Contractile Dysfunction Irrespective of the Mutant Protein in Human Hypertrophic Cardiomyopathy With Normal Systolic Function

Background-Hypertrophic cardiomyopathy (HCM), typically characterized by asymmetrical left ventricular hypertrophy, frequently is caused by mutations in sarcomeric proteins. We studied if changes in sarcomeric properties in HCM depend on the underlying protein mutation. Methods and Results-Comparisons were made between cardiac samples from patients carrying a MYBPC3 mutation (MYBPC3(mut); n = 17), mutation negative HCM patients without an identified sarcomere mutation (HCM(mn); n = 11), and nonfailing donors (n = 12). All patients had normal systolic function, but impaired diastolic function. Protein expression of myosin binding protein C (cMyBP-C) was significantly lower in MYBPC3(mut) by 33 +/- 5%, and similar in HCM(mn) compared with donor. cMyBP-C phosphory Conclusions-Changes in sarcomere function reflect the clinical HCM phenotype rather than the specific MYBPC3 mutation. Hypocontractile sarcomeres are a common deficit in human HCM with normal systolic left ventricular function and may contribute to HCM disease progression. (Circ Heart Fail. 2012; 5: 36-46.

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

Evidence indicates that anatomical and physiological phenotypes of hypertrophic cardiomyopathy (HCM) stem from genetically mediated, inefficient cardiomyocyte energy utilization, and subsequent cellular energy depletion. However, HCM often presents clinically with normal left ventricular (LV) systolic function or hyperkinesia. If energy inefficiency is a feature of HCM, why is it not manifest as resting LV systolic dysfunction? In this Perspectives article, we focus on an idiosyncratic form of reversible systolic dysfunction provoked by LV obstruction that we have previously termed the 'lobster claw abnormality' — a mid-systolic drop in LV Doppler ejection velocities. In obstructive HCM, this drop explains the mid-systolic closure of the aortic valve, the bifid aortic pressure trace, and why patients cannot increase stroke volume with exercise. This phenomenon is characteristic of a broader phenomenon in HCM that we have termed dynamic systolic dysfunction. It underlies the development of apical aneurysms, and rare occurrence of cardiogenic shock after obstruction. We posit that dynamic systolic dysfunction is a manifestation of inefficient cardiomyocyte energy utilization. Systolic dysfunction is clinically inapparent at rest; however, it becomes overt through the mechanism of afterload mismatch when LV outflow obstruction is imposed. Energetic insufficiency is also present in nonobstructive HCM. This paradigm might suggest novel therapies. Other pathways that might be central to HCM, such as myofilament Ca2+ hypersensitivity, and enhanced late Na+ current, are discussed

Challenges and best practices for big data-driven healthcare innovations conducted by profit–non-profit partnerships – a quantitative prioritization

Big data-driven innovations are key in improving healthcare system sustainability. Given the complexity, these are frequently conducted by public-private-partnerships (PPPs) between profit and non-profit parties. However, information on how to manage big data-driven healthcare innovations by PPPs is limited. This study elucidates challenges and best practices in managing big data-driven healthcare innovations by PPPs in the Netherlands. Fifteen technical, organizational, competence and ethical/legal challenges and best practices to overcome these challenges were identified in expert interviews with key opinion leaders (KOLs) and through literature review. They were prioritized by a second KOL-panel in an online questionnaire and results were interpreted by a focus-group. ‘Data variety’ was the main challenge, followed by ‘lack of data sharing’ and ‘insufficient data quality’. PPPrespondents ranked appropriate big data skills significantly lower (P = 0.049) and conservatism towards health care decisions significantly (P = 0.026) than non-PPP respondents. The profit sub-group ranked data access higher compared to the non-profit sub-group (P = 0.022). Continuous dialogue between stakeholders, cost-benefit analyses and pilot experiments might overcome conservatism. In conclusion, PPPs should blend skills and resources to maximize benefits of big data-driven healthcare innovations. Mitigating actions could overcome technical issues, whilst a better common support base might prevent conservatism and lack of data sharing

MeerLICHT and BlackGEM: custom-built telescopes to detect faint optical transients

Item does not contain fulltextGround-based and Airborne Telescopes VI, Edinburgh, United Kingdom, June 26, 201

3MeerLICHT and BlackGEM: custom-built telescopes to detect faint optical transients

We present the MeerLICHT and BlackGEM telescopes, which are wide-field optical telescopes that are currently being built to study transient phenomena, gravitational wave counterparts and variable stars. The telescopes have 65 cm primary mirrors and a 2.7 square degree field-of-view. The MeerLICHT and BlackGEM projects have different science goals, but will use identical telescopes. The first telescope, MeerLICHT, will be commissioned at Sutherland (South Africa) in the first quarter of 2017. It will co-point with MeerKAT to collect optical data commensurate with the radio observations. After careful analysis of MeerLICHT's performance, three telescopes of the same type will be commissioned in La Silla (Chile) in 2018 to form phase I of the BlackGEM array. BlackGEM aims at detecting and characterizing optical counterparts of gravitational wave events detected by Advanced LIGO and Virgo. In this contribution we present an overview of the science goals, the design and the status of the two projects

Intrinsic MYH7 expression regulation contributes to tissue level allelic imbalance in hypertrophic cardiomyopathy

HCM, the most common inherited cardiac disease, is mainly caused by mutations in sarcomeric genes. More than a third of the patients are heterozygous for mutations in the MYH7 gene encoding for the β-myosin heavy chain. In HCM-patients, expression of the mutant and the wildtype allele can be unequal, thus leading to fractions of mutant and wildtype mRNA and protein which deviate from 1:1. This so-called allelic imbalance was detected in whole tissue samples but also in individual cells. There is evidence that the severity of HCM not only depends on the functional effect of the mutation itself, but also on the fraction of mutant protein in the myocardial tissue. Allelic imbalance has been shown to occur in a broad range of genes. Therefore, we aimed to examine whether the MYH7-alleles are intrinsically expressed imbalanced or whether the allelic imbalance is solely associated with the disease. We compared the expression of MYH7-alleles in non-HCM donors and in HCM-patients with different MYH7-missense mutations. In the HCM-patients, we identified imbalanced as well as equal expression of both alleles. Also at the protein level, allelic imbalance was determined. Most interestingly, we also discovered allelic imbalance and balance in non-HCM donors. Our findings therefore strongly indicate that apart from mutation-specific mechanisms, also non-HCM associated allelic-mRNA expression regulation may account for the allelic imbalance of the MYH7 gene in HCM-patients. Since the relative amount of mutant mRNA and protein or the extent of allelic imbalance has been associated with the severity of HCM, individual analysis of the MYH7-allelic expression may provide valuable information for the prognosis of each patient