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. RESULTS: Among 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 (ß-coefficient = 10.73, 95% CI = 2.37-19.09, p = 0.01), and higher CoCo score (ß-coefficient = 0.08, 95% CI = 0.03-0.12, p < 0.001). Increasing weekly PA was associated with higher brain volume (ß-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.

Towards personalized antithrombotic management with drugs and devices across the cardiovascular spectrum.

Intravascular thrombus formation and embolization are among the most frequent events leading to a number of cardiovascular conditions with high morbidity and mortality. The underlying causes are stasis of the circulating blood, genetic and acquired coagulation disorders, and reduced antithrombotic or prothrombotic properties of the vascular wall (Virchow's triad). In the venous system, intravascular thrombi can cause venous thrombosis and pulmonary and even peripheral embolism including ischaemic stroke [through a patent foramen ovale (PFO)]. Thrombi in the left atrium and its appendage or ventricle form in the context of atrial fibrillation and infarction, respectively. Furthermore, thrombi can form on native or prosthetic aortic valves, within the aorta (in particular at sites of ulcers, aortic dissection, and abdominal aneurysms), and in cerebral and peripheral arteries causing stroke and critical limb ischaemia, respectively. Finally, thrombotic occlusion may occur in arteries supplying vital organs such the heart, brain, kidney, and extremities. Thrombus formation and embolization can be managed with anticoagulants and devices depending on where they form and embolize and on patient characteristics. Vitamin K antagonists are preferred in patients with mechanical valves, while novel oral anticoagulants are first choice in most other cardiovascular conditions, in particular venous thromboembolism and atrial fibrillation. As anticoagulants are associated with a risk of bleeding, devices such as occluders of a PFO or the left atrial appendage are preferred in patients with an increased bleeding risk. Platelet inhibitors such as aspirin and/or P2Y12 antagonists are preferred in the secondary prevention of coronary artery disease, stroke, and peripheral artery disease either alone or in combination depending on the clinical condition. A differential and personalized use of anticoagulants, platelet inhibitors, and devices is recommended and reviewed in this article.

Risk stratification of elderly patients with acute pulmonary embolism.

BACKGROUND: Combining high-sensitivity cardiac Troponin T (hs-cTnT), NT-pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) may improve risk stratification of patients with pulmonary embolism (PE) beyond the PESI risk score. METHODS: In the prospective multicentre SWITCO65+ study, we analysed 214 patients ≥ 65 years with a new submassive PE. Biomarkers and clinical information for the PESI risk score were ascertained within 1 day after diagnosis. Associations of hs-TnT, NT-proBNP, hs-CRP and the PESI risk score with the primary endpoint defined as 6-month mortality were assessed. The discriminative power of the PESI risk score and its combination with hs-cTnT, NT-proBNP and hs-CRP for 6-month mortality was compared using integrated discrimination improvement (IDI) index and net reclassification improvement (NRI). RESULTS: Compared with the lowest quartile, patients in the highest quartile had a higher risk of death during the first 6 months for hs-cTnT (adjusted HR 10.22; 95% CI 1.79-58.34; P = 0.009) and a trend for NT-proBNP (adjusted HR 4.3; 95% CI 0.9-20.41; P = 0.067) unlike hs-CRP (adjusted HR 1.97; 95% CI 0.48-8.05; P = 0.344). The PESI risk score (c-statistic 0.77 (95% CI 0.69-0.84) had the highest prognostic accuracy for 6-month mortality, outperforming hs-cTnT, NT-proBNP and hs-CRP (c-statistics of 0.72, 0.72, and 0.54), respectively. Combining all three biomarkers had no clinically relevant impact on risk stratification when added to the PESI risk score (IDI = 0.067; 95% CI 0.012-0.123; P = 0.018; NRI = 0.101 95% CI -0.099-0.302; P = 0.321). CONCLUSIONS: In elderly patients with PE, 6-month mortality can adequately be predicted by the PESI risk score alone.

