Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:Cardiovascular disease (CVD) is a leading cause of preventable morbidity and mortality globally, and retinal imaging modalities (old and new) are being explored as noninvasive tools to predict latent atherosclerosis and cardiovascular disease. This review focuses on the emerging promise of fundoscopy, optical coherence tomography (OCT), and optical coherence tomography angiography (OCTA) in CVD prognostication. RECENT FINDINGS/RESULTS:High-quality studies have established the utility of vessel-based parameters and discrete conditions diagnosable via fundoscopy in subclinical atherosclerosis detection or CVD prediction. Recent research shows OCT measurements of different retinal layers and specific imaging findings (such as retinal ischemic perivascular lesions) are widely accessible and objective biomarkers for incipient CVD and ensuing risk. Myriad OCTA metrics appear to reliably inform on current CVD burden and cardiovascular risk. Fundoscopy, OCT, and OCTA all have a growing body of literature supporting their utility as adjuncts in CVD prediction and risk stratification.

Androgen deprivation therapy (ADT), a key element of prostate cancer treatment, is associated with increased risk for cardiovascular morbidity and mortality. The underlying mechanisms include adverse metabolic alterations, but further mechanisms are likely. Animal studies suggest increased progression of atherosclerosis in androgen deprived conditions. Based on in vitro studies, lack of androgens may modulate immune cells including monocytes, macrophages, and T-cells towards a pro-inflammatory phenotype and pro-atherogenic function. As a novel aspect, this review summarizes existing data on the effect of androgens and androgen deprivation on platelet activity, which play a major role in inflammation and in the initiation and progression of atherosclerotic lesions. Testosterone modulates platelet aggregation responses which are affected by dose level, source of androgen, and age. Data on the effects of ADT on platelet activity and aggregation are limited and conflicting, as both increased and decreased aggregation responses during ADT have been reported. Gaps in knowledge about the mechanisms leading to increased cardiovascular risk during ADT remain and further research is warranted. Improved understanding of pathogenic pathways linking ADT to cardiovascular risk may help identify clinically useful diagnostic and prognostic biomarkers, and accelerate finding novel therapeutic targets, and thus optimize prostate cancer treatment outcomes.

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.

The authors investigated the impact of antiplatelet therapy on the megakaryocyte (MK) and platelet transcriptome. RNA-sequencing was performed on MKs treated with aspirin or P2Y₁₂ inhibitor, platelets from healthy volunteers receiving aspirin or P2Y₁₂ inhibition, and platelets from patients with systemic lupus erythematosus (SLE). P2Y₁₂ inhibition reduced gene expression and inflammatory pathways in MKs and platelets. In SLE, the interferon (IFN) pathway was elevated. In vitro experiments demonstrated the role of P2Y₁₂ inhibition in reducing IFNα-induced platelet-leukocyte interactions and IFN signaling pathways. These results suggest that P2Y₁₂ inhibition may have therapeutic potential for proinflammatory and autoimmune conditions like SLE.

BACKGROUND/UNASSIGNED:Clinical trials suggest that therapeutic-dose heparin may prevent critical illness and vascular complications due to COVID-19, but knowledge gaps exist regarding the efficacy of therapeutic heparin including its comparative effect relative to intermediate-dose anticoagulation. OBJECTIVES/UNASSIGNED:The authors performed 2 complementary secondary analyses of a completed randomized clinical trial: 1) a prespecified per-protocol analysis; and 2) an exploratory dose-based analysis to compare the effect of therapeutic-dose heparin with low- and intermediate-dose heparin. METHODS/UNASSIGNED:Patients who received initial anticoagulation dosed consistently with randomization were included. The primary outcome was organ support-free days (OSFDs), a combination of in-hospital death and days free of organ support through day 21. RESULTS/UNASSIGNED:Among 2,860 participants, 1,761 (92.8%) noncritically ill and 857 (89.1%) critically ill patients were treated per-protocol. Among noncritically ill per-protocol patients, the posterior probability that therapeutic-dose heparin improved OSFDs as compared with usual care was 99.3% (median adjusted OR: 1.36; 95% credible interval [CrI]: 1.07-1.74). Therapeutic heparin had a high posterior probability of efficacy relative to both low- (94.6%; adjusted OR: 1.26; 95% CrI: 0.95-1.64) and intermediate- (99.8%; adjusted OR: 1.80; 95% CrI: 1.22-2.62) dose thromboprophylaxis. Among critically ill per-protocol patients, the posterior probability that therapeutic heparin improved outcomes was low. CONCLUSIONS/UNASSIGNED:Among noncritically ill patients hospitalized for COVID-19 who were randomized to and initially received therapeutic-dose anticoagulation, heparin, compared with usual care, was associated with improved OSFDs, a combination of in-hospital death and days free of organ support. Therapeutic heparin appeared superior to both low- and intermediate-dose thromboprophylaxis.

BACKGROUND:(p-tau), as well as the trajectories of these CSF measures obtained longitudinally. RESULTS:A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β = -12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ + (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. CONCLUSIONS:We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.

BACKGROUND/UNASSIGNED:(p-tau), as well as the trajectories of these CSF measures obtained longitudinally. RESULTS/UNASSIGNED:A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β=-12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ+ (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. CONCLUSIONS/UNASSIGNED:in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.

BACKGROUND AND AIMS/OBJECTIVE:The aim of this study was to determine the prognostic value of coronary computed tomography angiography (CCTA)-derived atherosclerotic plaque analysis in ISCHEMIA. METHODS:Atherosclerosis imaging quantitative computed tomography (AI-QCT) was performed on all available baseline CCTAs to quantify plaque volume, composition, and distribution. Multivariable Cox regression was used to examine the association between baseline risk factors (age, sex, smoking, diabetes, hypertension, ejection fraction, prior coronary disease, estimated glomerular filtration rate, and statin use), number of diseased vessels, atherosclerotic plaque characteristics determined by AI-QCT, and a composite primary outcome of cardiovascular death or myocardial infarction over a median follow-up of 3.3 (interquartile range 2.2-4.4) years. The predictive value of plaque quantification over risk factors was compared in an area under the curve (AUC) analysis. RESULTS:Analysable CCTA data were available from 3711 participants (mean age 64 years, 21% female, 79% multivessel coronary artery disease). Amongst the AI-QCT variables, total plaque volume was most strongly associated with the primary outcome (adjusted hazard ratio 1.56, 95% confidence interval 1.25-1.97 per interquartile range increase [559 mm3]; P = .001). The addition of AI-QCT plaque quantification and characterization to baseline risk factors improved the model's predictive value for the primary outcome at 6 months (AUC 0.688 vs. 0.637; P = .006), at 2 years (AUC 0.660 vs. 0.617; P = .003), and at 4 years of follow-up (AUC 0.654 vs. 0.608; P = .002). The findings were similar for the other reported outcomes. CONCLUSIONS:In ISCHEMIA, total plaque volume was associated with cardiovascular death or myocardial infarction. In this highly diseased, high-risk population, enhanced assessment of atherosclerotic burden using AI-QCT-derived measures of plaque volume and composition modestly improved event prediction.