Role of plasma extracellular vesicles in prediction of cardiovascular risk and alterations in response to statin therapy in hypertensive patients

Abstract

Background:Rapid and accurate new biomarkers to predict risk of cardiovascular disease (CVD) are essential. The utility of extracellular vesicles in predicting the CVD risk is postulated, yet it remains unknown whether their expression is altered in response to statin therapy.Methods:We performed in-vitro studies with human umbilical vein endothelial cells (HUVEC) and vascular smooth muscle cells (hVSMC), and conducted a nested case–control study (nCCS) in hypertensive patients (n = 40) randomized to either atorvastatin or placebo in the ASCOT-LLA. Cases had a major adverse cardiovascular event or death (MACE) during 3.5 years of follow-up (median) from the time of extracellular vesicle characterization while controls, matched for age and duration of treatment, remained event-free. Conditional logistic regression models determined the risk of MACE. Additionally, the relationship of extracellular vesicle levels with statin therapy was assessed.Results:Added to HUVEC, extracellular vesicles increased neutrophil recruitment, and to hVSMC, aggravated calcification and proliferation. In the nCCS, compared with controls, cases (i.e. with MACE) had preceding higher levels of CD14+ and CD14+/CD41+ extracellular vesicles (P = 0.009 and P = 0.012, respectively) and a significant reduction in the median size of the vesicles (P = 0.037). On matched analysis, higher CD14+ extracellular vesicles were associated with a 3.7-fold increased risk of MACE (P = 0.032). Patients treated with atorvastatin (vs. placebo) had both reduced size of extracellular vesicles and the proportion of CD146+ extracellular vesicles (P = 0.034 and P = 0.020, respectively).Conclusion and relevance:These pilot analyses suggest a mechanistic role for extracellular vesicles in the development of CVD, with significant and differential changes in extracellular vesicles amongst those at risk of MACE, and those on atorvastatin therapy.

Breakthrough of extracellular vesicles in pathogenesis, diagnosis and treatment of osteoarthritis

“…Although a number of EVs-based biomarkers have entered clinical trials, covering the fields of tumors [ 133 , 134 ], cardiovascular diseases [ 135 ], and even infectious diseases [ 136 ], there is no relevant research in the field of OA. EVs have been used in clinical studies to diagnose diseases [ 137 ], predict progression [ 133 ], and evaluate efficacy and prognosis [ 135 , 138 , 139 ]. These studies further demonstrate the potential of EVs as biomarkers.…”

Vascular calcification: from the perspective of crosstalk

“…With the occurrence of CVD, circulating EVs of platelets and endothelial cells, among other sources, are significantly higher than in normal persons [ 297 , 298 ]. Oggero et al [ 299 ] during 3.5 years of follow-up (median) showed that in a population at risk for major adverse cardiovascular event or death (MACE) and receiving atorvastatin therapy (compared with controls and placebo, respectively), the biology of plasma-derived EVs was significantly different in size, level, and surface characteristics. MACE patients had preceding higher levels of CD14 + and CD14 + /CD41 + EVs, and higher CD14 + extracellular vesicles were associated with a 3.7-fold increased risk of MACE on matched analysis [ 299 ].…”

“…Oggero et al [ 299 ] during 3.5 years of follow-up (median) showed that in a population at risk for major adverse cardiovascular event or death (MACE) and receiving atorvastatin therapy (compared with controls and placebo, respectively), the biology of plasma-derived EVs was significantly different in size, level, and surface characteristics. MACE patients had preceding higher levels of CD14 + and CD14 + /CD41 + EVs, and higher CD14 + extracellular vesicles were associated with a 3.7-fold increased risk of MACE on matched analysis [ 299 ]. Patients treated with atorvastatin had both reduced size of extracellular vesicles and the proportion of CD146 + extracellular vesicles [ 299 ].…”

“…MACE patients had preceding higher levels of CD14 + and CD14 + /CD41 + EVs, and higher CD14 + extracellular vesicles were associated with a 3.7-fold increased risk of MACE on matched analysis [ 299 ]. Patients treated with atorvastatin had both reduced size of extracellular vesicles and the proportion of CD146 + extracellular vesicles [ 299 ]. Kanhai et al [ 300 ] conducted a large prospective cohort study including 1060 patients with CVD and found that elevated levels of Cystatin C, Serpin F2 and CD14 in plasma-derived EVs were associated with an elevated risk of future vascular events and death in patients with clinically manifest vascular disease.…”

Head-to-Head Comparison of Tissue Factor-Dependent Procoagulant Potential of Small and Large Extracellular Vesicles in Healthy Subjects and in Patients with SARS-CoV-2 Infection

“…The amount of circulating EVs increases in thrombotic, inflammatory or infectious diseases, and their molecular content changes with disease progression, reflecting the activation state of the involved cells and/or compartment [ 1 ]. Therefore, circulating EVs have emerged as both surrogate biomarkers of disease prognosis and potential pharmacological targets due to them being paracrine carriers able to influence target cells [ 5 , 6 , 7 , 8 , 9 ].…”