Physical activity and brain health in patients with atrial fibrillation

Background and purpose: Vascular brain lesions, such as ischemic infarcts, are common among patients with atrial fibrillation (AF) and are associated with impaired cognitive function. The role of physical activity (PA) in the prevalence of brain lesions and cognition in AF has not been investigated. Methods: Patients from the multicenter Swiss‐AF cohort study were included in this cross‐sectional analysis. We assessed regular exercise (RE; at least once weekly) and minutes of weekly PA using a validated questionnaire. We studied associations with ischemic infarcts, white matter hyperintensities, cerebral microbleeds, and brain volume on brain magnetic resonance imaging and with global cognition measured with a cognitive construct (CoCo) score.ResultsAmong 1490 participants (mean age = 72 ± 9 years), 730 (49%) engaged in RE. In adjusted regression analyses, RE was associated with a lower prevalence of ischemic infarcts (odds ratio [OR] = 0.78, 95% confidence interval [CI] = 0.63–0.98, p = 0.03) and of moderate to severe white matter hyperintensities (OR = 0.78, 95% CI = 0.62–0.99, p = 0.04), higher brain volume (β‐coefficient = 10.73, 95% CI = 2.37–19.09, p = 0.01), and higher CoCo score (β‐coefficient = 0.08, 95% CI = 0.03–0.12, p < 0.001). Increasing weekly PA was associated with higher brain volume (β‐coefficient = 1.40, 95% CI = 0.65–2.15, p < 0.001). Conclusions: In AF patients, RE was associated with a lower prevalence of ischemic infarcts and of moderate to severe white matter disease, with larger brain volume, and with better cognitive performance. Prospective studies are needed to investigate whether these associations are causal. Until then, our findings suggest that patients with AF should be encouraged to remain physically active

Association of pulmonary vein isolation and major cardiovascular events in patients with atrial fibrillation.

BACKGROUND Patients with atrial fibrillation (AF) face an increased risk of adverse cardiovascular events. Evidence suggests that early rhythm control including AF ablation may reduce this risk. METHODS To compare the risks for cardiovascular events in AF patients with and without pulmonary vein isolation (PVI), we analysed data from two prospective cohort studies in Switzerland (n = 3968). A total of 325 patients who had undergone PVI during a 1-year observational period were assigned to the PVI group. Using coarsened exact matching, 2193 patients were assigned to the non-PVI group. Outcomes were all-cause mortality, hospital admission for acute heart failure, a composite of stroke, transient ischemic attack and systemic embolism (Stroke/TIA/SE), myocardial infarction (MI), and bleedings. We calculated multivariable adjusted Cox proportional-hazards models. RESULTS Overall, 2518 patients were included, median age was 66 years [IQR 61.0, 71.0], 25.8% were female. After a median follow-up time of 3.9 years, fewer patients in the PVI group died from any cause (incidence per 100 patient-years 0.64 versus 1.87, HR 0.39, 95%CI 0.19-0.79, p = 0.009) or were admitted to hospital for acute heart failure (incidence per 100 patient-years 0.52 versus 1.72, HR 0.44, 95%CI 0.21-0.95, p = 0.035). There was no significant association between PVI and Stroke/TIA/SE (HR 0.94, 95%CI 0.52-1.69, p = 0.80), MI (HR 0.43, 95%CI 0.11-1.63, p = 0.20) or bleeding (HR 0.75, 95% CI 0.50-1.12, p = 0.20). CONCLUSIONS In our matched comparison, patients in the PVI group had a lower incidence rate of all-cause mortality and hospital admission for acute heart failure compared to the non-PVI group. CLINICALTRIALS GOV IDENTIFIER NCT02105844, April 7th 2014

Association of Statin Use and Lipid Levels with Cerebral Microbleeds and Intracranial Hemorrhage in Patients with Atrial Fibrillation: a Prospective Cohort Study.

