Autoantibodies against the chemokine receptor 3 predict cardiovascular risk.

BACKGROUND AND AIMS: Chronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear. METHODS: Anti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in 5000 participants (availability: 97.1%) of the population-based Gutenberg Health Study with extensive clinical phenotyping. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcome (i.e. all-cause mortality, cardiac death, heart failure, and major adverse cardiac events comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE(-/-) mice for preclinical validation. RESULTS: The analysis sample included 4195 individuals (48% female, mean age 55.5 ± 11 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional CV risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima-media thickness, left ventricular mass, and N-terminal pro-B-type natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) (95% confidence interval) 1.25 (1.02, 1.52), P = .029], driven by excess cardiac mortality [HR 2.51 (1.21, 5.22), P = .014]. A trend towards a higher risk for major adverse cardiac events [HR 1.42 (1.0, 2.0), P = .05] along with increased risk of incident heart failure [HR per standard deviation increase of anti-CXCR3 aAbs: 1.26 (1.02, 1.56), P = .03] may contribute to this observation. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine-cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE(-/-) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared to non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model. CONCLUSIONS: In individuals free of autoimmune disease, anti-CXCR3 aAbs were abundant, related to CV end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis.

Protein expression profiling suggests relevance of noncanonical pathways in isolated pulmonary embolism.

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.

Relationships between coagulation factors and thrombin generation in a general population with arterial and venous disease background.

BACKGROUND: The current study aims to identify the relationships between coagulation factors and plasma thrombin generation in a large population-based study by comparing individuals with a history of arterial or venous thrombosis to cardiovascular healthy individuals. METHODS: This study comprised 502 individuals with a history of arterial disease, 195 with history of venous thrombosis and 1402 cardiovascular healthy individuals (reference group) from the population-based Gutenberg Health Study (GHS). Calibrated Automated Thrombography was assessed and coagulation factors were measured by means of BCS XP Systems. To assess the biochemical determinants of TG variables, a multiple linear regression analysis, adjusted for age, sex and antithrombotic therapy, was conducted. RESULTS: The lag time, the time to form the first thrombin, was mainly positively associated with the natural coagulant and anti-coagulant factors in the reference group, i.e. higher factors result in a longer lag time. The same determinants were negative for individuals with a history of arterial or venous thrombosis, with a 10 times higher effect size. Endogenous thrombin potential, or area under the curve, was predominantly positively determined by factor II, VIII, X and IX in all groups. However, the effect sizes of the reported associations were 4 times higher for the arterial and venous disease groups in comparison to the reference group. CONCLUSION: This large-scale analysis demonstrated a stronger effect of the coagulant and natural anti-coagulant factors on the thrombin potential in individuals with a history of arterial or venous thrombosis as compared to healthy individuals, which implicates sustained alterations in the plasma coagulome in subjects with a history of thrombotic vascular disease, despite intake of antithrombotic therapy.

Protective behavior and SARS-CoV-2 infection risk in the population - Results from the Gutenberg COVID-19 study.

BACKGROUND: During the SARS-CoV-2 pandemic, preventive measures like physical distancing, wearing face masks, and hand hygiene have been widely applied to mitigate viral transmission. Beyond increasing vaccination coverage, preventive measures remain urgently needed. The aim of the present project was to assess the effect of protective behavior on SARS-CoV-2 infection risk in the population. METHODS: Data of the Gutenberg COVID-19 Study (GCS), a prospective cohort study with a representative population-based sample, were analyzed. SARS-CoV-2 infections were identified by sequential sampling of biomaterial, which was analyzed by RT-qPCR and two antibody immunoassays. Self-reported COVID-19 test results were additionally considered. Information on protective behavior including physical distancing, wearing face masks, and hand hygiene was collected via serial questionnaire-based assessments. To estimate adjusted prevalence ratios and hazard ratios, robust Poisson regression and Cox regression were applied. RESULTS: In total, 10,250 participants were enrolled (median age 56.9 [43.3/68.6] years, 50.8% females). Adherence to preventive measures was moderate for physical distancing (48.3%), while the use of face masks (91.5%) and the frequency of handwashing (75.0%) were high. Physical distancing appeared to be a protective factor with respect to SARS-CoV-2 infection risk independent of sociodemographic characteristics and individual pandemic-related behavior (prevalence ratio [PR] = 0.77, 95% confidence interval [CI] 0.62-0.96). A protective association between wearing face masks and SARS-CoV-2 transmission was identified (PR = 0.73, 95% CI 0.55-0.96). However, the protective effect declined after controlling for potential confounding factors (PR = 0.96, 95% CI 0.68-1.36). For handwashing, this investigation did not find a beneficial impact. The adherence to protective behavior was not affected by previous SARS-CoV-2 infection or immunization against COVID-19. CONCLUSION: The present study suggests primarily a preventive impact of physical distancing of 1.5 m, but also of wearing face masks on SARS-CoV-2 infections, supporting their widespread implementation. The proper fit and use of face masks are crucial for effectively mitigating the spread of SARS-CoV-2 in the population.

