Women present with pulmonary embolism (PE) more often than men, while the opposite is true for proximal deep vein thrombosis (DVT). We investigated whether sex-specific differences exist in the ...presenting location of acute symptomatic DVT among patients without concomitant PE.
We tested our hypothesis in a meta-analysis of studies selected by systematically reviewing PubMed, Embase, and the grey literature. Thereafter, we analysed data of a single-center cohort including patients with first isolated acute DVT to assess the additional impact of age and provoking risk factors on the presenting location of DVT.
We identified 7 studies for a total of 20,534 patients. The weighed pooled absolute difference in the proportion of distal DVT between women and men was +5.4% (95%CI: +0.7%; +9.5%), which corresponds to a pooled odds ratio (OR) of 1.30 (95%CI: 1.07–1.58). This difference was +6.5% (95%CI: +2.1%; +10.9%) for first distal DVT (OR 1.38; 95%CI: 1.11–1.72) and +5.3% (95%CI: +0.5%; +10.0%) for either first or recurrent distal DVT (OR 1.29; 95%CI: 1.03–1.61). In the cohort study, the larger difference in the proportion of distal DVT between women and men was observed among patients aged 51–70 (+9.5%; 95CI: +2.8%; +16.0% compared to those aged 18–50) or with unprovoked events (+8.5%; 95CI: −0.9%; +17.9%).
Among patients with first symptomatic isolated acute DVT, women presented with distal DVT more often than men, whereas men had a higher proportion of proximal DVT events. This pattern appeared to depend on age and the absence of provoking risk factors for VTE.
•The proportions of pulmonary embolism versus proximal deep vein thrombosis (DVT) events differ between sexes.•We investigated whether the distal versus proximal presenting location of isolated DVT is influenced by sex.•Women presented with distal DVT more often than men, whereas men had more often proximal DVT.•This pattern appeared to depend on age and the absence of provoking risk factors, but further studies are warranted.
Isolated PE is associated with a higher burden of atherosclerotic disease than other manifestations of VTE.
We hypothesized that the presence of isolated PE may signal a chronically elevated risk of ...arterial thrombotic disease.
Data from the VTEval Study, a prospective cohort study enrolling individuals with clinical suspicion and imaging-based diagnosis or exclusion of VTE, were analyzed. Patients with PE received whole-leg ultrasonography to assess presence of DVT. Regularized logistic regression identified features that discriminate between isolated PE and other VTE phenotypes at clinical presentation. Survival analyses were performed to evaluate the crude and adjusted 3-year risks of arterial thrombotic disease, recurrent VTE, and death.
The sample comprised 510 patients. Isolated PE patients (n = 63) had a distinct clinical profile from patients with other VTE phenotypes (n = 447). COPD, peripheral artery disease, atrial fibrillation, and coronary artery disease were significantly more prevalent among patients with isolated PE. Isolated PE patients had significantly higher risk (incidence rate ratio vs DVT-associated PE, 3.7 (95% CI, 1.3-10.8, P = .009); vs isolated DVT, 4.8 (1.7-14.3, P = .001) of arterial thrombotic events (ie, myocardial infarction, stroke/transient ischemic attack). After adjustment for clinical profile and medication intake, the risk of arterial thrombotic events for patients with isolated PE remained quadruple that of other VTE phenotypes (hazard ratio HR, 3.8 1.3-10.9, P = .01).
Patients with isolated PE are at higher risk for arterial thrombosis and may require screening for arterial disease and development of novel therapeutic strategies.
NCT02156401.
Patients with isolated pulmonary embolism (PE) have a distinct clinical profile from those with deep vein thrombosis (DVT)-associated PE, with more pulmonary conditions and atherosclerosis. These ...findings suggest a distinct molecular pathophysiology and the potential involvement of alternative pathways in isolated PE. To test this hypothesis, data from 532 individuals from the Genotyping and Molecular Phenotyping of Venous ThromboEmbolism Project, a multicenter prospective cohort study with extensive biobanking, were analyzed. Targeted, high-throughput proteomics, machine learning, and bioinformatic methods were applied to contrast the acute-phase plasma proteomes of isolated PE patients (n = 96) against those of patients with DVT-associated PE (n = 276) or isolated DVT (n = 160). This resulted in the identification of shared molecular processes between PE phenotypes, as well as an isolated PE-specific protein signature. Shared processes included upregulation of inflammation, response to oxidative stress, and the loss of pulmonary surfactant. The isolated PE-specific signature consisted of 5 proteins: interferon-γ, glial cell line–derived neurotrophic growth factor, polypeptide N-acetylgalactosaminyltransferase 3, peptidyl arginine deiminase type-2, and interleukin-15 receptor subunit α. These proteins were orthogonally validated using cis protein quantitative trait loci. External replication in an independent population-based cohort (n = 5778) further validated the proteomic results and showed that they were prognostic for incident primary isolated PE in individuals without history of VTE (median time to event: 2.9 years; interquartile range: 1.6-4.2 years), supporting their possible involvement in the early pathogenesis. This study has identified molecular overlaps and differences between VTE phenotypes. In particular, the results implicate noncanonical pathways more commonly associated with respiratory and atherosclerotic disease in the acute pathophysiology of isolated PE.
