Urinary vanin-1 as a novel biomarker for survival in peripheral artery disease.

BACKGROUND: Chronic kidney disease is associated with increased rates of incidence, morbidity, and mortality in lower-extremity peripheral artery disease (PAD). No specific marker for a functional risk assessment of kidney disease in PAD is known, especially at the early stages. Thus, we speculated that urinary vanin-1 (uVNN1), a marker of oxidative stress even in early kidney injury, could further stratify outcome assessment in patients with PAD. METHODS: Patients with stable PAD (n = 304) of the Vienna medical cohort were followed up for up to 10 years and the outcome was assessed by central death database queries. uVNN1 was measured by enzyme-linked immunosorbent assay (ELISA) at study inclusion and normalized to urinary creatinine (uVNN1/Cr). During the observation time (9.3, 7.0-9.8 years), 104 patients died, 54.8% of which were due to cardiovascular causes. RESULTS: uVNN1/Cr was associated with a urine albumin-creatinine ratio (UACR) (R = 0.166, p = 0.004) but not with an estimated glomerular filtration rate (R = 0.102, p = 0.077). Levels of uVNN1/Cr did not differ between asymptomatic and symptomatic PAD (p = 0.406). Kaplan-Meier curves showed a clear-cut association with higher all-cause (log-rank p = 0.034) and cardiovascular mortality (log-rank p = 0.032) with higher uVNN1/Cr levels. Similarly, significant associations for all-cause (hazard ratio [HR] 1.34, 95% CI [1.08-1.67], p = 0.009) and cardiovascular mortality (HR 1.45, 95% CI [1.06-1.99], p = 0.020) could be seen in multivariable Cox regression models. CONCLUSIONS: uVNN1/Cr showed an independent association with both all-cause and cardiovascular mortality in patients with PAD and was associated with early kidney disease. Thus, uVNN1 could be a useful marker for risk stratification of kidney disease in PAD.

Serum Trefoil Factor-3 Predicts Survival in Peripheral Artery Disease.

Trefoil factor 3 (TFF3) has been studied in processes leading to atherosclerosis. Data are scarce in manifest disease and missing in peripheral artery disease (PAD). This study aims to elucidate TFF3 with disease stages, degrees of atherosclerosis, and outcomes. TFF3 was measured in serum in 364 PAD patients without critical limb ischemia and mild to moderate chronic kidney disease (CKD). Mortality data were retrieved from the Austrian central death registry (median observation 9.6 years). Survival analyses were performed using Cox regression and the Kaplan-Meier method. A negative association between ankle-brachial index and TFF3 (P < .001) was observed, while levels were similar in asymptomatic and symptomatic PAD. TFF3 increased with history of cardiovascular and cerebrovascular disease (P < .001). TTF3 was associated with the estimated glomerular filtration rate (R = -0.617, P < .001) and urinary albumin-creatinine ratio (R = 0.229, P < .001). One SD increase in TFF3 showed a worsening in all-cause mortality (hazard ratio 1.68, CI 1.37-2.05) which persisted after multiple adjustment for cardiovascular risk, inflammatory, and angiogenetic markers (hazard ratio 1.35, CI 1.01-1.81). This study is the first to link TFF3 with both disease markers and outcomes in PAD. TFF3 demonstrated associations with renal function, PAD severity measured by ankle-brachial index, and additional atherosclerotic burden in PAD.

Capillaroscopic differences between primary Raynaud phenomenon and healthy controls indicate potential microangiopathic involvement in benign vasospasms.

