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Background: Although COVID-19 is predominantly a respiratory tract infection, current antibody treatments are administered by systemic dosing. We hypothesize that inhaled delivery of a monoclonal antibody may be a more effective and convenient route. We investigated the safety, tolerability, and pharmacokinetics of IN-006, a reformulation of regdanvimab for nebulized delivery by a handheld nebulizer., Methods: A Phase 1 study was conducted in healthy volunteers aged 18-55 a Phase 1 unit in Melbourne, Australia (ACTRN12621001235897). Study staff and participants were blinded to treatment assignment, except for pharmacy staff preparing the study drug. The ratio of active:placebo randomization to each cohort was set at 3:1. The primary outcomes were safety and tolerability. Exploratory outcomes were pharmacokinetics of IN-006 in nasal fluid and serum., Findings: Twenty-three participants were enrolled and randomized across two single dose and one multiple dose cohorts (30 mg or 90 mg single nebulized dose, or seven daily 90 mg doses). There were no serious adverse events. All enrolled participants completed the study without treatment interruption or discontinuation. All treatment-emergent adverse events were transient, non-dose dependent, and graded mild to moderate in severity. Nebulization was well-tolerated and completed in an average of 6 min. Geometric mean nasal fluid concentrations of IN-006 in the multiple dose cohort were 739.8 μg/mL at 30 min after dosing and 1.2 μg/mL at 22 h. Geometric mean serum levels in the multiple dose cohort peaked at 0.51 μg/mL 3 days after the final dose., Interpretation: IN-006 was well-tolerated and achieved concentrations in the respiratory tract orders of magnitude above the IC 50 range typical of antiviral mAbs. These data support further development of nebulized delivery of antiviral mAbs for respiratory infectious disease., Funding: This work was funded by the U.S. Army Medical Research and Development Command (W81XWH-15-9-0001) and regdanvimab was provided by Celltrion, Inc., Competing Interests: Declaration of interests TM, LB, BF, MH, MB, MM, ZR, JW, FF, and JH are employees of Inhalon Biopharma/Mucommune and may hold shares in Inhalon Biopharma, Inc. HK, YP, CK, JMC, and SYL are employees of Celltrion, Inc, which received funding from the government of Korea to advance Regdanvimab, which was used to cover salary for their work on this project. JL received partial salary support for his work on this project. SKL is founder of Mucommune, LLC and currently serves as its interim CEO. SKL is also founder of Inhalon Biopharma, Inc, and currently serves as its CSO as well as on its Board of Director and Scientific Advisory Board. S.K.L has equity interests in both Mucommune and Inhalon Biopharma; S.K.L's relationships with Mucommune and Inhalon are subject to certain restrictions under University policy. The terms of these arrangements are managed by UNC-CH in accordance with its conflict of interest policies., (Copyright © 2025. Published by Elsevier B.V.) more...

Dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) cause diverse and largely distinct channelopathies, including inherited forms of neuromuscular disease, skeletal dysplasias and arthropathy. Pathogenic TRPV4 mutations cause gain of ion channel function and toxicity that can be rescued by small molecule TRPV4 antagonists in cellular and animal models, suggesting that TRPV4 antagonism could be therapeutic for patients. Numerous variants in TRPV4 have been detected with targeted and whole exome/genome sequencing, but for the vast majority, their pathogenicity remains unclear. Here, we used a combination of clinical information and experimental structure-function analyses to evaluate 30 TRPV4 variants across various functional protein domains. We report clinical features of seven patients with TRPV4 variants of unknown significance and provide extensive functional characterization of these and an additional 17 variants, including structural position, ion channel function, subcellular localization, expression level, cytotoxicity and protein-protein interactions. We find that gain-of-function mutations within the TRPV4 intracellular ankyrin repeat domain target charged amino acid residues important for RhoA interaction, whereas ankyrin repeat domain residues outside of the RhoA interface have normal or reduced ion channel activity. We further identify a cluster of gain-of-function variants within the intracellular intrinsically disordered region that may cause toxicity via altered interactions with membrane lipids. In contrast, assessed variants in the transmembrane domain and other regions of the intrinsically disordered region do not cause gain of function and are likely benign. Clinical features associated with gain of function and cytotoxicity include congenital onset of disease, vocal cord weakness and motor-predominant disease, whereas patients with likely benign variants often demonstrated late-onset and sensory-predominant disease. These results provide a framework for assessing additional TRPV4 variants with respect to likely pathogenicity, which will yield critical information to inform patient selection for future clinical trials for TRPV4 channelopathies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.) more...

Dominant missense mutations of the calcium-permeable cation channel TRPV4 cause Charcot-Marie-Tooth disease (CMT) type 2C and two forms of distal spinal muscular atrophy. These conditions are collectively referred to as TRPV4-related neuromuscular disease and share features of motor greater than sensory dysfunction and frequent vocal fold weakness. Pathogenic variants lead to gain of ion channel function that can be rescued by TRPV4 antagonists in cellular and animal models. As small molecule TRPV4 antagonists have proven safe in trials for other disease indications, channel inhibition is a promising therapeutic strategy for TRPV4 patients. However, the current knowledge of the clinical features and natural history of TRPV4-related neuromuscular disease is insufficient to enable rational clinical trial design. To address these issues, we developed a TRPV4 patient database and administered a TRPV4-specific patient questionnaire. Here, we report demographic and clinical information, including CMT Examination Scores (CMTES), from 68 patients with known pathogenic TRPV4 variants, 40 of whom also completed the TRPV4 patient questionnaire. TRPV4 patients showed a bimodal age of onset, with the largest peak occurring in the first 2 years of life. Compared to CMT type 1A (CMT1A) patients, TRPV4 patients showed distinct symptoms and signs, manifesting more ambulatory difficulties and more frequent involvement of proximal arm and leg muscles. Although patients reported fewer sensory symptoms, sensory dysfunction was often detected clinically. Many patients were affected by vocal fold weakness (55%) and shortness of breath (55%), and 11% required ventilatory support. Skeletal abnormalities were common, including scoliosis (64%), arthrogryposis (33%) and foot deformities. Strikingly, patients with infantile onset of disease showed less sensory involvement and less progression of symptoms. These results highlight distinctive clinical features in TRPV4 patients, including motor-predominant disease, proximal arm and leg weakness, severe ambulatory difficulties, vocal fold weakness, respiratory dysfunction and skeletal involvement. In addition, patients with infantile onset of disease appeared to have a distinct phenotype with less apparent disease progression based on CMTES. These collective observations indicate that clinical trial design for TRPV4-related neuromuscular disease should include outcome measures that reliably capture non-length dependent motor dysfunction, vocal fold weakness and respiratory disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.) more...