•Isolated PE is well-differentiable from DVT-associated PE based on its acute plasma proteome, suggesting a distinct pathophysiology.•In an external validation in a population-based cohort, the majority of isolated PE-related proteins predicted incident primary isolated PE.
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To establish reference values and clinically relevant determinants for measures of heart rate variability (HRV) and to assess their relevance for clinical outcome prediction in individuals with heart ...failure.
Data from the MyoVasc study (NCT04064450; N = 3289), a prospective cohort on chronic heart failure with a highly standardized, 5 h examination, and Holter ECG recording were investigated. HRV markers were selected using a systematic literature screen and a data-driven approach. Reference values were determined from a healthy subsample. Clinical determinants of HRV were investigated via multivariable linear regression analyses, while their relationship with mortality was investigated by multivariable Cox regression analyses.
Holter ECG recordings were available for analysis in 1001 study participants (mean age 64.5 ± 10.5 years; female sex 35.4%). While the most frequently reported HRV markers in literature were from time and frequency domains, the data-driven approach revealed predominantly non-linear HRV measures. Age, sex, dyslipidemia, family history of myocardial infarction or stroke, peripheral artery disease, and heart failure were strongly related to HRV in multivariable models. In a follow-up period of 6.5 years, acceleration capacity HR
1.53 (95% CI 1.21/1.93), p = 0.0004, deceleration capacity HR
: 0.70 (95% CI 0.55/0.88), p = 0.002, and time lag HR
1.22 (95% CI 1.03/1.44), p = 0.018 were the strongest predictors of all-cause mortality in individuals with heart failure independently of cardiovascular risk factors, comorbidities, and medication.
HRV markers are associated with the cardiovascular clinical profile and are strong and independent predictors of survival in heart failure. This underscores clinical relevance and interventional potential for individuals with heart failure.
NCT04064450.
Individuals with acute venous thromboembolism (VTE) constitute a heterogeneous group of patients with diverse clinical characteristics and outcome.
To identify endotypes of individuals with acute VTE ...based on clinical characteristics at presentation through unsupervised cluster analysis and to evaluate their molecular proteomic profile and clinical outcome.
Data from 591 individuals from the Genotyping and Molecular phenotyping of Venous thromboembolism (GMP-VTE) project were explored. Hierarchical clustering was applied to 58 variables to define VTE endotypes. Clinical characteristics, three-year incidence of thromboembolic events or death, and acute-phase plasma proteomics were assessed.
Four endotypes were identified, exhibiting different patterns of clinical characteristics and clinical course. Endotype 1 (n = 300), comprising older individuals with comorbidities, had the highest incidence of thromboembolic events or death (HR 95 % CI: 3.76 1.96–7.19), followed by endotype 4 (n = 127) (HR 95 % CI: 2.55 1.26–5.16), characterised by men with history of VTE and provoking risk factors, and endotype 3 (n = 57) (HR 95 % CI: 1.57 0.63–3.87), composed of young women with provoking risk factors, vs. reference endotype 2 (n = 107). The reference endotype was constituted by individuals diagnosed with PE without comorbidities, who had the lowest incidence of the investigated endpoint. Differentially expressed proteins associated with the endotypes were related to distinct biological processes, supporting differences in molecular pathophysiology. The endotypes had superior prognostic ability compared to existing risk stratifications such as provoked vs unprovoked VTE and D-dimer levels.
Four endotypes of VTE were identified by unsupervised phenotype-based clustering that diverge in clinical outcome and plasmatic protein signature. This approach might support the future development of individualized treatment in VTE.
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•Unsupervised clustering of clinical features identified four endotypes in acute VTE.•Endotypes differed in recurrence of VTE, arterial events, death and bleeding.•Plasma protein profiling by immuno-PCR suggests pathomechanistic diversity.•The endotyping outperformed traditional tools for VTE risk stratification.