BACKGROUND: For primary Raynaud phenomenon (PRP), an otherwise unexplained vasospastic disposition is assumed. To test the hypothesis of an additional involvement of distinct ultrastructural microvascular alterations, we compared the nailfold capillary pattern of patients with PRP and healthy controls. METHODS: A total of 120 patients with PRP (with a median duration of vasospastic symptoms of 60 [IQR: 3-120] months) were compared against 125 controls. In both groups, nailfold capillaroscopy was performed to record the presence of dilatations, capillary edema, tortuous capillaries, ramifications, hemorrhages, and reduced capillary density and to determine a semiquantitative rating score. Further, the capacity of finger skin rewarming was investigated by performing infrared thermography in combination with cold provocation. RESULTS: Unspecific morphologic alterations were found in both, PRP, such as controls, whereby the risk for PRP was four times as high in the presence of capillary dilations (CI: 2.3-7.6) and five times as high if capillary density was reduced (CI: 1.9-13.5). Capillary density correlated with thermoregulatory capacity in both hands in the PRP group, but not in controls. In addition, a negative correlation between the microangiopathy score and the percentage degree of rewarming in both hands was found for patients with PRP only. CONCLUSION: We found specific differences within the microvascular architecture between patients with PRP and controls. As a conclusion, PRP may not be an entirely benign vasospastic phenomenon, but might be associated with subtle microcirculatory vasculopathy. In addition, we suggest that the implementation of a scoring system might serve as guidance in the diagnostic process at least of patients with long-standing PRP.

Rescue From Permanent Kidney Injury in Acute Thrombosis of Both Renal Veins, the Inferior Vena Cava, and Both Iliofemoral Veins by Catheter-Based Thrombectomy.

CASE: A 33-year-old man with previously diagnosed lupus membranous nephropathy presented with painful swelling in both legs. Laboratory tests revealed acute kidney injury, and imaging studies by duplex ultrasound and computed tomography scan showed acute thrombosis of both renal veins, the infrahepatic inferior vena cava, and both iliofemoral venous segments. Initially, pharmacomechanical thrombolysis led to an insufficient morphological result. The therapeutic breakthrough was achieved by catheter-based mechanical thrombectomy of the infrarenal vena cava and both renal veins, which successfully cleared all affected venous segments from thrombus, paralleled by improvement of the patient's condition. However, after 1 week, the patient experienced recurrent thrombosis of the right renal vein with hemorrhagic infarction of the right kidney. After further optimization of immunomodulatory and antithrombotic therapy, a repeated catheter-based mechanical thrombectomy resulted in sustained clinical improvement and preservation of renal venous drainage and kidney function. CONCLUSION: Extensive acute thrombosis of both renal veins, the inferior vena cava, and both iliofemoral venous segments is a rare emergency potentially threatening kidney function. Immediate effective thrombus removal is essential to preserve kidney function and can be achieved by catheter-based mechanical thrombectomy embedded in a comprehensive immunomodulatory and antithrombotic therapeutic concept. CLINICAL IMPACT: This case demonstrated the efficacy of a catheter-based therapeutic approach in patients with extensive thrombosis of the venous system. A catheter-based approach must be embedded in a comprehensive medical therapeutic concept, which is essential to achieve a sustainable result.

Impact of thrombosis location on walking capacity: a cohort study of patients with acute deep vein thrombosis.

Background: Data on walking impairment during the acute phase of deep vein thrombosis (DVT) are limited. Objectives: This study aimed to assess the degree of walking impairment in patients with acute DVT, with a particular focus on the relation to the DVT's anatomical location. Methods: Patients with sonographically confirmed DVT were eligible for inclusion in this cohort study. Pain-free walking distance (PWD) and maximum walking distance (MWD) were determined using standardized treadmill ergometer tests and analyzed in relation to DVT location. The impact of previous DVT on walking capacity was evaluated in an exploratory analysis. Results: The study included 64 patients (31% women; median age, 55 years). The median (IQR) time from diagnosis to exercise test was 3 (1-5) days. Patients with suprainguinal DVT demonstrated significantly shorter median (IQR) MWD than those with infrainguinal DVT (130 (61-202) m vs 565 (128-750) m; P < .01), while PWD did not significantly differ (PWD: 20 (0-30) m vs 40 (0-222) m; P = .14). The proportion of patients who had to terminate treadmill tests prematurely was higher in patients with suprainguinal DVT (91.7% vs 57.7%; P = .04). PWD and MWD seemed to be similar in patients with and without a history of DVT. Premature test termination and suprainguinal DVT location were associated with reduced quality of life, as measured by the EuroQoL Group 5-Dimension 5-Level questionnaire and visual analog scale. Conclusion: Suprainguinal DVT was linked to a more pronounced walking impairment compared with infrainguinal DVT. Limited walking capacity was associated with a reduced quality of life.

