Publications by authors named "Jürg H Beer"

66 Publications

Biomarkers of Inflammation and Risk of Hospitalization for Heart Failure in Patients With Atrial Fibrillation.

J Am Heart Assoc 2021 Apr 10:e019168. Epub 2021 Apr 10.

Population Health Research Institute McMaster University Hamilton Canada.

Background Hospitalization for heart failure (HF) is very common in patients with atrial fibrillation (AF). We hypothesized that biomarkers of inflammation can identify patients with AF at increased risk of this important complication. Methods and Results Patients with established AF were prospectively enrolled. Levels of hs-CRP (high-sensitivity C-reactive protein) and interleukin-6 were measured from plasma samples obtained at baseline. We calculated an inflammation score ranging from 0 to 4 (1 point for each biomarker between the 50th and 75th percentile, 2 points for each biomarker above the 75th percentile). Individual associations of biomarkers and the inflammation score with HF hospitalization were obtained from multivariable Cox proportional hazards models. A total of 3784 patients with AF (median age 72 years, 24% prior HF) were followed for a median of 4.0 years. The median (interquartile range) plasma levels of hs-CRP and interleukin-6 were 1.64 (0.81-3.69) mg/L and 3.42 (2.14-5.60) pg/mL, respectively. The overall incidence of HF hospitalization was 3.04 per 100 person-years and increased from 1.34 to 7.31 per 100 person-years across inflammation score categories. After multivariable adjustment, both biomarkers were significantly associated with the risk of HF hospitalization (per increase in 1 SD, adjusted hazard ratio [HR], 1.22; 95% CI, 1.11-1.34 for log-transformed hs-CRP; adjusted HR, 1.48; 95% CI, 1.35-1.62 for log-transformed interleukin-6). Similar results were obtained for the inflammation score (highest versus lowest score, adjusted HR, 2.43; 95% CI, 1.80-3.30; value for trend <0.001). Conclusions Biomarkers of inflammation strongly predicted HF hospitalization in a large, contemporary sample of patients with AF. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02105844.
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http://dx.doi.org/10.1161/JAHA.120.019168DOI Listing
April 2021

The Omega-3 Fatty Acid Eicosapentaenoic Acid (EPA) Correlates Inversely with Ischemic Brain Infarcts in Patients with Atrial Fibrillation.

Nutrients 2021 Feb 17;13(2). Epub 2021 Feb 17.

Department of Internal Medicine, Cantonal Hospital of Baden, 5404 Baden, Switzerland.

The omega-3 fatty acid (n-3 FA) eicosapentaenoic acid (EPA) reduces stroke in patients with atherosclerotic cardiovascular disease. Whether EPA affects stroke or cerebral small vessel dis-ease in patients with atrial fibrillation (AF) remains uncertain. EPA, docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and alpha-linolenic acid (ALA) were determined by gas chromatography in 1657 AF patients from the Swiss Atrial Fibrillation study. All patients underwent brain MRI to detect ischemic brain infarcts, classified as large noncortical or cortical infarcts (LNCCIs); markers of small vessel disease, classified as small noncortical infarcts (SNCIs), number of microbleeds, and white matter lesion (WML) volumes. Individual and total n-3 FAs (EPA + DHA + DPA + ALA) were correlated with LNCCIs and SNCIs using logistic regression, with numbers of microbleeds using a hurdle model, and WML volumes using linear regression. LNCCIs were detected in 372 patients (22.5%). EPA correlated inversely with the prevalence of LNCCIs (odds ratio [OR] 0.51 per increase of 1 percentage point EPA, 95% confidence interval [CI] 0.29-0.90). DPA correlated with a higher LNCCI prevalence (OR 2.48, 95%CI 1.49-4.13). No associations with LNCCIs were found for DHA, ALA, and total n-3 FAs. Neither individual nor total n-3 FAs correlated with markers of small vessel disease. In conclusion, EPA correlates inversely with the prevalence of ischemic brain infarcts, but not with markers of small vessel disease in patients with AF.
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http://dx.doi.org/10.3390/nu13020651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922349PMC
February 2021

Alcohol consumption and risk of cardiovascular outcomes and bleeding in patients with established atrial fibrillation.

CMAJ 2021 Jan;193(4):E117-E123

Cardiovascular Research Institute Basel (Reddiess, Aeschbacher, Meyre, Coslovsky, Kühne, Müller, Steiner, Sticherling, Osswald, Conen); Cardiology Division (Reddiess, Aeschbacher, Meyre, Coslovsky, Kühne, Müller, Steiner, Sticherling, Osswald); Clinical Trial Unit Basel, Department of Clinical Research (Coslovsky), University Hospital Basel, Switzerland; Institute of Primary Health Care (BIHAM) (Rodondi), University of Bern; Department of General Internal Medicine (Rodondi), Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Medicine (Beer), Cantonal Hospital of Baden and Molecular Cardiology, University Hospital of Zürich, Switzerland; Department of Cardiology (Kobza), Luzerner Kantonsspital, Switzerland; Department of Cardiology (Moschovitis), EOC Ospedale Regionale di Lugano, Switzerland; Department of Cardiology (Di Valentino), EOC Ospedale San Giovanni, Bellinzona, Switzerland; Department of Neurology and Stroke Center (Bonati), University Hospital Basel, University of Basel, Switzerland; Population Health Research Institute (Conen), McMaster University, Hamilton, Ont.

Background: Little is known about the association between alcohol consumption and risk of cardiovascular events in patients with established atrial fibrillation (AF). The main aim of the current study was to investigate the associations of regular alcohol intake with incident stroke or systemic embolism in patients with established AF.

Methods: To assess the association between alcohol consumption and cardiovascular events in patients with established AF, we combined data from 2 comparable prospective cohort studies that followed 3852 patients with AF for a median of 3.0 years. Patients were grouped into 4 categories of daily alcohol intake (none, > 0 to < 1, 1 to < 2 and ≥ 2 drinks/d). The primary outcome was a composite of stroke and systemic embolism. Secondary outcomes were all-cause mortality, myocardial infarction, hospital admission for acute heart failure, and a composite of major and clinically relevant nonmajor bleeding. Associations were assessed using time-updated, multivariable-adjusted Cox proportional hazards models.

Results: Mean age (± standard deviation) was 71 ± 10 years (28% were women and 84% were on oral anticoagulants). We observed 136 confirmed strokes or systemic emboli. Compared with nondrinkers, adjusted hazard ratios for the primary outcome event were 0.87, 95% confidence interval (CI) 0.55-1.37 for > 0 to < 1 drinks/d; 0.70, 95% CI 0.39-1.25 for 1 to < 2 drinks/d; and 0.96, 95% CI 0.56-1.67 for ≥ 2 drinks/d ( for linear [quadratic] trend 0.71 [0.22]). There was no significant association between alcohol consumption and bleeding, but there was a nonlinear association with heart failure ( for quadratic trend 0.01) and myocardial infarction ( for quadratic trend 0.007).