BACKGROUND An increased risk of intracranial hemorrhage (ICH) associated with statins has been reported; but data on the relationship between statin-use and cerebral microbleeds (CMBs) in patients with atrial fibrillation (AF), a population at high bleeding and cardiovascular risk are lacking. AIMS To explore the association between statin-use and blood lipid-levels with the prevalence and progression of CMBs in patients with atrial fibrillation with particular focus on anticoagulated patients. METHODS Data of Swiss-AF, a prospective cohort of patients with established AF were analyzed. Statin-use was assessed during baseline and throughout follow-up. Lipid values were measured at baseline. CMBs were assessed using magnetic resonance imagining (MRI) at baseline and at 2-years follow-up. Imaging data were centrally assessed by blinded investigators. Associations of statin-use and low-density lipoprotein (LDL) levels with CMB prevalence at baseline or CMB progression (at least one additional or new CMB on follow-up MRI at 2-years compared to baseline) were assessed using logistic regression models; the association with ICH was assessed using flexible parametric survival models. Models were adjusted for hypertension, smoking, body mass index, diabetes, stroke/transient ischemic attack, coronary heart disease, antiplatelet use, anticoagulant use and education. RESULTS Of the 1693 patients with CMB data at baseline MRI (mean±SD age 72.5±8.4y, 27.6% women, 90.1% on oral anticoagulants), 802 patients (47.4%) were statin users. The multivariable adjusted odds ratio (adjOR) for CMBs prevalence at baseline for statin users was 1.10 (95% CI, 0.83-1.45). AdjOR for 1 unit increase in LDL-levels was 0.95 (95% CI, 0.82-1.10). At 2-years, 1188 patients had follow-up MRI. CMBs progression was observed in 44 (8.0%) statin users and 47 (7.4%) non-statin users. Of these patients 64 (70.3%) developed a single new CMB, 14 (15.4%) developed 2 CMBs and 13 developed more than 3 CMBs. The multivariable adjOR for statin users was 1.09 (95% CI, 0.66-1.80). There was no association between LDL-levels and CMBs progression (adjOR 1.02, 95% CI, 0.79-1.32). At follow-up 14 (1.2%) statin users had ICH vs 16 (1.3%) non-users. The age and sex adjusted Hazard Ratio (adjHR) was 0.75 (95% CI, 0.36-1.55). Results remained robust in sensitivity analyses excluding participants without anticoagulants. CONCLUSIONS In this prospective cohort of patients with AF, a population at increased hemorrhagic risk due to anticoagulation, the use of statins was not associated with an increased risk of CMBs

Association of the biomarker bone morphogenetic protein 10 with adverse clinical outcomes