Micro- and Macrovascular Effects of Inflammation in Peripheral Artery Disease-Pathophysiology and Translational Therapeutic Approaches.

Inflammation has a critical role in the development and progression of atherosclerosis. On the molecular level, inflammatory pathways negatively impact endothelial barrier properties and thus, tissue homeostasis. Conformational changes and destruction of the glycocalyx further promote pro-inflammatory pathways also contributing to pro-coagulability and a prothrombotic state. In addition, changes in the extracellular matrix composition lead to (peri-)vascular remodelling and alterations of the vessel wall, e.g., aneurysm formation. Moreover, progressive fibrosis leads to reduced tissue perfusion due to loss of functional capillaries. The present review aims at discussing the molecular and clinical effects of inflammatory processes on the micro- and macrovasculature with a focus on peripheral artery disease.

Toll-like Receptors as Pro-Thrombotic Drivers in Viral Infections: A Narrative Review.

Toll-like receptors (TLRs) have a critical role in the pathogenesis and disease course of viral infections. The induced pro-inflammatory responses result in the disturbance of the endovascular surface layer and impair vascular homeostasis. The injury of the vessel wall further promotes pro-thrombotic and pro-coagulatory processes, eventually leading to micro-vessel plugging and tissue necrosis. Moreover, TLRs have a direct role in the sensing of viruses and platelet activation. TLR-mediated upregulation of von Willebrand factor release and neutrophil, as well as macrophage extra-cellular trap formation, further contribute to (micro-) thrombotic processes during inflammation. The following review focuses on TLR signaling pathways of TLRs expressed in humans provoking pro-thrombotic responses, which determine patient outcome during viral infections, especially in those with cardiovascular diseases.

NT-proBNP as a surrogate for unknown heart failure and its predictive power for peripheral artery disease outcome and phenotype.

Patients with peripheral artery disease (PAD) are at high risk of excess mortality despite major improvements in multimodal pharmacotherapy for cardiovascular disease. However, little is known about co-prevalences and implications for the combination of heart failure (HF) and PAD. Thus, NT-proBNP as a suggested surrogate for HF was evaluated in symptomatic PAD regarding long-term mortality. After approval by the institutional ethics committee a total of 1028 patients with PAD, both with intermittent claudication or critical limb ischemia were included after admission for endovascular repair and were followed up for a median of 4.6 years. Survival information was obtained from central death database queries. During the observation period a total of 336 patients died (calculated annual death rate of 7.1%). NT-proBNP (per one standard deviation increase) was highly associated with outcome in the general cohort in crude (HR 1.86, 95%CI 1.73-2.01) and multivariable-adjusted Cox-regression analyses with all-cause mortality (HR 1.71, 95%CI 1.56-1.89) and CV mortality (HR 1.86, 95% CI 1.55-2.15). Similar HR's were found in patients with previously documented HF (HR 1.90, 95% CI 1.54-2.38) and without (HR 1.88, 95%CI 1.72-2.05). NT-proBNP levels were independently associated with below-the-knee lesions or multisite target lesions (OR 1.14, 95% CI 1.01-1.30). Our data indicate that increasing NT-proBNP levels are independently associated with long-term mortality in symptomatic PAD patients irrespective of a previously documented HF diagnosis. HF might thus be highly underreported in PAD, especially in patients with the need for below-the-knee revascularization.

