Cell Specific Coxsackievirus B3 Replication

Myocarditis is an inflammatory disease caused by viral infection. Different subpopulations of leukocytes enter the cardiac tissue and lead to severe cardiac inflammation associated with myocyte loss and remodeling. Here, we study possible cell sources for viral replication using three compartments of the heart: fibroblasts, cardiomyocytes, and macrophages. We infected C57BL/6j mice with Coxsackievirus B3 (CVB3) and detected increased gene expression of anti-inflammatory and antiviral cytokines in the heart. Subsequently, we infected cardiac fibroblasts, cardiomyocytes, and macrophages with CVB3. Due to viral infection, the expression of TNF-α, IL-6, MCP-1, and IFN-β was significantly increased in cardiac fibroblasts compared to cardiomyocytes or macrophages. We found that in addition to cardiomyocytes cardiac fibroblasts were infected by CVB3 and displayed a higher virus replication (132-fold increase) compared to cardiomyocytes (14-fold increase) between 6 and 24 hours after infection. At higher virus concentrations, macrophages are able to reduce the viral copy number. At low virus concentration a persistent virus infection was determined. Therefore, we suggest that cardiac fibroblasts play an important role in the pathology of CVB3-induced myocarditis and are another important contributor of virus replication aggravating myocarditis

Current Treatment of Heart Failure with Preserved Ejection Fraction: Should We Add Life to the Remaining Years or Add Years to the Remaining Life?

According to the ejection fraction, patients with heart failure may be divided into two different groups: heart failure with preserved or reduced ejection fraction. In recent years, accumulating studies showed that increased mortality and morbidity rates of these two groups are nearly equal. More importantly, despite decline in mortality after treatment in regard to current guideline in patients with heart failure with reduced ejection fraction, there are still no trials resulting in improved outcome in patients with heart failure with preserved ejection fraction so far. Thus, novel pathophysiological mechanisms are under development, and other new viewpoints, such as multiple comorbidities resulting in increased non-cardiac deaths in patients with heart failure and preserved ejection fraction, were presented recently. In this review, we will focus on the tested as well as the promising therapeutic options that are currently studied in patients with heart failure with preserved ejection fraction, along with a brief discussion of pathophysiological mechanisms and diagnostic options that are helpful to increase our understanding of novel therapeutic strategies

Perspectives on the revised Ghent criteria for the diagnosis of Marfan syndrome

Three international nosologies have been proposed for the diagnosis of Marfan syndrome (MFS): the Berlin nosology in 1988; the Ghent nosology in 1996 (Ghent-1); and the revised Ghent nosology in 2010 (Ghent-2). We reviewed the literature and discussed the challenges and concepts of diagnosing MFS in adults. Ghent-1 proposed more stringent clinical criteria, which led to the confirmation of MFS in only 32%-53% of patients formerly diagnosed with MFS according to the Berlin nosology. Conversely, both the Ghent-1 and Ghent-2 nosologies diagnosed MFS, and both yielded similar frequencies of MFS in persons with a causative FBN1 mutation (90% for Ghent-1 versus 92% for Ghent-2) and in persons not having a causative FBN1 mutation (15% versus 13%). Quality criteria for diagnostic methods include objectivity, reliability, and validity. However, the nosology-based diagnosis of MFS lacks a diagnostic reference standard and, hence, quality criteria such as sensitivity, specificity, or accuracy cannot be assessed. Medical utility of diagnosis implies congruency with the historical criteria of MFS, as well as with information about the etiology, pathogenesis, diagnostic triggers, prognostic triggers, and potential complications of MFS. In addition, social and psychological utilities of diagnostic criteria include acceptance by patients, patient organizations, clinicians and scientists, practicability, costs, and the reduction of anxiety. Since the utility of a diagnosis or exclusion of MFS is context-dependent, prioritization of utilities is a strategic decision in the process of nosology development. Screening tests for MFS should be used to identify persons with MFS. To confirm the diagnosis of MFS, Ghent-1 and Ghent-2 perform similarly, but Ghent-2 is easier to use. To maximize the utility of the diagnostic criteria of MFS, a fair and transparent process of nosology development is essential

Prediction of cardiac worsening through to cardiogenic shock in patients with acute heart failure