Dietary α-linolenic acid increases the platelet count in ApoE-/- mice by reducing clearance.

Previously we reported that dietary intake of alpha-linolenic acid (ALA) reduces atherogenesis and inhibits arterial thrombosis. Here, we analyze the substantial increase in platelet count induced by ALA and the mechanisms of reduced platelet clearance. Eight-week-old male apolipoprotein E knockout (ApoE(-/-)) mice were fed a 0.21g% cholesterol diet complemented by either a high- (7.3g%) or low-ALA (0.03g%) content. Platelet counts doubled after 16 weeks of ALA feeding, whereas the bleeding time remained similar. Plasma glycocalicin and glycocalicin index were reduced, while reticulated platelets, thrombopoietin, and bone marrow megakaryocyte colony-forming units remained unchanged. Platelet contents of liver and spleen were substantially reduced, without affecting macrophage function and number. Glycoprotein Ib (GPIb) shedding, exposure of P-selectin, and activated integrin αIIbß3 upon activation with thrombin were reduced. Dietary ALA increased the platelet count by reducing platelet clearance in the reticulo-endothelial system. The latter appears to be mediated by reduced cleavage of GPIb by tumor necrosis factor-α-converting enzyme and reduced platelet activation/expression of procoagulant signaling. Ex vivo, there was less adhesion of human platelets to von Willebrand factor under high shear conditions after ALA treatment. Thus, ALA may be a promising tool in transfusion medicine and in high turnover/high activation platelet disorders.

Patients on vitamin K treatment: is switching to direct-acting oral anticoagulation cost-effective? A target trial on a prospective cohort.

AIMS: Direct-acting oral anticoagulants (DOACs) have, to a substantial degree, replaced vitamin K antagonists (VKA) as treatments for stroke prevention in atrial fibrillation (AF) patients. However, evidence on the real-world causal effects of switching patients from VKA to DOAC is lacking. We aimed to assess the empirical incremental cost-effectiveness of switching patients to DOAC compared with maintaining VKA treatment. METHODS: The target trial approach was applied to the prospective observational Swiss-AF cohort, which enrolled 2415 AF patients from 2014 to 2017. Clinical data, healthcare resource utilisation and EQ-5D-based utilities representing quality of life were collected in yearly follow-ups. Health insurance claims were available for 1024 patients (42.4%). Overall survival, quality-of-life, costs from the Swiss statutory health insurance perspective and cost-effectiveness were estimated by emulating a target trial in which patients were randomly assigned to switch to DOAC or maintain VKA treatment. RESULTS: 228 patients switching from VKA to DOAC compared with 563 patients maintaining VKA treatment had no overall survival advantage over a 5-year observation period (HR 0.99, 95% CI 0.45, 1.55). The estimated gain in quality-adjusted life years (QALYs) was 0.003 over the 5-year period at an incremental costs of CHF 23 033 (€ 20 940). The estimated incremental cost-effectiveness ratio was CHF 425 852 (€ 387 138) per QALY gained. CONCLUSIONS: Applying a causal inference method to real-world data, we could not demonstrate switching to DOACs to be cost-effective for AF patients with at least 1 year of VKA treatment. Our estimates align with results from a previous randomised trial.

Platelet production and platelet destruction: assessing mechanisms of treatment effect in immune thrombocytopenia.