Temporal association between COVID-19 vaccination and Raynaud's phenomenon: A case series.

COVID-19 vaccine-related adverse events are mostly minor to moderate, and serious events are rare. Single cases of Raynaud's phenomenon (RP) in temporal proximity to COVID-19 vaccination have been reported. Demographic data, medical history, and detailed information regarding vaccination status and RP characteristics were obtained from patients with confirmed RP after COVID-19 vaccination. Fifteen participants reported the initial manifestation of RP, which occurred in 40% after the first, in 33% after the second, and in 27% after the third vaccination. RP development and occurrence of episodes were not linked to any specific vaccine type. New onset of disease was observed in 40% of the vaccinees after BNT162b2, in 33% after mRNA-1273, and in 27% after ChAdOx1 vaccination. Three out of four participants with preexisting RP prior to COVID-19 vaccination reported aggravation in frequency and intensity after immunization. Although COVID-19 vaccination is pivotal in controlling the pandemic, the observed temporal association between vaccine administration and RP occurrence warrants global activities to support pharmacovigilance for the detection of adverse reactions, one of which may include RP.

Preprocedural imaging modalities in patients undergoing iliocaval venous recanalization and stent placement.

PURPOSE: To determine the diagnostic accuracy of preinterventional imaging modalities in patients being evaluated for iliocaval venous recanalization and stent placement. METHODS: Consecutive patients with iliocaval postthrombotic obstructions or nonthrombotic iliac vein lesions (NIVL), who were scheduled for recanalization, underwent duplex ultrasound (DUS), magnetic resonance venography (MRV), multiplanar venography (MPV), and intravascular ultrasound (IVUS). The diagnostic accuracies of DUS, MRV, and MPV were analyzed using IVUS as reference. RESULTS: A total of 216 limbs in 108 patients (80 patients with postthrombotic obstructions, 28 patients with NIVL) were examined. In patients with postthrombotic obstructions, the diagnostic sensitivities for the detection of lesions of the common femoral vein were 81% (95% CI 71-89%) for DUS, 76% (95% CI 65-85%) for MRV, and 86% (95% CI 76-93%) for MPV. The sensitivities for detecting lesions of the iliac veins were 96% (95% CI 89-99%) for DUS, 99% (95% CI 92-100%) for MRV, and 100% (95% CI 94-100%) for MPV. Regarding the inferior vena cava, the sensitivities were 44% (95% CI 24-65%) for DUS, 52% (95% CI 31-73%) for MRV, and 70% (95% CI 47-86%) for MPV. The sensitivities for detecting NIVL were 58% (95% CI 34-79%) for DUS, 90% (95% CI 68-97%) for MRV, and 95% (95% CI 73-99%) for MPV. CONCLUSION: In patients scheduled for recanalization of iliocaval postthrombotic obstructions, the sensitivities of DUS, MRV, and MPV were similar. In patients with suspected inferior vena cava involvement and in patients with NIVL, additional imaging with MR or conventional venography is required.

A Case of Autoimmune Small Fiber Neuropathy as Possible Post COVID Sequelae.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is reported to induce and augment autoimmune processes. Moreover, postinfectious effects of coronavirus disease 2019 (COVID-19) are still poorly understood and often resemble symptoms of the acute infection phase. A patient with swollen extremities was presented to the Department of Angiology at the Medical University of Vienna with complaints of muscle and joint pain, paresthesia, and arterial hypertension with intense headache. Prior to these complaints, she had been suffering from various symptoms since November 2020, following a SARS-CoV-2 infection in the same month. These included recurrent sore throat, heartburn, dizziness, and headache. Paresthesia and muscle and joint pain started in temporal relation to a human papillomavirus (HPV) vaccination. Since the patient was suffering from severe pain, intensive pain management was performed. Skin and nerve biopsies revealed autoimmune small fiber neuropathy. The patient's condition could be related to COVID-19, as her first symptoms began in temporal relation to the SARS-CoV-2 infection. Furthermore, in the disease course, antinuclear (ANA) and anti-Ro antibodies, as well as anti-cyclic citrullinated peptide (anti-CCP) antibodies, could be detected. Together with the symptoms of xerophthalmia and pharyngeal dryness, primary Sjögren's syndrome was diagnosed. In conclusion, though biopsy results could not distinguish a cause of the disease, SARS-CoV-2 infection can be discussed as a likely trigger for the patient's autoimmune reactions.