Background and Aims: Peripheral neuropathy (PN) is a common neurological condition in elderly adults. Vitamin D deficiency has been associated with diabetic and chemotherapy-induced neuropathy, but its role in idiopathic PN, in which no underlying cause of neuropathy can be identified, has not been investigated., Methods: Two hundred thirty patients with idiopathic PN enrolled in the Peripheral Neuropathy Research Registry (PNRR) at Johns Hopkins University School of Medicine had vitamin D testing information on record. Linear and logistic regressions were used to investigate the relationship between absolute vitamin D level or vitamin D insufficiency (<20 ng/mL) and both the severity of neuropathy as measured by the reduced total neuropathy score (TNSr) and severity of neuropathic pain., Results: Sixteen (7%) patients were vitamin D insufficient (<20 ng/mL). Controlling for factors known to correlate with severity of neuropathy, there was no correlation between absolute vitamin D levels and TNSr (correlation coefficient 0.01, 95% CI -0.03 to 0.07, p = .59) and no association between vitamin D insufficiency and TNSr (correlation coefficient 0.3, 95% CI -2.8 to 3.4, p = .86). Vitamin D insufficiency was not associated with the presence of neuropathic pain (OR 4.1, 95% CI 0.6-26.0, p = .13), and there was no correlation between vitamin D levels and pain score (correlation coefficient 0.01, 95% CI -0.02 to 0.03, p = .59)., Interpretation: In a single-center cohort of patients with idiopathic PN, there was no correlation between vitamin D levels and the severity of neuropathy or neuropathic pain., (© 2024 Peripheral Nerve Society.) more...

Background: The expansion of hematopoietic stem cells caused by acquired somatic mutations (clonal hematopoiesis [CH]) is a novel cardiovascular risk factor. The prognostic value of CH in patients with carotid atherosclerosis remains to be evaluated., Objectives: This study assessed the prognostic significance of CH in patients with atherosclerosis as detected by ultrasound of the carotid artery., Methods: We applied deep sequencing of selected genomic regions within the genes DNMT3A, TET2, ASXL1, and JAK2 to screen for CH in 968 prospectively collected patients with asymptomatic carotid atherosclerosis evaluated by duplex sonography., Results: We detected clonal markers at variant allele frequency ≥2% in 133 (13.7%) of 968 patients (median age 69.2 years), with increasing prevalence at advanced age. Multivariate analyses including age and established cardiovascular risk factors revealed overall presence of CH to be significantly associated with increased risk of cardiovascular death (HR: 1.50; 95% CI: 1.12-2.00; P = 0.007), reflected also at the single gene level. The effect of CH was more pronounced in older patients and independent of the patients' inflammatory status as measured by high-sensitivity C-reactive protein. Simultaneous assessment of CH and degree of carotid stenosis revealed combined effects on cardiovascular mortality, depicted by a superior risk for patients with >50% stenosis and concomitant CH (adjusted HR: 1.60; 95% CI: 1.08-2.38; P = 0.020)., Conclusions: CH status in combination with the extent of carotid atherosclerosis jointly predict long-term mortality. Determination of CH can provide additional prognostic information in patients with asymptomatic carotid atherosclerosis., Competing Interests: Funding Support and Author Disclosures This work was supported by the Österreichischer Herzfonds (to Dr Jäger), the Austrian Science Fund (F4702-B20 and P29018-B30, both to Dr Kralovics), the Vienna Science and Technology Fund (LS18-090 to Dr Binder), and the Leducq Foundation (Transatlantic Network of Excellence, TNE-20CVD03 to Dr Binder). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.) more...

Atherosclerosis is a chronic disease of the vascular wall driven by lipid accumulation and inflammation in the intimal layer of arteries, and its main complications, myocardial infarction and stroke, are the leading cause of mortality worldwide [1], [2]. Recent studies have identified Triggering receptor expressed on myeloid cells 2 (TREM2), a lipid-sensing receptor regulating myeloid cell functions [3], to be highly expressed in macrophage foam cells in experimental and human atherosclerosis [4]. However, the role of TREM2 in atherosclerosis is not fully known. Here, we show that hematopoietic or global TREM2 deficiency increased, whereas TREM2 agonism decreased necrotic core formation in early atherosclerosis. We demonstrate that TREM2 is essential for the efferocytosis capacities of macrophages, and to the survival of lipid-laden macrophages, indicating a crucial role of TREM2 in maintaining the balance between foam cell death and clearance of dead cells in atherosclerotic lesions, thereby controlling plaque necrosis., Competing Interests: Competing Interests statement Christian Haass is a collaborator of Denali Therapeutics and a member of the advisory board of AviadoBio. Other authors have no conflicts of interest to declare. more...

Background: Early studies assessing peripartum mood disorders during the COVID-19 pandemic have conflicting results. Objective: The primary aim was to examine if postpartum depression (PPD) was more common or more severe during the COVID-19 pandemic compared to earlier periods, and to assess what individual factors may worsen the impact of the pandemic. Methods: Electronic health records at an academic pediatric practice in Michigan identified 242 biological mother-child dyads with delivery between 1/1/2017 and 12/31/2021. PPD was evaluated using the Edinburgh Postnatal Depression Scale (EPDS) during well-child visits. Participants were divided into three groups for analysis: Pre-Pandemic ( n  = 100), Early Pandemic ( n  = 93), and Later Pandemic ( n  = 49). Logistic regression analysis was used to predict PPD development, controlling for background factors. Results: After controlling for confounders, the three groups did not differ significantly. Preexisting mental health conditions was a significant ( p <.001) moderator; PPD rates peaked early in the pandemic (60%), compared to late pandemic (42%) and pre-pandemic (36%). Women without a mental health diagnosis pre-pregnancy experienced the lowest levels of PPD during the pandemic. Conclusions: Rates of PPD were not significantly affected by the COVID-19 pandemic for most women. However, biological mothers with preexisting mental health conditions had significantly higher rates of PPD. more...

Background: With an unplanned pregnancy rate of 50% or more in many countries, there is an urgent need for contraceptives that are more accessible and acceptable. To meet the growing demand for new contraceptives, ZabBio developed ZB-06, a vaginal film containing HC4-N, a human contraceptive antibody that inactivates sperm., Objective: This study aimed to assess the potential contraceptive activity of the ZB-06 film using a surrogate assessment for contraceptive efficacy, the postcoital test. We also assessed clinical safety of film use among healthy heterosexual couples. Serum, cervical mucus, and vaginal fluid HC4-N antibody concentrations and sperm agglutination potency were determined after single film use. Changes in the concentration of soluble proinflammatory cytokines and vaginal Nugent score after film use were measured as subclinical safety endpoints., Study Design: This was a phase 1, first-in-woman, open-label, proof-of-concept, postcoital test and safety study., Results: A total of 20 healthy women were enrolled in the study, and 8 heterosexual couples completed all study visits. The product was safe for both female participants and their male sexual partners. The postcoital test performed on ovulatory cervical mucus at baseline (no product use) revealed a mean of 25.9 (±30.6) progressively motile sperm per high-power field. After use of a single ZB-06 film before intercourse, this number dropped to 0.04 (±0.06) progressively motile sperm per high-power field (P<.0001). At the follow-up postcoital test visit approximately 1 month later (no product use), a mean of 47.4 (±37.4) progressively motile sperm per high-power field was observed, indicating contraceptive reversibility., Conclusion: A single dose of the ZB-06 film applied before intercourse was safe and met efficacy surrogate benchmarks of excluding progressively motile sperm from ovulatory cervical mucus. These data indicate that ZB-06 is a viable contraceptive candidate warranting further development and testing., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.) more...