Cardiovascular disease (CVD) is the leading cause of death in patients with nonalcoholic fatty liver disease (NAFLD). The current analysis expands the knowledge on atherogenic lipid profiles in NAFLD ...by modeling changes in low‐density lipoprotein cholesterol (LDL‐C) and total cholesterol (TC) in a prospectively enrolling real‐life study cohort to inform physicians on the cardiovascular (CV) event risk based on these changes. A total of 304 patients with histologically confirmed NAFLD were included (mean age, 52 years; equal sex distribution). Of these, 129 (42.4%) patients exhibited a NAFLD activity score ≥4 and 186 (61.2%) had at least intermediate fibrosis ≥F2. The median TC levels were 209 mg/dL (interquartile range IQR, 183, 239), LDL‐C 131 mg/dL (IQR, 103, 152), and high‐density lipoprotein cholesterol (HDL‐C) 45 mg/dL (IQR, 38, 52). Only 16.9% of patients received lipid‐lowering therapy. According to the LDL/HDL ratio, 69 (23.7%) patients exhibited a high CV risk. The 10‐year CV event risk according to the Framingham risk score (FRS) was low in 91 (41.2%), intermediate in 59 (26.7%), and high in 71 (32.1%) patients and higher in the ≥F2 NAFLD population. A moderate increase in LDL‐C levels by 20 mg/dL led to a transition of 20% of patients into the high‐risk group when assessing the LDL/HDL ratio. According to the FRS, 6 (2.7%) patients moved from low to intermediate and 11 (4.9%) from intermediate to high CV risk. Conclusion: Patients with NAFLD exhibit a substantial CV event risk and are frequently undertreated with lipid‐lowering medication. Moderate increases in LDL‐C would result in worsening of the CV event risk in approximately 7.8% of all patients without a history of CVD.
NAFLD patients exhibit an increased cardiovascular mortality. Assessment of the cardiovascular event risk will help clinicians to manage these patients. The current analysis provides real‐world evidence in a cohort of biopsy‐proven NAFLD patients and segregates high and low risk categories for incident CVD disease. This data will support in the decision on pharmacotherapy and in particular NASH‐directed therapies in the future.
Abstract
Objective
Tissue factor pathway inhibitor (TFPI) is a potent anticoagulant protein in the extrinsic coagulation pathway. In the present study, we aim to identify the cardiovascular ...determinants for total TFPI activity and its association with cardiovascular disease (CVD) and total mortality.
Methods
Total TFPI activity was assessed in a selection of the population-based Gutenberg Health Study (
n
= 5,000). Statistical analysis was performed to identify the determinants for total TFPI activity as well as the associations with CVD and mortality.
Results
Multivariable linear regression analysis identified smoking (
β
0.095 0.054–0.136) as a positive determinant for total TFPI activity, while diabetes (
β
–0.072 –0.134 to –0.009), obesity (
β
–0.063 –0.101 to –0.024), and history of coronary artery disease (CAD) were negatively associated with total TFPI activity, independent of age, sex, and the remaining cardiovascular risk factors. After adjustment for lipoprotein levels, the association between total TFPI activity levels and obesity and CAD was lost. The analysis additionally revealed a strong positive association between total TFPI activity levels and low-density lipoprotein (
β
0.221 0.204–0.237). The Cox regression models revealed that a higher total TFPI activity, above 97.5th percentile of the reference group, was associated with an increased mortality risk (hazard ratio = 2.58 95% confidence interval: 1.49–4.47), independent of age, sex, and cardiovascular risk profile.
Conclusion
In the Gutenberg Health Study population-based cohort, the highest percentage of total TFPI correlated with an increased mortality risk. While elevated TFPI may reflect endothelial cell activation, the associations between total TFPI activity and obesity and CAD, points to additional mechanistic interactions.