Associations between nailfold capillary aberrations and autoantibodies in children and adults with Raynaud's phenomenon.

OBJECTIVE: To characterise associations between individual nailfold capillary aberrations with autoantibodies in a cross-sectional study on children and adults with Raynaud's phenomenon (RP). METHODS: Consecutive children and adults with RP and without previously known connective tissue disease (CTD) systemically underwent nailfold capillaroscopy and laboratory tests for the presence of antinuclear antibodies (ANA). The prevalence of individual nailfold capillary aberrations and ANA was assessed, and the associations between individual nailfold capillary aberrations and ANA were analysed separately in children and adolescents. RESULTS: In total, 113 children (median age 15 years) and 2858 adults (median age 48 years) with RP and without previously known CTD were assessed. At least one nailfold capillary aberration was detected in 72 (64%) of included children and in 2154 (75%) of included adults with RP (children vs adults p<0.05). An ANA titre ≥1:80, ≥1:160 or≥1:320 was observed in 29%, 21% or 16% of included children, and in 37%, 27% or 24% of screened adults, respectively. While the occurrence of individual nailfold capillary aberrations was related to the presence of an ANA titre of ≥1:80 in adults (reduced capillary density, avascular fields, haemorrhages, oedema, ramifications, dilations and giant capillaries: each p<0.001), no comparable association between nailfold capillary aberrations and ANA was observed in children with RP without previously known CTD. CONCLUSION: In contrast to adults, the association between nailfold capillary aberrations and ANA might be less pronounced in children. Further studies are warranted to validate these observations in children with RP.

Microvascular Thrombosis as a Critical Factor in Severe COVID-19.

Platelet-endothelial interactions have a critical role in microcirculatory function, which maintains tissue homeostasis. The subtle equilibrium between platelets and the vessel wall is disturbed by the coronavirus disease 2019 (COVID-19), which affects all three components of Virchow's triad (endothelial injury, stasis and a hypercoagulable state). Endotheliitis, vasculitis, glycocalyx degradation, alterations in blood flow and viscosity, neutrophil extracellular trap formation and microparticle shedding are only few pathomechanisms contributing to endothelial damage and microthrombosis resulting in capillary plugging and tissue ischemia. In the following opinion paper, we discuss major pathological processes leading to microvascular endothelial activation and thrombosis formation as a possible major adverse factor driving the deterioration of patient disease course in severe COVID-19.

Lipoprotein (a) and long-term outcome in patients with peripheral artery disease undergoing revascularization.

