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Introduction: Our study assessed the effectiveness of tele-coaching over written information in educating patients with chronic heart failure (CHF) at high risk of hospitalization about corona viru...

To compare the ability of cardiac magnetic resonance tomography (CMR) and transthoracic echocardiography (TTE) to predict the need for valve surgery in patients with chronic aortic regurgitation on a mid-term basis. 66 individuals underwent assessment of aortic regurgitation (AR) both in CMR and TTE between August 2012 and April 2017. The follow-up rate was 76% with a median of 5.1 years. Cox proportional hazards method was used to assess the association of the time-to-aortic-valve-surgery, including valve replacement and reconstruction, and imaging parameters. A direct comparison of most predictive CMR and echocardiographic parameters was performed by using nested-factor-models. Sixteen patients (32%) were treated with aortic valve surgery during follow-up. Aortic valve insufficiency parameters, both of echocardiography and CMR, showed good discriminative and predictive power regarding the need of valve surgery. Within all examined parameters AR gradation derived by CMR correlated best with outcome [χ2 = 27.1; HR 12.2 (95% CI: 4.56, 36.8); (p

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic cause of stroke and vascular dementia. Disease-causing mutations invariably affect cysteine residues within epidermal growth factor-like repeat domains in the extracellular domain of the NOTCH3 receptor (N3(ECD)). The biochemical and histopathological hallmark of CADASIL is the accumulation of N3(ECD) at the cell surface of vascular smooth muscle cells which degenerate over the course of the disease. The molecular mechanisms leading to N3(ECD) accumulation remain unknown. Here we show that both wild-type and CADASIL-mutated N3(ECD) spontaneously form oligomers and higher order multimers in vitro and that multimerization is mediated by disulfide bonds. Using single-molecule analysis techniques ('scanning for intensely fluorescent targets'), we demonstrate that CADASIL-associated mutations significantly enhance multimerization compared with wild-type. Taken together, our results for the first time provide experimental evidence for N3 self-association and strongly argue for a neomorphic effect of CADASIL mutations in disease pathogenesis.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common monogenic cause of stroke and vascular dementia. Accumulation and deposition of the NOTCH3 (N3) extracellular domain in small blood vessels has been recognized as a central pathological feature of the disease. Recent experiments suggested enhanced formation of higher order multimers for mutant N3 compared with wild-type (WT). However, the mechanisms and consequences of N3 multimerization are still poorly understood, in part because of the lack of an appropriate in vitro aggregation assay. We therefore developed and validated a robust assay based on recombinant N3 fragments purified from cell culture supernatants. Using single-molecule analysis techniques such as scanning for intensely fluorescent targets and single-particle fluorescence resonance energy transfer, we show that spontaneous aggregation is limited to CADASIL-mutant N3, recapitulating a central aspect of CADASIL pathology in vitro. N3 aggregation requires no co-factor and is facilitated by sulfhydryl crosslinking. Although WT N3 does not exhibit multimerization itself, it can participate in aggregates of mutant N3. Furthermore, we demonstrate that thrombospondin-2, a known interaction partner of N3, co-aggregates with mutant N3. Sequestration of WT N3 and other proteins into aggregates represents a potentially important disease mechanism. These findings in combination with a new assay for single-molecule aggregation analysis provide novel opportunities for the development of therapeutic strategies.