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The function of the right ventricle (RV) determines the prognosis of patients with pulmonary hypertension. While much progress has been made in the treatment of pulmonary hypertension, therapies for the RV are less well established. In this review of treatment strategies for the RV, first we focus on ways to reduce wall stress since this is the main determinant of changes to the ventricle. Secondly, we discuss treatment strategies targeting the detrimental consequences of increased RV wall stress. To reduce wall stress, afterload reduction is the essential. Additionally, preload to the ventricle can be reduced by diuretics, by atrial septostomy, and potentially by mechanical ventricular support. Secondary to ventricular wall stress, left-to-right asynchrony, altered myocardial energy metabolism, and neurohumoral activation will occur. These may be targeted by optimising RV contraction with pacing, by iron supplement, by angiogenesis and improving mitochondrial function, and by neurohumoral modulation, respectively. We conclude that several treatment strategies for the right heart are available; however, evidence is still limited and further research is needed before clinical application can be recommended.

Purpose Cardiomyocytes progenitor cells (CMPCs) are a candidate cell source for cardiac regenerative therapy. To assess their full potential for cardiac regeneration, it is essential to know if and how CMPCs sense and respond to the three-dimensional (3D) environment and the mechanical stimuli provided by the beating heart. Therefore, we study the response to cyclic strain of undifferentiated and predifferentiated human CMPCs in a 2D environment, as well as CMPC responses to unidirectionally constrained versus stress-free (unconstrained) 3D environments. The latter responses were studied using a hydrogel system that allows for interaction of the cells with a simulated ‘host’ tissue. Methods To test mechanosensitivity of CMPCs in 2D and 3D environments, the response of L9TB CMPCs to uniaxial (cyclic) strain (10% with 0.5 Hz) was investigated. To represent the 3D environment, CMPCs were cultured in unidirectionally constrained and stress-free collagen/Matrigel hydrogels, where the constrainment provides a static strain to the cells. The cellular mechanoresponse to the applied (cyclic) strain was quantified by cellular re-orientation away from the strain direction (strain avoidance). Next to cellular re-orientation, the effect of strain on cell differentiation was analyzed. Results Our results indicate that while undifferentiated cells maintain their original orientation, upon early cardiomyogenic differentiation (predifferentiated) CMPCs exhibit a distinct strain avoidance response during 48hrs of cyclic straining in a 2D environment. In 3D unidirectionally constrained hydrogels, undifferentiated CMPCs retain their cardiomyogenic profile. CMPCs cultured in 3D collagen/Matrigel hydrogels respond to static mechanical strains as expected by cell alignment. Conclusions Our results suggest that CMPCs respond to the presence of mechanical stimuli, in this research mimicked by the application of uniaxial (cyclic) strain in 2D and 3D environments, suggesting that CMPCs are indeed mechanosensitive. Although in 2D environments, mechanosensitivity of the CMPCs is dependent on their differentiation status. Our findings provide the first understanding of the ability of human CMPCs to sense mechanical stimuli, which is the first initial step in mechanotransduction. Mechanotransduction is essential for optimal recruitment, migration, and mechanical integration of progenitor cells into the injured myocardium. Therefore, the presented results can contribute to enhance efficacy of current treatments of cardiac disease, as well as to develop novel endogenous regeneration strategies.

Dissonances of ethnic nationalism have in Western cultural policy long been concealed by the universalist discourses of the international treaties on material heritage protection, as framed by the expansive heritage conservation apparatuses of the European nation states. Originally inspired by the 19th century romantic spirit of conservation, they became in the 20th century part of the modern, state-apparatus. Yet parallel with the European enlargements and new kinds of memory debates on the Holocaust and postcolonialism, these authorized heritage regimes have received more and more competition from a transnational counter-discourse on intangible cultural heritage. Like the earlier transformative, internationalist notion of world heritage, this intangible perception of cultural heritage is embraced by the European Community and promoted on a global scale by the Paris headquarters of the 1946 founded UNESCO. And yet, at the same time, it neglects much of the deep-rooted symbolic identifications with Europe’s dissonant pasts and identity crusades, and fosters the assumption of an almost touristic kind of bottom-up heritagization as a more democratic road to Europeanization. Altogether, such contradictory statements on what is analysed as an "intangible heritage turn", thus ask for a critical observation in the context of the current authoritarian revolt and the related revival of Identitarian discourses in large parts of Europe, both from the Left and from the Right (in defense of, respectively, minority cultures and national cultures). Sketching the past and current state of affairs in intangible heritage policy, and using examples from the Dutch postcolonial case of Black Pete to the Russian-Ukrainian folklore war on Kolobok, it is argued how by highlighting cultural diversity, the Intangible Heritage Convention takes the risk of becoming a legitimizing instrument for groups and communities claimingexclusive rights and values in competition with others. The protection of cultural traditions and expressions might then lead to the result that what is safeguarded as intangible heritage may actually be a community’s nostalgic brand identity, whereas such community values might at the same time be framed by populist governments and movements as being threatened by precisely the kind of cultural diversity, or the “creolization of the world”,3 which the Convention should help to support.

