Editorial: Myocardial fibrosis: What we know now.

Worldwide, cardiovascular diseases affect millions, cause serious economic burdens, and represent the number one cause of death. A broad range of pathological cardiac conditions is associated with myocardial tissue remodeling and fibrosis. Cardiac fibrosis reflects the exaggerated accumulation of extracellular matrix components, and activation of stromal cell compartments in the tissue, followed by acute or chronic inflammatory responses (see the Figure 1). Progressive cardiac fibrosis has been recognized to cause life-threatening arrhythmias. The development of life-saving therapeutic strategies and new medications requires extensive scientific efforts to understand the pathophysiology of pro-arrhythmogenic fibrosis, which is currently poorly understood. Understanding the cellular and molecular roots of cardiac fibrogenesis is crucial for identifying potential diagnostic and therapeutic targets in cardiovascular diseases. The aim of this Research Topic is a wide-ranging overview of the current understanding of the mechanisms of myocardial fibrosis across diverse cardiovascular disorders and its evaluation in patients

Pathophysiology and diagnosis of cancer drug induced cardiomyopathy

The clinical manifestations of anti-cancer drug associated cardiac side effects are diverse and can range from acutely induced cardiac arrhythmias to Q-T interval prolongation, changes in coronary vasomotion with consecutive myocardial ischemia, myocarditis, pericarditis, severe contractile dysfunction, and potentially fatal heart failure. The pathophysiology of these adverse effects is similarly heterogeneous and the identification of potential mechanisms is frequently difficult since the majority of cancer patients is not only treated with a multitude of cancer drugs but might also be exposed to potentially cardiotoxic radiation therapy. Some of the targets inhibited by new anti-cancer drugs also appear to be important for the maintenance of cellular homeostasis of normal tissue, in particular during exposure to cytotoxic chemotherapy. If acute chemotherapy-induced myocardial damage is only moderate, the process of myocardial remodeling can lead to progressive myocardial dysfunction over years and eventually induce myocardial dysfunction and heart failure. The tools for diagnosing anti-cancer drug associated cardiotoxicity and monitoring patients during chemotherapy include invasive and noninvasive techniques as well as laboratory investigations and are mostly only validated for anthracycline-induced cardiotoxicity and more recently for trastuzumab-associated cardiac dysfunctio

The Bland-Altman method should not be used when one of the two measurement methods has negligible measurement errors.

The Bland-Altman limits of agreement (LoA) method is almost universally used to compare two measurement methods when the outcome is continuous, despite warnings regarding the often-violated strong underlying statistical assumptions. In settings where only a single measurement per individual has been performed and one of the two measurement methods is exempt (or almost) from any measurement error, the LoA method provides biased results, whereas this is not the case for linear regression. Thus, our goal is to explain why this happens and illustrate the advantage of linear regression in this particular setting. For our illustration, we used two data sets: a sample of simulated data, where the truth is known, and data from a validation study on the accuracy of a smartphone image-based dietary intake assessment tool. Our results show that when one of the two measurement methods is exempt (or almost) from any measurement errors, the LoA method should not be used as it provides biased results. In contrast, linear regression of the differences on the precise method was unbiased. The LoA method should be abandoned in favor of linear regression when one of the two measurement methods is exempt (or almost) from measurement errors

Selection in monoculture vs. mixture alters plant metabolic fingerprints

Aims In grassland biodiversity experiments, positive biodiversity effects on primary productivity increase over time. Recent research has shown that differential selection in monoculture and mixed-species communities leads to the rapid emergence of monoculture and mixture types, adapted to their own biotic community. We used eight plant species selected for 8 years in such a biodiversity experiment to test if monoculture and mixture types differed in metabolic profiles using infrared spectroscopy. Methods Fourier transform infrared spectroscopy (FTIR) was used to assess metabolic fingerprints of leaf samples of 10 individuals of each species from either monocultures or mixtures. The FTIR spectra were analyzed using multivariate procedures to assess (i) whether individuals within species could be correctly assigned to monoculture or mixture history based on the spectra alone and (ii) which parts of the spectra drive the group assignment, i.e. which metabolic groups were subject to differential selection in monocultures vs. mixtures. Important Findings Plant individuals within each of the eight species could be classified as either from monoculture or mixture selection history based on their FTIR spectra. Different metabolic groups were differentially selected in the different species; some of them may be related to defense of pathogens accumulating more strongly in monocultures than in mixtures. The rapid selection of the monoculture and mixture types within the eight study species could have been due to a sorting-out process based on large initial genetic or epigenetic variation within the specie

«Verstehe ich dich, verstehst du mich?» – interprofessionelle Kommunikation von Studierenden im Fokus : ein Forschungsprojekt im Rahmen der ZIPAS® Sigg