BACKGROUND AND AIMS: Despite low LDL-C goals, the residual risk for further cardiovascular (CV) events in patients with peripheral artery disease (PAD) remains high. Lipoprotein (a) (Lp(a)) is a known risk factor for PAD incidence, but little is known regarding the outcome in patients with symptomatic PAD. Thus, this study investigates Lp(a) and CV mortality in PAD after endovascular repair. METHODS: A total of 1222 patients with PAD in two cohorts according to Lp(a) assay in nmol/L (n = 964, Lip-LEAD-A) or mg/dl (n = 258, Lip-LEAD-B) were followed up for 4.3 (IQR 3.0-5.6) or 7.6 (IQR 3.2-8.1) years. Lp(a) was measured before endovascular repair for either intermittent claudication (IC) or critical limb ischemia (CLI). Outcome information was obtained from the federal death registry. RESULTS: In Lip-LEAD-A, 141 CV-deaths occurred (annual calculated CV-death rate 3.4%), whereas 64 CV-deaths were registered in Lip-LEAD-B (annual calculated CV-death rate 3.3%). After adjustment for traditional CV risk factors Lp(a) was neither associated with outcome in Lip-LEAD-A (highest tertile HR 1.47, 95%CI [0.96-2.24]) nor in Lip-LEAD-B (highest tertile HR 1.34 [0.70-2.58]). Subanalyses for IC (HR 1.37 [0.74-2.55]; HR 1.10 [0.44-2.80], CLI (HR 1.55 [0.86-2.80], HR 3.01 [0.99-9.10]), or concomitant coronary artery disease (CAD; HR 1.34 [0.71-2.54]; HR 1.21 [0.46-3.17]) failed to show a significant association between Lp(a) and CV-mortality. CONCLUSIONS: In this large-scale cohort of symptomatic PAD no association of elevated Lp(a) with CV mortality was found over a median observation period of 5 years. Thus, an even longer study including asymptomatic patients is warranted.

Closure of Post-thrombotic Iliac Arteriovenous Fistulas by Iliac Vein Recanalization.

PURPOSE: The purpose of this study was to report the closure of iliac arteriovenous fistulas associated with a post-thrombotic iliac vein occlusion by iliac venous stent recanalization. CASE REPORT: An 80-year-old woman presented with a worsening painful swelling of her left leg after an iliofemoral deep vein thrombosis 6 months ago. Duplex ultrasound and magnetic resonance venography revealed a post-thrombotic obstruction of her iliac veins as well as several arteriovenous fistulas between branches of her left external and internal iliac arteries and adjacent diseased venous segments. In a first attempt, coil embolization did not sustainably close these iliac arteriovenous fistulas. Direct stent recanalization of the chronically diseased iliofemoral venous segment, however, resulted in an immediate closure of arteriovenous shunt flow and subsequent improvement of clinical symptoms. Six months after iliac vein stent recanalization, still no fistulas could be detected any more, venous stents were fully patent, and the patient was free of symptoms. CONCLUSION: Post-thrombotic iliofemoral obstructions might be associated with the development of arteriovenous fistulas. Direct stent recanalization of the chronically occluded veins results in closure of related arteriovenous fistulas. CLINICAL IMPACT: This case suggests that the combined occurrence of post-thrombotic venous obstructions with arteriovenous fistulas, which are related to aforementioned venous lesions, should be evaluated for primary venous stent recanalization rather than fistula embolization.

Platelet-to-Lymphocyte Ratio as Marker of Platelet Activation in Patients on Potent P2Y12 Inhibitors.

A high platelet-to-lymphocyte ratio (PLR) has recently been associated with ischemic outcomes in cardiovascular disease. Increased platelet reactivity and leukocyte-platelet aggregate formation are directly involved in the progress of atherosclerosis and have been linked to ischemic events following percutaneous coronary intervention (PCI). In order to understand the relation of PLR with platelet reactivity, we assessed PLR as well as agonist-inducible platelet aggregation and neutrophil-platelet aggregate (NPA) formation in 182 acute coronary syndrome (ACS) patients on dual antiplatelet therapy with aspirin and prasugrel (n = 96) or ticagrelor (n = 86) 3 days after PCI. PLR was calculated from the blood count. Platelet aggregation was measured by multiple electrode aggregometry and NPA formation was determined by flow cytometry, both in response to ADP and SFLLRN. A PLR ≥91 was considered as high PLR based on previous data showing an association of this threshold with adverse ischemic outcomes. In the overall cohort and in prasugrel-treated patients, high PLR was associated with higher SFLLRN-inducible platelet aggregation (67 AU [50-85 AU] vs 59.5 AU [44.3-71.3 AU], P = .01, and 73 AU [50-85 AU] vs 61.5 AU [46-69 AU], P = .02, respectively). Further, prasugrel-treated patients with high PLR exhibited higher ADP- (15% [11%-23%] vs 10.9% [7.6%-15.9%], P = .007) and SFLLRN-inducible NPA formation (64.3% [55.4%-73.8%] vs 53.8% [44.1%-70.1%], P = .01) as compared to patients with low PLR. These differences were not seen in ticagrelor-treated patients. In conclusion, high PLR is associated with increased on-treatment platelet reactivity in prasugrel-treated patients, but not in patients on ticagrelor.