Chronic venous insufficiency, cardiovascular disease, and mortality: a population study.

AIMS: Evidence regarding the health burden of chronic venous insufficiency (CVI), its clinical determinants, and impact on outcome is scarce. METHODS AND RESULTS: Systematic phenotyping of CVI according to established CEAP (Clinical-Etiologic-Anatomic-Pathophysiologic) classification was performed in 12 423 participants (age range: 40-80 years) of the Gutenberg Health Study from April 2012 to April 2017. Prevalence was calculated age- and sex-specifically. Multivariable Poisson regression models were calculated to evaluate the relation of CVI with cardiovascular comorbidities. Survival analyses were carried out to assess the CVI-associated risk of death. Replication of findings was done in an independent cohort study (MyoVasc, NCT04064450). The prevalence of telangiectasia/reticular, varicose veins, and CVI was 36.5% [95% confidence interval (CI), 35.6-37.4%], 13.3% [12.6-13.9%], and 40.8% [39.9-41.7%], respectively. Age, female sex, arterial hypertension, obesity, smoking, and clinically overt cardiovascular disease were identified as clinical determinants of CVI. Higher CEAP classes were associated with a higher predicted 10-year risk for incident cardiovascular disease in individuals free of cardiovascular disease (n = 9923). During a mean follow-up of 6.4 ± 1.6 years, CVI was a strong predictor of all-cause death independent of the concomitant clinical profile and medication [hazard ratio (HR) 1.46 (95% CI 1.19-1.79), P = 0. 0003]. The association of CVI with an increased risk of all-cause death was externally validated in the MyoVasc cohort [HR 1.51 (95% CI 1.11-2.05), P = 0.009]. CONCLUSION: Chronic venous insufficiency is highly prevalent in the population and is associated with the presence of cardiovascular risk factors and disease. Individuals with CVI experience an elevated risk of death, which is independent of age and sex, and present cardiovascular risk factors and comorbidities.

Thrombin generation in cardiovascular disease and mortality - results from the Gutenberg Health Study.

Thrombin generation may be a potential tool to improve risk stratification for cardiovascular diseases. This study aims to explore the relation between thrombin generation and cardiovascular risk factors, cardiovascular diseases, and total mortality. For this study, N=5000 subjects from the population-based Gutenberg Health Study were analysed in a highly standardized setting. Thrombin generation was assessed by the Calibrated Automated Thrombogram method at 1 and 5 pM tissue factors trigger in platelet poor plasma. Lag time, endogenous thrombin potential, and peak height were derived from the thrombin generation curve. Sex-specific multivariable linear regression analysis adjusted for age, cardiovascular risk factors, cardiovascular diseases and therapy, was used to assess clinical determinants of thrombin generation. Cox regression models adjusted for age, sex, cardiovascular risk factors and vitamin K antagonists investigated the association between thrombin generation parameters and total mortality. Lag time was positively associated with obesity and dyslipidaemia for both sexes (p<0.0001). Obesity was also positively associated with endogenous thrombin potential in both sexes (p<0.0001) and peak height in males (1 pM tissue factor, p=0.0048) and females (p<0.0001). Cox regression models showed an increased mortality in individuals with lag time (1 pM tissue factor, hazard ratio=1.46, [95% CI: 1.07; 2.00], p=0.018) and endogenous thrombin potential (5 pM tissue factor, hazard ratio = 1.50, [1.06; 2.13], p=0.023) above the 95th percentile of the reference group, independent of the cardiovascular risk profile. This large-scale study demonstrates traditional cardiovascular risk factors, particularly obesity, as relevant determinants of thrombin generation. Lag time and endogenous thrombin potential were found as potentially relevant predictors of increased total mortality, which deserves further investigation.