Aims: Secondary, or functional, mitral regurgitation (FMR) was recently recognized as a separate clinical entity, complicating heart failure with reduced ejection fraction (HFrEF) and entailing particularly poor outcome. Currently, there is a lack of targeted therapies for FMR due to the fact that pathomechanisms leading to FMR progression are incompletely understood. In this study, we sought to perform metabolomic profiling of HFrEF patients with severe FMR, comparing results to patients with no or mild FMR., Methods and Results: Targeted plasma metabolomics and untargeted eicosanoid analyses were performed in samples drawn from HFrEF patients (n = 80) on optimal guideline-directed medical therapy. Specifically, 17 eicosanoids and 188 metabolites were analysed. Forty-seven patients (58.8%) had severe FMR, and 33 patients (41.2%) had no or non-severe FMR. Comparison of eicosanoid levels between groups, accounting for age, body mass index, and sex, revealed significant up-regulation of six eicosanoids (11,12-EET, 13(R)-HODE, 12(S)-HETE, 8,9-DiHETrE, metPGJ2, and 20-HDoHE) in severe FMR patients. Metabolites did not differ significantly. In patients with severe FMR, but not in those without severe FMR, levels of 8,9-DiHETrE above a cut-off specified by receiver-operating characteristic analysis independently predicted all-cause mortality after a median follow-up of 43 [interquartile range 38, 48] months [hazard ratio 12.488 (95% confidence interval 3.835-40.666), P < 0.0001]., Conclusions: We report the up-regulation of various eicosanoids in patients with severe FMR, with 8,9-DiHETrE appearing to predict mortality. Our observations may serve as a nucleus for further investigations into the causes and consequences of metabolic derangements in this important valvular abnormality., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.) more...

Atherosclerotic cardiovascular disease causes heart attacks and strokes, which are the leading causes of mortality worldwide 1 . The formation of atherosclerotic plaques is initiated when low-density lipoproteins bind to heparan-sulfate proteoglycans (HSPGs) 2 and become trapped in the subendothelial space of large and medium size arteries, which leads to chronic inflammation and remodelling of the artery wall 2 . A proliferation-inducing ligand (APRIL) is a cytokine that binds to HSPGs 3 , but the physiology of this interaction is largely unknown. Here we show that genetic ablation or antibody-mediated depletion of APRIL aggravates atherosclerosis in mice. Mechanistically, we demonstrate that APRIL confers atheroprotection by binding to heparan sulfate chains of heparan-sulfate proteoglycan 2 (HSPG2), which limits the retention of low-density lipoproteins, accumulation of macrophages and formation of necrotic cores. Indeed, antibody-mediated depletion of APRIL in mice expressing heparan sulfate-deficient HSPG2 had no effect on the development of atherosclerosis. Treatment with a specific anti-APRIL antibody that promotes the binding of APRIL to HSPGs reduced experimental atherosclerosis. Furthermore, the serum levels of a form of human APRIL protein that binds to HSPGs, which we termed non-canonical APRIL (nc-APRIL), are associated independently of traditional risk factors with long-term cardiovascular mortality in patients with atherosclerosis. Our data reveal properties of APRIL that have broad pathophysiological implications for vascular homeostasis., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.) more...

Competing Interests: The authors declare no conflict of interest.

Models of acid-base balance include acid production from (1) oxidation of sulfur atoms on amino acids and (2) metabolically produced organic acid anions. Acid load is balanced by alkali from metabolism of GI anions; thus, net acid production is equivalent to the sum of urine sulfate and organic anion (measured by titration in urine), minus GI anion. However, the relative contributions of these three sources of acid production in people eating free choice diets, and presumably in acid-base balance, have not been well studied. We collected 26 urines from 18 normal subjects (10 male) and 43 urine samples from 34 stone formers (17 male) and measured sulfate, organic anion, and components of GI anion and acid excretion in each; values were expressed as mEq/mmol creatinine. Mean values of the urine components, except creatinine and pH, did not differ between the sexes or groups. Urine organic acid and acid production varied directly with age (p ≤ 0.03). In a general linear model of acid excretion, the coefficients for sulfate, organic anion, and GI anion were 0.34 ± 0.09, 0.49 ± 0.12, and -0.51 ± 0.06, respectively, p ≤ 0.005, and the model accounted for 54% of the variance. A model for urine ammonia gave similar results. Urine organic anion is a significant contributor to total acid production and may be responsible for an increase in acid production with age., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.) more...

Background: The effect of adalimumab and fumaric acid esters (FAE) on the cardiovascular risk associated with psoriasis has only been investigated scarcely in randomized controlled studies., Objective: The aim of this prospective, randomized controlled head-to-head trial was to compare the influence of adalimumab and FAE on cardiovascular disease markers in psoriasis patients., Methods: Sixty-five patients with moderate to severe plaque psoriasis were randomly assigned to adalimumab or FAE treatment for 6 months. Cardiovascular haemodynamic parameters [flow-mediated dilation (FMD), nitro-glycerine mediated dilation (NMD) and carotid intima-media thickness (CIMT), blood pressure] were assessed at baseline (v0) and after 6 months (v6). Cutaneous disease severity, inflammatory and lipid cardiovascular risk markers were analysed at baseline(v0), after 3 (v3) and 6 months (v6)., Results: After 6 months of treatment FMD in the adalimumab group increased significantly [v0 5.9% (6.4% SD), v6 8.0% (4.8% SD), P = 0.048) but not in the FAE group. (v0 7.0% (4.1% SD), v6 8.4% (6.1% SD), P = 0.753]. This was paralleled by a significant decrease of high sensitive C-reactive protein (hsCRP) in the adalimumab group in comparison to the FAE group (v0: 0.39 mg/dL (0.38 SD), v6: 0.39 mg/dL (0.48 SD), P = 0.043). No significant changes were observed in any other haemodynamic parameters. FAE, however, additionally decreased total cholesterol (P = 0.046) and apolipoprotein B (P = 0.041) levels compared to adalimumab. Mean Psoriasis Area and Severity Index (psoriasis area severity score) reduction was greater but not significant (P = 0.116) under adalimumab treatment compared to FAE treatment [-71.1% (29.9 SD) vs. -54.6% (45.7%)]., Conclusion: In our study, both treatments were documented to exert effects on the cardiovascular system. While adalimumab showed anti-inflammatory effects and improved FMD, FAE interacted favourably with the cholesterol metabolism., (© 2020 European Academy of Dermatology and Venereology.) more...

Osteoporosis is the most prevalent bone disease worldwide and predisposes affected individuals to fragility fractures. Exercise has been shown to have multiple health benefits in post-menopausal osteoporotic women, but often recommendations regarding the benefits of specific exercise types are vague. Improving bone mineral density (BMD) is an essential component in any program to prevent osteoporotic vertebral fractures. The objective of this report is to briefly review the current understanding on the impact of exercise on BMD in postmenopausal women as it pertains to fragility fractures. Broad categories of exercises include aerobic, resistance, stretching, and balance. Tai Chi, Yoga, and Pilates are a heterogeneous group of specific exercise modalities that can span multiple categories. Current literature suggests that only resistance type exercises have a convincing impact on BMD. Core-strengthening exercises and attention to posture/balance can help mitigate falls. A number of barriers affect patient compliance and accessibility to exercise. In summary, exercise should be included in any multi-modality osteoporosis treatment plan with the goal of sustained exercise throughout life. If possible, osteoporotic women should be on a resistance-based regimen incorporating weight-bearing exercises, and also target posture and balance. Healthcare providers and educators should have resources readily available for patients., (Copyright © 2020 Elsevier Ltd. All rights reserved.) more...