High-Density Lipoprotein Particle Subclasses in Statin-Treated Patients with Peripheral Artery Disease Predict Long-Term Survival.

Low-density lipoprotein-cholesterol reduction showed a strong reduction of cardiovascular (CV) event rates in CV disease. However, the residual risk of future CV events remains high, which especially extends to peripheral arterial disease (PAD). Nuclear magnetic resonance (NMR) spectroscopy offers a novel method for analysis of the lipoprotein spectrum. This study investigates lipoprotein subclasses using NMR spectroscopy and assesses implications for long-term survival in PAD. NMR spectroscopy was performed by Nightingale Inc., in 319 patients with stable PAD and well-controlled CV risk factors. Patients were followed-up for 10 years. During that period, 123 patients (38.5%) died, of those 68 (21.3%) were defined as CV deaths. Outcome data were analyzed by the Kaplan-Meier method and multivariable Cox-regression for lipoprotein particles. Small and medium high-density lipoprotein-particles (S-HDL-P and M-HDL-P) showed a significant inverse association with all-cause mortality in Cox-regression analyses after multivariable adjustment (S-HDL-P, hazard ratio [HR]: 0.71, 95% confidence interval [CI]: 0.57-0.88; M-HDL-P, HR: 0.72, 95% CI: 0.58-0.90) for each increase of one standard deviation. In contrast, cholesterol-rich X-large HDL-particles (XL-HDL-P) showed a positive association with all-cause mortality (HR: 1.51, 95% CI: 1.20-1.89). Only the association between XL-HDL-P and CV death sustained multivariable adjustment (HR: 1.49, 95% CI: 1.10-2.02), whereas associations for S-HDL-P and M-HDL-P were attenuated (HR: 0.76, 95% CI: 0.57-1.01; HR: 0.80, 95% CI: 0.60-1.06). This study shows a novel association for a beneficial role of S-HDL-P and M-HDL-P but a negative association with higher cholesterol-rich XL-HDL-P for long-term outcome in well-treated patients with PAD. Thus, these results provide evidence that NMR-measured HDL particles identify patients at high CV residual risk beyond adequate lipid-lowering therapy.

Microvascular rarefaction in patients with cerebrovascular events.

Capillary density rarefaction and endothelial dysfunction contribute to chronic hypoperfusion and cerebral small vessel disease. Previous animal experiments revealed spatiotemporal microvascular remodeling directing post-stroke brain reorganization. We hypothesized that microcirculatory changes during acute cerebrovascular events could be reflected systemically and visualized sublingually. In a prospective observational trial in vivo sublingual sidestream darkfield videomicroscopy was performed in twenty-one patients with either acute stroke (n = 13 ischemic, n = 1 ischemic with hemorrhagic transformation and n = 2 hemorrhagic stroke) or transitory ischemic attacks (n = 5) within 24 h after hospital admission and compared to an age- and sex-matched control group. Repetitive measurements were performed on the third day and after one week. Functional and perfused total capillary density was rarefied in the overall patient group (3060 vs 3717 µm/mm2, p = 0.001 and 5263 vs 6550 µm/mm2, p = 0.002, respectively) and in patients with ischemic strokes (2897 vs. 3717 µm/mm2, p < 0.001 and 5263 vs. 6550 µm/mm2, p = 0.006, respectively) when compared to healthy controls. The perfused boundary region (PBR), which was measured as an inverse indicator of glycocalyx thickness, was markedly related to red blood cell (RBC) filling percentage (regarded as an estimate of microvessel perfusion) in the overall patient group (r = -0.843, p < 0.001), in patients with ischemic strokes (r = -0.82, p = 0.001) as well as in healthy volunteers (r = -0.845, p < 0.001). In addition, there were significant associations between platelet count or platelet aggregation values (as measured by whole blood impedance aggregometry) and microvascular parameters in the overall patient collective, as well as in patients with ischemic strokes. In conclusion, cerebrovascular events are associated with altered systemic microvascular perfusion.

