Faculty Bibliography

Despite major advances in medical therapies and prevention strategies, the risk of cardiovascular complications in patients with both type I and type II diabetes remains substantially elevated. In 2019, the American Heart Association sought applications for a Strategically Focused Research Network on Cardiometabolic Health and Type 2 Diabetes. In 2020, 4 centers were named, including Brigham and Women's Hospital, Johns Hopkins University, New York University, and the University of Iowa. These centers performed basic, translational, and clinical studies to provide insights to explain the over 2-fold risk of cardiovascular complications in diabetes. Clinical studies and studies in cells and animals aimed to uncover new mechanisms responsible for disease development. Studies using human populations sought to uncover new biomarkers to prognosticate risk. In this review, we discuss several key issues and current and developing methods to understand why diabetes drives atherosclerotic cardiovascular disease and heart failure. Both human data and experimental models are considered. We integrate a review of these topics with work from the Strategically Focused Research Network and conclude with suggestions for identifying novel risk factors and future experimental research.

Insulin resistance impairs benefits of lipid-lowering treatment as evidenced by higher cardiovascular risk in individuals with type 2 diabetes versus those without. Because platelet activity is higher in insulin-resistant patients and promotes atherosclerosis progression, we questioned whether platelets impair inflammation resolution in plaques during lipid-lowering. In mice with obesity and insulin resistance, we induced advanced plaques, then implemented lipid-lowering to promote atherosclerotic plaque inflammation-resolution. Concurrently, mice were treated with either platelet-depleting or control antibodies for 3 weeks. Platelet activation and insulin resistance were unaffected by lipid-lowering. Both antibody-treated groups showed reduced plaque macrophages, but plaque cellular and structural composition differed. In platelet-depleted mice, scRNA seq revealed dampened inflammatory gene expression in plaque macrophages and an expansion of a subset of Fcgr4+ macrophages having features of inflammation-resolving, phagocytic cells. Necrotic core size was smaller and collagen content greater, resembling stable human plaques. Consistent with the mouse results, clinical data showed that patients with lower platelet counts had decreased pro-inflammatory signaling pathways in circulating non-classical monocytes after lipid-lowering. These findings highlight that platelets hinder inflammation-resolution in atherosclerosis during lipid-lowering treatment. Identifying novel platelet-targeted therapies following lipid-lowering treatment in individuals with insulin resistance may be a promising therapeutic approach to promote atherosclerotic plaque inflammation-resolution.

BACKGROUND:Patients with peripheral artery disease have an increased risk of cancer development. Aging-associated changes in hematopoietic stem and progenitor cells (HSPCs), including inflammation and increased myelopoiesis, are implicated in both cardiovascular disease and cancer, but their contributions to cardiovascular disease-driven tumor progression are unclear. OBJECTIVES/OBJECTIVE:This study sought to study tumor growth after peripheral ischemia and consequent changes within the HSPC bone marrow compartment to uncover mechanisms through which altered hematopoiesis promotes cancer. METHODS:Mammary cancer (E0771) growth was monitored in C57BL/6J mice after hind limb ischemia (HLI) or sham surgery. The tumor immune microenvironment, circulatory immune cells, and HSPC compartment were assessed by flow cytometry. Next-generation single-cell RNA and assay for transposase-accessible chromatin sequencing of bone marrow progenitors was performed to assess the distinct and synergistic transcriptomic and epigenetic changes of cancer and peripheral ischemia. The functional impact on tumor progression and persistence of ischemia-induced epigenetic reprogramming of HSPCs and their myeloid progeny was examined by bone marrow transplantation. RESULTS:myeloid-biased hematopoietic stem cells. This was associated with accelerated cancer growth and enrichment of tumors with myeloid cells (monocytes, macrophages, neutrophils) and regulatory T cells. Increased myelopoiesis was also supported by sequencing analyses showing HLI and tumor-induced transcriptional and epigenetic enrichment for inflammatory (NLRP3 inflammasome) and aging-associated neogenin-1, thrombospondin-1) signatures in subsets of monocyte/dendritic progenitors. HLI-accelerated tumor growth and myeloid-skewing was transmissible via bone marrow transplantation, indicating long-term reprogramming of innate immune responses. CONCLUSIONS:Peripheral ischemia enhances inflammaging of hematopoietic stem cells and long-lasting alterations to antitumoral immunity, accelerating breast tumor growth.

