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Background: Lower CD4 + cell count in people with HIV infection (PWH) is associated with increased cardiovascular disease (CVD) risk. Whether subsets of CD4 + T helper cells are linked with CVD is unclear., Objectives: The aim of this study was to explore the association between peripherally circulating CD4 + T cell subsets and incident CVD., Methods: Data from 1,860 participants (1,270 PWH) without prevalent CVD from the VACS (Veterans Aging Cohort Study), a prospective, observational cohort of veterans with and without HIV infection, were analyzed. T cell subsets were quantified in baseline samples using flow cytometry. Incident CVD events were identified using International Classification of Diseases-9th Revision and International Classification of Diseases-10th Revision diagnosis and procedure codes. Participants were followed from baseline date (2005-2006) to the first of CVD incidence, death, or September 30, 2016. Cox proportional hazards regression was used to model associations between these T cell subsets and the risk for incident CVD while adjusting for demographics and other CVD risk factors., Results: The median participant age at baseline was 51.6 years. Most were male (94%) and of Black race (69.1%). There were 344 incident CVD events (219 in PWH) during follow-up (median 9.8 years). In PWH, higher proportions (per SD increment) of T helper type 17 cells (adjusted HR: 1.19; 95% CI: 1.08-1.31), T effector memory cells re-expressing CD45RA (adjusted HR: 1.19; 95% CI: 1.07-1.34), and CD28 null cells (adjusted HR: 1.18; 95% CI: 1.03-1.34) were significantly associated with an increased risk for incident CVD. Among those without HIV infection, no T cell subsets were significantly associated with CVD., Conclusions: Among PWH, T helper type 17 cells, senescent cells, and CD4 + T effector memory cells re-expressing CD45RA were significantly associated with incident CVD that was not explained by CVD risk factors., Competing Interests: Funding Support and Author Disclosures This material is based upon work supported by the VA, the Veterans Health Administration, and the Office of Research and Development, National Institute on Alcohol Abuse and Alcoholism (grants U24-AA020794, U01-AA020790, U24-AA022001, and U10 AA013566), and grant R01HL125032. Dr So-Armah’s work on this project was supported by National Institutes of Health grants K01HL134147, R61DA047032, and P30AI042853. The funders had no role in the study design or the collection, analyses, and interpretation of data. The views expressed in this paper are those of the authors and do not necessarily reflect the position or policy of the VA. Dr Beckman is a consultant for AstraZeneca, Bristol Myers Squibb, Amgen, Merck, Sanofi, Antidote Pharmaceutical, and Boehringer Ingelheim; and serves on data and safety monitoring committees for Bayer and Novartis. Dr McDonnell is an employee and shareholder of 10x Genomics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Plasma levels of the fibrinogen degradation product D-dimer are higher among African Americans (AAs) compared with those of European ancestry and higher among women compared with men. Among AAs, little is known of the genetic architecture of D-dimer or the relationship of D-dimer to incident cardiovascular disease., Approach and Results: We measured baseline D-dimer in 4163 AAs aged 21 to 93 years from the prospective JHS (Jackson Heart Study) cohort and assessed association with incident cardiovascular disease events. In participants with whole genome sequencing data (n=2980), we evaluated common and rare genetic variants for association with D-dimer. Each standard deviation higher baseline D-dimer was associated with a 20% to 30% increased hazard for incident coronary heart disease, stroke, and all-cause mortality. Genetic variation near F3 was associated with higher D-dimer (rs2022030, β=0.284, P =3.24×10 -11 ). The rs2022030 effect size was nearly 3× larger among women (β=0.373, P =9.06×10 -13 ) than among men (β=0.135, P =0.06; P interaction =0.009). The sex by rs2022030 interaction was replicated in an independent sample of 10 808 multiethnic men and women ( P interaction =0.001). Finally, the African ancestral sickle cell variant ( HBB rs334) was significantly associated with higher D-dimer in JHS (β=0.507, P =1.41×10 -14 ), and this association was successfully replicated in 1933 AAs ( P =2.3×10 -5 )., Conclusions: These results highlight D-dimer as an important predictor of cardiovascular disease risk in AAs and suggest that sex-specific and African ancestral genetic effects of the F3 and HBB loci contribute to the higher levels of D-dimer among women and AAs., (© 2017 American Heart Association, Inc.)

Atherosclerosis is a chronic inflammatory disease characterized by T lymphocyte infiltration into the atherosclerotic plaque. Assessments of T cell subtypes have demonstrated a predominance of CD4(+) T helper (Th) cells, implicated Th1 and Th17 immunity in both human and mouse atherogenesis, and provided some evidence suggesting protective roles of Th2 and T regulatory cells. Observations that certain inbred mouse strains have an inherent T helper bias suggest a genetic predisposition toward developing a particular T helper phenotype. This review summarizes our current understanding of mechanisms of antigen processing for major histocompatibility complex molecules, describes the different T helper cell subsets and their roles in atherosclerosis, and discusses mechanisms of genetic predisposition toward Th1/Th2 bias in mice. We also present data from our laboratory demonstrating inherent Th1/Th2 phenotypes in apparently healthy human volunteers that are stable over time and discuss the potential implications for cardiovascular disease.