Interpretation: In patients with AF, we did not find a significant association between low to moderate alcohol intake and risk of stroke or other cardiovascular events. Our findings do not support special recommendations for patients with established AF with regard to alcohol consumption.

Trial Registration: ClinicalTrials.gov, no. NCT02105844.
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http://dx.doi.org/10.1503/cmaj.200778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954562PMC
January 2021

The Admit-AF risk score: A clinical risk score for predicting hospital admissions in patients with atrial fibrillation.

Eur J Prev Cardiol 2020 Mar 31. Epub 2020 Mar 31.

Cardiovascular Research Institute Basel, University Hospital Basel, Switzerland.

Aims: To develop and externally validate a risk score for all-cause hospital admissions in patients with atrial fibrillation.

Methods And Results: We used a prospective cohort of 2387 patients with established atrial fibrillation as derivation cohort. Independent risk factors were selected from a broad range of variables using the least absolute shrinkage and selection operator method fit to a Cox model. The risk score was validated in a separate prospective cohort of 1300 atrial fibrillation patients. The incidence of all-cause hospital admission was 19.1 per 100 person-years in the derivation cohort and it was 26.1 per 100 person-years in the validation cohort. The most important predictors for admission were age (75-79 years: adjusted hazard ratio (aHR), 1.34; 95% confidence interval (CI), 1.01-1.78; 80-84 years: aHR, 1.50; 95% CI, 1.11-2.03; ≥85 years: aHR, 1.88; 95% CI, 1.36-2.62), prior pulmonary vein isolation (aHR, 0.72; 95% CI, 0.58-0.88), hypertension (aHR, 1.16; 95% CI, 0.99-1.36), diabetes (aHR, 1.38; 95% CI, 1.17-1.62), coronary heart disease (aHR, 1.17; 95% CI, 1.02-1.36), prior stroke/transient ischaemic attack (aHR, 1.26; 95% CI, 1.18-1.47), heart failure (aHR, 1.19; 95% CI, 1.03-1.39), peripheral artery disease (aHR, 1.35; 95% CI, 1.08-1.67), cancer (aHR, 1.33; 95% CI, 1.12-1.57), renal failure (aHR, 1.17; 95% CI, 0.99-1.37) and previous falls (aHR, 1.40; 95% CI, 1.13-1.74). A risk score with these variables was well calibrated, and achieved a C-index of 0.64 in the derivation and 0.59 in the validation cohort.

Conclusions: Multiple risk factors were associated with hospital admissions in atrial fibrillation patients. This prediction tool selects high-risk patients who may benefit from preventive interventions.
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http://dx.doi.org/10.1177/2047487320915350DOI Listing
March 2020

Blood Pressure and Brain Lesions in Patients With Atrial Fibrillation.

Hypertension 2021 Feb 28;77(2):662-671. Epub 2020 Dec 28.

From the Cardiology Division, Department of Medicine (S.A., S.B., P.M., M.C., C.H., T.B., C.E., C.S.Z., C.S., S.O., M.K.), University of Basel, Switzerland.

The association of blood pressure (BP) and hypertension with the presence of different types of brain lesions in patients with atrial fibrillation is unclear. BP values were obtained in a multicenter cohort of patients with atrial fibrillation. Systolic and diastolic BP was categorized in predefined groups. All patients underwent brain magnetic resonance imaging and neurocognitive testing. Brain lesions were classified as large noncortical or cortical infarcts, small noncortical infarcts, microbleeds, or white matter lesions. White matter lesions were graded according to the Fazekas scale. Overall, 1738 patients with atrial fibrillation were enrolled in this cross-sectional analysis (mean age, 73 years, 73% males). Mean BP was 135/79 mm Hg, and 67% of participants were taking BP-lowering treatment. White matter lesions Fazekas ≥2 were found in 54%, large noncortical or cortical infarcts in 22%, small noncortical infarcts in 21%, and microbleeds in 22% of patients, respectively. Compared with patients with systolic BP <120 mm Hg, the adjusted odds ratios (95% CI) for Fazekas≥2 was 1.25 (0.94-1.66), 1.41 (1.03-1.93), and 2.54 (1.65-3.95) among patients with systolic BP of 120 to 140, 140 to 160, and ≥160 mm Hg ( for linear trend<0.001). Per 5 mm Hg increase in systolic and diastolic BP, the adjusted β-coefficient (95% CI) for log-transformed white matter lesions was 0.04 (0.02-0.05), <0.001 and 0.04 (0.01-0.06), =0.004. Systolic BP was associated with small noncortical infarcts (odds ratios [95% CI] per 5 mm Hg 1.05 [1.01-1.08], =0.006), microbleeds were associated with hypertension, but large noncortical or cortical infarcts were not associated with BP or hypertension. After multivariable adjustment, BP and hypertension were not associated with neurocognitive function. Among patients with atrial fibrillation, BP is strongly associated with the presence and extent of white matter lesions, but there is no association with large noncortical or cortical infarcts. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02105844.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803457PMC
February 2021

Insulin-like growth factor-binding protein 7 and risk of congestive heart failure hospitalization in patients with atrial fibrillation.

Heart Rhythm 2021 Apr 3;18(4):512-519. Epub 2020 Dec 3.

Cardiovascular Research Institute Basel, University Hospital Basel, University of Basel, Basel, Switzerland; Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada. Electronic address:

Background: The occurrence of congestive heart failure (CHF) hospitalization among patients with atrial fibrillation (AF) is a poor prognostic marker.

Objective: The purpose of this study was to assess whether insulin-like growth factor-binding protein 7 (IGFBP-7), a marker of myocardial damage, identifies AF patients at high risk for this complication.

Methods: We analyzed 2 prospective multicenter observational cohort studies that included 3691 AF patients. Levels of IGFBP-7 and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured from frozen plasma samples at baseline. The primary endpoint was hospitalization for CHF. Multivariable adjusted Cox regression analyses were constructed.

Results: Mean patient age was 69 ± 12 years, 1028 (28%) were female, and 879 (24%) had a history of CHF. The incidence per 1000 patient-years across increasing IGFBP-7 quartiles was 7, 10, 32, and 85. The corresponding multivariable adjusted hazard ratios (aHRs) (95% confidence interval [CI]) were 1.0, 1.05 (0.63-1.77), 2.38 (1.50-3.79), and 4.37 (2.72-7.04) (P for trend <.001). In a subgroup of 2812 patients without pre-existing CHF at baseline, the corresponding aHRs were 1.0, 0.90 (0.47-1.72), 1.69 (0.94-3.04), and 3.48 (1.94-6.24) (P for trend <.001). Patients with IGFBP-7 and NT-proBNP levels above the biomarker-specific median had a higher risk of incident CHF hospitalization (aHR 5.20; 3.35-8.09) compared to those with only 1 elevated marker (elevated IGFBP-7 aHR 2.17; 1.30-3.60); elevated NT-proBNP aHR 1.97; 1.17-3.33); or no elevated marker (reference).

