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Fibrosis accompanies most heart diseases and is associated with adverse patient outcomes. Transforming growth factor (TGF)β drives extracellular matrix remodelling and fibrosis in the failing heart. Some members of the ADAMTSL (a disintegrin-like and metalloproteinase domain with thrombospondin type 1 motifs-like) family of secreted glycoproteins bind to matrix microfibrils, and although their function in the heart remains largely unknown, they are suggested to regulate TGFβ activity. The aims of this study were to determine ADAMTSL2 levels in failing hearts, and to elucidate the role of ADAMTSL2 in fibrosis using cultured human cardiac fibroblasts (CFBs). Cardiac ADAMTSL2 mRNA was robustly increased in human and experimental heart failure, and mainly expressed by fibroblasts. Over-expression and treatment with extracellular ADAMTSL2 in human CFBs led to reduced TGFβ production and signalling. Increased ADAMTSL2 attenuated myofibroblast differentiation, with reduced expression of the signature molecules α-smooth muscle actin and osteopontin. Finally, ADAMTSL2 mitigated the pro-fibrotic CFB phenotypes, proliferation, migration and contractility. In conclusion, the extracellular matrix-localized glycoprotein ADAMTSL2 was upregulated in fibrotic and failing hearts of patients and mice. We identified ADAMTSL2 as a negative regulator of TGFβ in human cardiac fibroblasts, inhibiting myofibroblast differentiation and pro-fibrotic properties., (© 2021. The Author(s).)

Background Arrhythmogenic cardiomyopathy (AC) is characterized by biventricular dysfunction, exercise intolerance, and high risk of ventricular tachyarrhythmias and sudden death. Predisposing factors for left ventricular (LV) disease manifestation and its prognostic implication in AC are poorly described. We aimed to assess the associations of exercise exposure and genotype with LV dysfunction in AC, and to explore the impact of LV disease progression on adverse arrhythmic outcome. Methods and Results We included 168 patients with AC (50% probands, 45% women, 40±16 years old) with 715 echocardiographic exams (4.1±1.7 exams/patient, follow-up 7.6 [interquartile range (IQR), 5.4-10.9] years) and complete exercise and genetic data in a longitudinal study. LV function by global longitudinal strain was -18.8% [IQR, -19.2% to -18.3%] at presentation and was worse in patients with greater exercise exposure (global longitudinal strain worsening, 0.09% [IQR, 0.01%-0.17%] per 5 MET-hours/week, P =0.02). LV function by global longitudinal strain worsened, with 0.08% [IQR, 0.05%-0.12%] per year; ( P <0.001), and progression was most evident in patients with desmoplakin genotype ( P for interaction <0.001). Deterioration of LV function predicted incident ventricular tachyarrhythmia (aborted cardiac arrest, sustained ventricular tachycardia, or implantable cardioverter defibrillator shock) (adjusted odds ratio, 1.1 [IQR, 1.0-1.3] per 1% worsening by global longitudinal strain; P =0.02, adjusted for time and previous arrhythmic events). Conclusions Greater exercise exposure was associated with worse LV function at first visit of patients with AC but did not significantly affect the rate of LV progression during follow-up. Progression of LV dysfunction was most pronounced in patients with desmoplakin genotypes. Deterioration of LV function during follow-up predicted subsequent ventricular tachyarrhythmia and should be considered in risk stratification.