This study investigated the immature platelet fraction (IPF) in assessing treatment effects in immune thrombocytopenia (ITP). IPF was measured on the Sysmex XE2100 autoanalyzer. The mean absolute-IPF (A-IPF) was lower for ITP patients than for healthy controls (3.2 vs 7.8 × 109/L, P < .01), whereas IPF percentage was greater (29.2% vs 3.2%, P < .01). All 5 patients with a platelet response to Eltrombopag, a thrombopoietic agent, but none responding to an anti-FcγRIII antibody, had corresponding A-IPF responses. Seven of 7 patients responding to RhoD immuneglobulin (anti-D) and 6 of 8 responding to intravenous immunoglobulin (IVIG) did not have corresponding increases in A-IPF, but 2 with IVIG and 1 with IVIG anti-D did. This supports inhibition of platelet destruction as the primary mechanism of intravenous anti-D and IVIG, although IVIG may also enhance thrombopoiesis. Plasma glycocalicin, released during platelet destruction, normalized as glycocalicin index, was higher in ITP patients than controls (31.36 vs 1.75, P = .001). There was an inverse correlation between glycocalicin index and A-IPF in ITP patients (r² = -0.578, P = .015), demonstrating the relationship between platelet production and destruction. Nonresponders to thrombopoietic agents had increased megakaryocytes but not increased A-IPF, suggesting that antibodies blocked platelet release. In conclusion, A-IPF measures real-time thrombopoiesis, providing insight into mechanisms of treatment effect.

Association of chocolate consumption with neurological and cardiovascular outcomes in atrial fibrillation: data from two Swiss atrial fibrillation cohort studies (Swiss-AF and BEAT-AF).

AIM: To assess the associations of chocolate consumption with neurocognitive function, brain lesions on magnetic resonance imaging (MRI), and cardiovascular outcome in patients with atrial fibrillation (AF). METHODS: We analysed data from patients of two prospective multicentre Swiss atrial fibrillation cohort studies (Swiss-AF) and (BEAT-AF). Assessments of MRI findings and neurocognitive function were performed only in the Swiss-AF population (in 1727 of 2415 patients [71.5%] with a complete data set), as patients enrolled in BEAT-AF were not systematically evaluated for these outcomes. Otherwise, the two cohorts had an equivalent set of clinical assessments. Clinical outcome analysis was performed in 3931 patients of both cohorts. Chocolate consumption was assessed by questionnaire. Patients were categorised as no/low chocolate consumption (No/Low-Ch) ≤1 servings/week, moderate chocolate consumption (Mod-Ch) >1-6 servings/week, and high chocolate consumption (High-Ch) >6 servings/week, respectively. Brain lesions were evaluated by MRI. Assessment of cognitive function was performed by neurocognitive functional testing and included global cognition measurement with a cognitive construct score. Cerebral MRI and cognition were evaluated at baseline. Cross-sectional associations between chocolate consumption and MRI findings were analysed by multivariate logistic regression models and associations with neurocognitive function by multivariate linear regression models. Clinical outcome events during follow-up were recorded and assessed by a clinical event committee. The associations between chocolate consumption and clinical outcomes were evaluated by Cox regression models. The median follow-up time was 6 years. RESULTS: Chocolate consumption was not associated with prevalence or volume of vascular brain lesions on MRI, nor major adverse cardiac events (ischaemic stroke, myocardial infarction, cardiovascular death). However, No/Low-Ch was independently associated with a lower cognitive construct score compared to Mod-Ch (No/Low-Ch vs. Mod-Ch: coeff. -0.05, 95% CI -0.10-0), whereas other neurocognitive function tests were not independently associated with chocolate consumption categories. In addition, there was a higher risk of heart failure hospitalisation (No/Low-Ch vs. Mod-Ch: HR 1.24, 95% CI 1.01-1.52) and of all-cause mortality (No/Low-Ch vs. Mod-Ch: HR 1.29, 95% CI 1.06-1.58) in No/Low-Ch compared to Mod-Ch. No significant associations with the evaluated outcomes were observed when High-Ch was compared to Mod-Ch. CONCLUSION: While chocolate consumption was not associated with MRI findings and major adverse cardiac events in an atrial fibrillation population, No/Low-Ch was associated with a lower cognitive construct score, higher risk of heart failure hospitalisation and increased all-cause mortality compared to Mod-Ch. CLINICALTRIALS: gov Identifier: NCT02105844.

Mid-term changes in cognitive functions in patients with atrial fibrillation: a longitudinal analysis of the Swiss-AF cohort.