Background: A common complication of viral pulmonary infections, such as in the ongoing COVID-19 pandemic, is a phenomenon described as a "cytokine storm". While poorly defined, this hyperinflammatory response results in diffuse alveolar damage. The low molecular weight fraction of commercial human serum albumin (LMWF5A), a novel biologic in development for osteoarthritis, demonstrates beneficial in vitro immunomodulatory effects complimentary to addressing inflammation, thus, we hypothesize that LMWF5A could improve the clinical outcomes of COVID-19 by attenuating hyperinflammation and the potential development of a cytokine storm., Presentation of the Hypothesis: A variety of human in vitro immune models indicate that LMWF5A reduces the production of pro-inflammatory cytokines implicated in cytokine storm associated with COVID-19. Furthermore, evidence suggests LMWF5A also promotes the production of mediators required for resolving inflammation and enhances the barrier function of endothelial cultures., Testing the Hypothesis: A randomized controlled trial, to evaluate the safety and efficacy of nebulized LMWF5A in adults with Acute Respiratory Distress Syndrome (ARDS) secondary to COVID-19 infection, was developed and is currently under review by the Food and Drug Administration., Implications of Hypothesis: If successful, this therapy may attenuate the cytokine storm observed in these patients and potentially reduce mortality, increase ventilation free days, improve oxygenation parameters and consequently lessen the burden on patients and the intensive care unit., Conclusions: In conclusion, in vitro findings suggest that the immunomodulatory effects of LMWF5A make it a viable candidate for treating cytokine storm and restoring homeostasis to the immune response in COVID-19., Competing Interests: Competing interestsG.T and M. Hoke are employees, shareholders, and have been granted stock options at Ampio Pharmaceuticals. E.F. and L.G. are employees and have been granted stock options at Ampio Pharmaceuticals. M. Hausburg is a shareholder at Ampio Pharmaceuticals. D.B-O is a Director and shareholder at Ampio Pharmaceuticals. All other authors have nothing to declare., (© The Author(s) 2020.) more...

Background and Aims: Von Willebrand factor (VWF) plays an important role in thrombogenesis and mediates platelet adhesion particularly under high shear stress. Such conditions are generally found in stenotic arteries and can eventually cause myocardial infarction or stroke. We aimed to study whether levels of VWF antigen (VWF:Ag) predict future major adverse cardiovascular events (MACE) in patients suffering from carotid artery stenosis., Methods: Patients with atherosclerotic carotid artery disease defined by the presence of nonstenotic plaques or any degree of carotid stenosis were prospectively enrolled. Concentrations of VWF were measured by enzyme immunoassay., Results: VWF:Ag levels were more stable after 4 freeze-thaw cycles, when compared to VWF activity, and we showed similar concentrations of VWF in citrated plasma and serum (±4%). Levels of VWF:Ag predicted future cardiovascular events in 811 patients with carotid stenosis independent of known cardiovascular risk factors. Patients with VWF:Ag concentrations in the 4th quartile had a 44% event rate after an average 3-year follow up and a hazard ratio of 2.15 (95% confidence interval 1.46-3.16; p < 0.001)., Conclusions: High concentrations of VWF:Ag predict major cardiovascular events in patients with carotid stenosis, and given their high event rate may be useful for risk stratification of such patients., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.) more...

Background: Experimental and clinical data indicate a major influence of diabetes on atherogenesis. We aimed to assess whether the effect of diabetes on long-term mortality in asymptomatic patient with carotid stenosis is contingent upon the degree of the carotid atherosclerotic burden., Methods: 1065 patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex sonography were prospectively followed for cause-specific mortality., Results: During a median of 11.8 years, a total of 549 deaths, including 362 cardiovascular deaths, were recorded. Diabetes and glycohemoglobin A1c (Hba1c) levels were significantly associated with mortality. Diabetes displayed an independent risk for all-cause (adjusted HR 1.62; 95% CI 1.35-1.94) and cardiovascular death (adjusted HR 1.75, 95% CI 1.40-2.19). The adjusted hazard ratio per increase of 1% of Hba1c levels was 1.21 (P < 0.01) for all-cause and 1.31 (P < 0.01) for cardiovascular mortality, respectively. Patients with diabetes mellitus and a higher degree of carotid stenosis and were at great risk of adverse outcome. Only 21% of the asymptomatic diabetic patients with carotid narrowing over 50% survived, whereas 62% of the patients without diabetes and with carotid atherosclerosis below 50% were still alive after 12-years of follow-up. The high risk for all-cause and cardiovascular death of these patients remained significant after adjustment for various established cardiovascular risk factors in multivariable regression analysis (adjusted hazard ratio 2.4, P < 0.001; compared to patients without diabetes and < 50% carotid atherosclerosis)., Conclusion: Diabetic patients with carotid stenosis ≥ 50% are at exceptional high risk for all-cause and cardiovascular death. Thus, routinely ultrasound investigation of the carotid arteries might be a valuable prognostic tool for patients with diabetes mellitus. more...

Bladder pain syndrome (BPS) is a common cause of chronic pelvic pain with associated lower urinary symptoms. BPS is incurable; management requires an interdisciplinary team (nutritionist, physical therapist, behavioral health specialist) focusing on maximizing patient function. For patients, dietary changes (avoiding acidic, spicy, and caffeinated foods) are effective at relieving symptoms. Medications may be considered in patients who do not respond to these treatments. Referral to urology or urogynecology should be considered if bladder cancer is suspected (especially in patients who smoke or have environmental exposures) and in patients with refractive symptoms for consideration of intravesicular therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.) more...

Background and Purpose: Despite extensive research in the last decade, the role of serum amyloid A (SAA) in atherogenesis remains highly controversial. The aim of this study was therefore to assess whether SAA is associated with long-term mortality in patients with subclinical carotid artery disease., Methods: One thousand sixty-five patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex sonography were prospectively followed for cause-specific mortality., Results: During a median of 11.8 years, a total of 549 deaths, including 362 cardiovascular deaths, were recorded. Patients who died within the follow-up period had significantly higher baseline SAA serum levels compared to those who survived (12.9 vs 9.5 mg/dL; P < 0.001). In univariable Cox regression analysis, the risk of all-cause and cardiovascular mortality significantly increased in patients with elevated serum levels of SAA (crude hazard ratio for cardiovascular mortality per increase of 1 SD of SAA levels was 1.14, 95% CI 1.08-1.22], P < 0.0001). However, SAA lost its significance after adjusting for high-sensitivity C-reactive protein (hsCRP), suggesting that SAA might not be directly associated with atherogenesis, but rather be a mere reflection of the individual patient's inflammatory status., Conclusions: Serum amyloid A is not independently associated with (cardiovascular) mortality in patients with subclinical carotid atherosclerosis., (© 2019 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.) more...

