Publications by authors named "Deniz Akdis"

25 Publications

  • Page 1 of 1

The Link Between Sex Hormones and Susceptibility to Cardiac Arrhythmias: From Molecular Basis to Clinical Implications.

Front Cardiovasc Med 2021 17;8:644279. Epub 2021 Feb 17.

Arrhythmia and Electrophysiology, Department of Cardiology, University Heart Center, Zurich, Switzerland.

It is well-known that gender is an independent risk factor for some types of cardiac arrhythmias. For example, males have a greater prevalence of atrial fibrillation and the Brugada Syndrome. In contrast, females are at increased risk for the Long QT Syndrome. However, the underlying mechanisms of these gender differences have not been fully identified. Recently, there has been accumulating evidence indicating that sex hormones may have a significant impact on the cardiac rhythm. In this review, we describe in-depth the molecular interactions between sex hormones and the cardiac ion channels, as well as the clinical implications of these interactions on the cardiac conduction system, in order to understand the link between these hormones and the susceptibility to arrhythmias.
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http://dx.doi.org/10.3389/fcvm.2021.644279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925388PMC
February 2021

Familial Arrhythmogenic Cardiomyopathy: Clinical Determinants of Phenotype Discordance and the Impact of Endurance Sports.

J Clin Med 2020 Nov 23;9(11). Epub 2020 Nov 23.

University Heart Center Zurich, Division of Cardiology, 8091 Zurich, Switzerland.

Arrhythmogenic cardiomyopathy (ACM) is primarily a familial disease with autosomal dominant inheritance. Incomplete penetrance and variable expression are common, resulting in diverse clinical manifestations. Although recent studies on genotype-phenotype relationships have improved our understanding of the molecular mechanisms leading to the expression of the full-blown disease, the underlying genetic substrate and the clinical course of asymptomatic or oligo-symptomatic mutation carriers are still poorly understood. We aimed to analyze different phenotypic expression profiles of ACM in the context of the same familial genetic mutation by studying nine adult cases from four different families with four different familial variants (two plakophilin-2 and two desmoglein-2) from the Swiss Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Registry. The affected individuals with the same genetic variants presented with highly variable phenotypes ranging from no disease or a classical, right-sided disease, to ACM with biventricular presentation. Moreover, some patients developed early-onset, electrically unstable disease whereas others with the same genetic variants presented with late-onset electrically stable disease. Despite differences in age, gender, underlying genotype, and other clinical characteristics, physical exercise has been observed as the common denominator in provoking an arrhythmic phenotype in these families.
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http://dx.doi.org/10.3390/jcm9113781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700696PMC
November 2020

Impact of Genetic Variant Reassessment on the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy Based on the 2010 Task Force Criteria.

Circ Genom Precis Med 2021 Feb 24;14(1):e003047. Epub 2020 Nov 24.

Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, Switzerland (S.C., A.G., D.A., F.R., C.B.B., F.D., A.M.S.).

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy, which is associated with life-threatening ventricular arrhythmias. Approximately 60% of patients carry a putative disease-causing genetic variant, but interpretation of genetic test results can be challenging. The aims of this study were to systematically reclassify genetic variants in patients with ARVC and to assess the impact on ARVC diagnosis.

Methods: This study included patients from the Multicenter Zurich ARVC Registry who hosted a genetic variant deemed to be associated with the disease. Reclassification of pathogenicity was performed according to the modified 2015 American College of Medical Genetics criteria. ARVC diagnosis (categories: definite, borderline, possible) based on the 2010 Task Force Criteria was reclassified after genetic readjudication.

Results: In 79 patients bearing 80 unique genetic variants, n=47 (58.8%) genetic variants were reclassified, and reclassification was judged to be clinically relevant in n=33 (41.3%). Variants in plakophilin-2 () were shown to reclassify less frequently as compared with other genes (, n=1, 8.3%; desmosomal non-, n=20, 66.7%; nondesmosomal, n=26, 68.4%; =0.001for overall comparison; versus desmosomal non-=0.001; versus nondesmosomal, <0.001). Genetic reclassification impacted ARVC diagnosis. Eight patients (10.1%) were downgraded from definite to borderline/possible disease at the time of initial genetic testing as well as last follow-up, respectively. Separate genetic reclassification in family members led to downgrading of n=5 (38.5%) variants.

Conclusions: Given that approximately half of genetic variants were reclassified, with 10.1% of patients losing their definite disease status, accurate determination of variant pathogenicity is of utmost importance in the diagnosis of ARVC.
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http://dx.doi.org/10.1161/CIRCGEN.120.003047DOI Listing
February 2021

Differentiating hereditary arrhythmogenic right ventricular cardiomyopathy from cardiac sarcoidosis fulfilling 2010 ARVC Task Force Criteria.