Conclusion: Higher plasma levels of IGFBP-7 were strongly and independently associated with CHF hospitalization in AF patients. The prognostic information provided by IGFBP-7 was additive to that of NT-proBNP.
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http://dx.doi.org/10.1016/j.hrthm.2020.11.028DOI Listing
April 2021

Clinical Outcomes of Incidental Venous Thromboembolism in Cancer and Noncancer Patients: The SWIss Venous ThromboEmbolism Registry (SWIVTER).

Thromb Haemost 2020 Nov 17. Epub 2020 Nov 17.

Clinic of Angiology, University Hospital Zurich, Zurich, Switzerland.

Objective:  In patients with cancer-associated venous thromboembolism (VTE), the risk of recurrence is similar after incidental and symptomatic events. It is unknown whether the same applies to incidental VTE not associated with cancer.

Methods And Results:  We compared baseline characteristics, anticoagulation therapy, all-cause mortality, and VTE recurrence rates at 90 days between patients with incidental ( = 131; 52% without cancer) and symptomatic ( = 1,931) VTE included in the SWIss Venous ThromboEmbolism Registry (SWIVTER). After incidental VTE, 114 (87%) patients received anticoagulation therapy for at least 3 months. The mortality rate was 9.2% after incidental and 8.4% after symptomatic VTE for hazard ratio (HR) 1.10 (95% confidence interval [CI] 0.49-2.50). After adjustment for competing risk of death, recurrence rate was 3.1 versus 2.8%, respectively, for sub-HR 1.07 (95% CI 0.39-2.93). These results were consistent among cancer (mortality: 15.9% vs. 12.6%; HR 1.32, 95% CI 0.67-2.59; recurrence: 4.8% vs. 4.7%; HR 1.02, 95% CI 0.30-3.42) and noncancer patients (mortality: 2.9% vs. 2.1%; HR 1.37, 95% CI 0.33-5.73; recurrence: 1.5% vs. 2.3%; HR 0.63, 95% CI 0.09-4.58). Patients with incidental VTE who received anticoagulation therapy for at least 3 months had lower mortality (4% vs. 41%) and recurrence rate (1% vs. 18%) compared with those who did not.

Conclusion:  In SWIVTER, more than half of incidental VTE events occurred in noncancer patients who often received anticoagulation therapy. Among noncancer patients, early mortality and recurrence rates were similar after incidental versus symptomatic VTE. Our findings suggest that anticoagulation therapy for incidental VTE may be beneficial regardless of the presence of cancer.
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http://dx.doi.org/10.1055/s-0040-1720977DOI Listing
November 2020

[For Once Not Corona Virus - an Uncommon Cause of Fever and Hepatitis].

Praxis (Bern 1994) 2020 ;109(14):1150-1152

Departement Innere Medizin, Kantonsspital Baden.

For Once Not Corona Virus - an Uncommon Cause of Fever and Hepatitis Our case reports acute Q fever as uncommon cause of fever, typically accompanied by pneumonia and/or hepatitis. It is caused by Coxiella burnetii, a bacterium which is generally hosted by live stock and affects humans by inhaling aerosols of the animals' excrements. If detected, it may be treated effectively. It should be considered in patients living in a typical environment or with a typical history. The route of our patient's infection remains unclear since he plausibly denied contact with any animals.
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http://dx.doi.org/10.1024/1661-8157/a003557DOI Listing
November 2020

Sirtuin 5 promotes arterial thrombosis by blunting the fibrinolytic system.

Cardiovasc Res 2020 Sep 15. Epub 2020 Sep 15.

Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, Schlieren, Switzerland.

Aims: Arterial thrombosis as a result of plaque rupture or erosion is a key event in acute cardiovascular events. Sirtuin 5 (SIRT5) belongs to the lifespan-regulating sirtuin superfamily and has been implicated in acute ischemic stroke and cardiac hypertrophy. This project aims at investigating the role of SIRT5 in arterial thrombus formation.

Methods And Results: Sirt5 transgenic (Sirt5Tg/0) as well as knock-out (Sirt5-/-) mice underwent photochemically-induced carotid endothelial injury to trigger arterial thrombosis. Primary human aortic endothelial cells (HAECs) treated with SIRT5 silencing-RNA (si-SIRT5) as well as peripheral blood mononuclear cells (PBMCs) from acute coronary syndrome (ACS) patients and non-ACS controls (case-control study, total n = 171) were used to increase the translational relevance of our data. Compared to WT controls, Sirt5Tg/0 mice displayed accelerated arterial thrombus formation following endothelial-specific damage. Conversely, in Sirt5-/-mice arterial thrombosis was blunted. Platelet function was unaltered, as assessed by ex vivo collagen-induced aggregometry. Similarly, activation of the coagulation cascade as assessed by vascular and plasma tissue factor (TF) and TF pathway inhibitor (TFPI) expression was unaltered. Increased thrombus embolization episodes and circulating D-dimer levels suggested augmented activation of the fibrinolytic system in Sirt5-/- mice. Accordingly, Sirt5-/- mice showed reduced plasma and vascular expression of the fibrinolysis inhibitor plasminogen activator inhibitor (PAI)-1. In HAECs, SIRT5-silencing inhibited PAI-1 gene and protein expression in response to TNF-α. This effect was mediated by increased AMPK activation and reduced phosphorylation of the MAP kinase ERK 1/2, but not JNK and p38 as shown both in vivo and in vitro. Lastly, both PAI-1 and SIRT5 gene expression are increased in ACS patients compared to non-ACS controls after adjustment for cardiovascular risk factors, while PAI-1 expression increased across tertiles of SIRT5.

Conclusions: SIRT5 promotes arterial thrombosis by modulating fibrinolysis through endothelial PAI-1 expression. Hence, SIRT5 may be an interesting therapeutic target in the context of atherothrombotic events.

Translational Perspectives: This study illustrates a novel role for Sirtuin 5 in arterial thrombosis by regulating fibrinolysis through plasminogen activator inhibitor 1 (PAI-1). These results shed new light onto the pathophysiology of arterial thrombus formation which underlies most of the acute atherosclerotic complications. Also, they further affirm the intrinsic relationship between lifespan regulating genes, vascular dysfunction and age-related cardiovascular disease, thus indicating these genes as potential targets for cardiovascular prevention and therapy. Further studies will be needed to assess the predictive ability of SIRT5 in patients with acute cardiovascular or cerebrovascular events. Also, the design of specific SIRT5 inhibitors will allow trials aiming at investigating the efficacy of SIRT5 blockage in the clinical setting.
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http://dx.doi.org/10.1093/cvr/cvaa268DOI Listing
September 2020

Postischemic Administration of IL-1α Neutralizing Antibody Reduces Brain Damage and Neurological Deficit in Experimental Stroke.