Background and Purpose: Inflammatory responses play a key role in atherogenesis. The aim of this study was to assess the prognostic value of hsCRP (high-sensitivity C-reactive protein) and to evaluate whether degree of carotid stenosis and serum levels of hsCRP jointly predict long-term mortality in asymptomatic patients with carotid atherosclerosis., Methods: One thousand sixty-five patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex sonography were prospectively followed for cause-specific mortality., Results: During a median of 11.81 years, a total of 549 deaths, including 362 cardiovascular deaths, were recorded. The risk of all-cause and cardiovascular mortality significantly increased in patients with elevated serum levels of hsCRP (the adjusted hazard ratio for cardiovascular mortality per increase of 1 mg/dL of hsCRP levels was 1.47; P<0.001). Patients with a high degree of carotid stenosis and increased hsCRP levels were particularly at risk of adverse outcome. Patients with carotid narrowing over 50% and hsCRP levels >0.29 mg/dL (=median) had nearly twice as high a risk of cardiovascular mortality compared with patients with carotid stenosis of <50% and hsCRP levels <0.29 mg/dL (adjusted hazard ratio 1.89; P<0.001). Improvement in risk stratification with combined assessment of carotid stenosis and hsCRP was confirmed by an improvement of the continuous net reclassification improvement with 18% for all-cause mortality and 15% for cardiovascular mortality compared with the degree of carotid stenosis alone (P<0.01)., Conclusions: Measurement of hsCRP in combination with ultrasound investigations of the carotid arteries at a single time point provides additional prognostic information for patients with asymptomatic carotid atherosclerosis., (© 2016 American Heart Association, Inc.) more...

Anti-Müllerian hormone (AMH) and its type II receptor AMHR2, both previously thought to primarily function in gonadal tissue, were unexpectedly identified as potent regulators of transforming growth factor (TGF-β)/bone morphogenetic protein (BMP) signaling and epithelial-mesenchymal transition (EMT) in lung cancer. AMH is a TGF-β/BMP superfamily member, and AMHR2 heterodimerizes with type I receptors (ALK2, ALK3) also used by the type II receptor for BMP (BMPR2). AMH signaling regulates expression of BMPR2, ALK2, and ALK3, supports protein kinase B-nuclear factor κB (AKT-NF-κB) and SMAD survival signaling, and influences BMP-dependent signaling in non-small cell lung cancer (NSCLC). AMH and AMHR2 are selectively expressed in epithelial versus mesenchymal cells, and loss of AMH/AMHR2 induces EMT. Independent induction of EMT reduces expression of AMH and AMHR2. Importantly, EMT associated with depletion of AMH or AMHR2 results in chemoresistance but sensitizes cells to the heat shock protein 90 (HSP90) inhibitor ganetespib. Recognition of this AMH/AMHR2 axis helps to further elucidate TGF-β/BMP resistance-associated signaling and suggests new strategies for therapeutic targeting of EMT., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.) more...

Objective: To investigate the efficacy of para-aneurysmal saline injection for closure of postcatheterization pseudo-aneurysm (PA) at the vascular access site., Methods: Fifty-one consecutive patients with postcatheterization PA at the vascular access site were included to undergo percutaneous para-aneurysmal saline injection. In case of technical failure the day after, PA were treated by bovine thrombin injection. Anatomical properties of the PA were recorded as were details to injection., Results: Initially all patients exhibited success which was reduced to 43 % at day one. A saline volume of median 7 ml (interquartile range 6-8 ml) has been injected. The amount of injected saline was not different in patients with and without treatment success at day one (P = 0.6). Several anatomical properties of the PA exhibited marked differences in patients with or without success. The length (10.3 mm (7.8-12.0) vs. 12.5 mm (10.3-15.0); P = 0.009) and the angulation (110° (100-118) vs. 140° (129-146); P < 0.001) of the fistula/vessel axis was statistically different between groups. The peak systolic velocity failed to show significance with a tendency to higher values in the ineffective study group (P = 0.07). No peripheral complications occurred., Conclusion: Para-aneurysmal saline injection may be a therapeutic alternative to percutaneous thrombin injection in patients exhibiting favorable anatomical properties. more...

Background: Red cell distribution width (RDW) is associated with morbidity and mortality in chronic cardiac disease. The aim of the present study was to investigate the role of RDW as a predictor of adverse outcome in patients with carotid atherosclerosis., Materials and Methods: We prospectively studied 1065 of 1286 consecutive patients with neurological asymptomatic carotid artery stenosis as assessed by duplex Doppler sonography. The study end points were all-cause mortality and cardiovascular mortality respectively., Results: During a median follow-up time of 6·2 years (interquartile range 5·9-6·6), corresponding to 5551 overall person-years, 275 patients (25·8%) died. Of them, 182 patients (66·2%) died due to cardiovascular causes. RDW was significantly associated with adverse outcome. In a continuous multivariate Cox regression analysis, the adjusted hazard ratio for each per cent increase in RDW was 1·39 (95% CI 1·27-1·53; P < 0·001) for all-cause and 1·43 (95% CI 1·28-1·60; P < 0·001) for cardiovascular mortality respectively. Kaplan-Meier estimates showed a gradual relationship between increasing quartiles of RDW and death (log rank P < 0·001). Adjusted hazard ratios for all-cause death ranged from 0·89 to 1·94 for the highest vs. the lowest quartile (P < 0·001 for trend) and for cardiovascular death from 1·08 to 2·34 for the highest vs. the lowest quartile (P < 0·001 for trend) respectively., Conclusions: Red cell distribution width was significantly and independently associated with all-cause and cardiovascular death in patients with asymptomatic carotid atherosclerosis., (© 2016 Stichting European Society for Clinical Investigation Journal Foundation.) more...

Cellular adhesion molecules also known as selectins promote recruitment of inflammatory cells into the arterial wall where they interact with lipid particles leading subsequently to plaque formation. The intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule-1 (VCAM-1) and the endothelial-leukocyte adhesion molecule 1 (ELAM-1) also known as E-selectin mediate the attachment of leukocytes and have been implicated in the destabilisation of atherosclerotic plaques. Therefore, we hypothesised that plasma selectin levels are associated with adverse clinical outcome. We prospectively studied 855 patients with sonographically confirmed carotid atherosclerosis. During a median follow-up of 6.2 years, corresponding to 5,551 overall person-years, 275 patients (26 %) died. We detected a significant association between cardiovascular mortality and ICAM-1 (adjusted hazard ratio [HR]: 3.43, 95 % confidence interval [CI] 2.00-5.88, p< 0.001) as well as VCAM-1 (adjusted HR: 2.51, 95 %CI 1.45-4.34, p=0.001) when comparing the fourth with the first quartile. Comparable results were obtained for all-cause mortality. In contrast, we could not detect a significant association between E-selectin and all-cause or cardiovascular mortality. We identified the selectins ICAM-1 and VCAM-1 as strong and independent predictors of all-cause and cardiovascular mortality in patients with stable carotid atherosclerosis. These molecules are elevated in states of endothelial activation and might assist to monitor anti-atherosclerotic therapy and select those patients with carotid atherosclerosis, who are at higher risk for cardiovascular events. more...