Heart Rhythm 2021 Feb 22;18(2):231-238. Epub 2020 Sep 22.

University Heart Center, University Hospital Zurich, Switzerland. Electronic address:

Background: The clinical presentation of cardiac sarcoidosis (CS) may resemble that of arrhythmogenic right ventricular cardiomyopathy (ARVC).

Objective: The purpose of this study was to identify clinical variables to better discriminate between patients with genetically determined ARVC and those with CS fulfilling definite 2010 ARVC Task Force Criteria (TFC).

Methods: In this multicenter study, 10 patients with CS fulfilling definite 2010 ARVC TFC were age and gender matched with 10 genetically proven ARVC patients. A cardiac F-fluorodeoxyglucose positron emission tomographic (F-FDG PET) scan was required for patients to be included in the study.

Results: The 2010 ARVC TFC did not reliably differentiate between the 2 diseases. CS patients presented with longer PR intervals, advanced atrioventricular block (AVB), and longer QRS duration (P <.001 and P = .009, respectively), whereas T-wave inversions (TWIs) in the peripheral leads were more common in ARVC patients (P = .009). CS patients presented with more extensive left ventricular involvement and lower left ventricular ejection fraction (LVEF), whereas ARVC patients had a larger right ventricular outflow tract (RVOT) (P = .044). PET scan positivity was only present in CS patients (90% vs 0%).

Conclusion: The 2010 ARVC TFC do not reliably differentiate between CS patients fulfilling 2010 ARVC TFC and those with hereditary ARVC. Prolonged PR interval, advanced AVB, longer QRS duration, right ventricular apical involvement, reduced LVEF, and positive F-FDG PET scan should raise the suspicion of CS, whereas larger RVOT dimensions, subtricuspid involvement and peripheral TWI favor a diagnosis of hereditary ARVC.
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http://dx.doi.org/10.1016/j.hrthm.2020.09.015DOI Listing
February 2021

Immunology of COVID-19: Mechanisms, clinical outcome, diagnostics, and perspectives-A report of the European Academy of Allergy and Clinical Immunology (EAACI).

Allergy 2020 10;75(10):2445-2476

Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

With the worldwide spread of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulting in declaration of a pandemic by the World Health Organization (WHO) on March 11, 2020, the SARS-CoV-2-induced coronavirus disease-19 (COVID-19) has become one of the main challenges of our times. The high infection rate and the severe disease course led to major safety and social restriction measures worldwide. There is an urgent need of unbiased expert knowledge guiding the development of efficient treatment and prevention strategies. This report summarizes current immunological data on mechanisms associated with the SARS-CoV-2 infection and COVID-19 development and progression to the most severe forms. We characterize the differences between adequate innate and adaptive immune response in mild disease and the deep immune dysfunction in the severe multiorgan disease. The similarities of the human immune response to SARS-CoV-2 and the SARS-CoV and MERS-CoV are underlined. We also summarize known and potential SARS-CoV-2 receptors on epithelial barriers, immune cells, endothelium and clinically involved organs such as lung, gut, kidney, cardiovascular, and neuronal system. Finally, we discuss the known and potential mechanisms underlying the involvement of comorbidities, gender, and age in development of COVID-19. Consequently, we highlight the knowledge gaps and urgent research requirements to provide a quick roadmap for ongoing and needed COVID-19 studies.
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http://dx.doi.org/10.1111/all.14462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361752PMC
October 2020

Clinical predictors of left ventricular involvement in arrhythmogenic right ventricular cardiomyopathy.

Am Heart J 2020 05 7;223:34-43. Epub 2020 Feb 7.

Department of Cardiology, University Heart Center Zurich, Switzerland; Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. Electronic address:

Aim: The impact of clinical characteristics for predicting patterns of ventricular involvement in arrhythmogenic right ventricular cardiomyopathy (ARVC) are not well defined. The aims of this study were to characterize different patterns of ventricular involvement in patients with ARVC and to stratify them based on clinical characteristics exercise and underlying genetic mutations.

Methods: Sixty-four patients with definite ARVC from the Swiss ARVC Registry were enrolled. Right and left ventricular functions were assessed at baseline and most recent follow-up. All patients received genetic testing. Serum high-sensitivity cardiac Troponin T (hs-cTNT) and N-terminal of pro-brain natriuretic peptide (NT-proBNP) were determined at baseline.

Results: Thirty-five patients (55%) had isolated right ventricular (RV) involvement, 12 patients (19%) had biventricular (BiV) involvement at baseline and 17 patients (26%) had no left ventricular (LV) involvement at baseline, but revealed new onset LV involvement at mean follow-up of 7.5 years. Patients with BiV involvement at baseline harbored significantly more desmoplakin and multiple mutations and patients with new-onset LV involvement at follow-up frequently showed non-desmosomal mutations. Patients engaging in competitive sports more often showed LV involvement during follow-up. Baseline hs-cTNT and NT-proBNP levels were higher in patients developing BiV involvement.