Targeted proteomics utilizing antibody-based proximity extension assays provides sensitive and highly specific quantifications of plasma protein levels. Multivariate analysis of this data is hampered ...by frequent missing values (random or left censored), calling for imputation approaches. While appropriate missing-value imputation methods exist, benchmarks of their performance in targeted proteomics data are lacking. Here, we assessed the performance of two methods for imputation of values missing completely at random, the previously top-benchmarked 'missForest' and the recently published 'GSimp' method. Evaluation was accomplished by comparing imputed with remeasured relative concentrations of 91 inflammation related circulating proteins in 86 samples from a cohort of 645 patients with venous thromboembolism. The median Pearson correlation between imputed and remeasured protein expression values was 69.0% for missForest and 71.6% for GSimp (p = 5.8e-4). Imputation with missForest resulted in stronger reduction of variance compared to GSimp (median relative variance of 25.3% vs. 68.6%, p = 2.4e-16) and undesired larger bias in downstream analyses. Irrespective of the imputation method used, the 91 imputed proteins revealed large variations in imputation accuracy, driven by differences in signal to noise ratio and information overlap between proteins. In summary, GSimp outperformed missForest, while both methods show good overall imputation accuracy with large variations between proteins.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aims:
Cigarette smoking is one of the most complex and least understood cardiovascular risk factors. Importantly, differences in the tobacco-related pathophysiology of endothelial dysfunction, an ...early event in atherogenesis, between circulatory beds remain elusive. Therefore, this study evaluated how smoking impacts endothelial function of conduit and resistance arteries in a large population-based cohort.
Methods and results:
15,010 participants (aged 35–74 years) of the Gutenberg Health Study were examined at baseline from 2007 to 2012. Smoking status, pack-years of smoking, and years since quitting smoking were assessed by a computer-assisted interview. Endothelial function of conduit and resistance arteries was determined by flow-mediated dilation (FMD) of the brachial artery, reactive hyperemia index (RHI) using peripheral arterial tonometry, as well as by reflection index (RI) derived from digital photoplethysmography, respectively. Among all subjects, 45.8% had never smoked, 34.7% were former smokers, and 19.4% were current smokers. Mean cumulative smoking exposure was 22.1 ± 18.1 pack-years in current smokers and mean years since quitting was 18.9 ± 12.7 in former smokers. In multivariable linear regression models adjusted for typical confounders, smoking status, pack-years of smoking, and years since quitting smoking were independently associated with RHI and RI, while no association was found for FMD. Overall, no clear dose-dependent associations were observed between variables, whereby higher exposure tended to be associated with pronounced resistance artery endothelial dysfunction.
Conclusions:
Cigarette smoking is associated with altered endothelial function of resistance, but not conduit arteries. The present results suggest that smoking-induced endothelial dysfunction in different circulatory beds may exhibit a differential picture.
BACKGROUND
Although polypharmacy is associated with a negative clinical outcome in various settings and commonly observed in patients receiving oral anticoagulation therapy, evidence on the relevance ...for the clinical outcome of anticoagulated patients is currently limited. The aim of the study was to investigate the effect of polypharmacy on the clinical outcomes among patients taking phenprocoumon.
DESIGN
Prospective cohort study.
SETTING
Regular medical care.
PARTICIPANTS
Information on 2011 individuals receiving vitamin K antagonists was available for analysis from the prospective multicenter thrombEVAL study.
MEASUREMENTS
Data were obtained from clinical visits, computer‐assisted interviews, and laboratory measurements. Information on clinical outcome was obtained during a 3‐year follow‐up period and subsequently validated via medical records.
RESULTS
The prevalence of polypharmacy (five drugs or more) was 84.1% (n = 1691). Quality of anticoagulation therapy assessed by time in therapeutic range was lower in individuals on five to eight drugs and nine drugs or more (70.7% and 64.7%, respectively) compared with subjects without polypharmacy (73.4%). In addition, a significantly higher variability of international normalized ratio measurements was found in the presence of polypharmacy. The cumulative incidence of bleeding, hospitalization, and all‐cause mortality, but not for thromboembolic events, increased across groups of medication. In adjusted Cox regression analysis, polypharmacy is an independent risk factor for bleeding (hazard ratio HR≥ 9 drugs vs 1‐4 drugs = 1.62; 95% confidence interval CI = 1.04‐2.52; p = .033); hospitalization (HR≥ 9 drugs vs 1‐4 drugs = 1.60; 95% CI = 1.26‐2.03; p < .001; and all‐cause mortality (HR≥ 9 drugs vs 1‐4 drugs = 2.16; 95% CI = 1.43‐3.27; p < .001) in a dose‐dependent relationship. Per additional drug, bleeding risk was increased by 4%.
CONCLUSIONS
Polypharmacy influences the quality of anticoagulation therapy and translates into an elevated risk of adverse events in anticoagulated patients. This suggests that additional medication intake in such patients should be critically reviewed by physicians, and it highlights the importance of initiating investigations aimed at reducing multiple medication intake. J Am Geriatr Soc 67:463–470, 2019.
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