Acute exposure to nocturnal train noise induces endothelial dysfunction and pro-thromboinflammatory changes of the plasma proteome in healthy subjects.

Nocturnal train noise exposure has been associated with hypertension and myocardial infarction. It remains unclear whether acute nighttime train exposure may induce subclinical atherosclerosis, such as endothelial dysfunction and other functional and/or biochemical changes. Thus, we aimed to expose healthy subjects to nocturnal train noise and to assess endothelial function, changes in plasma protein levels and clinical parameters. In a randomized crossover study, we exposed 70 healthy volunteers to either background or two different simulated train noise scenarios in their homes during three nights. After each night, participants visited the study center for measurement of vascular function and assessment of other biomedical and biochemical parameters. The three nighttime noise scenarios were exposure to either background noise (control), 30 or 60 train noise events (Noise30 or Noise60), with average sound pressure levels of 33, 52 and 54 dB(A), respectively. Flow-mediated dilation (FMD) of the brachial artery was 11.23 ± 4.68% for control, compared to 8.71 ± 3.83% for Noise30 and 8.47 ± 3.73% for Noise60 (p < 0.001 vs. control). Sleep quality was impaired after both Noise30 and Noise60 nights (p < 0.001 vs. control). Targeted proteomic analysis showed substantial changes of plasma proteins after the Noise60 night, mainly centered on redox, pro-thrombotic and proinflammatory pathways. Exposure to simulated nocturnal train noise impaired endothelial function. The proteomic changes point toward a proinflammatory and pro-thrombotic phenotype in response to nocturnal train noise and provide a molecular basis to explain the increased cardiovascular risk observed in epidemiological noise studies.

Quality of oral anticoagulation with phenprocoumon in regular medical care and its potential for improvement in a telemedicine-based coagulation service--results from the prospective, multi-center, observational cohort study thrombEVAL.

BACKGROUND: The majority of studies on quality of oral anticoagulation (OAC) therapy with vitamin K-antagonists are performed with short-acting warfarin. Data on long-acting phenprocoumon, which is frequently used in Europe for OAC therapy and is considered to enable more stable therapy adjustment, are scarce. In this study, we aimed to assess quality of OAC therapy with phenprocoumon in regular medical care and to evaluate its potential for optimization in a telemedicine-based coagulation service. METHODS: In the prospective observational cohort study program thrombEVAL we investigated 2,011 patients from regular medical care in a multi-center cohort study and 760 patients from a telemedicine-based coagulation service in a single-center cohort study. Data were obtained from self-reported data, computer-assisted personal interviews, and laboratory measurements according to standard operating procedures with detailed quality control. Time in therapeutic range (TTR) was calculated by linear interpolation method to assess quality of OAC therapy. Study monitoring was carried out by an independent institution. RESULTS: Overall, 15,377 treatment years and 48,955 international normalized ratio (INR) measurements were analyzed. Quality of anticoagulation, as measured by median TTR, was 66.3% (interquartile range (IQR) 47.8/81.9) in regular medical care and 75.5% (IQR 64.2/84.4) in the coagulation service (P <0.001). Stable anticoagulation control within therapeutic range was achieved in 63.8% of patients in regular medical care with TTR at 72.1% (IQR 58.3/84.7) as compared to 96.4% of patients in the coagulation service with TTR at 76.2% [(IQR 65.6/84.7); P = 0.001)]. Prospective follow-up of coagulation service patients with pretreatment in regular medical care showed an improvement of the TTR from 66.2% (IQR 49.0/83.6) to 74.5% (IQR 62.9/84.2; P <0.0001) in the coagulation service. Treatment in the coagulation service contributed to an optimization of the profile of time outside therapeutic range, a 2.2-fold increase of stabile INR adjustment and a significant decrease in TTR variability by 36% (P <0.001). CONCLUSIONS: Quality of anticoagulation with phenprocoumon was comparably high in this real-world sample of regular medical care. Treatment in a telemedicine-based coagulation service substantially improved quality of OAC therapy with regard to TTR level, frequency of stable anticoagulation control, and TTR variability. TRIAL REGISTRATION: ClinicalTrials.gov, unique identifier NCT01809015, March 8, 2013.