Conclusion: Multiple mutations are more common in ARVC patients with BiV involvement. Competitive exercise is associated with disease progression resulting in BiV involvement. Hs-cTNT and NT-proBNP are elevated in patients with BiV involvement and may help to identify ARVC patients at risk for developing BiV disease.
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http://dx.doi.org/10.1016/j.ahj.2020.01.019DOI Listing
May 2020

Clinical Characteristics of Patients with a Right Ventricular Thrombus in Arrhythmogenic Right Ventricular Cardiomyopathy.

Thromb Haemost 2019 Aug 10;119(8):1373-1378. Epub 2019 Jun 10.

University Heart Center Zurich, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.

Background:  Thrombus formation within the left ventricle (LV) is a well-known clinical entity and is often associated with underlying myocardial disease, whereas right ventricular (RV) thrombi are rarely observed. This study aimed to investigate the clinical characteristics of patients with arrhythmogenic RV cardiomyopathy (ARVC) who developed an RV thrombus.

Methods And Results:  This study included patients with an RV thrombus from the ARVC databases of the University Heart Center in Zurich, Switzerland, and the Fuwai Hospital in Beijing, China. In total, there were 13 ARVC patients who had an RV thrombus detected. The mean age was 33 ± 15 (range: 11-51) years. Eight patients (62%) were male. The mean Task Force score was 6 ± 1. Nine of these patients (69%) had an RV thrombus only whereas four patients had biventricular thrombi. All 13 ARVC patients had a severely impaired RV function (RV fractional area change 16 ± 9% and RV ejection fraction 15 ± 4%); LV ejection fraction (LVEF) was 40 ± 15%. ARVC patients with an additional LV thrombus had a lower LVEF than the others (24 ± 11 vs. 47 ± 11,  = 0.02). Under therapeutic anticoagulation, complete thrombus resolution was observed in 9/13 patients (69%).

Conclusion:  RV thrombus formation is a potential complication of ARVC with impaired RV function. In patients with biventricular involvement, thrombi may also occur within the LV. Anticoagulation is generally effective to dissolve RV thrombi. This study highlights the need for awareness during cardiac imaging to detect this rare complication of ARVC.
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http://dx.doi.org/10.1055/s-0039-1688829DOI Listing
August 2019

Risk score for the exclusion of arrhythmic events in arrhythmogenic right ventricular cardiomyopathy at first presentation.

Int J Cardiol 2019 09 1;290:100-105. Epub 2019 May 1.

Cardiomyopathy Service, Royal Brompton Hospital, London, UK.

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart muscle disorder associated with an increased risk of life-threatening arrhythmias in some patients. Risk stratification remains challenging. Therefore, we sought a non-invasive, easily applicable risk score to predict sustained ventricular arrhythmias in these patients.

Methods: Cohort of Patients who fulfilled the 2010 ARVC task force criteria were consecutively recruited. Detailed clinical data were collected at baseline and during follow up. The clinical endpoint was a composite of recurrent sustained ventricular arrhythmias and hospitalization due to ventricular arrhythmias. Multivariable logistic regression was used to develop models to predict the arrhythmic risk. A cohort including patients from other registries in UK, Canada and Switzerland was used as a validation population.

Results: One hundred and thirty-five patients were included of whom 35 patients (31.9%) reached the endpoint. A model consisting of filtered QRS duration on signal-averaged ECG, non-sustained VT (NSVT) on 24 h-ECG, and absence of negative T waves in lead aVR on 12‑lead surface ECG was able to predict arrhythmic events with a sensitivity of 81.8%, specificity of 84.0% and a negative predictive value of 95.5% at the first presentation of the disease. This risk score was validated in international ARVC registry patients.

Conclusion: A risk score consisting of a filtered QRS duration ≥117 ms, presence of NSVT on 24 h-ECG and absence of negative T waves in lead aVR was able to predict arrhythmic events at first presentation of the disease.
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http://dx.doi.org/10.1016/j.ijcard.2019.04.090DOI Listing
September 2019

Hemodynamic Changes in the Right Ventricle Induced by Variations of Cardiac Output: A Possible Mechanism for Arrhythmia Occurrence in the Outflow Tract.

Sci Rep 2019 01 14;9(1):100. Epub 2019 Jan 14.

University Heart Center, Department of Cardiology, Zurich, 8091, Switzerland.

