Case Report: Four cases of cardiac sarcoidosis in patients with inherited cardiomyopathy—a phenotypic overlap, co-existence of two rare cardiomyopathies or a second-hit disease

Cardiac sarcoidosis (CS), a rare condition characterized by non-caseating granulomas, can manifest with symptoms such as atrioventricular block and ventricular tachycardia (VT), as well as mimic inherited cardiomyopathies. A 48-year-old male presented with recurrent VT. The initial 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) scan showed uptake of the mediastinal lymph node. Cardiovascular magnetic resonance (CMR) demonstrated intramyocardial fibrosis. The follow-up 18FDG-PET scan revealed the presence of tracer uptake in the left ventricular (LV) septum, suggesting the likelihood of CS. Genetic testing identified a pathogenic LMNA variant. A 47-year-old female presented with complaints of palpitations and syncope. An Ajmaline provocation test confirmed Brugada syndrome (BrS). CMR revealed signs of cardiac inflammation. An endomyocardial biopsy (EMB) confirmed the diagnosis of cardiac sarcoidosis. Polymorphic VT was induced during an electrophysiological study, and an implantable cardioverter-defibrillator (ICD) was implanted. A 58-year-old woman presented with sustained VT with a prior diagnosis of hypertrophic cardiomyopathy (HCM). A genetic work-up identified the presence of a heterozygous MYBC3 variant of unknown significance (VUS). CMR revealed late gadolinium enhancement (LGE), while the 18FDG-PET scan demonstrated LV tracer uptake. The immunosuppressive therapy was adjusted, and no further VTs were observed. A 28-year-old male athlete with right ventricular dilatation and syncope experienced a cardiac arrest during training. Genetic testing identified a pathogenic mutation in PKP2. The autopsy has confirmed the presence of ACM and a distinctive extracardiac sarcoidosis. Cardiac sarcoidosis and inherited cardiomyopathies may interact in several different ways, altering the clinical presentation. Overlapping pathologies are frequently overlooked. Delayed or incomplete diagnosis risks inadequate treatment. Thus, genetic testing and endomyocardial biopsies should be recommended to obtain a clear diagnosis

Potential Contributors to Increased Pulmonary Embolism Hospitalizations During the COVID-19 Pandemic: Insights From the German-Wide Helios Hospital Network

Background: After the first COVID-19 infection wave, a constant increase of pulmonary embolism (PE) hospitalizations not linked with active PCR-confirmed COVID-19 was observed, but potential contributors to this observation are unclear. Therefore, we analyzed associations between changes in PE hospitalizations and (1) the incidence of non-COVID-19 pneumonia, (2) the use of computed tomography pulmonary angiography (CTPA), (3) volume depletion, and (4) preceding COVID-19 infection numbers in Germany. Methods: Claims data of Helios hospitals in Germany were used, and consecutive cases with a hospital admission between May 6 and December 15, 2020 (PE surplus period), were analyzed and compared to corresponding periods covering the same weeks in 2016–2019 (control period). We analyzed the number of PE cases in the target period with multivariable Poisson general linear mixed models (GLMM) including (a) cohorts of 2020 versus 2016–2019, (b) the number of cases with pneumonia, (c) CTPA, and (d) volume depletion and adjusted for age and sex. In order to associate the daily number of PE cases in 2020 with the number of preceding SARS-CoV-2 infections in Germany, we calculated the average number of daily infections (divided by 10,000) occurring between 14 up to 90 days with increasing window sizes before PE cases and modeled the data with Poisson regression. Results: There were 2,404 PE hospitalizations between May 6 and December 15, 2020, as opposed to 2,112–2,236 (total 8,717) in the corresponding 2016–2019 control periods (crude rate ratio [CRR] 1.10, 95% CI 1.05–1.15, P < 0.01). With the use of multivariable Poisson GLMM adjusted for age, sex, and volume depletion, PE cases were significantly associated with the number of cases with pneumonia (CRR 1.09, 95% CI 1.07–1.10, P < 0.01) and with CTPA (CRR 1.10, 95% CI 1.09–1.10, P < 0.01). The increase of PE cases in 2020 compared with the control period remained significant (CRR 1.07, 95% CI 1.02–1.12, P < 0.01) when controlling for those factors. In the 2020 cohort, the number of preceding average daily COVID-19 infections was associated with increased PE case incidence in all investigated windows, i.e., including preceding infections from 14 to 90 days. The best model (log likelihood −576) was with a window size of 4 days, i.e., average COVID-19 infections 14–17 days before PE hospitalization had a risk of 1.20 (95% CI 1.12–1.29, P < 0.01). Conclusions: There is an increase in PE cases since early May 2020 compared to corresponding periods in 2016–2019. This surplus was significant even when controlling for changes in potential modulators such as demographics, volume depletion, non-COVID-19 pneumonia, CTPA use, and preceding COVID-19 infections. Future studies are needed (1) to investigate a potential causal link for increased risk of delayed PE with preceding SARS-CoV-2 infection and (2) to define optimal screening for SARS-CoV-2 in patients presenting with pneumonia and PE

PR Interval Associated Genes, Atrial Remodeling and Rhythm Outcome of Catheter Ablation of Atrial Fibrillation—A Gene-Based Analysis of GWAS Data