Aims: Acute heart failure (AHF) can result in worsening of heart failure (WHF), cardiogenic shock (CS), or death. Risk factors for these adverse outcomes are not well characterized. This study aimed to identify predictors for WHF or new‐onset CS in patients hospitalized for AHF. Methods and results: Prospective cohort study enrolling consecutive patients with AHF admitted to a large tertiary care centre with follow‐up until death or discharge. WHF was defined by the RELAX‐AHF‐2 criteria. CS was defined as SCAI stages B–E. Potential predictors were assessed by fitting logistic regression models adjusted for age and sex. N = 233 patients were enrolled, median age was 78 years, and 80 were women (35.9%). Ischaemic cardiomyopathy was present in 82 patients (40.8%). Overall, 96 (44.2%) developed WHF and 18 (9.7%) CS. In‐hospital death (8/223, 3.6%) was related to both events (WHF: OR 6.64, 95% CI 1.21–36.55, P = 0.03; CS: OR 38.27, 95% CI 6.32–231.81, P < 0.001). Chronic kidney disease (OR 2.20, 95% CI 1.25–3.93, P = 0.007), logarithmized serum creatinine (OR 2.90, 95% CI 1.51–5.82, P = 0.002), cystatin c (OR 1.86, 95% CI 1.27–2.77, P = 0.002), tricuspid valve regurgitation (OR 2.08, 95% CI 1.11–3.94, P = 0.023) and logarithmized pro‐adrenomedullin (OR 3.01, 95% CI 1.75–5.38, P < 0.001) were significant predictors of WHF. Chronic kidney disease (OR 3.17, 95% CI 1.16–9.58, P = 0.03), cystatin c (OR 1.88, 95% CI 1.00–3.53, P = 0.045), logarithmized pro‐adrenomedullin (OR 2.90, 95% CI 1.19–7.19, P = 0.019), and tricuspid valve regurgitation (OR 10.44, 95% CI 2.61–70.00, P = 0.003) were significantly with new‐onset CS. Conclusions: Half of patients admitted with AHF experience WHF or new‐onset CS. Chronic kidney disease, tricuspid valve regurgitation, and elevated pro‐adrenomedullin concentrations predict these events. They could potentially serve as early warning signs for further deterioration in AHF patients

Association of systemic inflammation with shock severity, 30-day mortality, and therapy response in patients with cardiogenic shock

Background: Mortality in cardiogenic shock (CS) remains high even when mechanical circulatory support (MCS) restores adequate circulation. To detect a potential contribution of systemic inflammation to shock severity, this study determined associations between C-reactive protein (CRP) concentrations and outcomes in patients with CS. Methods: Unselected, consecutive patients with CS and CRP measurements treated at a single large cardiovascular center between 2009 and 2019 were analyzed. Adjusted regression models were fitted to evaluate the association of CRP with shock severity, 30-day in-hospital mortality and treatment response to MCS. Results: The analysis included 1116 patients [median age: 70 (IQR 58–79) years, 795 (71.3%) male, lactate 4.6 (IQR 2.2–9.5) mmol/l, CRP 17 (IQR 5–71) mg/l]. The cause of CS was acute myocardial infarction in 530 (48%) patients, 648 (58%) patients presented with cardiac arrest. Plasma CRP concentrations were equally distributed across shock severities (SCAI stage B–E). Higher CRP concentrations were associated with 30-day in-hospital mortality (8% relative risk increase per 50 mg/l increase in CRP, range 3–13%; p < 0.001), even after adjustment for CS severity and other potential confounders. Higher CRP concentrations were only associated with higher mortality in patients not treated with MCS [hazard ratio (HR) for CRP > median 1.50; 95%-CI 1.21–1.86; p < 0.001], but not in those treated with MCS (HR for CRP > median 0.92; 95%-CI 0.67–1.26; p = 0.59; p-interaction = 0.01). Conclusion: Elevated CRP concentrations are associated with increased 30-day in-hospital mortality in unselected patients with cardiogenic shock. The use of mechanical circulatory support attenuates this association

Comparison of calling pipelines for whole genome sequencing: an empirical study demonstrating the importance of mapping and alignment

Rapid advances in high-throughput DNA sequencing technologies have enabled the conduct of whole genome sequencing (WGS) studies, and several bioinformatics pipelines have become available. The aim of this study was the comparison of 6 WGS data pre-processing pipelines, involving two mapping and alignment approaches (GATK utilizing BWA-MEM2 2.2.1, and DRAGEN 3.8.4) and three variant calling pipelines (GATK 4.2.4.1, DRAGEN 3.8.4 and DeepVariant 1.1.0). We sequenced one genome in a bottle (GIAB) sample 70 times in different runs, and one GIAB trio in triplicate. The truth set of the GIABs was used for comparison, and performance was assessed by computation time, F1 score, precision, and recall. In the mapping and alignment step, the DRAGEN pipeline was faster than the GATK with BWA-MEM2 pipeline. DRAGEN showed systematically higher F1 score, precision, and recall values than GATK for single nucleotide variations (SNVs) and Indels in simple-to-map, complex-to-map, coding and non-coding regions. In the variant calling step, DRAGEN was fastest. In terms of accuracy, DRAGEN and DeepVariant performed similarly and both superior to GATK, with slight advantages for DRAGEN for Indels and for DeepVariant for SNVs. The DRAGEN pipeline showed the lowest Mendelian inheritance error fraction for the GIAB trios. Mapping and alignment played a key role in variant calling of WGS, with the DRAGEN outperforming GATK