The rationale of this paper is to investigate right ventricular (RV) hemodynamics in relation to changes in cardiac output, and in particular to study exercise-induced stresses at the RV outflow tract (RVOT), which is a common site of ventricular arrhythmias in the athlete's heart. We hypothesize that the thin-walled RVOT is exposed to high wall shear stresses (WSS) during physiological states associated with high cardiac output such as exercise, and therefore, may be particularly prone to substrate formation leading to ventricular tachyarrhythmias. 3D Particle Tracking Velocimetry (3D-PTV), an optical imaging method, has been performed in a novel anatomically accurate compliant silicone right heart model derived from a high resolution MRI heart scan of a healthy male proband. RV and RVOT flow patterns at resting conditions were obtained from two healthy athletic male proband's hearts and two patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) via phase contrast magnetic resonance imaging (PC-MRI). The healthy case was used as a reference for validating the in vitro flow patterns of the silicone model, while the diseased cases were used to generalize our findings and investigate possible changes in hemodynamic stresses with RV morphological remodelling. Our results showed that both healthy and diseased geometries consistently displayed an increased WSS in the RVOT relative to the rest of the RV. We found that increases in cardiac output may lead to increases of mean kinetic energy (MKE), laminar viscous dissipation and WSS at the RVOT. Furthermore, higher peak WSS magnitudes were found for the diseased cases. The identified high WSS regions may correlate with the common site of RVOT ventricular tachycardia in athletes and patients with ARVC/D. Our results imply that exercise, as well as anatomical and functional remodeling might alter RV wall shear stress both in magnitude and spatial distribution, leading to increased hemodynamic stresses in the RVOT.
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http://dx.doi.org/10.1038/s41598-018-36614-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331649PMC
January 2019

An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis.

Eur Heart J 2018 11;39(44):3932-3944

The Labatt Family Heart Centre (Department of Pediatrics) and Translational Medicine, The Hospital for Sick Children & Research Institute and the University of Toronto, Room 1725D, 555 University Avenue, Toronto, Ontario, Canada.

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by right ventricular myocardial replacement and life-threatening ventricular arrhythmias. Desmosomal gene mutations are sometimes identified, but clinical and genetic diagnosis remains challenging. Desmosomal skin disorders can be caused by desmosomal gene mutations or autoantibodies. We sought to determine if anti-desmosome antibodies are present in subjects with ARVC.

Methods And Results: We evaluated ARVC subjects and controls for antibodies to cardiac desmosomal cadherin proteins. Desmoglein-2 (DSG2), desmocollin-2, and N-cadherin proteins on western blots were exposed to sera, in primary and validation cohorts of subjects and controls, as well as the naturally occurring Boxer dog model of ARVC. We identified anti-DSG2 antibodies in 12/12 and 25/25 definite ARVC cohorts and 7/8 borderline subjects. Antibody was absent in 11/12, faint in 1/12, and absent in 20/20 of two control cohorts. Anti-DSG2 antibodies were present in 10/10 Boxer dogs with ARVC, and absent in 18/18 without. In humans, the level of anti-DSG2 antibodies correlated with the burden of premature ventricular contractions (r = 0.70), and antibodies caused gap junction dysfunction, a common feature of ARVC, in vitro. Anti-DSG2 antibodies were present in ARVC subjects regardless of whether an underlying mutation was identified, or which mutation was present. A disease-specific DSG2 epitope was identified.

Conclusion: Anti-DSG2 antibodies are a sensitive and specific biomarker for ARVC. The development of autoimmunity as a result of target-related mutations is unique. Anti-DSG2 antibodies likely explain the cardiac inflammation that is frequently identified in ARVC and may represent a new therapeutic target.
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http://dx.doi.org/10.1093/eurheartj/ehy567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247665PMC
November 2018

Value of a novel 16-lead High-Definition ECG machine to detect conduction abnormalities in structural heart disease.

Pacing Clin Electrophysiol 2018 06 4;41(6):643-655. Epub 2018 May 4.

Cardiology Institute, Rhythmology Unit, Hôpital Universitaire La Pitié-Salpêtrière, Paris, France.

Background: Depolarization abnormalities are hardly detectable by standard 12-lead electrocardiogram (ECG) in some patients.

Objective: To evaluate the value of the 16-lead High-Definition (HD)-ECG machine to record conduction abnormalities including Epsilon waves in patients with structural heart disease.

Methods: Tracings with 12-lead ECG, 16-lead HD-ECG, and signal-averaged ECG were studied.

