak values of high-sensitivity C-reactive protein (hs-CRP), white blood cell count (WBCc) and fibrinogen were determined serially until 96 hours after pPCI. Infarct healing, defined as relative IS reduction from baseline to 4 months after STEMI, was assessed using late gadolinium enhanced CMR imaging. Results IS significantly decreased from 16% of left ventricular mass (LVM) (Interquartile range [IQR]:8–24) at baseline to 10% (IQR:5–17) at 4 months (p&lt;0.001). Relative IS reduction was 35% (IQR:8–50). Whereas peak WBCc (p=0.926) and peak fibrinogen (p=0.161) were not significantly associated with relative IS reduction, peak hs-CRP showed a significant association with IS reduction (p=0.003). In multivariable logistic regression analysis, the association between peak hs-CRP and relative IS reduction remained significant after adjustment for baseline IS, hypertension, hs-cardiac troponin T and N-terminal pro B-type natriuretic peptide (odds ratio:0.35 [95% confidence interval:0.19–0.63]; p=0.001). Conclusions In STEMI patients treated with pPCI, hs-CRP was independently associated with 4 months IS reduction as determined by CMR, suggesting a pathophysiological interplay between inflammation and adverse infarct healing in survivors of acute STEMI. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Austrian Society of Cardiology

Model First and Ask Questions Later: Confessions of a Reformed Experimentalist

This paper is an invited perspective written in association with the awarding of the 2018 American Society of Mechanical Engineers Van C. Mow Medal. Inspired by Professor Mow's collaboration with Professor Michael Lai and the role mathematical modeling played in their work on cartilage biomechanics, this article uses our group's work on myocardial infarct healing as an example of the potential value of models in modern experimental biomechanics. Focusing more on the thought process and lessons learned from our studies on infarct mechanics than on the details of the science, this article argues that the complexity of current research questions and the wealth of information already available about almost any cell, tissue, or organ should change how we approach problems and design experiments. In particular, this paper proposes that constructing a mathematical or computational model is now in many cases a critical prerequisite to designing scientifically useful, informative experiments.

Pericytes in the infarcted heart

The adult mammalian heart lacks regenerative capacity and heals through activation of an inflammatory cascade that leads to the formation of a collagen-based scar. Although scar formation is important to preserve the structural integrity of the ventricle, unrestrained inflammation and excessive fibrosis have been implicated in the pathogenesis of adverse post-infarction remodeling and heart failure. Interstitial cells play a crucial role in the regulation of cardiac repair. Although recent studies have explored the role of fibroblasts and immune cells, the cardiac pericytes have been largely ignored by investigators interested in myocardial biology. This review manuscript discusses the role of pericytes in the regulation of inflammation, fibrosis and angiogenesis following myocardial infarction. During the inflammatory phase of infarct healing, pericytes may regulate microvascular permeability and may play an important role in leukocyte trafficking. Moreover, pericyte activation through Toll-like receptor-mediated pathways may stimulate cytokine and chemokine synthesis. During the proliferative phase, pericytes may be involved in angiogenesis and fibrosis. To what extent pericyte to fibroblast conversion and pericyte-mediated growth factor synthesis contribute to the myocardial fibrotic response remains unknown. During the maturation phase of infarct healing, coating of infarct neovessels with pericytes plays an important role in scar stabilization. Implementation of therapeutic approaches targeting pericytes in the infarcted and remodeling heart remains challenging, due to the lack of systematic characterization of myocardial pericytes, their phenotypic heterogeneity and the limited knowledge on their functional role.