Circulation 2020 Jul 13;142(2):187-189. Epub 2020 Jul 13.

Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland (L.L, N.R.B., Y.M.P., L.S., A.A., J.H.B., T.F.L., G.G.C.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046301DOI Listing
July 2020

Symptoms and quality of life in patients with coexistent atrial fibrillation and atrial flutter.

Int J Cardiol Heart Vasc 2020 Aug 16;29:100556. Epub 2020 Jun 16.

Cardiovascular Research Institute Basel, University Hospital Basel, University of Basel, Switzerland.

Aims: Atrial fibrillation (AF) and atrial flutter (AFL) are two of the most common atrial arrhythmias and often coexist. Many patients with AF or AFL are symptomatic, which impacts their quality of life (QoL). The purpose of this study was to determine whether coexistent AFL represents an added burden for AF patients.

Methods: We combined baseline data from two large prospective, observational, multicenter cohort studies (BEAT-AF and Swiss-AF). All 3931 patients included in this analysis had documented AF. We obtained information on comorbidities, medication, and lifestyle factors All participants had a clinical examination and a resting ECG. Symptom burden and QoL at the baseline examination were compared between patients with and without coexistent AFL using multivariable adjusted regression models.

Results: Overall, 809 (20.6%) patients had a history of AFL. Patients with coexistent AFL more often had history of heart failure (28% vs 23%, p = 0.01), coronary artery disease (30% vs 26%, p = 0.007), failed therapy with antiarrhythmic drugs (44% vs 29%, p < 0.001), and more often underwent AF-related interventions (36% vs 17%, p < 0.001). They were more often symptomatic (70% vs 66%, p = 0.04) and effort intolerant (OR: 1.14; 95% CI: 1.01-1.28; p = 0.04). Documented AFL on the baseline ECG was associated with more symptoms (OR: 2.30; 95% CI: 1.26-4.20; p = 0.007).

Conclusion: Our data indicates that patients with coexistent AF and AFL are more often symptomatic and report poorer quality of life compared to patients suffering from AF only.
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http://dx.doi.org/10.1016/j.ijcha.2020.100556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303549PMC
August 2020

Apelin-potential therapy for COVID-19?

J Mol Cell Cardiol 2020 08 18;145:84-87. Epub 2020 Jun 18.

Center for Molecular Cardiology, University of Zurich, 8952 Schlieren, Switzerland; Department of Internal Medicine, Cantonal Hospital Baden, Baden, Switzerland. Electronic address:

We believe that, in parallel to the attempts for direct blockade of the SARS-CoV-2 penetration into host cell and repurposing drugs, finding new therapeutic strategies for patients with lung injury or cardiovascular complications/coagulopathies associated with COVID-19 should be paid particular attention. Apelin or its receptor agonists are of great potential treatment for COVID-19 through suppressing angiotensin-converting enzyme (ACE) and angiotensin II (Ang-II) production, as well as, down-regulating angiotensin receptor 1 (AT1R) and ACE2 up-regulation. These drugs have potential to improve acute lung injury and cardiovascular/coagulopathy complications in COVID-19 which are associated with elevated Ang-II/Ang(1-7) ratio.
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http://dx.doi.org/10.1016/j.yjmcc.2020.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299869PMC
August 2020

Associations of symptoms and quality of life with outcomes in patients with atrial fibrillation.

Heart 2020 Dec 31;106(23):1847-1852. Epub 2020 Mar 31.

Population Health Research Institute and Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada

Objective: We aimed to investigate changes in atrial fibrillation (AF)-related symptoms and quality of life (QoL) over time, and their impact on prognosis.

Methods: We prospectively followed 3836 patients with known AF for a mean of 3.7 years. Information on AF-related symptoms and QoL was obtained yearly. The primary end point was a composite of stroke or systemic embolism. Main secondary end points included stroke subtypes, all-cause mortality, cardiovascular death, hospitalisation for congestive heart failure (CHF), myocardial infarction and major bleeding. We assessed associations using multivariable, time-updated Cox proportional hazards models.

Results: Mean age was 72 years, 72% were male. Patients with AF-related symptoms (66%) were younger (70 vs 74 years, p<0.0001), more often had paroxysmal AF (56% vs 37%, p<0.0001) and had lower QoL (71 vs 72 points, p=0.009). The incidence of the primary end point was 1.05 and 1.02 per 100 person-years in patients with and without symptoms, respectively. The multivariable adjusted HR (aHR) (95% CIs) for the primary end point was 1.11 (0.77 to 1.59; p=0.56) for AF-related symptoms. AF-related symptoms were not associated with any of the secondary end points. QoL was not significantly related to the primary end point (aHR per 5-point increase 0.98 (0.94 to 1.03; p=0.37)), but was significantly related to CHF hospitalisations (0.92 (0.90 to 0.94; p<0.0001)), cardiovascular death (0.90 (0.86 to 0.95; p<0.0001)) and all-cause mortality (0.88 (0.86 to 0.90; p<0.0001)).

Conclusions: AF-related symptoms were not associated with adverse outcomes and should therefore not be the basis for prognostic treatment decisions. QoL was strongly associated with CHF, cardiovascular death and all-cause mortality.
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http://dx.doi.org/10.1136/heartjnl-2019-316314DOI Listing
December 2020

Not even a zebra: when an 'ordinary acute coronary syndrome' turns out to be a thyrotoxicosis-associated takotsubo syndrome.

Eur Heart J 2020 10;41(37):3589

Department of Internal Medicine, Cantonal Hospital of Baden, Im Ergel 1, CH-5404 Baden, Switzerland.

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http://dx.doi.org/10.1093/eurheartj/ehaa022DOI Listing
October 2020

Frailty to predict unplanned hospitalization, stroke, bleeding, and death in atrial fibrillation.

Eur Heart J Qual Care Clin Outcomes 2021 Jan;7(1):42-51

Cardiovascular Research Institute Basel, University Hospital Basel, University of Basel, Petersgraben 4, 4031 Basel, Switzerland.

Aims: Atrial fibrillation (AF) and frailty are common, and the prevalence is expected to rise further. We aimed to investigate the prevalence of frailty and the ability of a frailty index (FI) to predict unplanned hospitalizations, stroke, bleeding, and death in patients with AF.