Results: (1) Case of severe coronary artery disease (CAD): On 16-lead HD-ECG, a tiny intra-QRS signal was noted in lead III, a prolonged P wave in lead II, and fragmentation on top of lead aVL and lead aVF. Proper automatic measurement of the prolonged P wave measuring 190 ms was noted. Signal-averaging by 16-lead HD-ECG in lead III showed the intra-QRS fragmentation and P wave prolongation of 180 ms. (2) First patient with arrhythmogenic right ventricular dysplasia (ARVD): Standard 12-lead ECG indicated Epsilon waves in lead III, V2, V3, and inverted T waves in V1-V3. 16-lead HD-ECG indicated QRS prolongation in lead II, III, aVL, aVF, V2, V3 as opposed to V6, and low amplitudes of QRS complexes in V4R and V3R as a new possible sign of ARVD. Notches in lead V2, widening of QRS complexes in all precordial leads, but shorter QRS in V8-V9 are also considered as a potential new diagnostic sign of ARVD. (3) Second ARVD patient: Notches at the end of the QRS in lead III and a negative initial deflection of the QRS in V1 and V2 were detected by standard 12-lead ECG. On 16-lead HD-ECG, a more pronounced QRS fragmentation was visible.

Conclusion: 16-lead HD-ECG in both CAD and ARVD seems to be more sensitive than 12-lead ECG to record electrocardiographic abnormalities.
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http://dx.doi.org/10.1111/pace.13338DOI Listing
June 2018

Intramyocardial block in patients with atrioventricular block.

J Investig Med 2018 06 7;66(5):1-4. Epub 2018 Mar 7.

Unité de Rythmologie, Institut de Cardiologie, Hôpital de la Salpetrière, Paris, France.

Atrioventricular (AV) block has been extensively studied. However, conduction inside the myocardium in patients with AV block has not been reported. In this study, we aimed to demonstrate the presence of intramyocardial block in patients with AV block. Five consecutive patients with spontaneous high-grade AV block and Torsades de pointes (TdP) were prospectively studied with standard United States Catheter Instruments (USCI) endocardial temporary catheter located at the right ventricle (RV) apex. The morphology of endocardial potentials observed in the basic QRS complexes as well as during episodes of TdP was studied. The electrogram (EGM) of the basic rhythm showed a sharp deflection of high amplitude preceded and/or followed by a smooth potential of low amplitude interpreted as far-field potentials in all patients. The sharp potential can be observed at the beginning, in the middle or at the end of the smooth potential. All these potentials were reproduced from beat to beat and were falling inside the QRS complex of the surface ECG. Therefore, these aspects are zones of electrically depressed or silent myocardium larger than the interelectrode distance of 12 mm. This situation is in agreement with recent genetic factors. In this study, we demonstrated for the first time that patients with spontaneous AV block also have trouble in ventricular activation located on the AV conduction system and inside the myocardium. It is then possible to speculate that the presence of diffuse non-conducting myocardium explains why most TdPs do not degenerate into ventricular fibrillation (VF) and generally stop spontaneously.
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http://dx.doi.org/10.1136/jim-2017-000682DOI Listing
June 2018

Investigation of Atrial Vortices Using a Novel Right Heart Model and Possible Implications for Atrial Thrombus Formation.

Sci Rep 2017 12 1;7(1):16772. Epub 2017 Dec 1.

University Heart Center, Department of Cardiology, Zurich, 8091, Switzerland.

The main aim of this paper is to characterize vortical flow structures in the healthy human right atrium, their impact on wall shear stresses and possible implications for atrial thrombus formation. 3D Particle Tracking Velocimetry is applied to a novel anatomically accurate compliant silicone right heart model to study the phase averaged and fluctuating flow velocity within the right atrium, inferior vena cava and superior vena cava under physiological conditions. We identify the development of two vortex rings in the bulk of the right atrium during the atrial filling phase leading to a rinsing effect at the atrial wall which break down during ventricular filling. We show that the vortex ring formation affects the hemodynamics of the atrial flow by a strong correlation (ρ = 0.7) between the vortical structures and local wall shear stresses. Low wall shear stress regions are associated with absence of the coherent vortical structures which might be potential risk regions for atrial thrombus formation. We discuss possible implications for atrial thrombus formation in different regions of the right atrium.
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http://dx.doi.org/10.1038/s41598-017-17117-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711865PMC
December 2017

Right ventricular outflow tract dimensions in arrhythmogenic right ventricular cardiomyopathy/dysplasia-a multicentre study comparing echocardiography and cardiovascular magnetic resonance.

Eur Heart J Cardiovasc Imaging 2018 05;19(5):516-523

Department of Cardiology, University Heart Center, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.

Aims: Right ventricular outflow tract (RVOT) dilation is one of the echocardiographic criteria in the 2010 revised Task Force Criteria (TFC) of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). However, studies comparing cardiac magnetic resonance (CMR) and transthoracic echocardiography (TTE) suggest a lower diagnostic accuracy of TTE due to its operator dependence and limited reproducibility. The goal of this study was to compare the 2010 TFC measures of RVOT dilation with three alternative measures for improving the echocardiographic assessment of RVOT in patients with ARVC/D.