Galectin-3 is linked to peripheral artery disease severity, and urinary excretion is associated with long-term mortality.

BACKGROUND AND AIMS: Galectin-3 (Gal-3) is a biomarker involved in fibrosis and vascular inflammation. Gal-3 has been linked to chronic kidney disease (CKD) and patients with peripheral artery disease (PAD). Conflicting reports exist about the relevance of Gal-3 in PAD. The study aims to elucidate a possible link between serum and urinary Gal-3 and long-term survival in PAD patients without critical limb ischemia and mild to moderate CKD. METHODS: Galectin-3 (Gal-3) was measured in serum (n = 311) and urine (n = 266) of PAD patients (age 69 (62-77) years) by bead-based multiplex assay. Urinary Gal-3 concentration was normalized to urine creatinine (cr) levels. Mortality data were retrieved from the Austrian central death registry after a median observation period of 9.2 years. Survival analyses were performed by the Kaplan-Meier method and Cox-regression. RESULTS: Serum Gal-3 was higher in patients with claudication symptoms (p = 0.001) and correlated inversely with the patients' ankle-brachial index (R = -0.168, p = 0.009). Serum Gal-3 and urinary Gal-3 (uGal-3/cr) were associated with the estimated glomerular filtration rate (R = -0.359, p < 0.001; R = -0.285, p < 0.001). Serum Gal-3 was not linked to all-cause mortality [HR 1.17 (CI 0.96-1.42)] over 9.2 years. However, uGal-3/cr was associated with all-cause mortality [HR 1.60 (CI 1.31-1.95)]. This association sustained multivariable adjustment for cardiovascular risk factors and renal function [HR 1.71 (CI 1.35-2.17)]. CONCLUSIONS: This study is the first to show an association of uGal-3/cr and long-term mortality in patients with PAD. Gal-3 was not predictive of long-term mortality but seems to be a marker of PAD severity in patients without critical limb ischemia.

Angiogenin-A Proposed Biomarker for Cardiovascular Disease-Is Not Associated With Long-Term Survival in Patients With Peripheral Artery Disease.

We evaluated angiogenin as a prospective biomarker in peripheral artery disease (PAD) patients with and without claudication symptoms. A pilot study suggested an elevation of angiogenin in critical limb ischemia. However, in PAD patients, the predictive value of angiogenin has not yet been evaluated. For this purpose, 342 patients with PAD (age: 69 ± 10 years, 34.5% women) were followed-up for 7 years in a cross-sectional study. Angiogenin was measured by enzyme-linked immunosorbent assay. All-cause and cardiovascular mortality were analyzed by Cox regression. Angiogenin levels were higher in men (P = .001) and were associated with patient waist-to-hip ratio (P < .001), fasting triglycerides (P = .011), and inversely with estimated glomerular filtration rate (P = .009). However, angiogenin showed no association with age, characteristics of diabetes, markers of lipid metabolism, or C-reactive protein. Angiogenin did not correlate with markers of angiogenesis such as vascular endothelial growth factor, angiopoietin-2, or tie-2. Furthermore, angiogenin was not associated with PAD Fontaine stages or with patient ankle-brachial index in addition to all-cause mortality (hazard ratio [HR] = 1.09 [95% CI: 0.89-1.34]) or cardiovascular morality (HR = 1.05 [0.82-1.35]). These results suggest that angiogenin does not provide further information regarding outcome prediction in patients with PAD.