Systems approach to the study of stretch and arrhythmias in right ventricular failure induced in rats by monocrotaline.

We demonstrate the synergistic benefits of using multiple technologies to investigate complex multi-scale biological responses. The combination of reductionist and integrative methodologies can reveal novel insights into mechanisms of action by tracking changes of in vivo phenomena to alterations in protein activity (or vice versa). We have applied this approach to electrical and mechanical remodelling in right ventricular failure caused by monocrotaline-induced pulmonary artery hypertension in rats. We show arrhythmogenic T-wave alternans in the ECG of conscious heart failure animals. Optical mapping of isolated hearts revealed discordant action potential duration (APD) alternans. Potential causes of the arrhythmic substrate; structural remodelling and/or steep APD restitution and dispersion were observed, with specific remodelling of the Right Ventricular Outflow Tract. At the myocyte level, [Ca(2+)]i transient alternans were observed together with decreased activity, gene and protein expression of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA). Computer simulations of the electrical and structural remodelling suggest both contribute to a less stable substrate. Echocardiography was used to estimate increased wall stress in failure, in vivo. Stretch of intact and skinned single myocytes revealed no effect on the Frank-Starling mechanism in failing myocytes. In isolated hearts acute stretch-induced arrhythmias occurred in all preparations. Significant shortening of the early APD was seen in control but not failing hearts. These observations may be linked to changes in the gene expression of candidate mechanosensitive ion channels (MSCs) TREK-1 and TRPC1/6. Computer simulations incorporating MSCs and changes in ion channels with failure, based on altered gene expression, largely reproduced experimental observations

Rapid quantification of myocardial fibrosis: a new macro-based automated analysis

Background: Fibrosis is associated with various cardiac pathologies and dysfunction. Current quantification methods are time-consuming and laborious. We describe a semi-automated quantification technique for myocardial fibrosis and validated this using traditional methods

Therapeutic efficacy of TBC3711 in monocrotaline-induced pulmonary hypertension

Background: Endothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension. Although different endothelin-A receptor antagonists are developed, a novel therapeutic option to cure the disease is still needed. This study aims to investigate the therapeutic efficacy of the selective endothelin-A receptor antagonist TBC3711 in monocrotaline-induced pulmonary hypertension in rats. Methods: Monocrotaline-injected male Sprague-Dawley rats were randomized and treated orally from day 21 to 35 either with TBC3711 (Dose: 30 mg/kg body weight/day) or placebo. Echocardiographic measurements of different hemodynamic and right-heart hypertrophy parameters were performed. After day 35, rats were sacrificed for invasive hemodynamic and right-heart hypertrophy measurements. Additionally, histologic assessment of pulmonary vascular and right-heart remodelling was performed. Results: The novel endothelin-A receptor antagonist TBC3711 significantly attenuated monocrotaline-induced pulmonary hypertension, as evident from improved hemodynamics and right-heart hypertrophy in comparison with placebo group. In addition, muscularization and medial wall thickness of distal pulmonary vessels were ameliorated. The histologic evaluation of the right ventricle showed a significant reduction in fibrosis and cardiomyocyte size, suggesting an improvement in right-heart remodelling. Conclusion: The results of this study suggest that the selective endothelin-A receptor antagonist TBC3711 demonstrates therapeutic benefit in rats with established pulmonary hypertension, thus representing a useful therapeutic approach for treatment of pulmonary hypertension