Background: Longitudinal association studies of atrial fibrillation (AF) and cognitive functions have shown an unclear role of AF-type and often differ in methodological aspects. We therefore aim to investigate longitudinal changes in cognitive functions in association with AF-type (non-paroxysmal vs. paroxysmal) and comorbidities in the Swiss-AF cohort. Methods: Seven cognitive measures were administered up to five times between 2014 and 2022. Age-education standardized scores were calculated and association between longitudinal change in scores and baseline AF-type investigated using linear mixed-effects models. Associations between AF-type and time to cognitive drop, an observed score of at least one standard deviation below individual's age-education standardized cognitive scores at baseline, were studied using Cox proportional hazard models of each cognitive test, censoring patients at their last measurement. Models were adjusted for baseline covariates. Results: 2,415 AF patients (mean age 73.2 years; 1,080 paroxysmal, 1,335 non-paroxysmal AF) participated in this Swiss multicenter prospective cohort study. Mean cognitive scores increased longitudinally (median follow-up 3.97 years). Non-paroxysmal AF patients showed smaller longitudinal increases in Digit Symbol Substitution Test (DSST), Cognitive Construct Score (CoCo)and Trail Making Test part B (TMT-B) scores vs. paroxysmal AF patients. Diabetes, history of stroke/TIA and depression were associated with worse performance on all cognitive tests. No differences in time to cognitive drop were observed between AF-types in any cognitive test. Conclusion: This study indicated preserved cognitive functioning in AF patients, best explained by practice effects. Smaller practice effects were found in non-paroxysmal AF patients in the DSST, TMT-B and the CoCo and could indicate a marker of subtle cognitive decline. As diabetes, history of stroke/TIA and depression-but not AF-type-were associated with cognitive drop, more attention should be given to risk factors and underlying mechanisms of AF.

Thrombin Generation Is Associated with Venous Thromboembolism Recurrence, but Not with Major Bleeding and Death in the Elderly: A Prospective Multicenter Cohort Study.

It is currently unknown whether thrombin generation is associated with venous thromboembolism (VTE) recurrence, major bleeding, or mortality in the elderly. Therefore, our aim was to prospectively study the association between thrombin generation and VTE recurrence, major bleeding, and mortality in elderly patients with acute VTE. Consecutive patients aged ≥65 years with acute VTE were followed for 2 years, starting from 1 year after the index VTE. Primary outcomes were VTE recurrence, major bleeding, and mortality. Thrombin generation was assessed in 551 patients 1 year after the index VTE. At this time, 59% of the patients were still anticoagulated. Thrombin generation was discriminatory for VTE recurrence, but not for major bleeding and mortality in non-anticoagulated patients. Moreover, peak ratio (adjusted subhazard ratio 4.09, 95% CI, 1.12-14.92) and normalized peak ratio (adjusted subhazard ratio 2.18, 95% CI, 1.28-3.73) in the presence/absence of thrombomodulin were associated with VTE recurrence, but not with major bleeding and mortality after adjustment for potential confounding factors. In elderly patients, thrombin generation was associated with VTE recurrence, but not with major bleeding and/or mortality. Therefore, our study suggests the potential usefulness of thrombin generation measurement after anticoagulation completion for VTE to help identify among elderly patients those at higher risk of VTE recurrence.

Prevalence and risk of inappropriate dosing of direct oral anticoagulants in two Swiss atrial fibrillation registries.