Methods And Results: In this multicentre study, CMR and TTE were performed in 38 patients with a definite, borderline, or possible ARVC/D diagnosis and in 10 healthy controls. Besides the echocardiographic RVOT measurements listed by the 2010 TFC, we assessed three additional end-diastolic RVOT diameters. These included the RVOT diameter defined by the parasternal long axis M-mode of the aortic sinus portion (RVOT3), that defined by the parasternal long axis M-mode of the left ventricle (RVOT4), and that obtained by the parasternal short axis view of the distal RVOT proximal to the pulmonary valve (RVOT5). RVOT4 provided the best correlation between CMR and TTE (r = 0.92, [95% confidence interval (CI): 0.84-0.96; P < 0.0001]) and enhanced diagnostic accuracy for diagnosing ARVC/D (area under the curve 0.92 [95% CI, 0.78-0.98]).

Conclusion: Among all RVOT diameters examined, that defined by the parasternal long axis M-mode of the left ventricle (RVOT4) provides the best agreement between CMR and TTE and exhibits the best diagnostic accuracy for ARVC/D. This novel RVOT4 measurement carries the potential for improving the echocardiographic diagnosis of ARVC/D.
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http://dx.doi.org/10.1093/ehjci/jex092DOI Listing
May 2018

Sex hormones affect outcome in arrhythmogenic right ventricular cardiomyopathy/dysplasia: from a stem cell derived cardiomyocyte-based model to clinical biomarkers of disease outcome.

Eur Heart J 2017 May;38(19):1498-1508

Department of Cardiology, University Heart Center Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.

Aims: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is characterized by fibrofatty infiltration of the myocardium and ventricular arrhythmias that may lead to sudden cardiac death. It has been observed that male patients develop the disease earlier and present with more severe phenotypes as compared to females. Thus, we hypothesized that serum levels of sex hormones may contribute to major arrhythmic cardiovascular events (MACE) in patients with ARVC/D.

Methods And Results: The serum levels of five sex hormones, sex hormone-binding globulin, high sensitivity troponin T, pro-brain natriuretic peptide, cholesterol, triglycerides, insulin, and glucose were measured in 54 ARVC/D patients (72% male). Twenty-six patients (48%) experienced MACE. Total and free testosterone levels were significantly increased in males with MACE as compared to males with a favourable outcome, whereas estradiol was significantly lower in females with MACE as compared to females with a favourable outcome. Increased testosterone levels remained independently associated with MACE in males after adjusting for age, body mass index, Task Force criteria, ventricular function, and desmosomal mutation status. Furthermore, an induced pluripotent stem cell-derived ARVC/D cardiomyocyte model was used to investigate the effects of sex hormones. In this model, testosterone worsened and estradiol improved ARVC/D-related pathologies such as cardiomyocyte apoptosis and lipogenesis, strongly supporting our clinical findings.

Conclusions: Elevated serum testosterone levels in males and decreased estradiol levels in females are independently associated with MACE in ARVC/D, and directly influence disease pathology. Therefore, determining the levels of sex hormones may be useful for risk stratification and may open a new window for preventive interventions.
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http://dx.doi.org/10.1093/eurheartj/ehx011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837563PMC
May 2017

Arrhythmogenic Cardiomyopathy: Electrical and Structural Phenotypes.

Arrhythm Electrophysiol Rev 2016 Aug;5(2):90-101

Department of Cardiology, University Heart Center, Zurich, Switzerland.

This overview gives an update on the molecular mechanisms, clinical manifestations, diagnosis and therapy of arrhythmogenic cardiomyopathy (ACM). ACM is mostly hereditary and associated with mutations in genes encoding proteins of the intercalated disc. Three subtypes have been proposed: the classical right-dominant subtype generally referred to as ARVC/D, biventricular forms with early biventricular involvement and left-dominant subtypes with predominant LV involvement. Typical symptoms include palpitations, arrhythmic (pre)syncope and sudden cardiac arrest due to ventricular arrhythmias, which typically occur in athletes. At later stages, heart failure may occur. Diagnosis is established with the 2010 Task Force Criteria (TFC). Modern imaging tools are crucial for ACM diagnosis, including both echocardiography and cardiac magnetic resonance imaging for detecting functional and structural alternations. Of note, structural findings often become visible after electrical alterations, such as premature ventricular beats, ventricular fibrillation (VF) and ventricular tachycardia (VT). 12-lead ECG is important to assess for depolarisation and repolarisation abnormalities, including T-wave inversions as the most common ECG abnormality. Family history and the detection of causative mutations, mostly affecting the desmosome, have been incorporated in the TFC, and stress the importance of cascade family screening. Differential diagnoses include idiopathic right ventricular outflow tract (RVOT) VT, sarcoidosis, congenital heart disease, myocarditis, dilated cardiomyopathy, athlete's heart, Brugada syndrome and RV infarction. Therapeutic strategies include restriction from endurance and competitive sports, β-blockers, antiarrhythmic drugs, heart failure medication, implantable cardioverter-defibrillators and endocardial/epicardial catheter ablation.
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http://dx.doi.org/10.15420/AER.2016.4.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013177PMC
August 2016

Severe Hyponatremia Leading to Complete Atrioventricular Block.

