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.

BACKGROUND:Coronary artery calcium (CAC) scoring is strongly associated with cardiovascular (CV) events among the general population; however, its prognostic value among individuals with immune-mediated inflammatory diseases (IMIDs) is not well characterized. OBJECTIVES/OBJECTIVE:This study aims to assess the prevalence of CAC derived from routine chest computed tomography (CT) using a validated artificial intelligence (AI) algorithm and its association with adverse CV events among those with IMIDs. METHODS:The authors studied a retrospective cohort of all patients 40 to 70 years of age with a diagnosis of systemic lupus erythematosus, rheumatoid arthritis, or psoriatic disease, and no prior atherosclerotic cardiovascular disease who underwent chest CT at 2 medical centers in Boston, Massachusetts, USA, from 2000 to 2023 as part of routine care. The presence and severity of CAC was determined using a validated AI methodology. Cox proportional hazards modeling was used to assess the association of CAC-AI categories (CAC-AI = 0, CAC-AI = 1-99, and CAC-AI ≥100) with all-cause mortality and major adverse cardiovascular events (MACE) (nonfatal myocardial infarction, coronary revascularization, nonfatal stroke, or CV mortality). All models were adjusted for age, sex, and traditional CV risk factors. RESULTS:In total, 2,546 individuals with IMIDs (median age 59 years [Q1-Q3: 53-65 years]; 1,694 [66.5%] women) were included with a median follow-up of 8.1 years. Among this cohort, 53% had CAC-AI >0 while only 6.0% were on a statin. A low burden of CAC (CAC-AI = 1-99) was associated with an increased risk of all-cause mortality (adjusted HR: 1.41; P = 0.010) and MACE (adjusted HR: 2.05; P < 0.001) with even greater risk observed among individuals with CAC-AI ≥100 (adjusted HR: 2.45; P < 0.001) and MACE (adjusted HR: 3.24; P < 0.001). CONCLUSIONS:Among those with IMIDs, incidental CAC-AI was highly prevalent and significantly associated with both all-cause mortality and MACE. These findings suggest that CAC-AI may provide important prognostic information, allowing for improved risk stratification and treatment within an already high-risk and undertreated population.

BACKGROUNDPlatelets are increasingly recognized as active participants in immune signaling and systemic inflammation. Upon activation, platelets form monocyte platelet aggregates (MPA) representing the crossroads of thrombosis and inflammation. We hypothesized that platelet transcriptomics could capture this thromboinflammatory axis and identify individuals at elevated cardiovascular risk.METHODS: MPA levels, defined as CD14+CD61+ cells, were measured using flow cytometry at 2 time points, 4 weeks apart, in healthy individualsPlatelets were isolated and sequenced. Individuals were categorized as MPAhi or MPAlo based on consistently high or low MPA levels across time points.RESULTSAmong 149 participants (median age 52 years, 57% female, 50% non-White), MPAhi individuals exhibited increased expression of platelet activation markers P-selectin (P < 0.001), PAC-1 (P = 0.021), and CD40L (P < 0.001) and enriched immune signaling pathways. Informed by MPA levels and derived from the platelet transcriptome, we developed a 42-gene thromboinflammation platelet signature (TIPS), which correlated with MPA levels in multiple cohorts and was reproducible over time. TIPS was elevated in patients with COVID-19 (P = 0.0002) and myocardial infarction (Padj = 0.008), and as in predicted future cardiovascular events in patients who underwent lower extremity revascularization after a median follow-up of 18 months (adjusted for age, sex, race, and ethnicity [adjHR] 1.55, P = 0.006). Notably, TIPS was modifiable by ticagrelor (P = 0.002) but not aspirin.CONCLUSIONThese findings establish MPA as a biomarker of thromboinflammation and introduce TIPS, a platelet RNA signature, that captures thromboinflammation and provides a promising tool for cardiovascular risk stratification and a potential therapeutic target.TRIAL REGISTRATIONNCT04369664FUNDINGNIH R35HL144993, NIH R01HL139909, and AHA 16SFRN2873002 to JSB, DFG Walter-Benjamin-Programme 537070747 to AB.

There is a growing body of evidence supporting the safety and utility of interleukin-1 inhibitors for treatment of recurrent pericarditis. This therapy has not been investigated specifically as related to postpericardiotomy syndrome or after thoracic organ transplantation. We report on rilonacept use for treatment of recurrent pericarditis in 4 patients after lung or heart transplantation, describing the clinical presentation, infectious complications, and outcomes of these cases. Our single-center experience of this highly comorbid patient population highlights the major considerations of interleukin-1 inhibitor use within these patients, particularly as related to infectious complications and immunosuppression management.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with an increased risk of vascular dysfunction and cardiovascular disease. We validate our previously developed Systemic Lupus Erythematosus Activity Platelet-Gene Expression Signature (SLAP-GES) score and investigate its relationship with platelet activity and vascular health. SLAP-GES was associated with the SLE Disease Activity Index (Padj < 0.001) and consistent over time (r = 0.76; P = 9 × 10^-5). Moreover, SLAP-GES was associated increased platelet aggregation in response to submaximal epinephrine (P = 0.084), leukocyte platelet aggregates (P = 0.014), and neutrophil platelet aggregates (P = 0.043). SLAP-GES was also associated with impaired glycocalyx (P = 0.011) and brachial artery flow-mediated dilation (P = 0.045). Altogether, SLAP-GES is associated with SLE disease activity, platelet activity, and impaired vascular health.