Local hyperactivation of L-type Ca2+ channels increases spontaneous Ca2+ release activity and cellular hypertrophy in right ventricular myocytes from heart failure rats

Right ventricle (RV) dysfunction is an independent predictor of patient survival in heart failure (HF). However, the mechanisms of RV progression towards failing are not well understood. We studied cellular mechanisms of RV remodelling in a rat model of left ventricle myocardial infarction (MI)-caused HF. RV myocytes from HF rats show significant cellular hypertrophy accompanied with a disruption of transverse-axial tubular network and surface flattening. Functionally these cells exhibit higher contractility with lower Ca2+ transients. The structural changes in HF RV myocytes correlate with more frequent spontaneous Ca2+ release activity than in control RV myocytes. This is accompanied by hyperactivated L-type Ca2+ channels (LTCCs) located specifically in the T-tubules of HF RV myocytes. The increased open probability of tubular LTCCs and Ca2+ sparks activation is linked to protein kinase A-mediated channel phosphorylation that occurs locally in T-tubules. Thus, our approach revealed that alterations in RV myocytes in heart failure are specifically localized in microdomains. Our findings may indicate the development of compensatory, though potentially arrhythmogenic, RV remodelling in the setting of LV failure. These data will foster better understanding of mechanisms of heart failure and it could promote an optimized treatment of patients

Local hyperactivation of L-type Ca2+ channels increases spontaneous Ca2+ release activity and cellular hypertrophy in right ventricular myocytes from heart failure rats

Right ventricle (RV) dysfunction is an independent predictor of patient survival in heart failure (HF). However, the mechanisms of RV progression towards failing are not well understood. We studied cellular mechanisms of RV remodelling in a rat model of left ventricle myocardial infarction (MI)-caused HF. RV myocytes from HF rats show significant cellular hypertrophy accompanied with a disruption of transverse-axial tubular network and surface flattening. Functionally these cells exhibit higher contractility with lower Ca2+ transients. The structural changes in HF RV myocytes correlate with more frequent spontaneous Ca2+ release activity than in control RV myocytes. This is accompanied by hyperactivated L-type Ca2+ channels (LTCCs) located specifically in the T-tubules of HF RV myocytes. The increased open probability of tubular LTCCs and Ca2+ sparks activation is linked to protein kinase A-mediated channel phosphorylation that occurs locally in T-tubules. Thus, our approach revealed that alterations in RV myocytes in heart failure are specifically localized in microdomains. Our findings may indicate the development of compensatory, though potentially arrhythmogenic, RV remodelling in the setting of LV failure. These data will foster better understanding of mechanisms of heart failure and it could promote an optimized treatment of patients

Functional LTCC-β₂AR complex needs Caveolin-3 and is disrupted in heart failure

Background: Beta-2 adrenergic receptors (β2ARs) but not beta-2 adrenergic receptors (β1ARs) form a functional complex with L-type Ca2+ channels (LTCCs) on the cardiomyocyte membrane. However, how microdomain localization in the plasma membrane affects the function of these complexes is unknown. We aim to study the coupling between LTCC and β adrenergic receptors in different cardiomyocyte microdomains, the distinct involvement of PKA and CAMKII (Ca2+/calmodulin-dependent protein kinase II) and explore how this functional complex is disrupted in heart failure. Methods: Global signaling between LTCCs and β adrenergic receptors was assessed with whole-cell current recordings and western blot analysis. Super-resolution scanning patch-clamp was used to explore the local coupling between single LTCCs and β1AR or β2AR in different membrane microdomains in control and failing cardiomyocytes. Results: LTCC open probability (Po) showed an increase from 0.054±0.003 to 0.092±0.008 when β2AR was locally stimulated in the proximity of the channel (<350 nm) in the transverse tubule microdomain. In failing cardiomyocytes, from both rodents and humans, this transverse tubule coupling between LTCC and β2AR was lost. Interestingly, local stimulation of β1AR did not elicit any change in the Po of LTCCs, indicating a lack of proximal functional interaction between the two, but we confirmed a general activation of LTCC via β1AR. By using blockers of PKA and CaMKII and a Caveolin-3-knockout mouse model, we conclude that the β2AR-LTCC regulation requires the presence of caveolin-3 and the activation of the CaMKII pathway. By contrast, at a cellular “global” level PKA plays a major role downstream β1AR and results in an increase in LTCC current. Conclusions: Regulation of the LTCC activity by proximity coupling mechanisms occurs only via β2AR, but not β1AR. This may explain how β2ARs tune the response of LTCCs to adrenergic stimulation in healthy conditions. This coupling is lost in heart failure; restoring it could improve the adrenergic response of failing cardiomyocytes

ЗНАЧЕНИЕ ИНТЕГРИРОВАННОГО ЛЕГОЧНОГО ИНДЕКСА В ОЦЕНКЕ ТЯЖЕСТИ ТЕЧЕНИЯ ПОСЛЕОПЕРАЦИОННОГО ПЕРИОДА ПРИ АОРТОКОРОНАРНОМ ШУНТИРОВАНИИ НА РАБОТАЮЩЕМ СЕРДЦЕ