Methods And Results: Patients with known AF were enrolled in a prospective cohort study in Switzerland. Information on medical history, lifestyle factors, and clinical measurements were obtained. The primary outcome was unplanned hospitalization; secondary outcomes were all-cause mortality, bleeding, and stroke. The FI was measured using a cumulative deficit approach, constructed according to previously published criteria and divided into three groups (non-frail, pre-frail, and frail). The association between frailty and outcomes was assessed using multivariable-adjusted Cox regression models. Of the 2369 included patients, prevalence of pre-frailty and frailty was 60.7% and 10.6%, respectively. Pre-frailty and frailty were associated with a higher risk of unplanned hospitalizations [adjusted hazard ratio (aHR) 1.82, 95% confidence interval (CI) 1.49-2.22; P < 0.001; and aHR 3.59, 95% CI 2.78-4.63, P < 0.001], all-cause mortality (aHR 5.07, 95% CI 2.43-10.59; P < 0.001; and aHR 16.72, 95% CI 7.75-36.05; P < 0.001), and bleeding (aHR 1.53, 95% CI 1.11-2.13; P = 0.01; and aHR 2.46, 95% CI 1.61-3.77; P < 0.001). Frailty, but not pre-frailty, was associated with a higher risk of stroke (aHR 3.29, 95% CI 1.2-8.39; P = 0.01).

Conclusion: Over two-thirds of patients with AF are pre-frail or frail. These patients have a high risk for unplanned hospitalizations and other adverse events. These findings emphasize the need to carefully evaluate these patients. However, whether screening for pre-frailty and frailty and targeted prevention strategies improve outcomes needs to be shown in future studies.

Clinical Trial Registration: Clinicaltrials.gov identifier number: NCT02105844.
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http://dx.doi.org/10.1093/ehjqcco/qcaa002DOI Listing
January 2021

Sirt6 deletion in bone marrow-derived cells increases atherosclerosis - Central role of macrophage scavenger receptor 1.

J Mol Cell Cardiol 2020 02 21;139:24-32. Epub 2020 Jan 21.

Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland; Department of Cardiology, University Heart Center, Zurich University Hospital, Zurich, Switzerland. Electronic address:

Aims: Sirtuin 6 (Sirt6) is a NAD-dependent deacetylase that plays a key role in DNA repair, inflammation and lipid regulation. Sirt6-null mice show severe metabolic defects and accelerated aging. Macrophage-foam cell formation via scavenger receptors is a key step in atherogenesis. We determined the effects of bone marrow-restricted Sirt6 deletion on foam cell formation and atherogenesis using a mouse model.

Methods And Results: Sirt6 deletion in bone marrow-derived cells increased aortic plaques, lipid content and macrophage numbers in recipient Apoe mice fed a high-cholesterol diet for 12 weeks (n = 12-14, p < .001). In RAW macrophages, Sirt6 overexpression reduced oxidized low-density lipoprotein (oxLDL) uptake, Sirt6 knockdown enhanced it and increased mRNA and protein levels of macrophage scavenger receptor 1 (Msr1), whereas levels of other oxLDL uptake and efflux transporters remained unchanged. Similarly, in human primary macrophages, Sirt6 knockdown increased MSR1 protein levels and oxLDL uptake. Double knockdown of Sirt6 and Msr1 abolished the increase in oxLDL uptake observed upon Sirt6 single knockdown. FACS analyses of macrophages from aortic plaques of Sirt6-deficient bone marrow-transplanted mice showed increased MSR1 protein expression. Double knockdown of Sirt6 and the transcription factor c-Myc in RAW cells abolished the increase in Msr1 mRNA and protein levels; c-Myc overexpression increased Msr1 mRNA and protein levels.

Conclusions: Loss of Sirt6 in bone marrow-derived cells is proatherogenic; hereby macrophages play an important role given a c-Myc-dependent increase in MSR1 protein expression and an enhanced oxLDL uptake in human and murine macrophages. These findings assign endogenous SIRT6 in macrophages an important atheroprotective role.
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http://dx.doi.org/10.1016/j.yjmcc.2020.01.002DOI Listing
February 2020

Health-related quality of life in patients with atrial fibrillation: The role of symptoms, comorbidities, and the type of atrial fibrillation.

PLoS One 2019 23;14(12):e0226730. Epub 2019 Dec 23.

Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.

Aims: This study aimed to analyse health related quality of life (HRQoL) for patients with different atrial fibrillation (AF) types and to identify patient characteristics, symptoms and comorbidities that influence HRQoL.

Methods: We used baseline data from the Swiss Atrial Fibrillation (Swiss-AF) study, a prospective multicentre observational cohort study conducted in 13 clinical centres in Switzerland. Between April 2014 and August 2017, 2415 AF patients were recruited. Patients were included in this analysis if they had baseline HRQoL data as assessed with EQ-5D-based utilities and visual analogue scale (VAS) scores. Patient characteristics and HRQoL were described stratified by AF type. The impact of symptoms, comorbidities and socio-economic factors on HRQoL was analysed using multivariable regression analysis.

Results: Based on 2412 patients with available baseline HRQoL data, the lowest unadjusted mean HRQoL was found in patients with permanent AF regardless of whether measured with utilities (paroxysmal: 0.83, persistent: 0.84, permanent: 0.80, p<0.001) or VAS score (paroxysmal: 73.6, persistent: 72.8, permanent: 69.2, p<0.001). In multivariable analysis of utilities and VAS scores, higher European Heart Rhythm Association (EHRA) score, recurrent falls and several comorbidities showed a strong negative impact on HRQoL while AF type was no longer associated with HRQoL.

Conclusions: Multiple factors turned out to influence HRQoL in AF patients. After controlling for several comorbidities, the EHRA score was one of the strongest predictors independent of AF type. The results may be valuable for better patient assessment and provide a reference point for further QoL and health economic analyses in AF populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226730PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927649PMC
April 2020

Apold1 deficiency associates with increased arterial thrombosis in vivo.

Eur J Clin Invest 2020 Feb;50(2):e13191

Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.

Background: Endothelial cells regulate the formation of blood clots; thus, genes selectively expressed in these cells could primarily determine thrombus formation. Apold1 (apolipoprotein L domain containing 1) is a gene expressed by endothelial cells; whether Apold1 directly contributes to arterial thrombosis has not yet been investigated. Here, we assessed the effect of Apold1 deletion on arterial thrombus formation using an in vivo model of carotid thrombosis induced by photochemical injury.

Material And Methods: Apold1 knockout (Apold1 ) mice and wild-type (WT) littermates underwent carotid thrombosis induced by photochemical injury, and time to occlusion was recorded. Tissue factor (TF) activity and activation of mitogen-activated protein kinases (MAPKs) and phosphatidyl-inositol-3 kinase (PI3K)/Akt pathways were analysed by colorimetric assay and Western blotting in both Apold1 and WT mice. Finally, platelet reactivity was assessed using light transmission aggregometry.