Background: Serum uric acid (SUA) has been discussed to be related to cardiovascular (CV) disease and outcome. We investigated whether levels of SUA predict long-term mortality in neurologically asymptomatic patients with carotid atherosclerotic disease., Methods: We prospectively studied 959 consecutive patients with carotid atherosclerosis as evaluated by duplex Doppler sonography for all-cause and CV death, respectively., Results: During a median follow-up time of 6.3 years (interquartile range [IQR], 5.4-7.1 years), 246 deaths (25.7%), including 160 CV deaths (16.7%), were recorded. Median baseline SUA levels were 5.9 mg/dL (IQR, 5.0-7.0 mg/dL). SUA was significantly associated with all-cause death and CV death. Adjusted hazard ratios (HRs) for an increase of 1 mg/dL of SUA levels were 1.12 (95% confidence interval [CI], 1.04-1.21; P = .003) and 1.20 (95% CI, 1.11-1.30; P < .001) for all-cause and CV death, respectively. Quartiles of SUA levels showed a significant association with CV mortality (log-rank P = .002). For CV death, adjusted HRs for quartiles of increasing SUA levels were 1.45 (95% CI, .87-2.43), 1.44 (95% CI, .85-2.46), and 2.26 (95% CI, 1.36-3.76; P < .01), compared with the lowest quartile, respectively. Patients with baseline carotid stenosis of more than 50% and/or increased levels of SUA (≥median) had an approximately 2-fold increase in risk of (CV) death, compared with patients with carotid narrowing of less than 50% and/or SUA levels less than the median (P < .001)., Conclusions: Levels of SUA represent independent predictors for CV mortality in a cohort of patients with asymptomatic carotid atherosclerosis., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.) more...

Flavonoid-rich dark chocolate has positive effects on vascular function in healthy subjects and in patients at risk of atherosclerosis. The impact of dark chocolate on endothelial and microvascular function in patients with symptomatic peripheral artery disease (PAD) has not been investigated so far. In an investigator blinded, randomized, controlled, cross-over trial we assessed the effect of flavonoid-rich dark chocolate and cocoa-free control chocolate on flow-mediated dilatation (FMD) of the brachial artery and on microvascular function (assessed by Laser Doppler fluxmetry) in 21 patients with symptomatic (Fontaine stage II) PAD. Measurements were done in each patient on 2 single days, with an interval of 7 days, at baseline and at 2 hours after ingestion of 50 g dark chocolate or 50 g white chocolate, respectively. FMD remained unchanged after intake of dark chocolate (baseline and 2 hours after ingestion, %: 5.1 [IQR 4.4 to 7.3] and 5.5 [IQR 3.9 to 10.4]; p = 0.57, and after intake of white chocolate (baseline and 2 hours after ingestion, %: 6.4 [IQR 4.5 to 11.4] and 4.4 [IQR 2.6 to 8.7]; p = 0.14. Similarly, microcirculatory parameters were not significantly altered after intake of any chocolate compared with the respective baseline values. In conclusion, a single consumption of 50 g dark chocolate has no effect on endothelial and microvascular function in patients with symptomatic PAD. more...

Background and Objective: Platelets play a pivotal role in atherothrombosis and are potentially involved in the pathogenesis of atherosclerosis. We investigated whether mean platelet volume (MPV) predicts clinical outcome and progression of atherosclerosis in patients with asymptomatic carotid artery disease., Methods: We studied 1006 of 1268 prospectively collected consecutive patients with asymptomatic carotid atherosclerosis who were evaluated by duplex sonography. Patients were followed up clinically for the occurrence of a major adverse cardiovascular event (MACE), a composite of myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, stroke and death., Results: During a median follow-up of 3.1 years (interquartile range, 2.5-3.5), a total of 316 (31.5%) MACEs were recorded. Increased levels of MPV were significantly associated with increased risk of the occurrence of MACEs (adjusted hazard ratio [HR] for an increase in one standard deviation [SD] of MPV 1.22, confidence interval [CI] 1.05-1.35, P < 0.01). Patients with MPV levels above 11.8 femtolitre (= fifth quintile) had a significantly higher event rate (41.3% vs. 29.3%, P < 0.001) with an adjusted HR for MACEs of 1.65 (95% CI 1.26-2.16, P < 0.001) compared with patients with MPV levels in the first to fourth quintile. No significant association was found between baseline MPV levels with either baseline degree or progression during a 6-month follow-up of carotid stenosis., Conclusion: Mean platelet volume was independently and significantly associated with adverse cardiovascular outcome in patients with asymptomatic carotid atherosclerosis., (© 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.) more...

Background: Inflammation is associated with atherosclerotic disease. In this context, it has been shown that an increased neutrophil count is a risk factor for cardiovascular events in patients with coronary and peripheral artery disease. However, the impact of neutrophils on long-term mortality in patients with carotid atherosclerosis is not yet fully understood., Methods: We prospectively studied 853 of 1268 consecutive patients with neurologically asymptomatic carotid stenosis for all-cause and cardiovascular death, respectively., Results: During a median follow-up time of 6.3 years (IQR 5.8-6.7 years) a total of 203 deaths (23.8%), including 134 cardiovascular deaths (15.7%), were recorded. An increase of 1 G/L of neutrophil count indicated an increased risk for all-cause mortality of 1.20 (CI [95%] 1.10-1.31, P < 0.001) and of cardiovascular death of 1.30 (CI 1.17-1.45, P < 0.001), respectively. For the second to the fourth quartile of the neutrophil count, adjusted hazard ratios for all-cause mortality were 1.12 (CI, 0.71-1.75), 1.46 (CI, 0.96-2.21), and 1.76 (CI, 1.15-2.69; P = 0.03 for trend); and 1.41 (CI, 0.80-2.49), 1.53 (CI, 0.88-2.68), and 2.54 (CI, 1.49-4.33; P < 0.01 for trend) for cardiovascular mortality, compared to the lowest quartile, respectively. Patients with baseline carotid stenosis of more than 50% and/or increased neutrophil count (≥median), had a 1.9-2.4 fold increase in risk of (CV-) death, compared to patients with carotid narrowing of less than 50% and/or neutrophil count less than the median (P < 0.001). After adjusting for cardiovascular risk factors, only neutrophils, but not eosinophils, basophils, monocytes, lymphocytes, or the total leukocyte count showed a significant association with long-term mortality. No significant association was found between white blood cell subtypes with either baseline degree or progression during a 6 month follow-up of carotid stenosis., Conclusion: The baseline neutrophil count was an independent predictor for all-cause and cardiovascular mortality in neurologically asymptomatic patients with carotid stenosis. Thus, the measurement of neutrophils could provide prognostic information on outcome in patients at risk., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.) more...

Chronic inflammation is a potentially important pathway through which psychosocial stressors increase risk for cardiovascular disease. However, prior research on stress and inflammation has been conducted almost exclusively in high income, industrialized populations with low levels of infectious disease. In this study we test the hypothesis that psychosocial stressors are associated with elevated concentrations of C-reactive protein (CRP) among young adults in the Philippines (n=1622), who have grown up in an ecological and epidemiological setting that differs substantially from that of the US. In addition, we apply a developmental, ecological perspective to consider whether microbial and nutritional environments in infancy alter patterns of association between stressors and CRP. Data come from the Cebu Longitudinal Health and Nutrition Survey, a prospective cohort study that began collecting data in 1983-1984 when participants were in utero. A series of regression models indicate trends toward significant interactions between perceived stress and environmental factors in infancy, including exposure to animal feces, season of birth, and birth weight. Parental absence in childhood was a significant predictor of CRP in adulthood in interaction with exposure to animal feces in infancy. Positive associations between stressors and CRP were only evident for individuals with lower levels of microbial exposure in infancy, or lower birth weight. These results suggest that early environments influence the development of inflammatory phenotypes in ways that moderate sensitivity to psychosocial stressors in adulthood, and they underscore the value of a comparative, developmental approach to research on social environments, inflammation, and disease., (Copyright © 2012 Elsevier Inc. All rights reserved.) more...