Background: We assessed the influence of interventricular septal thickness (IVSd) on the clinical outcome and survival after alcohol septal ablation (ASA) in patient with hypertrophic cardiomyopathy., Methods and Results: We analyzed 531 patients with hypertrophic cardiomyopathy (age: 56±14 years, men 55%) treated with ASA. Survival status was obtained 7.9±4.0 years after ASA. Baseline IVSd was inversely associated with survival (hazard ratio [HR] for 1 mm increment, 1.13; confidence interval, 1.05-1.21; P<0.001) after adjustment for age, sex, body mass index, and ASA-performing center. Compared with patients with baseline IVSd <20 mm, patients with baseline IVSd ≥25 mm had reduced survival (HR, 5.0; CI, 2.1-12), whereas patients with baseline IVSd 20 to 24 mm had similar survival (HR, 1.4; CI, 0.7-2.8). Baseline IVSd was not correlated with New York Heart Association class, Canadian Cardiology Society class, or syncope. Clinical outcome was assessed 0.6±0.6 years after ASA. IVSd was not related to left ventricular outflow tract gradient reduction at rest (P=0.883) or during Valsalva maneuver (P=0.885). The proportion of patients in New York Heart Association class 3 to 4 was reduced from 86% to 10%; in Canadian Cardiology Society class 3 to 4 from 26% to 2%; and with syncope from 25% to 2%. There were no correlations between baseline IVSd and New York Heart Association class (P=0.067), Canadian Cardiology Society class (P=0.106), or syncope (P=0.426) after ASA., Conclusions: ASA had equal effects on left ventricular outflow tract gradients and symptoms throughout the spectrum of septal hypertrophy. Severe septal hypertrophy before ASA remained a marker of reduced survival after ASA with a 5-fold increased risk of all-cause mortality in patients with baseline IVSd >25 mm compared with patients with baseline IVSd <20 mm., (© 2016 American Heart Association, Inc.)

Uncertainty often becomes problematic when science is used to support decision making in the policy process. Scientists can contribute to a more constructive approach to uncertainty by making their uncertainties transparent. In this article, an approach to systematic uncertainty diagnosis is demonstrated on the case study of transgene silencing and GMO risk assessment. Detailed interviews were conducted with five experts on transgene silencing to obtain quantitative and qualitative information on their perceptions of the uncertainty characterising our knowledge of the phenomena. The results indicate that there are competing interpretations of the cause-effect relationships leading to gene silencing (model structure uncertainty). In particular, the roles of post-transcriptional gene silencing, position effects, DNA-DNA interactions, direct-repeat DNA structures, recognition factors and dsRNA and aberrant zRNA are debated. The study highlights several sources of uncertainty beyond the statistical uncertainty commonly reported in risk assessment. The results also reveal a discrepancy between the way in which uncertainties would be prioritized on the basis of the uncertainty analysis conducted, and the way in which they would be prioritized on the basis of expert willingness to pay to eliminate uncertainty. The results also reveal a diversity of expert opinions on the uncertainty characterizing transgene silencing. Because the methodology used to diagnose uncertainties was successful in revealing a broad spectrum of uncertainties as well as a diversity of expert opinion, it is concluded that the methodology used could contribute to increasing transparency and fostering a critical discussion on uncertainty in the decision making process.

Objectives: A prospective outcome study designed to evaluate a simple strategy for the management of outpatients with suspected pulmonary embolism (PE), based on clinical probability, D-dimer, and multi-slice computed tomography (MSCT)., Methods: A cohort of 432 consecutive patients admitted to the emergency department with suspected PE was managed by sequential non-invasive testing. Patients in whom PE was ruled out were not given anticoagulants, but were followed-up for 3 months., Results: Normal D-dimer and low-intermediate clinical probability ruled out PE in 103 patients [24% (95% CI 20-28)]. Seventeen patients had normal D-dimer, but high clinical probability and proceeded to MSCT. All patients proved negative for PE. A total of 329 (76%) patients underwent MSCT examination. Pulmonary embolism was diagnosed in 93 patients [21.5% (95% CI 18-26)] and was ruled out by negative MSCT in 221 patients [51% (95% CI 46-56)]. MSCT scans were determined as inconclusive in 15 (4.5%) patients. No patient developed objectively verified venous thromboembolism (VTE) during the 3-month follow-up period. However, the cause of death was adjudicated as possibly related to PE in two patients, resulting in an overall 3-month VTE risk of 0.6% (95% CI 0-2.2%). The diagnostic algorithm yielded a definite diagnosis in 96.5% of the patients., Conclusions: This simple and non-invasive strategy combining clinical probability, D-dimer, and MSCT for the management of outpatients with suspected PE appears to be safe and effective.