Das Ziel dieser Arbeit ist herauszufinden, welche unterstützenden und hemmenden Faktoren in der Kommunikation zwischen Studierenden im interprofessionellen Team der ZIPAS® auftreten und wie die Zufriedenheit der Studierenden beeinflusst wird. Daraus ergibt sich folgende Fragestellung: Was unterstützt und/oder hemmt Studierende in der Kommunikation bei der Besprechung von Patient*innen im interprofessionellen Team der Zürcher interprofessionellen klinischen Ausbildungsstationen? Um die Fragestellung beantworten zu können, wurden Daten von ZIPAS®-Durchläufen aus vier Spitälern im Kanton Zürich verwendet. Aus diesen Durchläufen wurden sieben semi-strukturierte Prä-Forschungsgruppeninterviews mithilfe von Codierungen retrospektiv ausgewertet. Weiter wurden Logbücher, welche von Studierenden und Facilitator*innen ausgefüllt wurden, mit den Interviewdaten verglichen. Aus den Ergebnissen wird ersichtlich, dass das Zeitmanagement und die Organisationsstrukturen Herausforderungen in ZIPAS®-Durchläufen darstellen. Gesamthaft zeigt sich, dass sich das Rollenverständnis durch die gemeinsam genutzten Räume und das miteinander Lernen verbessert. Das erhöhte Rollenverständnis führt zu einer klareren interprofessionellen Kommunikation und einer besseren Zusammenarbeit. Deshalb entstehen weniger Missverständnisse, was sich positiv auf die Zufriedenheit der Studierenden auswirkt. Der Zusammenhang zwischen Rollenverständnis und Lernen bedarf an weiterer Forschung

Effects of doxorubicin cancer therapy on autophagy and the ubiquitin-proteasome system in long-term cultured adult rat cardiomyocytes

The clinical use of anthracyclines in cancer therapy is limited by dose-dependent cardiotoxicity that involves cardiomyocyte injury and death. We have tested the hypothesis that anthracyclines affect protein degradation pathways in adult cardiomyocytes. To this aim, we assessed the effects of doxorubicin (Doxo) on apoptosis, autophagy and the proteasome/ubiquitin system in long-term cultured adult rat cardiomyocytes. Accumulation of poly-ubiquitinated proteins, increase of cathepsin-D-positive lysosomes and myofibrillar degradation were observed in Doxo-treated cardiomyocytes. Chymotrypsin-like activity of the proteasome was initially increased and then inhibited by Doxo over a time-course of 48 h. Proteasome 20S proteins were down-regulated by higher doses of Doxo. The expression of MURF-1, an ubiquitin-ligase specifically targeting myofibrillar proteins, was suppressed by Doxo at all concentrations measured. Microtubule-associated protein1 light chain 3B (LC3)-positive punctae and both LC3-I and -II proteins were induced by Doxo in a dose-dependent manner, as confirmed by using lentiviral expression of green fluorescence protein bound to LC3 and live imaging. The lysosomotropic drug chloroquine led to autophagosome accumulation, which increased with concomitant Doxo treatment indicating enhanced autophagic flux. We conclude that Doxo causes a downregulation of the protein degradation machinery of cardiomyocytes with a resulting accumulation of poly-ubiquitinated proteins and autophagosomes. Although autophagy is initially stimulated as a compensatory response to cytotoxic stress, it is followed by apoptosis and necrosis at higher doses and longer exposure times. This mechanism might contribute to the late cardiotoxicity of anthracyclines by accelerated aging of the postmitotic adult cardiomyocytes and to the susceptibility of the aging heart to anthracycline cancer therap

The role of cell death and myofibrillar damage in contractile dysfunction of long-term cultured adult cardiomyocytes exposed to doxorubicin

In failing hearts cardiomyocytes undergo alterations in cytoskeleton structure, contractility and viability. It is not known presently, how stress-induced changes of myofibrils correlate with markers for cell death and contractile function in cardiomyocytes. Therefore, we have studied the progression of contractile dysfunction, myofibrillar damage and cell death in cultured adult cardiomyocytes exposed to the cancer therapy doxorubicin. We demonstrate, that long-term cultured adult cardiomyocytes, a well-established model for the study of myofibrillar structure and effects of growth factors, can also be used to assess contractility and calcium handling. Adult rat ventricular myocytes (ARVM) were isolated and cultured for a total of 14days in serum containing medium. The organization of calcium-handling proteins and myofibrillar structure in freshly isolated and in long-term cultured adult cardiomyocytes was studied by immunofluorescence and electron microscopy. Excitation contraction-coupling was analyzed by fura 2 and video edge detection in electrically paced cardiomyocytes forming a monolayer, and cell death and viability was measured by TUNEL assay, LDH release, MTT assay, and Western blot for LC3. Adult cardiomyocytes treated with Doxo showed apoptosis and necrosis only at supraclinical concentrations. Treated cells displayed merely alterations in cytoskeleton organization and integrity concomitant with contractile dysfunction and up-regulation of autophagosome formation, but no change in total sarcomeric protein content. We propose, that myofibrillar damage contributes to contractile dysfunction prior to cell death in adult cardiomyocytes exposed to clinically relevant concentrations of anthracycline