Background The biomarker bone morphogenetic protein 10 (BMP10) belongs to the transforming growth factor β (TGF β) superfamily. BMP10 is primarily expressed in the cardiomyocytes of the right atrial chamber of the heart, which is a distinctive feature that sets it apart from other cardiac biomarkers. Furthermore, BMP10 is involved in cardiac development and structural changes in adults. BMP10 was recently identified as an essential biomarker in atrial fibrillation (AF), the most prevalent cardiac arrhythmia. BMP10 was associated with rhythm status in patients with AF undergoing cardioversion, and furthermore, an experimental study showed that BMP10 identifies patients with a higher risk of AF recurrence after catheter ablation (CA). The latter study revealed that BMP10 is regulated by the paired-like homeodomain transcription factor 2 (PITX2), an important gene strongly associated with AF and AF recurrence after CA. The identification of patients with a high risk for AF recurrence is fundamental in clinical routine, however, the validation of BMP10's association with AF recurrence after CA had not been performed. Moreover, AF patients remain at increased risk for mortality and morbidity compared to patients without AF. Identifying those high-risk patients is crucial, but current risk assessment tools are insufficient. The potential role of BMP10 in identifying such high-risk AF patients was unclear. Recent evidence also suggests a role of BMP10 in pulmonary hypertension (PH), a severe and complex disease characterized by abnormally high pressure in the pulmonary arteries. Elevation of the pulmonary vascular resistance (PVR; pre-capillary component) and elevation of the left atrial filling pressure (pulmonary arterial wedge pressure, PAWP; post-capillary component) contribute to an increase of the mean pulmonary arterial pressure (mPAP). An invasive hemodynamic assessment by means of right heart catheterization (RHC) is currently the only way to confirm diagnosis and distinguish between pre- and post-capillary PH. Pulmonary vascular remodeling is a major factor in the pathophysiology of PH. BMP10 is a ligand for two important receptors in PH, bone morphogenetic protein receptor type 2 (BMPR2) and activin receptor-like kinase-1 (ALK1). BMP10 was found to contribute to the tonic quiescent signals to the pulmonary vascular endothelium trough those receptors and it also directly acts on vascular smooth muscle cells for induction and maintenance of their contractile state. Furthermore, BMP10 was designated as a new gene in heritable PAH. Whether BMP10 is associated with PVR because of its role in pulmonary vascular remodeling and therefore reflects the pre-capillary component of PH was unknown. Aims As a blood-based biomarker, BMP10 can provide an option for the diagnosis, monitoring, and prognosis of disease. However, further research is necessary to understand the role of BMP10 in patients with AF and PH and to assess its value in the clinical setting. This was thus the overall aim of this PhD project. The specific aims were: 1. To validate the association of BMP10 with AF recurrence after CA in a large cohort of AF patients, 2. To explore the association of BMP10 with AF-related adverse outcomes, namely all-cause death and major adverse cardiovascular events (MACE), 3. To explore the association of BMP10 with hemodynamic parameters which define the diagnosis of PH (mPAP), and the pre- and post-capillary component of PH (PVR, PAWP). Methods We measured BMP10 concentrations in three observational studies: Swiss-AF-PVI, Swiss-AF, and PH Study. For the first specific aim, we analyzed patients from Swiss-AF-PVI, an ongoing prospective cohort study since 2010, which includes patients ≥ 18 years undergoing CA for AF. Venous blood samples were obtained before CA. Patients received follow-ups at 3, 6, and 12 months after CA, including a 12-lead electrocardiogram (ECG) and a 7-day Holter ECG to assess AF recurrence. For the second specific aim, we analyzed patients from Swiss-AF, an ongoing prospective multicenter cohort study since 2014, which includes patients ≥ 65 years (and a limited number of younger patients) with diagnosed AF. Venous blood samples were obtained at baseline, and patients received yearly follow-up visits to assess death and MACE. For the third specific aim, we analyzed patients from the PH Study, a prospective single-center cross-sectional study, which includes patients ≥ 18 years undergoing RHC for suspected or established PH between 2021-2022. Venous blood samples were obtained during RHC. We performed multivariable cox proportional hazard and linear regression analyses to assess the association of BMP10 with the different outcomes of interest. Results In the first analysis, we included 1112 AF patients undergoing CA (mean ± SD age 61 ± 10 years, 74% male, 60% paroxysmal AF). 374 patients (34%) experienced AF recurrence within 12 months of follow-up. In the multivariable cox proportional hazard model, a per-unit increase in log-transformed BMP10 was associated with a hazard ratio (HR) of 1.98 (95% CI 1.14 - 3.42, p = 0.01) for AF recurrence. In the second analysis, we included 2219 AF patients (median follow-up 4.3 years [interquartile range 3.9, 5.1], mean ± SD age 73 ± 9 years, 73% male). In the multivariable cox proportional hazard models, the HR associated with 1 ng/mL increase of BMP10 was 1.60 (95% CI 1.37 - 1.87, p < 0.001) for all-cause death, and 1.54 (95% CI 1.35 - 1.76, p < 0.001) for MACE. The concordance index of this model was 0.78 (95% CI 0.76 - 0.81) for all-cause death, and 0.73 (95% CI 0.72 - 0.75) for MACE. For the third analysis, we included 127 patients with suspected or established PH undergoing RHC (mean ± SD age 66 ± 13 years, 46% male). PH was diagnosed in 93 (73%) patients. In the multivariable linear regression model, a per standard deviation increase of log-transformed BMP10 was associated with a beta coefficient of 5.05 (95% CI 2.58 - 7.52, p < 0.001) for mPAP, 0.29 (95% CI 0.15 - 0.43, p < 0.001) for PVR, and -0.10 (95% CI -1.29 - 1.08, p = 0.86) for PAWP. Conclusion BMP10 was strongly associated with AF recurrence after CA as well as with all-cause death and MACE in AF patients. Randomized controlled trials are necessary to investigate if a BMP10-guided risk prediction and management can improve outcomes. In patients undergoing RHC, BMP10 was strongly associated with mPAP and PVR (reflecting the pre-capillary component of PH), but not with the left atrial filling pressure (PAWP), which reflects the post-capillary component of PH. Further studies should investigate the combination of BMP10 with non-invasive imaging for the diagnosis and monitoring of PH

