NETs-Induced Thrombosis Impacts on Cardiovascular and Chronic Kidney Disease.

Arterial and venous thrombosis constitute a major source of morbidity and mortality worldwide. Association between thrombotic complications and cardiovascular and other chronic inflammatory diseases are well described. Inflammation and subsequent initiation of thrombotic events, termed immunothrombosis, also receive growing attention but are still incompletely understood. Nevertheless, the clinical relevance of aberrant immunothrombosis, referred to as thromboinflammation, is evident by an increased risk of thrombosis and cardiovascular events in patients with inflammatory or infectious diseases. Proinflammatory mediators released from platelets, complement activation, and the formation of NETs (neutrophil extracellular traps) initiate and foster immunothrombosis. In this review, we highlight and discuss prominent and emerging interrelationships and functions between NETs and other mediators in immunothrombosis in cardiovascular disease. Also, with patients with chronic kidney disease suffering from increased cardiovascular and thrombotic risk, we summarize current knowledge on neutrophil phenotype, function, and NET formation in chronic kidney disease. In addition, we elaborate on therapeutic targeting of NETs-induced immunothrombosis. A better understanding of the functional relevance of antithrombotic mediators which do not increase bleeding risk may provide opportunities for successful therapeutic interventions to reduce thrombotic risk beyond current treatment options.

Sex-specific and hormone-related differences in vascular remodelling in atherosclerosis.

Atherosclerosis, a lipid-driven inflammatory disease, is the main underlying cause of cardiovascular diseases (CVDs) both in men and women. Sex-related dimorphisms regarding CVDs and atherosclerosis were observed since more than a decade ago. Inflammatory mediators such as cytokines, but also endothelial dysfunction, vascular smooth muscle cell migration and proliferation lead to vascular remodelling but are differentially affected by sex. Each year a greater number of men die of CVDs compared with women and are also affected by CVDs at an earlier age (40-70 years old) while women develop atherosclerosis-related complications mainly after menopause (60+ years). The exact biological reasons behind this discrepancy are still not well-understood. From the numerous animal studies on atherosclerosis, only a few include both sexes and even less investigate and highlight the sex-specific differences that may arise. Endogenous sex hormones such as testosterone and oestrogen modulate the atherosclerotic plaque composition and the frequency of such plaques. In men, testosterone seems to act like a double-edged sword as its decrease with ageing correlates with an increased risk of atherosclerotic CVDs, while testosterone is also reported to promote inflammatory immune cell recruitment into the atherosclerotic plaque. In premenopausal women, oestrogen exerts anti-atherosclerotic effects, which decline together with its level after menopause resulting in increased CVD risk in ageing women. However, the interplay of sex hormones, sex-specific immune responses and other sex-related factors is still incompletely understood. This review highlights reported sex differences in atherosclerotic vascular remodelling and the role of endogenous sex hormones in this process.

Criteria to predict midterm outcome after stenting of chronic iliac vein obstructions (PROMISE trial).

BACKGROUND: Endovenous stent placement has become a first-line approach to prevent post-thrombotic syndrome in patients with chronic post-thrombotic obstruction (PTO) or nonthrombotic iliac vein lesions if conservative management fails. This study aims to identify factors associated with loss of patency to facilitate patient selection for endovenous stenting. METHODS: We retrospectively analyzed 108 consecutive patients after successful endovenous stenting for chronic vein obstruction performed at a single institution from January 2008 to July 2020. Using multivariable logistic regression, we explored potential predictive factors for loss of stent patency, including baseline demographics, post-thrombotic changes, and peak flow velocities measured in the common femoral vein (CFV), deep femoral vein, and femoral vein (FV) using duplex ultrasound examination. RESULTS: The mean follow-up duration was 41 ± 26 months, and participants had a mean age of 47.4 ± 15.4 years with 46.3% women. Ninety (83.3%) patients had PTO and 18 (16.7%) had nonthrombotic iliac vein lesions, predominantly due to May-Thurner syndrome. Loss of patency occurred in 20 (18.5%) patients, all treated for PTO. Comorbidities, side of intervention, and sex did not differ between patients with occluded and patent stents. Stent occlusion was more common with increasing number of stents implanted (P < .001) and with distal stent extension into and beyond the CFV (P < .001). Preinterventional predictive factors for stent occlusion were lower duplex ultrasound peak velocity in the CFV (odds ratio [OR]: 7.52, 95% confidence interval [CI]: 2.54-22.28; P < .001) and FV (OR: 10.75, 95% CI: 2.07-55.82; P < .005), and post-thrombotic changes in the deep femoral vein (OR: 4.51, 95% CI: 1.53-13.25; P = .006) and FV (OR: 3.62: 95% CI: 1.11-11.84; P = .033). Peak velocities of ≤7 cm/s (interquartile range: 0-20 cm/s) in the CVF and ≤8 cm/s (interquartile range: 5-10 cm/s) in the FV were significantly associated with loss of patency. CONCLUSIONS: Insufficient venous inflow as assessed by low peak velocities in the CFV and FV as well as post-thrombotic findings represent reliable risk predictors for stent occlusions, warranting their inclusion into the decision-making process for invasive treatment of PTO.

Inflammatory Mediators in Atherosclerotic Vascular Remodeling.

Atherosclerotic vascular disease remains the most common cause of ischemia, myocardial infarction, and stroke. Vascular function is determined by structural and functional properties of the arterial vessel wall, which consists of three layers, namely the adventitia, media, and intima. Key cells in shaping the vascular wall architecture and warranting proper vessel function are vascular smooth muscle cells in the arterial media and endothelial cells lining the intima. Pathological alterations of this vessel wall architecture called vascular remodeling can lead to insufficient vascular function and subsequent ischemia and organ damage. One major pathomechanism driving this detrimental vascular remodeling is atherosclerosis, which is initiated by endothelial dysfunction allowing the accumulation of intimal lipids and leukocytes. Inflammatory mediators such as cytokines, chemokines, and modified lipids further drive vascular remodeling ultimately leading to thrombus formation and/or vessel occlusion which can cause major cardiovascular events. Although it is clear that vascular wall remodeling is an elementary mechanism of atherosclerotic vascular disease, the diverse underlying pathomechanisms and its consequences are still insufficiently understood.