Development of recommendations to continue anticoagulation with one of the two types of oral anticoagulants based on the identification of patients' preference.

Patients with indication for anticoagulation may prefer treatment with a vitamin K antagonist (VKA) or non-vitamin K antagonist oral anticoagulant (NOAC). A questionnaire may help to identify the preference of patients for one of the two types of oral anticoagulants and to develop a score for the recommendation to continue or to change the anticoagulant. A score was developed using a questionnaire containing biographic data and eight statements on attitudes on anticoagulation and was derived to trigger continuation or change the type of anticoagulant by defining ranges of terms and weighting of the significant statements identified by logistic regression analysis. Participating patients received either anticoagulation with VKA (group 1, n = 690), were transferred from VKA to NOAC (group 2, n = 158), received NOAC de novo (group 3, n = 137) or were transferred from NOAC to VKA (group 4, n = 19). Four statements were significantly (p values between 0.0347 and < 0.0001) associated with recommendations to maintain or to change the type of anticoagulant for patients in groups 1, 2, or 3 with predictive values of c = 0.83 between groups 1 and 2 and c = 0.71 between groups 1 and 3. From the total number of replies to the statements a score of three grades and two strengths (A = strong, B = moderate) was derived for the recommendations. This tool supports recommendations as to continue or to change the presently used type of oral anticoagulant based on the identification of patients' preferences.

Obesity-related inflammatory protein signature in cardiovascular clinical outcomes: results from the Gutenberg Health Study.

OBJECTIVE: The objective of this study was to investigate whether an obesity-related inflammatory protein signature (OIPS) is associated with adverse cardiovascular events. METHODS: The Olink Target 96 Inflammation panel was performed in 6662 participants from the population-based Gutenberg Health Study (GHS). The OIPS was selected by a logistic regression model, and its association with cardiovascular outcomes was evaluated by Cox regression analysis. The GHS-derived OIPS was externally validated in the MyoVasc study. RESULTS: The identified OIPS entailed 21 proteins involved in chemokine activity, tumor necrosis factor (TNF) receptor binding, and growth factor receptor binding. The signature revealed a novel positive association of axis inhibition protein 1 with obesity. The OIPS was associated with increased risk of all-cause and cardiac deaths, major adverse cardiovascular events, and incident coronary artery disease, independent of clinical covariates and established risk instruments. A BMI-stratified analysis confirmed the association of OIPS with increased death in those with obesity and overweight and with increased risk for coronary artery disease in those with obesity. The association of OIPS with increased risk of all-cause and cardiac deaths was validated in the MyoVasc cohort. CONCLUSIONS: The OIPS showed a significant association with adverse clinical outcomes, particularly in those with overweight and obesity, and represents a promising tool for identifying patients at higher risk for worse cardiovascular outcomes.

Renin, aldosterone, the aldosterone-to-renin ratio, and incident hypertension among normotensive subjects from the general population.

AIMS: To investigate the predictive ability of direct plasma renin and aldosterone concentrations as well as their ratio [aldosterone-to-renin (ARR)] for incident hypertension in the general population. METHODS AND RESULTS: Concentration of renin and aldosterone were measured by a chemiluminescence immunoassay using the fully automated LIAISON® platform (DiaSorin) among 5362 participants of the population-based Gutenberg Health Study, who were normotensive and had no clinically overt cardiovascular disease at baseline. During a follow-up period of 5 years, 18.6% (n = 996) developed a new-onset hypertension. Comparing extreme quartiles of biomarker distribution, the relative risk (RR) for incident arterial hypertension was found to be 1.58 [95% confidence interval (CI) 1.25-2.00; P = 0.00015; Q1 vs. Q4ref] for renin; 1.29 (95% CI 1.05-1.59, P = 0.018; Q4 vs. Q1ref) for aldosterone and 1.70 (95% CI 1.33-2.12; P < 0.0001; Q4 vs. Q1ref) for ARR after multivariable adjustment in men. In females, only high ARR was independently predictive for incident hypertension over 5 years [RR 1.29 (95% CI 1.04-1.62); P = 0.024]. Even in the subgroup of individuals having biomarker concentrations within the reference range, high ARR was predictive for new-onset hypertension in men [RR 1.44 (95% CI 1.13-1.83); P = 0.003]. Finally, synergistic effects of co-prevalent obesity and ARR on incident hypertension were also demonstrated, resulting in markedly higher risk estimates as seen for biomarker alone [RR of 2.70 (95% CI 2.05-3.6) for Q4 of ARR and having body mass index ≥ 30 kg/m2 vs. low ARR (Q1ref) and normal weight; P < 0.0001]. CONCLUSION: Among normotensives from the general population ARR possesses a stronger predictive value for incident hypertension than renin or aldosterone alone. The prediction of arterial hypertension by ARR was even stronger in obese subjects.