Summary The capacity to regenerate damaged tissues, such as the heart, various enormously amongst species. While heart regeneration is generally very low in mammals 1–3, it can regenerate efficiently in certain amphibian and fish species 4,5. Zebrafish has been used extensively to study heart regeneration, resulting in the identification of proliferating cardiomyocytes that drive this process 5–7. However, mechanisms that drive cardiomyocyte proliferation are largely unknown. Here, using a single-cell mRNA-sequencing approach, we find a transcriptionally distinct population of dedifferentiated and proliferating cardiomyocytes in regenerating zebrafish hearts. While adult cardiomyocytes are known to rely on mitochondrial oxidative phosphorylation (OXPHOS) for energy production, these proliferating cardiomyocytes show reduced mitochondrial gene expression and decreased OXPHOS activity. Strikingly, we find that genes encoding rate-limiting enzymes of the glycolysis pathway are induced in the proliferating cardiomyocytes, and inhibiting glycolysis impairs cardiomyocyte cell cycle reentry. Mechanistically, glycolytic gene expression is induced by Nrg1/Erbb2 signaling, and this is conserved in a mouse model of enhanced regeneration. Moreover, inhibiting glycolysis in murine cardiomyocytes abrogates the mitogenic effects of Nrg1/ErbB2 signaling. Together these results reveal a conserved mechanism in which cardiomyocytes undergo metabolic reprogramming by activating glycolysis, which is essential for cell cycle reentry and heart regeneration. This could ultimately help develop therapeutic interventions that promote the regenerative capacity of the mammalian heart.

Background: Reactive oxygen species (ROS) play a crucial role in the pathogenesis of pulmonary arterial hypertension (PAH). Monoamine oxidases (MAO), a class of enzymes located in the outer mitochondrial membrane, are important ROS sources. Increased MAO-A expression in endothelial cells and cardiomyocytes was found to contribute to vascular dysfunction and left heart failure. MAO-A inhibition can improve vascular dysfunction and heart failure. Collectively, given the effects of MAO-A on both vascular and cardiac function, we hypothesized that inhibition of MAO-A can be used to treat PAH. Methods: PAH was induced in male Sprague-Dawley rats by a single injection of SU5416 (25 mg/kg) followed by 4-weeks exposure to hypoxia and 2-weeks of normoxia. At week 8, animals were randomized to receive either intraperitoneal injection of saline or the MAO-A inhibitor clorgyline 10 mg/kg, followed by 2 mg/kg every 3 days until week 10. Echocardiography and RV catheterization was performed at week 10 and heart and lung tissues were collected for further analysis. Results: Compared to the vehicle group, clorgyline treatment reduced right ventricular (RV) systolic pressure and RV afterload. Moreover, clorgyline improved RV function by reducing RV hypertrophy and stiffness. Further tissue analysis by histology revealed that clorgyline reduced pulmonary vascular remodeling by reducing intima layer thickness. Conclusion: Clorgyline partly reversed RV systolic pressure and RV afterload in established experimental PAH. Together with the observed reduced RV remodeling, MAO-A inhibition may be a promising intervention for PAH.

The memory of the War is not only a national phenomenon. Rightly because of its international character, transnational memory offers space for nuances and contradictions. We should be aware, however, for a political use of the past.