CMR in Patients With Severe Myocarditis Diagnostic Value of Quantitative Tissue Markers Including Extracellular Volume Imaging

AbstractObjectivesThis study evaluated the accuracy of T2, T1, and extracellular volume (ECV) quantification as novel quantitative tissue markers in comparison with standard “Lake-Louise” cardiac magnetic resonance (CMR) criteria to diagnose myocarditis.BackgroundNovel approaches using T2 and T1 mapping may overcome the limitations of signal intensity-based parameters, which would potentially result in a better diagnostic accuracy compared with standard CMR techniques in suspected myocarditis.MethodsCMR was performed in 104 patients with myocarditis and 21 control subjects at 1.5-T. Patients with myocarditis underwent CMR 2 weeks (interquartile range: 1 to 7 weeks) after presentation with new-onset heart failure (n = 66) or acute chest pain (n = 38). T2 and T1 mapping were implemented into a standard protocol including T2-weighted (T2w), early gadolinium enhancement (EGE) CMR, and late gadolinium enhancement (LGE) CMR. T2 quantification was performed using a free-breathing, navigator-gated multiecho sequence. T1 quantification was performed using the modified Look-Locker inversion recovery sequence before and after administration of 0.075 mmol/kg gadobenate dimeglumine. T2, T1, and ECV maps were generated using a plug-in for the OsiriX software (Pixmeo, Bernex, Switzerland) to calculate mean global myocardial T2, T1, and ECV values.ResultsThe diagnostic accuracies of conventional CMR were 70% (95% confidence interval [CI]: 61% to 77%) for T2w CMR, 59% (95% CI: 56% to 73%) for EGE, and 67% (95% CI: 59% to 75%) for LGE. The diagnostic accuracies of mapping techniques were 63% (95% CI: 53% to 73%) for myocardial T2, 69% (95% CI: 60% to 76%) for native myocardial T1, and 76% (95% CI: 68% to 82%) for global myocardial ECV. The diagnostic accuracy of CMR was significantly improved to 90% (95% CI: 84% to 95%) by a stepwise approach, using the presence of LGE and myocardial ECV ≥27% as diagnostic criteria, compared with 79% (95% CI: 71% to 85%; p = 0.0043) for the Lake-Louise criteria.ConclusionsIn patients with clinical evidence for subacute, severe myocarditis, ECV quantification with LGE imaging significantly improved the diagnostic accuracy of CMR compared with standard Lake-Louise criteria

The ophthalmic branch of the Gutenberg Health Study: study design, cohort profile and self-reported diseases

This paper describes the study design, methodology, cohort profile and self-reported diseases in the ophthalmological branch of the Gutenberg Health Study (GHS).The GHS is an ongoing, prospective, interdisciplinary, single-center, population-based cohort study in Germany. The main goals of the ophthalmological section are to assess the prevalence and incidence of ocular diseases and to explore risk factors, genetic determinants and associations with systemic diseases and conditions. The eye examination at baseline included a medical history, self-reported eye diseases, visual acuity, refractive errors, intraocular pressure, visual field, pachymetry, keratometry, fundus photography and tear sampling. The 5-year follow-up visit additionally encompassed optical coherence tomography, anterior segment imaging and optical biometry. The general examination included anthropometry; blood pressure measurement; carotid artery ultrasound; electrocardiogram; echocardiography; spirometry; cognitive tests; questionnaires; assessment of mental conditions; and DNA, RNA, blood and urine sampling.Of 15,010 participants (aged 35-74 years at the time of inclusion), ocular data are available for 14,700 subjects (97.9%). The mean visual acuity (standard deviation), mean spherical equivalent, median decimal visual acuity, and mean intraocular pressure were 0.08 (0.17) logMar, -0.42 (2.43) diopters, 0.9 and 14.24 (2.79) mm Hg, respectively. The frequencies of self-reported strabismus, glaucoma, surgery for retinal detachment and retinal vascular occlusions were 2.7%, 2.3%, 0.2% and 0.4%, respectively.The GHS is the most extensive dataset of ophthalmic diseases and conditions and their risk factors in Germany and one of the largest cohorts worldwide. This dataset will provide new insight in the epidemiology of ophthalmic diseases and related medical specialties