Results: After photochemical injury, Apold1 mice exhibited shorter time to occlusion as compared to WT mice. Moreover, TF activity was increased in carotid arteries of Apold1 when compared to WT mice. Underlying mechanistic markers such as TF mRNA and MAPKs activation were unaffected in Apold1 mice. In contrast, phosphorylation of Akt was reduced in Apold1 as compared to WT mice. Additionally, Apold1 mice displayed increased platelet reactivity to stimulation with collagen compared with WT animals.

Conclusions: Deficiency of Apold1 results in a prothrombotic phenotype, accompanied by increased vascular TF activity, decreased PI3K/Akt activation and increased platelet reactivity. These findings suggest Apold1 as an interesting new therapeutic target in the context of arterial thrombosis.
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http://dx.doi.org/10.1111/eci.13191DOI Listing
February 2020

Interleukin-1β Mediates Arterial Thrombus Formation via NET-Associated Tissue Factor.

J Clin Med 2019 Nov 26;8(12). Epub 2019 Nov 26.

Center for Molecular Cardiology, Schlieren Campus, University of Zurich, 8952 Schlieren, Switzerland.

CANTOS reported reduced secondary atherothrombotic events in patients with residual inflammatory risk treated with the inhibitory anti-IL-1β antibody, Canakinumab. Yet, mechanisms that underlie this benefit remain elusive. Recent work has implicated formation of neutrophil extracellular traps (NETosis) in arterial thrombosis. Hence, the present study explored the potential link between IL-1β, NETs, and tissue factor (TF)-the key trigger of the coagulation cascade-in atherothrombosis. To this end, ST-elevation myocardial infarction (STEMI) patients from the Swiss multicenter trial SPUM-ACS were retrospectively and randomly selected based on their CRP levels. In particular, 33 patients with STEMI and high C-reactive protein (CRP) levels (≥ 10 mg/L) and, 33 with STEMI and low CRP levels (≤ 4 mg/L) were investigated. High CRP patients displayed elevated circulating IL-1β, NETosis, and NET-associated TF plasma levels compared with low CRP ones. Additionally, analysis of patients stratified by circulating IL-1β levels yielded similar results. Moreover, NETosis and NET-associated TF plasma levels correlated positively in the whole population. In addition to the above, translational research experiments provided mechanistic confirmation for the clinical data identifying IL-1β as the initial trigger for the release of the pro-coagulant, NET-associated TF. In conclusion, blunted TF presentation by activated neutrophils undergoing NETosis may provide a mechanistic explanation to reduced secondary atherothrombotic events as observed in canakinumab-treated patients in CANTOS.
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http://dx.doi.org/10.3390/jcm8122072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947515PMC
November 2019

Venous Thromboembolism and Renal Impairment: Insights from the SWIss Venous ThromboEmbolism Registry (SWIVTER).

Semin Thromb Hemost 2019 Nov 17;45(8):851-858. Epub 2019 Oct 17.

Clinic of Angiology, University Hospital Zurich, Zurich, Switzerland.

Renal impairment (RI) has increased substantially over the last decades. In the absence of data from confirmatory research, real-life data on anticoagulation treatment and clinical outcomes of venous thromboembolism (VTE) in patients with RI are needed. In the SWIss Venous ThromboEmbolism Registry (SWIVTER), 2,062 consecutive patients with objectively confirmed VTE were enrolled. In the present analysis, we compared characteristics, initial and maintenance anticoagulation, and adjusted 90-day clinical outcomes of those with (defined as estimated creatinine clearance < 30 mL/min) and without severe RI. Overall, 240 (12%) patients had severe RI; they were older, and more frequently had chronic and acute comorbidities. VTE severity was similar between patients with and without severe RI. Initial anticoagulation in patients with severe RI was more often performed with unfractionated heparin (44 vs. 24%), and less often with low-molecular-weight heparin (LMWH) (52 vs. 61%) and direct oral anticoagulants (DOACs; 4 vs. 12%). Maintenance anticoagulation in patients with severe RI was more frequently managed with vitamin K antagonists (70 vs. 60%) and less frequently with DOAC (12 vs. 21%). Severe RI was associated with increased risk of 90-day mortality (9.2 vs. 4.2%, hazard ratio [HR]: 2.27, 95% confidence interval [CI]: 1.41-3.65), but with similar risk of recurrent VTE (3.3 vs. 2.8%, HR: 1.19, 95% CI: 0.57-2.52) and major bleeding (2.1 vs. 2.0%, HR: 1.05, 95% CI: 0.41-2.68). In patients with severe RI, the use of LMWH versus any other treatment was associated with reduced mortality (HR: 0.37; 95% CI: 0.14-0.94;  = 0.036) and similar rate of major bleeding (HR: 0.59, 95% CI: 0.17-2.00;  = 0.39). Acute or chronic comorbidities rather than VTE severity or recurrence may explain increased early mortality in patients with severe RI. The higher rate of VTE recurrence, specifically fatal events, than major bleeding reinforces the need for effective anticoagulation in VTE patients with severe RI.
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http://dx.doi.org/10.1055/s-0039-1698770DOI Listing
November 2019

Endothelial SIRT6 blunts stroke size and neurological deficit by preserving blood-brain barrier integrity: a translational study.

Eur Heart J 2020 04;41(16):1575-1587

Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, Schlieren 8952, Switzerland.

Aims: Aging is an established risk factor for stroke; genes regulating longevity are implicated in the pathogenesis of ischaemic stroke where to date, therapeutic options remain limited. The blood-brain barrier (BBB) is crucially involved in ischaemia/reperfusion (I/R) brain injury thus representing an attractive target for developing novel therapeutic agents. Given the role of endothelial cells in the BBB, we hypothesized that the endothelial-specific expression of the recently described longevity gene SIRT6 may exhibit protective properties in stroke.

Methods And Results: SIRT6 endothelial expression was reduced following stroke. Endothelial-specific Sirt6 knockout (eSirt6-/-) mice, as well as animals in which Sirt6 overexpression was post-ischaemically induced, underwent transient middle cerebral artery occlusion (tMCAO). eSirt6-/- animals displayed increased infarct volumes, mortality, and neurological deficit after tMCAO, as compared to control littermates. Conversely, post-ischaemic Sirt6 overexpression decreased infarct size and neurological deficit. Analysis of ischaemic brain sections revealed increased BBB damage and endothelial expression of cleaved caspase-3 in eSIRT6-/- mice as compared to controls. In primary human brain microvascular endothelial cells (HBMVECs), hypoxia/reoxygenation (H/R) reduced SIRT6 expression and SIRT6 silencing impaired the barrier function (transendothelial resistance) similar to what was observed in mice exposed to I/R. Further, SIRT6-silenced HBMVECs exposed to H/R showed reduced viability, increased cleaved caspase-3 expression and reduced activation of the survival pathway Akt. In ischaemic stroke patients, SIRT6 expression was higher in those with short-term neurological improvement as assessed by NIHSS scale and correlated with stroke outcome.