Situation d’urgence: violence ­domestique

En Suisse, une personne décède toutes les deux semaines à la suite de violences domestiques. La pandémie de COVID-19 représente un défi pour la cohabitation du fait de l’isolement social et des inquiétudes concernant la maladie et l’existence. Il peut en résulter une escalade des conflits avec des violences domestiques, et une sensibilisation du personnel médical est dès lors primordiale

Notfallsituation: häusliche Gewalt

In der Schweiz stirbt alle zwei Wochen eine Person infolge häuslicher Gewalt. Die Pandemie mit COVID-19 stellt durch soziale Isolation und Sorgen um Krankheit und Existenz eine Herausforderung an das Zusammenleben dar. Konflikteskalation mit häuslicher Gewalt kann die Folge sein, weshalb eine Sensibilisierung des medizinischen Personals besonders wichtig ist

Heart rate variability and stroke or systemic embolism in patients with atrial fibrillation.

BACKGROUND Stroke remains one of the most serious complications in atrial fibrillation (AF) patients and has been linked to disturbances of the autonomic nervous system. OBJECTIVE We hypothesized that impaired cardiac autonomic function might be associated with an enhanced stroke risk in AF patients. METHODS We enrolled 1922 AF patients who were either in sinus rhythm (SR-group, n=1121) or AF (AF-group, n=801) on a 5-minute resting ECG recording. HRV triangular index (HRVI), standard deviation of normal-to-normal intervals, root mean square root of successive differences of normal-to-normal intervals, mean heart rate, 5-min total power and power in the high frequency, low frequency and very low frequency range were calculated. We constructed Cox regression models to examine the association of HRV parameters with the composite endpoint of stroke or systemic embolism. RESULTS Mean age was 71±8 years in the SR group and 75±8 in the AF group. 37 patients in the SR group (3.4%) and 60 patients in the AF group (8.0%) experienced a stroke or systemic embolism during a follow-up time of 5 years. In patients with SR, HRVI <15 was the strongest HRV parameter to be associated with stroke or systemic embolism (hazard ratio 3.04; 95% confidence interval 1.3-7.0; p=0.009) after adjustment for multiple confounders. In the AF group, we found no HRV parameter to be associated with the composite endpoint. CONCLUSION HRVI measured during SR on a single 5-minute ECG recording is independently associated with stroke or systemic embolism in AF patients. HRV analysis in SR may help to improve risk stratification in AF patients

Bone Morphogenetic Protein 10—A Novel Biomarker to Predict Adverse Outcomes in Patients With Atrial Fibrillation

Background Patients with atrial fibrillation (AF) face an increased risk of death and major adverse cardiovascular events (MACE). We aimed to assess the predictive value of the novel atrial‐specific biomarker BMP10 (bone morphogenetic protein 10) for death and MACE in patients with AF in comparison with NT‐proBNP (N‐terminal prohormone of B‐type natriuretic peptide). Methods and Results BMP10 and NT‐proBNP were measured in patients with AF enrolled in Swiss‐AF (Swiss Atrial Fibrillation Study), a prospective multicenter cohort study. A total of 2219 patients were included (median follow‐up 4.3 years [interquartile range 3.9, 5.1], mean age 73±9 years, 73% male). In multivariable Cox proportional hazard models, the adjusted hazard ratio (aHR) associated with 1 ng/mL increase of BMP10 was 1.60 (95% CI, 1.37–1.87) for all‐cause death, and 1.54 (95% CI, 1.35–1.76) for MACE. For all‐cause death, the concordance index was 0.783 (95% CI, 0.763–0.809) for BMP10, 0.784 (95% CI, 0.765–0.810) for NT‐proBNP, and 0.789 (95% CI, 0.771–0.815) for both biomarkers combined. For MACE, the concordance index was 0.732 (95% CI, 0.715–0.754) for BMP10, 0.747 (95% CI, 0.731–0.768) for NT‐proBNP, and 0.750 (95% CI, 0.734–0.771) for both biomarkers combined. When grouping patients according to NT‐proBNP categories (900 ng/L), higher aHRs were observed in patients with high BMP10 in the categories of low NT‐proBNP (all‐cause death aHR, 2.28 [95% CI, 1.15–4.52], MACE aHR, 1.88 [95% CI, 1.07–3.28]) and high NT‐proBNP (all‐cause death aHR, 1.61 [95% CI, 1.14–2.26], MACE aHR, 1.38 [95% CI, 1.07–1.80]). Conclusions BMP10 strongly predicted all‐cause death and MACE in patients with AF. BMP10 provided additional prognostic information in low‐ and high‐risk patients according to NT‐proBNP stratification. Registration https://www.clinicaltrials.gov ; Unique identifier: NCT02105844