Coronary artery disease (CAD) is a major cause of global morbidity and mortality. Macrophages play a central role in orchestrating this disease process. In 2016, we initiated the STARNET primary blood macrophage study, followed by the multi-ethnic NGS-PREDICT primary blood macrophage study in 2018. We applied integrative systems genetics analysis to explore and validate the role of macrophage gene regulatory co-expression networks (GRNs) in clinically significant CAD. This study included 318 CAD cases and 134 CAD-free controls in STARNET, and 95 CAD cases and 35 CAD-free controls in NGS-PREDICT. Primary leukocytes were isolated from blood and differentiated into macrophages in vitro, followed by RNA extraction and deep sequencing (RNAseq). In STARNET, we analyzed differentially expressed genes, inferred macrophage GRNs, assessed the phenotypic associations and functions of these GRNs, and determined their key driver genes. Integrative analysis of STARNET expression quantitative traits (eQTLs) with genotype data from genome-wide association studies was performed to determine the content of CAD candidate genes in these GRNs, and their contributions to CAD heritability. Five independent RNAseq datasets were used to retrospectively validate CAD-associated macrophage GRNs, followed by prospective validation in the NGS-PREDICT study. Using the STARNET datasets, we identified 23 macrophage GRNs. Of these, GRN_GREEN stood out as being causally associated with CAD severity (SYNTAX score) and comprised 729 genes and 90 key drivers, with the top key driver being NEIL1. GRN_GREEN accounted for 3.73% of CAD heritability and contained 34 candidate genes previously identified by GWAS of CAD. Functional analysis of GRN_GREEN revealed a large portion of genes involved in the biological process of SRP-dependent co-translational protein targeting to the membrane. GRN_GREEN replicated retrospectively in five independent human arterial wall RNAseq datasets, and prospectively in the NGS-PREDICT study. To prevent clinically significant CAD, GRN_GREEN and its top key driver NEIL1 may be suitable therapeutic targets to modify SRP-dependent co-translational targeting of proteins to the endoplasmic reticulum in macrophages.

Cardiovascular diseases including atherosclerosis and heart failure, arise from the intricate interplay of metabolic, immune, and neural dysregulation within vascular and cardiac tissues: This review focuses on integrating recent advances in metabolic and immune crosstalk of the cardiac vasculature that affects cardiometabolic health and disease progression. Coronary and lymphatic endothelial cells regulate cardiac metabolism, and their dysfunction is linked to cardiovascular diseases. Lymphatics maintain tissue homeostasis, including clearing metabolic waste, lipids, and immune cells, and their maladaptation in metabolic diseases worsens outcomes. Altered vascular endothelial metabolism in heart failure drives immune-mediated inflammation, fibrosis, and adverse cardiac remodeling. Concurrently, artery tertiary lymphoid organs formed in the adventitia of advanced atherosclerotic arteries, serve as pivotal neuroimmune hubs, coordinating local immunity through T and B cell activation and neurovascular signaling via artery-brain circuits. T cells within plaques and artery tertiary lymphoid organs undergo clonal expansion as a result of peripheral tolerance breakdown, with proinflammatory CD4⁺ and CD8⁺ subsets amplifying atherosclerosis, effects further shaped by systemic immune activation. Therapeutic strategies targeting endothelial cell metabolism, lymphatic dysfunction, neuroimmune crosstalk, and T cell plasticity hold promise for integrated cardiovascular disease management.