Correlation of systolic and diastolic blood pressure with echocardiographic phenotypes of cardiac structure and function from three German population-based studies.

Arterial hypertension is considered a risk factor for the development of heart failure. Here we investigate cross-sectional associations of systolic and diastolic blood pressure with subtle functional and morphological changes of left ventricular echocardiographic parameters representing early dysfunction in three representative German population-based studies. We assessed 26,719 individuals without symptomatic heart failure from the Hamburg City Health Study (HCHS, n = 7396, derivation cohort), the Gutenberg Health Study (GHS, 14,715, validation cohort) and the Study of Health in Pomerania (SHIP, 4608, validation cohort). Multivariable linear regression analyses with systolic and diastolic blood pressure as continuous exposure variables were adjusted for common cardiovascular risk factors and antihypertensive medication. Both systolic and diastolic blood pressure were consistently associated with measures of left ventricular hypertrophy (ß per standard deviation (SD) for LV mass (g) and systolic blood pressure: 5.09 (p < 0.001); diastolic blood pressure: 2.29 (p < 0.001) in HCHS). Systolic blood pressure correlated with declining diastolic function (ß per SD for E/e': 0.29, p < 0.001 in HCHS) and diastolic blood pressure with declining systolic function (ß per SD for LVEF, in %: - 0.15; p = 0.041 in HCHS) in all cohorts. Pending further validation, our results from three independent German population samples suggest differential effects of systolic versus diastolic blood pressure on left ventricular structure and function.

Quality of life in patients with transcatheter aortic valve implantation: an analysis from the INTERVENT project.

Background: Transcatheter aortic valve implantation (TAVI) is a standard treatment for patients with aortic valve stenosis due to its very low mortality and complication rates. However, survival and physical integrity are not the only important factors. Quality of life (QoL) improvement is a crucial part in the evaluation of therapy success. Methods: Patients with TAVI were questioned about their QoL before, one month and one year after the intervention as part of the INTERVENT registry trial at Mainz University Medical Center. Three different questionnaires were included in the data collection (Katz ADL, EQ-5D-5l, PHQ-D). Results: We included 285 TAVI patients in the analysis (mean age 79.8 years, 59.4% male, mean EuroSCORE II 3.8%). 30-day mortality was 3.6%, complications of any kind occurred in 18.9% of the patients. Main finding was a significant increase in the general state of health measured on the visual analog scale by an average of 4.53 (± 23.58) points (BL to 1-month follow-up, p = 0.009) and by 5.19 (± 23.64) points (BL to 12-month follow-up, p = 0.016). There was also an improvement of depression symptoms, which was reflected in a decrease in the total value of the PHQ-D by 1.67 (± 4.75) points (BL to 12-month follow-up, p = 0.001). The evaluation of the EQ-5D-5l showed a significant improvement in mobility after one month (M = -0.41 (± 1.31), p < 0.001. Regarding the independence of the patients, no significant difference could be found. Apart from that, patients with risk factors, comorbidities or complications also benefited from the intervention despite their poor starting position. Conclusion: We could show an early benefit of QoL in TAVI patients with significant improvement in the subjective state of health and a decrease in symptoms of depression. These findings were consistent over 1 year of follow up.

Heart rate variability: reference values and role for clinical profile and mortality in individuals with heart failure.