Association of statin use and lipid levels with cerebral microbleeds and intracranial hemorrhage in patients with atrial fibrillation: A prospective cohort study

BACKGROUND An increased risk of intracranial hemorrhage (ICH) associated with statins has been reported, but data on the relationship between statin use and cerebral microbleeds (CMBs) in patients with atrial fibrillation (AF), a population at high bleeding and cardiovascular risk, are lacking. AIMS To explore the association between statin use and blood lipid levels with the prevalence and progression of CMBs in patients with AF with a particular focus on anticoagulated patients. METHODS Data of Swiss-AF, a prospective cohort of patients with established AF, were analyzed. Statin use was assessed during baseline and throughout follow-up. Lipid values were measured at baseline. CMBs were assessed using magnetic resonance imagining (MRI) at baseline and at 2 years follow-up. Imaging data were centrally assessed by blinded investigators. Associations of statin use and low-density lipoprotein (LDL) levels with CMB prevalence at baseline or CMB progression (at least one additional or new CMB on follow-up MRI at 2 years compared with baseline) were assessed using logistic regression models; the association with ICH was assessed using flexible parametric survival models. Models were adjusted for hypertension, smoking, body mass index, diabetes, stroke/transient ischemic attack, coronary heart disease, antiplatelet use, anticoagulant use, and education. RESULTS Of the 1693 patients with CMB data at baseline MRI (mean ± SD age 72.5 ± 8.4 years, 27.6% women, 90.1% on oral anticoagulants), 802 patients (47.4%) were statin users. The multivariable adjusted odds ratio (adjOR) for CMBs prevalence at baseline for statin users was 1.10 (95% CI = 0.83-1.45). AdjOR for 1 unit increase in LDL levels was 0.95 (95% CI = 0.82-1.10). At 2 years, 1188 patients had follow-up MRI. CMBs progression was observed in 44 (8.0%) statin users and 47 (7.4%) non-statin users. Of these patients, 64 (70.3%) developed a single new CMB, 14 (15.4%) developed 2 CMBs, and 13 developed more than 3 CMBs. The multivariable adjOR for statin users was 1.09 (95% CI = 0.66-1.80). There was no association between LDL levels and CMB progression (adjOR 1.02, 95% CI = 0.79-1.32). At follow-up 14 (1.2%) statin users had ICH versus 16 (1.3%) non-users. The age and sex adjusted hazard ratio (adjHR) was 0.75 (95% CI = 0.36-1.55). The results remained robust in sensitivity analyses excluding participants without anticoagulants. CONCLUSIONS In this prospective cohort of patients with AF, a population at increased hemorrhagic risk due to anticoagulation, the use of statins was not associated with an increased risk of CMBs

Langerhans Cells Facilitate Epithelial DNA Damage and Squamous Cell Carcinoma

Polyaromatic hydrocarbons (PAHs) are prevalent, potent carcinogens, and 7,12-dimethylbenz[a]anthracene (DMBA) is a model PAH widely used to study tumorigenesis. Mice lacking Langerhans cells (LCs), a signatory epidermal dendritic cell (DC), are protected from cutaneous chemical carcinogenesis, independent of T cell immunity. Investigation of the underlying mechanism revealed that LC-deficient skin was relatively resistant to DMBA-induced DNA damage. LCs efficiently metabolized DMBA to DMBA-trans-3,4-diol, an intermediate proximal to oncogenic Hras mutation, and DMBA-treated LC-deficient skin contained significantly fewer Hras mutations. Moreover, DMBA-trans-3,4-diol application bypassed tumor resistance in LC-deficient mice. Additionally, the genotoxic impact of DMBA on human keratinocytes was significantly increased by prior incubation with human-derived LC. Thus, tissue-associated DC can enhance chemical carcinogenesis via PAH metabolism, highlighting the complex relation between immune cells and carcinogenesis