Am J Med 2016 Oct 16;129(10):e243-4. Epub 2016 Jun 16.

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

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http://dx.doi.org/10.1016/j.amjmed.2016.05.033DOI Listing
October 2016

Arrhythmogenic right ventricular cardiomyopathy: implications of next-generation sequencing in appropriate diagnosis.

Europace 2017 Jun;19(6):1063-1069

Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland.

Aims: To evaluate potential differences in the genetic profile of cases with 'definite', 'borderline', and 'possible' arrhythmogenic right ventricular cardiomyopathy (ARVC) phenotype by 2010 task force criteria using a custom genetic panel after whole-exome analysis.

Methods And Results: We performed whole-exome sequencing in 14 cases with the clinical diagnosis ARVC using an 'Illumina HighSeq 2000' system. We presented our initial results focused on 96 known cardiomyopathy and channelopathy genes. According to the 2010 task force criteria, 7/14 cases (50%) were classified as 'definite' phenotype, 4/14 (29%) were 'borderline', and 3/14 (21%) were diagnosed with the 'possible' phenotype. Nine out of 14 patients (64%) were males, and all were Caucasians, with an average age at genetic diagnosis of 50 ± 15 years. Among the seven cases with the 'definite' phenotype, six (86%) had a putative desmosomal mutation, while none of the seven patients with a 'possible' or borderline task force classification phenotype hosted putative mutations in desmosomal genes. Four (57%) of them had rare variants in other dilated cardiomyopathy (DCM) genes.

Conclusions: Most of the patients with 'definite' ARVC phenotype by task force 2010 host mutations in desmosomal genes. Weaker ARVC phenotypes host variants/mutations in other DCM genes and result in a disease spectrum, including DCM or phenocopies of ARVC.
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http://dx.doi.org/10.1093/europace/euw098DOI Listing
June 2017

Successful epicardial ablation of ventricular tachycardia in a patient with arrhythmogenic right ventricular cardiomyopathy.

Int J Cardiol 2016 May 24;211:22-4. Epub 2016 Feb 24.

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

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http://dx.doi.org/10.1016/j.ijcard.2016.02.119DOI Listing
May 2016

[ECG 52. Incidental finding].

Praxis (Bern 1994) 2016 Mar;105(5):292-5

1 Klinik für Kardiologie, Universitäres Herzzentrum Zürich, -Universitätsspital Zürich1.

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http://dx.doi.org/10.1024/1661-8157/a002277DOI Listing
March 2016

Arrhythmogene rechtsventrikuläre Kardiomyopathie / Dysplasie: Pathogenese, Diagnose und Therapie.

Ther Umsch 2016;73(12):745-751

1 Universitäres Herzzentrum Zürich, Universitätsspital Zürich.

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http://dx.doi.org/10.1024/0040-5930/a000859DOI Listing
June 2017

Myocardial expression profiles of candidate molecules in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia compared to those with dilated cardiomyopathy and healthy controls.

Heart Rhythm 2016 Mar 10;13(3):731-41. Epub 2015 Nov 10.

Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland; Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. Electronic address:

Background: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is mainly an autosomal dominant disease characterized by fibrofatty infiltration of the right ventricle, leading to ventricular arrhythmias. Mutations in desmosomal proteins can be identified in about half of the patients. The pathogenic mechanisms leading to disease expression remain unclear.

Objective: The purpose of this study was to investigate myocardial expression profiles of candidate molecules involved in the pathogenesis of ARVC/D.

Methods: Myocardial messenger RNA (mRNA) expression of 62 junctional molecules, 5 cardiac ion channel molecules, 8 structural molecules, 4 apoptotic molecules, and 6 adipogenic molecules was studied. The averaged expression of candidate mRNAs was compared between ARVC/D samples (n = 10), nonfamilial dilated cardiomyopathy (DCM) samples (n = 10), and healthy control samples (n = 8). Immunohistochemistry and quantitative protein expression analysis were performed. Genetic analysis using next generation sequencing was performed in all patients with ARVC/D.