AIMS: 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. METHODS: 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. RESULTS: 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 [HRperSD 1.53 (95% CI 1.21/1.93), p = 0.0004], deceleration capacity [HRperSD: 0.70 (95% CI 0.55/0.88), p = 0.002], and time lag [HRperSD 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. CONCLUSION: 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. GOV IDENTIFIER: NCT04064450.

Chronic cigarette smoking is associated with increased arterial stiffness in men and women: evidence from a large population-based cohort.

BACKGROUND: Cigarette smoking is a threat to global human health and a leading cause of the cardiovascular disease (CVD) morbidity and mortality. Importantly, sex-specific differences in smoking-induced arterial stiffness, an early key event in the development of atherosclerotic CVD, remain still elusive. Thus, this study sought out to investigate sex-specific associations between smoking and measures of arterial stiffness. METHODS AND RESULTS: Overall, 15,010 participants (7584 men and 7426 women aged 35-74 years) of the Gutenberg Health Study were examined at baseline during 2007-2012. Smoking status, pack-years of smoking, and years since quitting smoking were assessed by a standardized computer-assisted interview. Arterial stiffness and wave reflection were determined by stiffness index (SI) and augmentation index (AI). In the total sample, 45.8% had never smoked, 34.7% were former smokers, and 19.4% were current smokers. Median cumulative smoking exposure was 22.0 pack-years in current male smokers and 16.0 in current female smokers. In general, multivariable linear regression models adjusted for a comprehensive set of confounders revealed that smoking status, pack-years of smoking, and years since quitting smoking were dose-dependently associated with markers of arterial stiffness. In sex-specific analyses, these associations were overall more pronounced in men and SI was stronger related to the male sex, whereas differences between men and women in the case of AI appeared to be less substantial. DISCUSSION: The present results indicate that chronic smoking is strongly and dose-dependently associated with increased arterial stiffness in a large population-based cohort regardless of sex but with a stronger association in men.

Clinical profile and outcome of isolated pulmonary embolism: a systematic review and meta-analysis.

Background: Isolated pulmonary embolism (PE) appears to be associated with a specific clinical profile and sequelae compared to deep vein thrombosis (DVT)-associated PE. The objective of this study was to identify clinical characteristics that discriminate both phenotypes, and to characterize their differences in clinical outcome. Methods: We performed a systematic review and meta-analysis of studies comparing PE phenotypes. A systematic search of the electronic databases PubMed and CENTRAL was conducted, from inception until January 27, 2023. Exclusion criteria were irrelevant content, inability to retrieve the article, language other than English or German, the article comprising a review or case study/series, and inappropriate study design. Data on risk factors, clinical characteristics and clinical endpoints were pooled using random-effects meta-analyses. Findings: Fifty studies with 435,768 PE patients were included. In low risk of bias studies, 30% [95% CI 19-42%, I 2 = 97%] of PE were isolated. The Factor V Leiden [OR: 0.47, 95% CI 0.37-0.58, I 2 = 0%] and prothrombin G20210A mutations [OR: 0.55, 95% CI 0.41-0.75, I 2 = 0%] were significantly less prevalent among patients with isolated PE. Female sex [OR: 1.30, 95% CI 1.17-1.45, I 2 = 79%], recent invasive surgery [OR: 1.31, 95% CI 1.23-1.41, I 2 = 65%], a history of myocardial infarction [OR: 2.07, 95% CI 1.85-2.32, I 2 = 0%], left-sided heart failure [OR: 1.70, 95% CI 1.37-2.10, I 2 = 76%], peripheral artery disease [OR: 1.36, 95% CI 1.31-1.42, I 2 = 0%] and diabetes mellitus [OR: 1.23, 95% CI 1.21-1.25, I 2 = 0%] were significantly more frequently represented among isolated PE patients. In a synthesis of clinical outcome data, the risk of recurrent VTE in isolated PE was half that of DVT-associated PE [RR: 0.55, 95% CI 0.44-0.69, I 2 = 0%], while the risk of arterial thrombosis was nearly 3-fold higher [RR: 2.93, 95% CI 1.43-6.02, I 2 = 0%]. Interpretation: Our findings suggest that isolated PE appears to be a specific entity that may signal a long-term risk of arterial thrombosis. Randomised controlled trials are necessary to establish whether alternative treatment regimens are beneficial for this patient subgroup. Funding: None.