The role of pulmonary arterial stiffness in COPD

AbstractCOPD is the second most common cause of pulmonary hypertension, and is a common complication of severe COPD with significant implications for both quality of life and mortality. However, the use of a rigid diagnostic threshold of a mean pulmonary arterial pressure (mPAP) of ≥25mHg when considering the impact of the pulmonary vasculature on symptoms and disease is misleading. Even minimal exertion causes oxygen desaturation and elevations in mPAP, with right ventricular hypertrophy and dilatation present in patients with mild to moderate COPD with pressures below the threshold for diagnosis of pulmonary hypertension. This has significant implications, with right ventricular dysfunction associated with poorer exercise capability and increased mortality independent of pulmonary function tests.The compliance of the pulmonary artery (PA) is a key component in decoupling the right ventricle from the pulmonary bed, allowing the right ventricle to work at maximum efficiency and protecting the microcirculation from large pressure gradients. PA stiffness increases with the severity of COPD, and correlates well with the presence of exercise induced pulmonary hypertension. A curvilinear relationship exists between PA distensibility and mPAP and pulmonary vascular resistance (PVR) with marked loss of distensibility before a rapid rise in mPAP and PVR occurs with resultant right ventricular failure. This combination of features suggests PA stiffness as a promising biomarker for early detection of pulmonary vascular disease, and to play a role in right ventricular failure in COPD. Early detection would open this up as a potential therapeutic target before end stage arterial remodelling occurs

Czasopismo „Uzwyszsza” 1944 jako unikat archiwalny

Тэкст артыкула прысвечаны аднаўленню гісторыі стварэння і апісанню адзінага вядомага на сёння асобніка часопіса “Узвышша”, які рыхтаваўся да друку ў Мінску ў 1944 г. у часе нямецкай акупацыі. Стваральнікам гэтага амаль невядомага спецыялістам выдання выступіла Беларускае культурнае згуртаванне, заснаванае ў 1944 г. Галоўным рэдактарам стаў пісьменнік Юрка Віцьбіч, былы сябра літаратурнага аб’яднання “Узвышша”, што дзейнічала ў БССР у 1926—1931 гг. Апошняе і перадвызначыла тое, што адроджаны ў часы акупацыі літаратурны часопіс таксама атрымаў назву “Узвышша” і ўспрымаўся стваральнікам як працяг таго, рэпрэсаванага савецкімі ўладамі таварыства і часопіса. Часопіс “Узвышша” ў 1944 г. не паспеў пабачыць свет. Застаўся толькі адзіны вядомы на сёння няпоўны нумар, прызначаны для карэктуры, які захоўваецца ў Беларускім дзяржаўным архіве-музеі літаратуры і мастацтва. Яго змест дазваляе ацаніць асаблівасці літаратурнага працэсу ў часы нямецкай акупацыі.Text of the article is dedicated to the history and description of a single known issue of the magazine “Uzvyshsha” which was going to publish in Minsk in 1944, during the German occupation. This almost unknown for specialists periodical was created by Belarusian Cultural Association, founded in 1944. The chief editor of the magazine was a writer Yuri Vitbich, a former member of the Literary Association “Uzvyshsha” acting in the Byelorussian SSR in 1926-1931. That`s why the revived during the occupation literary magazine was also called “Uzvyshsha” and was seen by the creators as a continuation of the periodical had been earlier repressed by the Soviet regime. Magazine “Uzvyshsha” wasn`t published in 1944. There is only one non completed copy assigned for proofreading. It is in Belarusan State Archive-Museum of Literature and Art. The magazine`s content permits to study features of the literary process during the German occupation.W artykule przedstawiona została historia powstania jedynego znanego dziś egzemplarza czasopisma „Uzwyszsza”, który był przygotowywany do druku w Mińsku  w 1944 roku, w czasie okupacji niemieckiej. Jego inicjatorem było Białoruskie Stowarzyszenie Kulturalne założone w 1944 roku. Głównym redaktorem wydania był pisarz Jurka Wićbicz, były członek stowarzyszenia literackiego „Uzwyszsza”, działającego w BSRR w latach 1926-1931, co wpłynęło na fakt, że odrodzone w czasach okupacji czasopismo literackie także otrzymało nazwę „Uzwyszsza” i było postrzegane przez twórców jako kontynuacja tego represjonowanego przez władze radzieckie ugrupowania i periodyku. Czasopismo „Uzwyszsza” w 1944 roku nie zostało jednak opublikowane. Zachował się tylko jeden znany na dzień dzisiejszy niepełny numer przeznaczony do korekty, który przechowywany jest w Białoruskim Państwowym Archiwum-Muzeum Literatury i Sztuki. Jego treść pozwala ocenić specyfikę procesu literackiego w okresie okupacji niemieckiej