BACKGROUND: Direct oral anticoagulants (DOACs) have a favourable risk-benefit profile compared to vitamin K-antagonists (VKAs) in atrial fibrillation (AF). Dosing is based on age, weight and renal function, without need of routine monitoring. METHODS AND RESULTS: In two prospective, multicentre AF cohorts (Swiss-AF, BEAT-AF) patients were stratified as receiving VKAs or adequately-, under- or overdosed DOACs, according to label. Primary outcome was a composite of major adverse clinical events (MACE), defined as cardiovascular death, myocardial infarction (MI), ischaemic stroke and systemic embolism. Secondary outcomes included major bleeding. Adjustment for confounding was performed. Median follow-up was 4 years. Of 3236 patients, 1875 (58%) were on VKAs and 1361 (42%) were on DOACs, of which 1137 (83%) were adequately-, 134 (10%) over- and 90 (7%) under-dosed. Compared to adequately dosed individuals, overdosed patients were more likely to be older and female. Underdosing correlated with concomitant aspirin therapy and coronary artery disease. Both groups had higher CHA2DS2-VASc scores. Patients on overdosed DOACs had higher incidence of MACE (HR 1.75; CI 1.10-2.79; adjusted-HR: 1.22) and major bleeding (HR 1.99; CI 1.14-3.48; adjusted-HR: 1.51). Underdosing was not associated with a higher incidence of MACE (HR 0.94; CI 0.46-1.92; adjusted-HR 0.61) or major bleeding (HR 1.07; CI 0.46-2.46; adjusted-HR 0.82). After adjustment, all CIs crossed 1.0. CONCLUSION: Inappropriate DOAC-dosing was more prevalent in multimorbid patients, but did not correlate with higher risks of adverse events after adjusting for confounders. DOAC prescription should follow label.

Platelet receptor gain-of-function single nucleotide polymorphisms in carotid and vertebral stenosis patients.

The role of platelet receptor gain-of-function single nucleotide polymorphisms (SNP) in cardiovascular disease is controversial. We hypothesised that certain SNPs may accelerate the development of carotid artery stenosis. The intronic PAR-1 receptor intervening sequence-14 A/T (IVSn-14 A/T) polymorphism and three additional platelet receptor polymorphisms, i.e. GPIa (807C/T), GPIbα (5T/C) and HPA-1a/HPA-1b (Pl (A1/A2)) of GPIIIa were studied. The interaction of SNPs with conventional risk factors including male gender, hypertension, high cholesterol, diabetes, advanced age and smoking were investigated. The hypothesis was tested in 114 well-characterised patients with symptomatic carotid or vertebral stenosis from the British CAVATAS population and compared the results with 97 unrelated controls. The allele frequency of the platelet gain-of-function SNP was not significantly different in the CAVATAS population as compared to controls (PAR-1A/T (P = 0.13), GPIa C/T (P = 0.25), GPIIIa HPA-1a/HPA-1b (PlA1/A2) (P = 0.66) and GPIb T/C (P = 0.20)). In the subgroup of smokers, however, the prothrombotic GPIbα C mutated allele was found in a significantly higher frequency in the patient as compared to the control group (P = 0.04). Contrary to the primary hypothesis, the PAR-1A/T SNP as well as the other SNPs tested were not over- or underrepresented in the CAVATAS population. However, a significantly increased prevalence of GPIb-α (5C/T) was found in the subgroup of smokers and may represent an important cofactor in this patient group of our hypothesis-generating study.

Blood Omega-3 Fatty Acids Are Inversely Associated With Albumin-Creatinine Ratio in Young and Healthy Adults (The Omega-Kid Study).