DNA methylation and cardiovascular disease in humans: a systematic review and database of known CpG methylation sites.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death worldwide and considered one of the most environmentally driven diseases. The role of DNA methylation in response to the individual exposure for the development and progression of CVD is still poorly understood and a synthesis of the evidence is lacking. RESULTS: A systematic review of articles examining measurements of DNA cytosine methylation in CVD was conducted in accordance with PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. The search yielded 5,563 articles from PubMed and CENTRAL databases. From 99 studies with a total of 87,827 individuals eligible for analysis, a database was created combining all CpG-, gene- and study-related information. It contains 74,580 unique CpG sites, of which 1452 CpG sites were mentioned in ≥ 2, and 441 CpG sites in ≥ 3 publications. Two sites were referenced in ≥ 6 publications: cg01656216 (near ZNF438) related to vascular disease and epigenetic age, and cg03636183 (near F2RL3) related to coronary heart disease, myocardial infarction, smoking and air pollution. Of 19,127 mapped genes, 5,807 were reported in ≥ 2 studies. Most frequently reported were TEAD1 (TEA Domain Transcription Factor 1) and PTPRN2 (Protein Tyrosine Phosphatase Receptor Type N2) in association with outcomes ranging from vascular to cardiac disease. Gene set enrichment analysis of 4,532 overlapping genes revealed enrichment for Gene Ontology molecular function "DNA-binding transcription activator activity" (q = 1.65 × 10-11) and biological processes "skeletal system development" (q = 1.89 × 10-23). Gene enrichment demonstrated that general CVD-related terms are shared, while "heart" and "vasculature" specific genes have more disease-specific terms as PR interval for "heart" or platelet distribution width for "vasculature." STRING analysis revealed significant protein-protein interactions between the products of the differentially methylated genes (p = 0.003) suggesting that dysregulation of the protein interaction network could contribute to CVD. Overlaps with curated gene sets from the Molecular Signatures Database showed enrichment of genes in hemostasis (p = 2.9 × 10-6) and atherosclerosis (p = 4.9 × 10-4). CONCLUSION: This review highlights the current state of knowledge on significant relationship between DNA methylation and CVD in humans. An open-access database has been compiled of reported CpG methylation sites, genes and pathways that may play an important role in this relationship.

Development and Phenotype of Heart Failure in Long-Term Survivors of Childhood Cancer: The CVSS Study.

Background The CVSS (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer) study aimed to investigate the prevalence of different stages of heart failure (HF) in childhood cancer survivors (CCSs) compared with the general population. Methods and Results A total of 1002 CCSs (age range, 23-48 years) diagnosed with neoplasia before an age of 15 years underwent a comprehensive cardiovascular screening. An age- and sex-matched sample from the population-based GHS (Gutenberg Health Study) served as a comparison group. Although prevalence of HF was significantly higher in CCSs, prevalence of different HF stages varied strongly by specific tumor history. Compared with the population, the prevalence ratio was 2.6 (95% CI, 2.4-2.8) for HF stage A and 4.6 (95% CI, 4.1-5.1) for the composite of HF stage B to D in an age- and sex-adjusted Poisson regression model. Multivariable linear regression, adjusting for tumor entities, age, sex, and cardiovascular risk factors, revealed a lower left ventricular ejection fraction in patients with history of bone tumors (ß, -4.30 [95% CI, -5.70 to -2.80]), soft tissue sarcoma (ß, -1.60 [95% CI, -2.90 to -0.30]), and renal tumors (ß, -1.60 [95% CI, -2.80 to -0.29]) compared with the population. The same model for the diastolic marker, ratio of the peak early diastolic filling velocity/lateral mitral annular early diastolic velocity, showed an association only with cardiovascular risk factors but not with tumor entities. Conclusions The prevalence of HF stage A to D was significantly higher among long-term CCSs compared with the population and varied strongly by tumor entity. Systolic dysfunction was primarily associated with tumor entities, whereas diastolic dysfunction was associated with a higher burden of cardiovascular risk factors in CCSs.