BACKGROUND:New evidence has emerged that plastic polymers and their chemical additives, particularly di-2-ethylhexylphthalate (DEHP), contribute to cardiovascular disease (CVD). Phthalates are commonly used in the production of plastic materials and have been linked to increased oxidative stress, metabolic dysfunction, and cardiovascular disease. Estimates of phthalate-attributable cardiovascular mortality have been made for the US, but global estimates are needed to inform ongoing negotiations of a Global Plastics Treaty. METHODS:Cardiovascular mortality data from the Institute for Health Metrics and Evaluation (IHME) and regional DEHP exposure estimates from several sources were used to estimate burden. Hazard ratios of CV mortality were calculated using published exposure estimates, and country-level cardiovascular mortality rates were used to calculate excess deaths and years of life lost (YLL) due to DEHP exposure. FINDINGS/RESULTS:In 2018, an estimated 356,238 deaths globally were attributed to DEHP exposure, representing 13.497% of all cardiovascular deaths among individuals aged 55-64. Of these, 349,113 were attributed to the use of plastics. Geographic disparities were evident, with South Asia and the Middle East suffering the greatest percentage of cardiovascular deaths attributable to DEHP exposure (16.807%). The Middle East, South Asia, East Asia, and the Pacific accounted for the largest shares of DEHP-attributable CVD deaths (73.163%). Globally, DEHP resulted in 10.473 million YLL. INTERPRETATION/CONCLUSIONS:Plastics pose a significant risk to increased cardiovascular mortality, disproportionately impacting regions which have developing plastic production sectors. The findings underscore the need for urgent global and local regulatory interventions to kerb mortality from DEHP exposure. FUNDING/BACKGROUND:Bloomberg Philanthropies and the National Institutes of Health.

Despite the development of potent drugs for modifiable risk factors and advances in mechanistic biomedical research, cardiovascular diseases (CVDs) collectively remain the leading cause of death globally, indicating a need for new, more effective therapies. A foundational challenge is the multilevel heterogeneity that characterizes CVDs-from their complex pathobiological mechanisms at the molecular and cellular levels, to their clinical presentations and therapeutic responses at the individual and population levels. This variability arises from individuals' unique genomic and exposomic characteristics, underscoring the need for precision approaches. Other key challenges include the long navigation times, high costs, and low success rates for drug development, often compounded by the poor "druggability" of new targets. In this article, we explore how these challenges have inspired novel technologies that offer promise in improving health outcomes globally through an integrative precision medicine approach. Key to this transformation is the use of systems biology and network medicine, whereby the application of artificial intelligence to "big data", ranging from clinical information to unbiased multiomics (e.g., genomics, transcriptomics, proteomics, and metabolomics) can elucidate disease mechanisms, yield novel biomarkers for disease progression, and identify potential drug targets. In parallel, new computational approaches are helping translate these discoveries into novel therapies and overcome druggability barriers. The transition to a precision-based research and innovation paradigm in cardiovascular medicine will require greater interdisciplinary collaboration, data science implementation at every stage, and new partnerships between academia and industry. Global policy leadership is also essential to implement suitable models of research funding and organization, data infrastructures and policies, medicines regulations, and patient access policies promoting equity.

Immune checkpoint inhibitor (ICI) therapies can increase the risk of cardiovascular events in survivors of cancer by worsening atherosclerosis. Here we map the expression of immune checkpoints (ICs) within human carotid and coronary atherosclerotic plaques, revealing a network of immune cell interactions that ICI treatments can unintentionally target in arteries. We identify a population of mature, regulatory CCR7⁺FSCN1⁺ dendritic cells, similar to those described in tumors, as a hub of IC-mediated signaling within plaques. Additionally, we show that type 2 diabetes and lipid-lowering therapies alter immune cell interactions through PD-1, CTLA4, LAG3 and other IC targets in clinical development, impacting plaque inflammation. This comprehensive map of the IC interactome in healthy and cardiometabolic disease states provides a framework for understanding the potential adverse and beneficial impacts of approved and investigational ICIs on atherosclerosis, setting the stage for designing ICI strategies that minimize cardiovascular disease risk in cancer survivors.