Conclusion: Endothelial SIRT6 exerts a protective role in ischaemic stroke by blunting I/R-mediated BBB damage and thus, it may represent an interesting novel therapeutic target to be explored in future clinical investigation.
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http://dx.doi.org/10.1093/eurheartj/ehz712DOI Listing
April 2020

Incidence and Predictors of Atrial Fibrillation Progression.

J Am Heart Assoc 2019 10 8;8(20):e012554. Epub 2019 Oct 8.

Division of Cardiology Department of Medicine University Hospital Basel University of Basel Basel Switzerland.

Background The incidence and predictors of atrial fibrillation (AF) progression are currently not well defined, and clinical AF progression partly overlaps with rhythm control interventions (RCIs). Methods and Results We assessed AF type and intercurrent RCIs during yearly follow-ups in 2869 prospectively followed patients with paroxysmal or persistent AF. Clinical AF progression was defined as progression from paroxysmal to nonparoxysmal or from persistent to permanent AF. An RCI was defined as pulmonary vein isolation, electrical cardioversion, or new treatment with amiodarone. During a median follow-up of 3 years, the incidence of clinical AF progression was 5.2 per 100 patient-years, and 10.9 per 100 patient-years for any RCI. Significant predictors for AF progression were body mass index (hazard ratio [HR], 1.03; 95% CI, 1.01-1.05), heart rate (HR per 5 beats/min increase, 1.05; 95% CI, 1.02-1.08), age (HR per 5-year increase 1.19; 95% CI, 1.13-1.27), systolic blood pressure (HR per 5 mm Hg increase, 1.03; 95% CI, 1.00-1.05), history of hyperthyroidism (HR, 1.71; 95% CI, 1.16-2.52), stroke (HR, 1.50; 95% CI, 1.19-1.88), and heart failure (HR, 1.69; 95% CI, 1.34-2.13). Regular physical activity (HR, 0.80; 95% CI, 0.66-0.98) and previous pulmonary vein isolation (HR, 0.69; 95% CI, 0.53-0.90) showed an inverse association. Significant predictive factors for RCIs were physical activity (HR, 1.42; 95% CI, 1.20-1.68), AF-related symptoms (HR, 1.84; 95% CI, 1.47-2.30), age (HR per 5-year increase, 0.88; 95% CI, 0.85-0.92), and paroxysmal AF (HR, 0.61; 95% CI, 0.51-0.73). Conclusions Cardiovascular risk factors and comorbidities were key predictors of clinical AF progression. A healthy lifestyle may therefore reduce the risk of AF progression.
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http://dx.doi.org/10.1161/JAHA.119.012554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818023PMC
October 2019

Glycoprotein Ib clustering in platelets can be inhibited by α-linolenic acid as revealed by cryo-electron tomography.

Haematologica 2020 06 22;105(6):1660-1666. Epub 2019 Aug 22.

Laboratory for Platelet Research, Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland

Platelet adhesion to the sub-endothelial matrix and damaged endothelium occurs through a multi-step process mediated in the initial phase by glycoprotein Ib binding to von Willebrand factor (vWF), which leads to the subsequent formation of a platelet plug. The plant-derived ω-3 fatty acid α-linolenic acid is an abundant alternative to fish-derived n-3 fatty acids and has anti-inflammatory and antithrombotic properties. In this study, we investigated the impact of α-linolenic acid on human platelet binding to vWF under high-shear flow conditions (mimicking blood flow in stenosed arteries). Pre-incubation of fresh human blood from healthy donors with α-linolenic acid at dietary relevant concentrations reduced platelet binding and rolling on vWF-coated microchannels at a shear rate of 100 dyn/cm Depletion of membrane cholesterol by incubation of platelet-rich plasma with methyl-β cyclodextrin abrogated platelet rolling on vWF. Analysis of glycoprotein Ib by applying cryo-electron tomography to intact platelets revealed local clusters of glycoprotein Ib complexes upon exposure to shear force: the formation of these complexes could be prevented by treatment with α-linolenic acid. This study provides novel findings on the rapid local rearrangement of glycoprotein Ib complexes in response to high-shear flow and highlights the mechanism of inhibition of platelet binding to and rolling on vWF by α-linolenic acid.
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http://dx.doi.org/10.3324/haematol.2019.220988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271563PMC
June 2020

AP-1 (Activated Protein-1) Transcription Factor JunD Regulates Ischemia/Reperfusion Brain Damage via IL-1β (Interleukin-1β).

Stroke 2019 02;50(2):469-477

From the Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland (C.D.-C., M.F.R., N.R.B., L.L., P.W., H.A., S.B.-S., J.H.B., A.A., T.F.L., G.G.C.).

Background and Purpose- Inflammation is a major pathogenic component of ischemia/reperfusion brain injury, and as such, interventions aimed at inhibiting inflammatory mediators promise to be effective strategies in stroke therapy. JunD-a member of the AP-1 (activated protein-1) family of transcription factors-was recently shown to regulate inflammation by targeting IL (interleukin)-1β synthesis and macrophage activation. The purpose of the present study was to assess the role of JunD in ischemia/reperfusion-induced brain injury. Methods- WT (wild type) mice randomly treated with either JunD or scramble (control) siRNA were subjected to 45 minutes of transient middle cerebral artery occlusion followed by 24 hours of reperfusion. Stroke size, neurological deficit, plasma/brain cytokines, and oxidative stress determined by 4-hydroxynonenal immunofluorescence staining were evaluated 24 hours after reperfusion. Additionally, the role of IL-1β was investigated by treating JunD siRNA mice with an anti-IL-1β monoclonal antibody on reperfusion. Finally, JunD expression was assessed in peripheral blood monocytes isolated from patients with acute ischemic stroke. Results- In vivo JunD knockdown resulted in increased stroke size, reduced neurological function, and increased systemic inflammation, as confirmed by higher neutrophil count and lymphopenia. Brain tissue IL-1β levels were augmented in JunD siRNA mice as compared with scramble siRNA, whereas no difference was detected in IL-6, TNF-α (tumor necrosis factor-α), and 4-hydroxynonenal levels. The deleterious effects of silencing of JunD were rescued by treating mice with an anti-IL-1β antibody. In addition, JunD expression was decreased in peripheral blood monocytes of patients with acute ischemic stroke at 6 and 24 hours after onset of stroke symptoms compared with sex- and age-matched healthy controls. Conclusions- JunD blunts ischemia/reperfusion-induced brain injury via suppression of IL-1β.
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http://dx.doi.org/10.1161/STROKEAHA.118.023739DOI Listing
February 2019

Gut microbiota-dependent trimethylamine-N-oxide (TMAO) shows a U-shaped association with mortality but not with recurrent venous thromboembolism.

