Extracellular vesicle Cystatin C and CD14 are associated with both renal dysfunction and heart failure.

AIMS: Extracellular vesicles (EVs) are small double-membrane plasma vesicles that play key roles in cellular crosstalk and mechanisms such as inflammation. The role of EVs in combined organ failure such as cardiorenal syndrome has not been investigated. The aim of this study is to identify EV proteins that are associated with renal dysfunction, heart failure, and their combination in dyspnoeic patients. METHODS AND RESULTS: Blood samples were prospectively collected in 404 patients presenting with breathlessness at the emergency department at National University Hospital, Singapore. Renal dysfunction was defined as estimated glomerular filtration rate < 60 mL/min/1.73 m2 . The presence of heart failure was independently adjudicated by two clinicians on the basis of the criteria of the European Society of Cardiology guidelines. Protein levels of SerpinG1, SerpinF2, Cystatin C, and CD14 were measured with a quantitative immune assay within three EV sub-fractions and in plasma and were tested for their associations with renal dysfunction, heart failure, and the concurrence of both conditions using multinomial regression analysis, thereby correcting for confounders such as age, gender, ethnicity, and co-morbidities. Renal dysfunction was found in 92 patients (23%), while heart failure was present in 141 (35%). In total, 58 patients (14%) were diagnosed with both renal dysfunction and heart failure. Regression analysis showed that Cystatin C was associated with renal dysfunction, heart failure, and their combination in all three EV sub-fractions and in plasma. CD14 was associated with both renal dysfunction and the combined renal dysfunction and heart failure in all EV sub-fractions, and with presence of heart failure in the high density lipoprotein sub-fraction. SerpinG1 and SerpinF2 were associated with heart failure in, respectively, two and one out of three EV sub-fractions and in plasma, but not with renal dysfunction. CONCLUSIONS: We provide the first data showing that Cystatin C and CD14 in circulating EVs are associated with both renal dysfunction and heart failure in patients presenting with acute dyspnoea. This suggests that EV proteins may be involved in the combined organ failure of the cardiorenal syndrome and may represent possible targets for prevention or treatment.

Causes and prevention of postoperative myocardial injury.

Over the past few years non-cardiac surgery has been recognised as a serious circulatory stress test which may trigger cardiovascular events such as myocardial infarction, in particular in patients at high risk. Detection of these postoperative cardiovascular events is difficult as clinical symptoms often go unnoticed. To improve detection, guidelines advise to perform routine postoperative assessment of cardiac troponin. Troponin elevation - or postoperative myocardial injury - can be caused by myocardial infarction. However, also non-coronary causes, such as cardiac arrhythmias, sepsis and pulmonary embolism, may play a role in a considerable number of patients with postoperative myocardial injury. It is crucial to acquire more knowledge about the underlying mechanisms of postoperative myocardial injury because effective prevention and treatment options are lacking. Preoperative administration of beta-blockers, aspirin, statins, clonidine, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and preoperative revascularisation have all been investigated as preventive options. Of these, only statins should be considered as the initiation or reload of statins may reduce the risk of postoperative myocardial injury. There is also not enough evidence for intraoperative measures such blood pressure optimisation or intensified medical therapy once patients have developed postoperative myocardial injury. Given the impact, better preoperative identification of patients at risk of postoperative myocardial injury, for example using preoperatively measured biomarkers, would be helpful to improve cardiac optimisation.

LDL extracellular vesicle coagulation protein levels change after initiation of statin therapy. Findings from the METEOR trial.

BACKGROUND: Statins are thought to have pleiotropic properties, including anticoagulant effects, in addition to reducing lipoprotein (LDL) levels. Plasma extracellular vesicles (EVs) are small bilayer membrane vesicles involved in various biological processes including coagulation. Since subsets of EVs in the LDL plasma fraction (LDL-EVs) correlate with thrombin activity, we hypothesized that changes in LDL-EVs after statin therapy may differ from that of serum levels of coagulation proteins, providing insight into the effects of statins on coagulation. METHODS: The study was conducted in 666 subjects with available serum from the METEOR trial, a trial of the effect of rosuvastatin versus placebo in patients with subclinical atherosclerosis. Changes in protein levels of von Willebrand Factor (VWF), SerpinC1 and plasminogen were measured in serum and in LDL-EVs, and were compared between the rosuvastatin and placebo groups. RESULTS: LDL-EV levels of plasminogen and VWF increased with rosuvastatin treatment compared to placebo (mean change of 126 ±â€¯8 versus 17 ±â€¯12 µg/mL for plasminogen (p < 0.001) and 310 ±â€¯60 versus 64 ±â€¯55 µg/mL for VWF (p = 0.015)). There was no difference between groups for change in LDL-EV-SerpinC1. In contrast, serum plasminogen levels increased to a lesser extent with rosuvastatin compared to placebo (23 ±â€¯29 versus 67 ±â€¯17 µg/mL, p = 0.024) and serum VWF levels showed no significant difference between both groups. CONCLUSIONS: Rosuvastatin increases LDL-EV coagulation proteins plasminogen and VWF in patients with subclinical atherosclerosis, an effect that is different from the effect of rosuvastatin on the same proteins in serum. This identifies LDL-EVs as a newly detected possible intermediate between statin therapy and coagulation.