Background: Omega-3 fatty acids are associated with a lower risk of cardiovascular disease (CVD) and with beneficial effects on CV risk factors. The albumin-creatinine ratio (ACR) is a risk factor for CVD, all-cause mortality and accelerated glomerular filtration rate (GFR) decline in the general population. We aimed to investigate the association between n-3 PUFAS and ACR in heathy individuals with preserved GFR. Design and Methods: The present cross-sectional analysis is part of the GAPP study, a population-based cohort of healthy adults aged 25-41 years. Individuals with known CVD, diabetes, or a BMI >35 kg/m2 were excluded. eGFR was calculated according to the combined Creatinine/Cystatin C CKD-EPI formula. ACR was obtained from a fasting morning urine sample. The Omega-3 Index (relative amount of EPA and DHA of total fatty acids in %) was obtained from whole blood aliquots. Results: Overall, 2001 participants (median age 37 years IQR 31; 40, 53% female) were included in this analysis. Median Omega-3 Index was 4.59 (IQR 4.06; 5.25) and median eGFR 111 ml/min/1.73 m2 (IQR 103; 118). Median ACR was 0.14 mg/mmol (IQR 0; 0.43). We found a significant inverse association of the Omega-3 Index with ACR (ratio 0.84, 95%CI 0.73-0.96; p = 0.011) which remained after comprehensive adjustment (ratio 0.86, 95%CI 0.74-1.00; p = 0.048). No association of the Omega-3 Index with eGFR was found. The adjusted difference in eGFR per 1-unit increase in Omega3-Index was -0.21 (95%CI -0.76; 0.35; p = 0.47). Conclusions: A higher Omega-3 Index was significantly associated with lower ACR in this young and healthy population with preserved eGFR. Omega-3 fatty acids may exhibit cardio- and nephroprotective effects in healthy individuals through modulation of ACR.

Association of psychosocial factors with all-cause hospitalizations in patients with atrial fibrillation.

BACKGROUND: A high burden of cardiovascular comorbidities puts patients with atrial fibrillation (AF) at high risk for hospitalizations, but the role of other factors is less clear. HYPOTHESIS: To determine the relationship between psychosocial factors and the risk of unplanned hospitalizations in AF patients. METHODS: Prospective observational cohort study of 2378 patients aged 65 or older with previously diagnosed AF across 14 centers in Switzerland. Marital status and education level were defined as social factors, depression and health perception were psychological components. The pre-defined outcome was unplanned all-cause hospitalization. RESULTS: During a median follow-up of 2.0 years, a total of 1713 hospitalizations occurred in 37% of patients. Compared to patients who were married, adjusted rate ratios (aRR) for all-cause hospitalizations were 1.28 (95% confidence interval [CI], 0.97-1.69) for singles, 1.31 (95%CI, 1.06-1.62) for divorced patients, and 1.02 (95%CI, 0.82-1.25) for widowed patients. The aRRs for all-cause hospitalizations across increasing quartiles of health perception were 1.0 (highest health perception), 1.15 (95%CI, 0.84-1.59), 1.25 (95%CI, 1.03-1.53), and 1.66 (95%CI, 1.34-2.07). No different hospitalization rates were observed in patients with a secondary or primary or less education as compared to patients with a college degree (aRR, 1.06; 95%CI, 0.91-1.23 and 1.05; 95%CI, 0.83-1.33, respectively). Presence of depression was not associated with higher hospitalization rates (aRR, 0.94; 95%CI, 0.68-1.29). CONCLUSIONS: The findings suggest that psychosocial factors, including marital status and health perception, are strongly associated with the occurrence of hospitalizations in AF patients. Targeted psychosocial support interventions may help to avoid unnecessary hospitalizations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02105844.

Heart rate and adverse outcomes in patients with prevalent atrial fibrillation.

OBJECTIVE: The optimal target heart rate in patients with prevalent atrial fibrillation (AF) is not well defined. The aim of this study was to analyse the associations between heart rate and adverse outcomes in a large contemporary cohort of patients with prevalent AF. METHODS: From two prospective cohort studies, we included stable AF outpatients who were in AF on the baseline ECG. The main outcome events assessed during prospective follow-up were heart failure hospitalisation, stroke or systemic embolism and death. The associations between heart rate and adverse outcomes were evaluated using multivariable Cox regression models. RESULTS: The study population consisted of 1679 patients who had prevalent AF at baseline. Mean age was 74 years, and 24.6% were women. The mean heart rate on the baseline ECG was 78 (±19) beats per minute (bpm). The median follow-up was 3.9 years (IQR 2.2-5.0). Heart rate was not significantly associated with heart failure hospitalisation (adjusted HR (aHR) per 10 bpm increase, 1.00, 95% CI 0.94 to 1.07, p=0.95), stroke or systemic embolism (aHR 0.95, 95% CI 0.84 to 1.07, p=0.38) or death (aHR 1.02, 95% CI 0.95 to 1.09, p=0.66). There was no evidence of a threshold effect for heart rates <60 bpm or >100 bpm. CONCLUSIONS: In this large contemporary cohort of outpatients with prevalent AF, we found no association between heart rate and adverse outcome events. These data are in line with recommendations that strict heart rate control is not needed in otherwise stable outpatients with AF.

Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01.

BACKGROUND: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing. METHODS: We analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany (n = 135), Spain (n = 133), Switzerland (n = 20) and the United States (n = 147), who had been enrolled from March 2020 to August 2020. This study included patients older than 18 years, diagnosed with COVID-19 and representing the full spectrum of the disease. Finally, we tested our results by meta-analysing data from prior genome-wide association studies (GWAS). FINDINGS: We describe a potential association of HLA-C*04:01 with severe clinical course of COVID-19. Carriers of HLA-C*04:01 had twice the risk of intubation when infected with SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1-2.1], odds ratio 3.5 [95% CI 1.9-6.6], adjusted p-value = 0.0074). These findings are based on data from four countries and corroborated by independent results from GWAS. Our findings are biologically plausible, as HLA-C*04:01 has fewer predicted bindings sites for relevant SARS-CoV-2 peptides compared to other HLA alleles. INTERPRETATION: HLA-C*04:01 carrier state is associated with severe clinical course in SARS-CoV-2. Our findings suggest that HLA class I alleles have a relevant role in immune defense against SARS-CoV-2. FUNDING: Funded by Roche Sequencing Solutions, Inc.

[To prevent myocardial infarction with a tooth brush?]. / "Mit der Zahnbürste dem Herzinfarkt vorbeugen?" oder "Brush your Brain too!"

UNLABELLED: The association of periodontal disease and cardiovascular events is discussed. Low grade inflammation, with elevated CRP and elevated fibrinogen might contribute. A recent study from Scotland in which the dental brushing was evaluated found a relative risk for a cardiovascular event of 1.69 associated with rare tooth brushing. However, there was a bias with elderly patients, male gender and low socioeconomic status. CONCLUSION: The common risk factor is smoking; active "dentogenic" inflammation should be checked before surgery, particularly before surgery with implants.

A significant increase in exercise test performance with virtual group motivation: a randomised open-label controlled trial.

AIMS: Exercise stress testing is frequently used for the assessment of coronary artery disease. As the validity of the test result is highly dependent on the patient’s cooperation and motivation, we hypothesised that virtual group motivation would result in a higher exercise capacity and may increase the test’s validity. METHODS: 108 patients at a Swiss teaching hospital with an indication for exercise testing were included in a controlled, open-label trial and randomised 1:1 to treadmill exercise testing whilst either watching a video of a walking group (video group, n = 43), or watching a static image of flowers (image group, n = 43). The video showed a group of five amateur runners, giving the patients the impression of running within the group. As primary outcomes, the performance achieved and the perceived level of comfort during the test were analysed. RESULTS: The video group achieved significantly higher percentages of their age-predicted METs (149 ± 32% vs 135 ± 29%, p = 0.041) and longer exercise durations (11:12 ± 2:54 min vs 08:54 ± 02:39 min, p <0.001). Levels of comfort (8.4 ± 1.4 vs 7.5 ± 1.7 analogue scale, p = 0.011) and closeness to their physical limits (8.9 ± 0.8 vs 8.1 ± 1.5, p = 0.005) were rated significantly higher by patients in the video group. CONCLUSIONS: Patients watching a video of a running group achieved significantly higher maximum exercise levels and longer test durations. This may have implications for the test’s validity. Furthermore, the virtual setting enhanced patient comfort. (This trial was formally registered at clinicaltrials.gov: trial ID NCT03704493.).