To the Editor: We previously described a multiplex liquid chromatography–mass spectrometry (LC-MS)1 method for the quantification of 6 apolipoproteins (apo): A-I, B, C-I, C-II, C-III, and E (1). Analytical method validation was performed according to the Clinical and Laboratory Standards Institute (CLSI) protocols, and the intraassay CVs were 2.3% to 5.5% and total CVs were 2.5% to 5.9%. Moreover, results were interchangeable with immunoturbidimetric assays for apo A-I (Deming slope, 1.014) and for apo B-100 (Deming slope, 1.016) (1). Our laboratory-developed test has now been used intermittently during a 2-year period in various studies on clinical cohorts. Here we demonstrate the robustness and analytical performance of mass spectrometry-based apolipoprotein quantification using stable isotope dilution and multiple reaction monitoring (SID-MRM) on a triple quadrupole for routine practice in clinical laboratories. To evaluate performance of the LC-MS test with regard to precision and bias of test results, 2 native serum pools were included as internal quality control (QC) on each of the 96-well plate batches analyzed (both in triplicate) over this period. The measurements were compared with assigned values to assess bias and precision by analysis of repeated QC observations in …

Purpose: The aims of this study were (i) to design a new high-dose-rate (HDR) brachytherapy applicator for treating surface lesions with planning target volumes larger than 3 cm in diameter and up to 5 cm in size, using the microSelectron-HDR or Flexitron afterloader (Elekta Brachytherapy) with a 192Ir source; (ii) to calculate by means of the Monte Carlo(MC) method the dose distribution for the new applicator when it is placed against a water phantom; and (iii) to validate experimentally the dose distributions in water. Methods: The penelope2008MC code was used to optimize dwell positions and dwell times. Next, the dose distribution in a water phantom and the leakage dose distribution around the applicator were calculated. Finally, MC data were validated experimentally for a 192Ir mHDR-v2 source by measuring (i) dose distributions with radiochromic EBT3 films (ISP); (ii) percentage depth–dose (PDD) curve with the parallel-plate ionization chamber Advanced Markus (PTW); and (iii) absolute dose rate with EBT3 films and the PinPoint T31016 (PTW) ionization chamber. Results: The new applicator is made of tungsten alloy (Densimet) and consists of a set of interchangeable collimators. Three catheters are used to allocate the source at prefixed dwell positions with preset weights to produce a homogenous dose distribution at the typical prescription depth of 3 mm in water. The same plan is used for all available collimators. PDD, absolute dose rate per unit of air kerma strength, and off-axis profiles in a cylindrical water phantom are reported. These data can be used for treatment planning. Leakage around the applicator was also scored. The dose distributions, PDD, and absolute dose rate calculated agree within experimental uncertainties with the doses measured: differences of MC data with chamber measurements are up to 0.8% and with radiochromic films are up to 3.5%. Conclusions: The new applicator and the dosimetric data provided here will be a valuable tool in clinical practice, making treatment of large skin lesions simpler, faster, and safer. Also the dose to surrounding healthy tissues is minimal.

V̇o2 maxduring whole body exercise is presumably constrained by oxygen delivery to mitochondria rather than by mitochondria's ability to consume oxygen. Humans and animals have been reported to exploit only 60-80% of their mitochondrial oxidative capacity at maximal oxygen uptake (V̇o2 max). However, ex vivo quantification of mitochondrial overcapacity is complicated by isolation or permeabilization procedures. An alternative method for estimating mitochondrial oxidative capacity is via enzyme histochemical quantification of succinate dehydrogenase (SDH) activity. We determined to what extent V̇o2 maxattained during cycling exercise differs from mitochondrial oxidative capacity predicted from SDH activity of vastus lateralis muscle in chronic heart failure patients, healthy controls, and cyclists. V̇o2 maxwas assessed in 20 healthy subjects and 28 cyclists, and SDH activity was determined from biopsy cryosections of vastus lateralis using quantitative histochemistry. Similar data from our laboratory of 14 chronic heart failure patients and 6 controls were included. Mitochondrial oxidative capacity was predicted from SDH activity using estimated skeletal muscle mass and the relationship between ex vivo fiber V̇o2 maxand SDH activity of isolated single muscle fibers and myocardial trabecula under hyperoxic conditions. Mitochondrial oxidative capacity predicted from SDH activity was related ( r2= 0.89, P < 0.001) to V̇o2 maxmeasured during cycling in subjects with V̇o2 maxranging from 9.8 to 79.0 ml·kg−1·min−1. V̇o2 maxmeasured during cycling was on average 90 ± 14% of mitochondrial oxidative capacity. We conclude that human V̇o2 maxis related to mitochondrial oxidative capacity predicted from skeletal muscle SDH activity. Mitochondrial oxidative capacity is likely marginally limited by oxygen supply to mitochondria.