Background: PR interval prolongation has recently been shown to associate with advanced left atrial remodeling and atrial fibrillation (AF) recurrence after catheter ablation. While different genome-wide association studies (GWAS) have implicated 13 loci to associate with the PR interval as an AF endophenotype their subsequent associations with AF remodeling and response to catheter ablation are unknown. Here, we perform a gene-based analysis of GWAS data to test the hypothesis that PR interval candidate genes also associate with left atrial remodeling and arrhythmia recurrence following AF catheter ablation.Methods and Results: Samples from 660 patients with paroxysmal (n = 370) or persistent AF (n = 290) undergoing AF catheter ablation were genotyped for ~1,000,000 SNPs. Gene-based association was investigated using VEGAS (versatile gene-based association study). Among the 13 candidate genes, SLC8A1, MEIS1, ITGA9, SCN5A, and SOX5 associated with the PR interval. Of those, ITGA9 and SOX5 were significantly associated with left atrial low voltage areas and left atrial diameter and subsequently with AF recurrence after radiofrequency catheter ablation.Conclusion: This study suggests contributions of ITGA9 and SOX5 to AF remodeling expressed as PR interval prolongation, low voltage areas and left atrial dilatation and subsequently to response to catheter ablation. Future and larger studies are necessary to replicate and apply these findings with the aim of designing AF pathophysiology-based multi-locus risk scores

Prevalence of clinically apparent hypertrophic cardiomyopathy in Germany-An analysis of over 5 million patients.

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease. Reported prevalence rates vary substantially between 1:500 (0.2%) and 1:3,000 (0.03%), which may be attributed to different study designs and population characteristics. Prevalence data for Germany is not available. Consequently, this study aimed (1) to quantify age- and gender-specific clinically diagnosed HCM prevalence in Germany based on the analysis of health care claims data of > 5 million insurants in 2015, and (2) to analyze temporal prevalence trends from 2011 to 2015.Data were extracted from the InGef (Insitute for Applied Health Research) database, which is an anonymized healthcare claims database with longitudinal data from patients insured in one of approximately 70 German social health insurances (SHIs). Patients were classified as HCM prevalent, if they had at least one verified ambulatory or one hospital main- or secondary discharge diagnosis of HCM (I42.1 or I42.2).In 2015, HCM was prevalent in 4,000 out of 5,490,810 patients (0.07%; 1:1,372). HCM prevalence increased gradually with age from 7.4/100,000 persons (95% CI 5.2-10.1) in 0-9 years old to 298.7/100,000 persons (95% CI 276.4-322.4) in patients > 80 years. In all age categories, men had a numerically higher prevalence than women with significant differences in patients > 30 years. There was a gradual annual prevalence increase from 75.8 (95% CI 75.2-76.4) in 2011 to 84.2 (95% CI 83.5-84.8) in 2015 per 100,000 persons.Overall, prevalence of clinically diagnosed HCM in Germany is lower than in systematic population studies based on echocardiographic diagnosis. Prevalence increased with advancing age and showed a constant yearly rise. Those observations may improve our understanding of the burden of this genetic heart disease on the health care system in Germany, increase the diagnostic awareness among clinicians and shape future screening and management strategies

Association of atrial fibrillation susceptibility genes, atrial fibrillation phenotypes and response to catheter ablation: a gene-based analysis of GWAS data

Abstract Background Previous studies have suggested PITX2, KCNN3 and ZFHX3 as atrial fibrillation (AF) susceptibility genes. Single common genetic polymorphisms of those genes have been linked with AF phenotypes and rhythm outcome of AF catheter ablation although their mechanisms remain elusive. New gene-based association tests may help clarifying genotype–phenotype correlations. Therefore, we hypothesized that PITX2, KCNN3 and ZFHX3 associate with left atrial enlargement and persistent AF and subsequently with ablation outcome. Methods and results Samples from 660 patients with paroxysmal (n = 370) or persistent AF (n = 290) undergoing AF catheter ablation were genotyped for ~1,000,000 SNPs. Gene-based association was investigated using two different gene-based association tests (VEGAS, minSNP). Among the three candidate genes, only ZFHX3 associated with left atrial dilatation and AF recurrence after catheter ablation. Conclusion This study suggests a contribution of ZFHX3 to AF remodeling and response to therapy. Future and larger studies are necessary to replicate and apply these findings with an emphasis on designing AF pathophysiology-based multi-locus risk scores

Identification of Central Regulators of Calcium Signaling and ECM–Receptor Interaction Genetically Associated With the Progression and Recurrence of Atrial Fibrillation

Atrial fibrillation (AF) is a multifactorial disease with a strong genetic background. It is assumed that common and rare genetic variants contribute to the progression and recurrence of AF. The pathophysiological impact of those variants, especially when they are synonymous or non-coding, is often elusive and translation into functional experiments is difficult. In this study, we propose a method to go straight from genetic variants to defined gene targets. We focused on 55 genes from calcium signaling and 26 genes from extra cellular matrix ECM–receptor interaction that we found to be associated with the progression and recurrence of AF. These genes were mapped on protein–protein interaction data from three different databases. Based on the concept that central regulators are highly connected with their neighbors, we identified central hub proteins according to random walk analysis derived scores representing interaction grade. Our approach resulted in the identification of EGFR, RYR2, and PRKCA (calcium signaling) and FN1 and LAMA1 (ECM–receptor interaction) which represent promising targets for further functional characterization or pharmaceutical intervention

Pharmacological and Non-pharmacological Treatments for Stroke Prevention in Patients with Atrial Fibrillation

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