Protocols for recipient desensitization may allow for successful kidney transplantation across major immunological barriers. Desensitized recipients, however, still face a considerable risk of antibody-mediated rejection (AMR), which underscores the need for risk stratification tools to individually tailor treatment. Here, we investigated whether solid phase detection of complement-fixing donor-specific antibodies (DSA) has the potential to improve AMR prediction in high-risk transplants. The study included 68 sensitized recipients of deceased donor kidney allografts who underwent peritransplant immunoadsorption for alloantibody depletion (median cytotoxic panel reactivity: 73%; crossmatch conversion: n = 21). Pre and post-transplant sera were subjected to detection of DSA-triggered C4d deposition ([C4d]DSA) applying single-antigen bead (SAB) technology. While standard crossmatch and [IgG]SAB testing failed to predict outcomes in our desensitized patients, detection of preformed [C4d]DSA (n = 44) was tightly associated with C4d-positive AMR [36% vs. 8%, P = 0.01; binary logistic regression: odds ratio: 10.1 (95% confidence interval: 1.6-64.2), P = 0.01]. Moreover, long-term death-censored graft survival tended to be worse among [C4d]DSA-positive recipients (P = 0.07). There were no associations with C4d-negative AMR or cellular rejection. [C4d]DSA detected 6 months post-transplantation were not related to clinical outcomes. Our data suggest that pretransplant SAB-based detection of complement-fixing DSA may be a valuable tool for risk stratification., (© 2012 The Authors Transplant International © 2012 European Society for Organ Transplantation. Published by Blackwell Publishing Ltd.) more...

Background: Periprocedural outcome has been extensively investigated in patients undergoing carotid artery stenting. However, risk factors contributing to long-term mortality have not been comprehensively assessed. We aimed to establish a validated clinical risk score for long-term mortality in patients after carotid artery stenting., Methods and Results: Two independent cohorts after successful carotid artery stenting (602 and 552 patients) were prospectively investigated. Multivariable Cox regression and bootstrap variable selection were used to select the best-fitting multivariable model. The mortality rate was 35% in the derivation and 39% in the validation cohort during a median follow-up of 6.5 and 7.4 years, respectively. The following variables were identified as most robust risk factors in the derivation cohort: age, heart failure, diabetes mellitus, relative lymphocyte count, prothrombin time, peripheral artery disease, and contralateral carotid occlusion. A weighted multimarker risk score yielded an area under the receiver operating characteristic curve of 0.79 in the derivation (P<0.001) and of 0.69 (P<0.001) in the validation cohort. In comparison, the best area under the receiver operating characteristic curves for single risk factors were 0.67 and 0.63, respectively. For optimal clinical use, a simplified risk score was also developed, which discriminated very well from very low to very high risk. The risk of all-cause mortality ranged from 8% for a score of 1 to 93% for a score of 7 (P<0.001) in the derivation and from 11% to 100% in the validation cohort (P<0.001)., Conclusions: A multimarker risk score outperformed the prognostic value of single risk factors for the prediction of long-term mortality. more...

Anemia is associated with the cardiovascular outcome in healthy subjects but its impact on outcome in patients with cardiovascular disease has not yet been fully understood. Therefore, we assessed the long-term influence of hemoglobin on all-cause and cardiovascular mortality in patients with atherosclerotic disease. We prospectively studied 1,065 of 1,286 consecutive patients with asymptomatic carotid narrowing. During a median follow-up of 6.2 years, corresponding to 5,551 overall person-years, 275 patients (25.8%) died. Continuous measures of hemoglobin displayed a significant inverse effect on all-cause mortality and cardiovascular mortality (adjusted hazard ratio [HR] for increase of 1 SD of hemoglobin 0.73, 95% confidence interval [CI] 0.64 to 0.83; p <0.001) and adjusted HR 0.76, 95% CI 0.64 to 0.89; p = 0.001, respectively). The cumulative 6-year survival rate was 61%, 79%, 80%, and 81% in the first, second, third, and fourth quartile of hemoglobin (log-rank p <0.001). Patients within the first quartile (<12.9 g/dl) had a significantly increased risk of all-cause mortality (adjusted HR 1.93, 95% CI 1.46 to 2.54, p <0.001) and cardiovascular mortality (adjusted HR 1.68, 95% CI 1.19 to 2.36, p = 0.003) compared to patients with greater levels. In conclusion, our study has demonstrated a significant association with hemoglobin levels and all-cause and cardiovascular mortality in patients with carotid narrowing. Nevertheless, additional research, in terms of randomized controlled trials, is needed to warrant these findings and to evaluate potential therapeutic interventions., (Copyright © 2012 Elsevier Inc. All rights reserved.) more...

Unlabelled: von Willebrand factor antigen (vWF-Ag) is elevated in patients with liver cirrhosis, but the clinical significance is unclear. We hypothesized that vWF-Ag levels may correlate with portal pressure, measured by hepatic venous pressure gradient (HVPG), and predict clinically significant portal hypertension (CSPH; HVPG ≥ 10 mmHg), decompensation and mortality. Portal hemodynamics were assessed by HVPG measurement, whereas vWF-Ag levels were measured by enzyme-linked immunosorbent assay. During follow-up, complications of liver cirrhosis, death or transplantation were recorded. Two hundred and eighty-six patients (205 male and 81 female; mean age, 56 years) with liver cirrhosis were included. vWF-Ag correlated with HVPG (r = 0.69; P < 0.0001) and predicted CSPH independently of Child Pugh score. Higher vWF-Ag levels were associated with varices (odds ratio [OR] = 3.27; P < 0.001), ascites (OR = 3.93; P < 0.001) and mortality (hazard ratio: 4.41; P < 0.001). Using a vWF-Ag cut-off value of ≥ 241%, the AUC for detection of CSPH in compensated patients was 0.85, with a positive predictive value and negative predictive value of 87% and 80%, respectively. Compensated patients had 25% mortality after 53 months if the vWF-Ag was <315% compared to 15 months in patients with vWF-Ag >315% (P < 0.001). Decompensated patients had a mortality of 25% after 37 and 7 months if their vWF-Ag was <315% and >315%, respectively (P = 0.002). In compensated patients with a vWF-Ag >315% median time to decompensation or death was 32 months compared with 59 months in patients with vWF-Ag <315%. vWF-Ag equals Model for End-Stage Liver Disease (MELD) in mortality prediction (area under the curve [AUC] = 0.71 for vWF-Ag versus AUC = 0.65 for MELD; P = 0.2)., Conclusion: vWF-Ag is a new, simple and noninvasive predictor of CSPH. A vWF-Ag cut-off value at 315% can clearly stratify patients with compensated and decompensated liver cirrhosis in two groups with completely different survival. vWF-Ag may become a valuable marker for the prediction of mortality in patients with liver cirrhosis in clinical practice., (Copyright © 2012 American Association for the Study of Liver Diseases.) more...

