RESUMO
Chronic systemic inflammation contributes to a substantially elevated risk of myocardial infarction in people living with HIV (PLWH). Endothelial cell dysfunction disrupts vascular homeostasis regulation, increasing the risk of vasoconstriction, inflammation, and thrombosis that contribute to cardiovascular disease. Our objective was to study the effects of plasma from PLWH on endothelial cell (EC) function, with the hypothesis that cytokines and chemokines are major drivers of EC activation. We first broadly phenotyped chemokine and cytokine receptor expression on arterial ECs, capillary ECs, venous ECs, and vascular smooth muscle cells (VSMCs) in adipose tissue in the subcutaneous adipose tissue of 59 PLWH using single cell transcriptomic analysis. We used CellChat to predict cell-cell interactions between ECs and other cells in the adipose tissue and Spearman correlation to measure the association between ECs and plasma cytokines. Finally, we cultured human arterial ECs (HAECs) in plasma-conditioned media from PLWH and performed bulk sequencing to study the direct effects ex-vivo. We observed that arterial and capillary ECs expressed higher interferon and tumor necrosis factor (TNF) receptors. Venous ECs had more interleukin (IL)-1R1 and ACKR1 receptors, and VSMCs had high significant IL-6R expression. CellChat predicted ligand-receptor interactions between adipose tissue immune cells as senders and capillary ECs as recipients in TNF-TNFRSF1A/B interactions. Chemokines expressed largely by capillary ECs were predicted to bind ACKR1 receptors on venous ECs. Beyond the adipose tissue, the proportion of venous ECs and VSMCs were positively plasma IL-6. In ex-vivo experiments, HAECs cultured with plasma-conditioned media from PLWH expressed transcripts that enriched for the TNF-α and reactive oxidative phosphorylation pathways. In conclusion, ECs demonstrate heterogeneity in cytokine and chemokine receptor expression. Further research is needed to fully elucidate the role of cytokines and chemokines in EC dysfunction and to develop effective therapeutic strategies.
RESUMO
OBJECTIVE: To determine the significance of transient ischemic dilatation (TID) in patients with normal perfusion on adenosine stress/rest. METHODS: We analyzed 430 consecutive patients with normal perfusion on 2-day adenosine stress/rest 99mTc-sestamibi. A group of 70 patients with Framingham 10-year coronary heart disease risk < 10% was used to derive abnormal TID thresholds (derivation group). The significance of TID at these thresholds was validated in the remaining 360 patients (validation group) followed for cardiac events for 31.2 ± 9.7 (mean ± SD) months. RESULTS: Transient ischemic dilatation in the derivation group was 1.05 ± 0.13. Three definitions of an abnormal TID were used: > mean + 2SD (TID ≥ 1.32), > mean + 1SD (TID ≥ 1.19) and a TID in the group's highest quartile (TID ≥ 1.15). Of the 360 validation group patients, 12 (3.3%), 48 (13.3%) and 70 (19.4%) had TID ≥ 1.32, 1.19 and 1.15, respectively. Age, gender, family history of coronary artery disease (CAD), known CAD, smoking, hypertension, diabetes, dyslipidemia, rest LVEF, post-stress LVEF, ΔLVEF, ≥ 5% or 10% decrease in LVEF did not predict TID ≥ 1.32. However, TID ≥ 1.19 was predicted by rest LVEF and ≥ 5% decrease in LVEF (P = 0.04 and 0.02, respectively) and TID ≥ 1.15 was predicted by ≥ 5% decrease in LVEF (P = 0.02). Cardiac event-free survivals were similar in patients with a TID ≥ and < 1.32 (P = 0.68), ≥ and < 1.19 (P = 0.40) and ≥ and < 1.15 (P = 0.79). CONCLUSIONS: Transient ischemic dilatation does not confer adverse prognosis in patients with normal perfusion on adenosine stress/rest 99mTc-sestamibi irrespective of the threshold used for its definition.