Thromb Res 2019 02 6;174:40-47. Epub 2018 Dec 6.

Center for Molecular Cardiology, Laboratory for Platelet Research, University of Zurich, Schlieren, Switzerland; Department of Internal Medicine, Cantonal Hospital of Baden, Baden, Switzerland. Electronic address:

Introduction: Gut microbiota-dependent trimethylamine-N-oxide (TMAO) correlates with arterial thrombotic events including myocardial infarction and stroke, and mortality. However, the association of TMAO with recurrent venous thromboembolism (VTE) and mortality remains unknown.

Methods: TMAO plasma levels were assessed by high performance liquid chromatography in 859 patients aged ≥65 years with acute VTE and categorized into low (<2.28 μmol/L), medium (2.28-6.57 μmol/L), and high levels (>6.57 μmol/L) based on the 25th and 75th percentile. Associations of TMAO with recurrent VTE, major or non-major bleeding, and mortality were investigated.

Results: During a mean follow-up of 28 months, 106 patients developed recurrent VTE, 259 had major or non-major bleeding events, and 179 patients died. The risk of recurrent VTE did not differ significantly between patients with low, medium (adjusted subhazard ratio [SHR], 1.38; 95% confidence interval [CI], 0.81 to 2.36; p = 0.232) and high TMAO levels (SHR, 1.44; 95% CI, 0.80 to 2.58, p = 0.221). Compared with low TMAO levels, the adjusted hazard ratio [HR] for mortality was 0.68 (95% CI, 0.47 to 0.98, p = 0.039) in patients with medium TMAO levels and 1.02 (95% CI, 0.68 to 1.52, p = 0.922) in patients with high TMAO levels. Fractional polynomial Cox-regression confirmed a U-shaped association (adjusted p = 0.045), with the lowest mortality risk in patients with TMAO around 4 μmol/L. TMAO was not associated with major or non-major bleeding.

Conclusion: TMAO showed a U-shaped association with mortality in elderly patients with acute VTE and was not associated with recurrent VTE and major or non-major bleeding.
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http://dx.doi.org/10.1016/j.thromres.2018.12.011DOI Listing
February 2019

Deleterious role of endothelial lectin-like oxidized low-density lipoprotein receptor-1 in ischaemia/reperfusion cerebral injury.

J Cereb Blood Flow Metab 2019 11 3;39(11):2233-2245. Epub 2018 Aug 3.

Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Schlieren, Switzerland.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is implicated in cardiovascular disease by modulating apoptosis and oxidative stress. We hypothesized that LOX-1 may be involved in pathophysiology of stroke by mediating ischaemia/reperfusion (I/R)-dependent cell death. Transient middle cerebral artery occlusion (tMCAO) was performed in wild-type (WT) mice, endothelial-specific LOX-1 transgenic mice (eLOX-1TG) and WT animals treated with LOX-1 silencing RNA (siRNA). In WT mice exposed to tMCAO, LOX-1 expression and function were increased in the MCA. Compared to WT animals, eLOX-1TG mice displayed increased stroke volumes and worsened outcome after I/R. Conversely, LOX-1-silencing decreased both stroke volume and neurological impairment. Similarly, in HBMVECs, hypoxia/reoxygenation increased LOX-1 expression, while LOX-1 overexpressing cells showed increased death following hypoxia reoxygenation. Increased caspase-3 activation was observed following LOX-1 overexpression both in vivo and in vitro, thus representing a likely mediator. Finally, monocytes from ischaemic stroke patients exhibited increased LOX-1 expression which also correlated with disease severity. Our data unequivocally demonstrate a key role for LOX-1 in determining outcome following I/R brain damage. Our findings could be corroborated in human brain endothelial cells and monocytes from patients, underscoring their translational relevance and suggesting siRNA-mediated LOX-1 knockdown as a novel therapeutic strategy for stroke patients.
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http://dx.doi.org/10.1177/0271678X18793266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827115PMC
November 2019

Corrigendum to 'Sirtuin 5 as a novel target to blunt blood-brain barrier damage induced by cerebral ischemia/reperfusion injury' [Int. J. Cardiol. 260 (2018) 148-155].

Int J Cardiol 2018 11 13;271:405. Epub 2018 Jul 13.

Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland; Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland; Zurich Neuroscience Center (ZNZ), Zurich, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2018.07.004DOI Listing
November 2018

Post-ischaemic administration of the murine Canakinumab-surrogate antibody improves outcome in experimental stroke.

Eur Heart J 2018 10;39(38):3511-3517

Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, Schlieren, Switzerland.

Aims: The CANTOS trial underscored the efficacy of selective antibody-based interleukin (IL)-1β inhibition with Canakinumab in secondary prevention of cardiovascular events. Despite the success of the trial, incidence of stroke was not reduced likely due to the low number of events and the relatively young age of patients enrolled. Given the established role of IL-1β in stroke, we tested the efficacy of the murine Canakinumab-equivalent antibody in a mouse model of ischaemic stroke. To mimic the clinical scenario of modern stroke management, IL-1β inhibition was performed post-ischaemically upon reperfusion as it would be the case in patients presenting to the emergency room and eligible for thrombolytic therapy.

Methods And Results: Transient middle cerebral artery occlusion (tMCAO) was performed in wild type mice; upon reperfusion, mice were randomly allocated to anti-IL-1β antibody or vehicle treatment. Following tMCAO, cerebral IL-1β levels, unlike tumour necrosis factor-α, were increased underscoring a role for this cytokine. Post-ischaemic treatment with IL-1β antibody reduced infarct size, cerebral oedema and improved neurological performance as assessed by 2,3,5-triphenyltetrazolium chloride staining, Bederson and RotaRod tests. Antibody-treated animals also exhibited a reduced neutrophil and matrix metalloproteinase (MMP)-2 but not MMP-9, activity in ipsilateral hemispheres as compared to vehicle-treated mice. Noteworthy, tMCAO associated vascular endothelial-cadherin reduction was blunted in IL-1β antibody-treated mice compared to vehicle-treated, likely providing the mechanistic explanation for the improved outcome.

Conclusion: Our data for the first time demonstrate the efficacy of selective post-ischaemic IL-1β blockade in improving outcome following experimental ischaemia/reperfusion brain injury in the mouse and encourage further focused clinical studies assessing the potential of the approved IL-1β antibody Canakinumab, as an adjuvant therapy to thrombolysis in acute ischaemic stroke patients.
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http://dx.doi.org/10.1093/eurheartj/ehy286DOI Listing
October 2018