Results: Following mRNA levels were significantly increased in patients with ARVC/D compared to those with DCM and healthy controls: phospholamban (P ≤ .001 vs DCM; P ≤ .001 vs controls), healthy tumor protein 53 apoptosis effector (P = .001 vs DCM; P ≤ .001 vs controls), and carnitine palmitoyltransferase 1β (P ≤ .001 vs DCM; P = 0.008 vs controls). Plakophillin-2 (PKP-2) mRNA was downregulated in patients with ARVC/D with PKP-2 mutations compared with patients with ARVC/D without PKP-2 mutations (P = .04). Immunohistochemistry revealed significantly increased protein expression of phospholamban, tumor protein 53 apoptosis effector, and carnitine palmitoyltransferase 1β in patients with ARVC/D and decreased PKP-2 expression in patients with ARVC/D carrying a PKP-2 mutation.

Conclusion: Changes in the expression profiles of sarcolemmal calcium channel regulation, apoptosis, and adipogenesis suggest that these molecular pathways may play a critical role in the pathogenesis of ARVC/D, independent of the underlying genetic mutations.
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http://dx.doi.org/10.1016/j.hrthm.2015.11.010DOI Listing
March 2016

Electrocardiographic features of disease progression in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

BMC Cardiovasc Disord 2015 Jan 19;15. Epub 2015 Jan 19.

Department of Cardiology, University Heart Center Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland.

Background: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is considered a progressive cardiomyopathy. However, data on the clinical features of disease progression are limited. The aim of this study was to assess 12-lead surface electrocardiographic (ECG) changes during long-term follow-up, and to compare these findings with echocardiographic data in our large cohort of patients with ARVC/D.

Methods: Baseline and follow-up ECGs of 111 patients from three tertiary care centers in Switzerland were systematically analyzed with digital calipers by two blinded observers, and correlated with findings from transthoracic echocardiography.

Results: The median follow-up was 4 years (IQR 1.9-9.2 years). ECG progression was significant for epsilon waves (baseline 14% vs. follow-up 31%, p = 0.01) and QRS duration (111 ms vs. 114 ms, p = 0.04). Six patients with repolarization abnormalities according to the 2010 Task Force Criteria at baseline did not display these criteria at follow-up, whereas in all patients with epsilon waves at baseline these depolarization abnormalities also remained at follow-up. T wave inversions in inferior leads were common (36% of patients at baseline), and were significantly associated with major repolarization abnormalities (p = 0.02), extensive echocardiographic right ventricular involvement (p = 0.04), T wave inversions in lateral precordial leads (p = 0.05), and definite ARVC/D (p = 0.05).

Conclusions: Our data supports the concept that ARVC/D is generally progressive, which can be detected by 12-lead surface ECG. Repolarization abnormalities may disappear during the course of the disease. Furthermore, the presence of T wave inversions in inferior leads is common in ARVC/D.
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http://dx.doi.org/10.1186/1471-2261-15-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407546PMC
January 2015

IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses.

J Allergy Clin Immunol 2013 Apr 26;131(4):1204-12. Epub 2013 Feb 26.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland.

Background: IL-10-producing regulatory B cells suppress immune responses, and lack of these cells leads to exacerbated symptoms in mouse models of chronic inflammation, transplantation, and chronic infection. IgG4 is a blocking antibody isotype with anti-inflammatory potential that is induced in human high-dose antigen tolerance models.

Objective: We sought to characterize human inducible IL-10-secreting B regulatory 1 (BR1) cells and to investigate their immunoregulatory capacity through suppression of cellular immune responses and production of anti-inflammatory immunoglobulins.

Methods: Highly purified IL-10-secreting B cells were phenotypically and functionally characterized by means of whole-genome expression analysis, flow cytometry, suppression assay, and antibody production. B cells specific for the major bee venom allergen phospholipase A2 (PLA) were isolated from beekeepers who displayed tolerance to bee venom antigens and allergic patients before and after specific immunotherapy.

Results: Human IL-10+ BR1 cells expressed high surface CD25 and CD71 and low CD73 levels. Sorting of CD73-CD25+CD71+ B cells allowed enrichment of human BR1 cells, which produced high levels of IL-10 and potently suppressed antigen-specific CD4+ T-cell proliferation. IgG4 was selectively confined to human BR1 cells. B cells specific for the major bee venom allergen PLA isolated from nonallergic beekeepers show increased expression of IL-10 and IgG4. Furthermore, the frequency of IL-10+ PLA-specific B cells increased in allergic patients receiving allergen-specific immunotherapy.

Conclusion: Our data show the characterization of IL-10+ BR1 cells and in vivo evidence for 2 essential features of allergen tolerance: the suppressive B cells and IgG4-expressing B cells that are confined to IL-10+ BR1 cells in human subjects.
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http://dx.doi.org/10.1016/j.jaci.2013.01.014DOI Listing
April 2013