Background: Humoral mediators of inflammation, in particular the complement system, have been described to play an important role in atherogenesis. Previously, we found a single-nucleotide polymorphism (SNP) in the complement 5 gene (C5 rs17611, A>G) independently associated with stroke. Up to now, the impact of C5 rs17611 on the progression of atherosclerosis and cardiovascular outcome in patients with asymptomatic atherosclerosis was unclear., Materials and Methods: We investigated C5 rs17611 in a cohort of 1065 consecutive patients with asymptomatic carotid atherosclerosis. All patients were prospectively followed for the progression of carotid atherosclerosis and the development of a first major cardiovascular event (MACE), respectively., Results: Three hundred and thirty-seven patients (31·6%) experienced a MACE during a median follow-up of 3·0 years. The homozygous GG genotype of the C5 rs17611 was significantly associated with adverse cardiovascular outcome (adjusted HR: 1·36 [95% CI, 1·07-1·73]; P = 0·01). After stratification for sex, C5 rs17611 CC was found to be an independent risk factor for MACE in men (HR 1·50 [95% CI, 1·12-1·83]). No association of C5 rs17611 with progression of carotid stenosis, observed in 93 (8·7%) patients, was detectable. Performance of ELISA indicated a significant association of the C5 rs17611 variant with C5a plasma levels., Conclusion: The C5 rs17611 GG genotype is associated with increased C5a plasma levels and represents a risk factor for adverse cardiovascular outcome in male patients with carotid atherosclerosis., (© 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.) more...

Background: Low-density lipoprotein (LDL) cholesterol lowering has been established as one of the principal targets in preventive cardiology. Recently, assessment of LDL particle size and number as well as other lipid moieties has been presented as a more reliable method to quantify atherogenicity of the lipoprotein fractions. Thus, it was our aim to assess the influence of different lipoprotein fractions on premature myocardial infarction (≤ 40 years of age)., Methods and Results: We enrolled 302 patients into our multicentre case-control study, including 102 patients with myocardial infarction and 200 age-, gender- and centre-matched controls. The LDL and HDL Lipoprint System were used for lipid subfraction quantification. The lipid risk factors most strongly associated with premature acute myocardial infarction (AMI) in the adjusted model were non-HDL C (OR 5·02, 95% CI 2·75-9·15, P-value = 0·001), LDL-C (OR 4·35, 95% CI 2·5-7·57, P-value = 0·001), VLDL-C (OR 3·66, 95% CI 2·14-6·28, P-value = 0·001), large IDL-C (OR 3·15, 95% CI 1·94-5·12, P-value = 0·001), large LDL-C (OR 3·67, 95% CI 2·19-6·15, P-value = 0·001) and intermediate LDL-C (OR 1·96, 95% CI 1·25-3·06, P-value = 0·003). In contrast, small dense LDL was not significantly associated with premature myocardial infarction., Conclusion: Non-HDL cholesterol is most strongly associated with premature coronary artery disease and could serve as preferred risk predictor and therapeutic target in this young patient population (≤ 40 years). Besides, VLDL, LDL-C, large LDL, intermediate LDL and large IDL were significantly associated with premature myocardial infarction. Furthermore, our data suggest that risk prediction using small dense LDL particles might not be useful in young AMI survivors., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.) more...

Renal dysfunction is a risk factor for mortality in patients with atherosclerosis. Estimated glomerular filtration rate (eGFR), cystatin C (CysC) and beta-2-microglobulin (B2M) are measures of renal function. It remains unclear, which of these parameters is the strongest predictor of outcome in patients with atherosclerosis. All-cause and cardiovascular mortality were prospectively investigated in 1,065 consecutive patients with asymptomatic carotid atherosclerosis. During a median follow-up of 6.3 years 275 patients died (25.8%), including 182 (66.2%) from cardiovascular causes. Estimated GFR, CysC and B2M were all significantly and independently associated with mortality. Inclusion of the renal parameters CysC and B2M but not of eGFR into a model with established cardiovascular risk factors improved the C-statistics significantly (p=0.0035 and 0.036, respectively; p=0.182 for eGFR). The net reclassification improvement (NRI) was 32.4% (p<0.0001) for CysC, 29% (p<0.0001) for B2M, and 16.5% (p=0.019) for eGFR. The integrated discrimination improvement (IDI) was 0.014 (p=0.0009) for CysC and 0.011 (p=0.005) for B2M while it was not significant for eGFR. Results were consistent for various subgroups with different extent of atherosclerosis. In summary, CysC and B2M were found to be independent predictors for mortality and had superior predictive value compared to eGFR in patients with asymptomatic carotid atherosclerosis. The clinical importance of these findings has to be validated in larger studies with a community-based approach. more...

Background and Purpose: Markers of apoptosis are associated with cardiovascular disease. The soluble apoptosis-stimulating fragment (sFAS) was found to be a predictor for outcome in patients with heart failure, but its importance in patients with atherosclerotic disease has not been fully understood as yet. The aim of the present study was to investigate the impact of sFAS on all-cause and cardiovascular mortality in patients with atherosclerosis in the carotid arteries., Methods: We studied 981 of 1286 consecutive patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex Doppler sonography. Patients were prospectively followed for long-term all-cause and cardiovascular mortality., Results: During a median follow-up of 6.2 years (interquartile range, 5.9 to 6.6 years), a total of 250 deaths (25.5%), including 165 (66%) cardiovascular deaths, were recorded. The risk for all-cause and for cardiovascular mortality, respectively, increased significantly with sFAS concentrations (P<0.001). The hazard ratio for all-cause death was elevated by 2.3-fold (P<0.001) and for cardiovascular death by 2.4-fold (P<0.001) in patients within the highest quintile of sFAS compared with patients within the lowest quintile, respectively. Results remained significant after adjustment for potential confounders and established cardiovascular risk factors, including high-sensitivity C-reactive protein. Patients with high sFAS but low high-sensitivity C-reactive protein had a comparable survival rate with those with elevated high-sensitivity C-reactive protein only (P=0.50)., Conclusions: Markers of apoptosis, as measured by sFAS, were found to be independent risk predictors for death in patients with atherosclerotic disease in the carotid arteries. more...

Background and Purpose: Atherosclerosis is a chronic inflammatory disease. Ongoing inflammation is associated with elevated levels of beta 2 microglobulin (B2M). We investigated B2M levels in a large cohort of patients with carotid atherosclerosis for the occurrence of major adverse cardiovascular events., Methods: One thousand five of 1286 consecutive, neurologically asymptomatic patients with carotid atherosclerosis were followed for a median of 3 years (interquartile range, 2.5 to 3.5) for the occurrence of major adverse cardiovascular events, a composite of myocardial infarction, percutaneous coronary intervention, coronary bypass graft, stroke, and death., Results: We recorded 359 major cardiovascular events in 271 (27%) patients. B2M was significantly associated with the occurrence of major adverse cardiovascular events. With increasing quartiles of B2M, the adjusted hazard ratios were 1.19 (95% CI, 0.81 to 1.73), 1.51 (95% CI, 1.05 to 2.18), and 1.88 (95% CI, 1.26 to 2.79) compared with the lowest quartile, respectively (P<0.001). Adjusted hazard ratios for the occurrence of death, myocardial infarction, and stroke for increasing quartiles of B2M were 1.25 (95% CI, 0.92 to 1.70), 1.52 (95% CI, 1.12 to 2.06), and 1.62 (95% CI, 1.16 to 2.67) compared with the lowest quartile, respectively (P<0.001). Through statistical estimation of improvement in risk stratification, addition of B2M to baseline risk factors improved the risk stratification for major cardiovascular events, at least as much as high-sensitivity C-reactive protein or even better., Conclusions: B2M was independently and significantly associated with adverse cardiovascular outcome in patients with prevalent asymptomatic carotid atherosclerosis. more...