Forty patients after elective off-pump coronary artery bypass grafting (OPCAB) were enrolled into a prospective observational study and monitored using SpO2, EtCO2, pulse rate and respiratory rate. In addition, the Integrated Pulmonary Index (IPI, CapnostreamTM 20p, Covidien) was registered prior tracheal extubation and at 2, 6, 12, and 18 hrs after extubation. The hemodynamics was monitored using continuous non-invasive cardiac index (esCCO, Nihon Kohden) and left ventricular ejection fraction (EF) before and after the intervention. The value of IPI registered during the respiratory support correlated with cardiac index (p = 0.04). In the subgroup of the patients with IPI below 8 at 2 hrs after extubation, we found lower ejection fraction (p = 0.007). In addition, the IPI value ≤ 9 was a predictor of complicated early postoperative period (AUC = 0,7; p = 0, 04). Thus, IPI reflects the hemodynamic status and the course of postoperative stay after OPCAB. У 40 пациентов после аортокоронарного шунтирования (АКШ) на работающем сердце на фоне респираторной поддержки и после экстубации трахеи осуществляли мониторинг газового состава артериальной крови, SpO2 , EtCO2 , частоты дыханий, частоты пульса и интегрированного легочного индекса (IPI, CapnostreamTM 20p, Covidien). Мониторинг показателей гемодинамики включал непрерывную регистрацию сердечного индекса (СИ) (esCCO, Nihon Kohden) и оценку фракции изгнания левого желудочка (ФИлж) до и после операции. Значение IPI, зарегистрированное на фоне респираторной поддержки в отделении реанимации, коррелировало с СИ (p = 0,04), а значение IPI &lt;  8 через 2 ч после экстубации ассоциировалось с более низкой ФИлж после операции (p = 0,007). Кроме того, значения IPI &lt; 8 через 2 ч после экстубации ассоциировалось с более низкой ФИлжпосле операции (p = 0,007). Кроме того, значения IPI ≤ 9 через 6 ч после экстубации трахеи выступили как пре- диктор осложненного течения раннего послеоперационного периода (AUC = 0,7 p = 0,04). Таким образом, показатель IPI отражает состояние гемодинамики и тяжесть течения послеоперацион- ного периода при АКШ на работающем сердце. Ключевые слова: послеоперационная дыхательная недостаточность, аортокоронарное шунтирование, мониторинг.&gt;≤  9 через 6 ч после экстубации трахеи выступили как пре- диктор осложненного течения раннего послеоперационного периода (AUC = 0,7 p = 0,04). Таким образом, показатель IPI отражает состояние гемодинамики и тяжесть течения послеоперационного периода при АКШ на работающем сердце.

Дослідження резервів економічного розвитку підприємств готельноресторанного господарства методом системного аналізу

The purpose of the research. The purpose of this paper is the determination based on the method of system analysis of reserves of economic development of the enterprises of hotel and restaurant services by constructing multiple regression models of industrial and commercial activities and calculation on the basis of factors that characterize development reserves resource potentials and directions of growth of efficiency of business entities. Methodology. The methodology is based on the fundamentals of business Economics, econometrics, mathematical statistics, and publications of domestic and foreign scientists on the problems of economic development of enterprises. To identify, assess and substantiate the results of the study used methods of theoretical justification, grouping, economic-mathematical modeling, factorial, statistical, stochastic, correlation and regression analysis, etc. Results. In the work on the basis of the objective function the model of multiple regression of industrial and commercial activities, which mathematically described the communication patterns and quantitative relationships of its elements (factors or input intensities), defined a differentiated and integrated the impact of costs of operating activities on the profitability of hotel and restaurant management. By calculating βKi-coefficients set share changes standard deviation values of the resultant variable due to changes in relevant economic indicators regression equation on the value of its standard deviation. According to the calculated βKicoefficients that characterize the degree of a variation factor parameter defined by reserves economic development and possibilities of improving the productive performance of enterprises, as reflected in economic and mathematical models. It is proved that the increase in the costs of labor resource development and administrative expenses increases the level of income of the enterprise, and the increase of material costs and expenses on the basic production funds have a negative impact on the efficiency of functioning and, consequently, the development of economic entities. It has also been found that the largest reserves for raising the income level of the hotel and restaurant business are laid down in the cost of OVF and administrative and marketing activities. Practical meaning. The proposed research method-ology was used in forecasting and planning the results of the enterprises. The prospects for further research are to identify trends and to form an effective mechanism for sustainable economic development of hotel and restaurant businesses.Мета дослідження. Метою статті є визначення на основі методу системного аналізу резервів економічного розвитку підприємств готельно-ресторанного господарства шляхом побудови моделі множинної регресії виробничо-комерційної діяльності та розрахунку на її основі коефіцієнтів, що характеризують резерви розвитку ресурсних потенціалів і напрями зростання ефективності суб’єктів господарювання. Методологія. Методологія дослідження базується на фундаментальних положеннях економіки підприємства, економетрики, математичної статистики, а також публікаціях вітчизняних і зарубіжних учених з проблематики економічного розвитку підприємств. Для визначення, оцінки та обґрунтування результатів дослідження використано методи теоретичного обґрунтування, групування, економікоматематичного моделювання, факторного, статистичного, стохастичного, кореляційнорегресійного аналізу та ін. Результати. У роботі на основі функції цілі побудовано модель множинної регресії виробничо-комерційної діяльності, за допомогою якої математично описано закономірності взаємодії та кількісного взаємозв’язку її складових елементів (факторів впливу або показників витратомісткості), визначено диференційований та інтегрований вплив витрат з операційної діяльності на рівень доходності підприємства готельно-ресторанного господарства. Шляхом розрахунку βKi-коефіцієнтів встановлено частку зміни середньоквадратичного відхилення значення результативної ознаки за рахунок зміни відповідного економічного показника регресійного рівняння на величину його середньоквадратичного відхилення. За розрахованими βKi-коефіцієнтами, які характеризують ступінь варіювання факторного параметра, визначено резерви економічного розвитку і встановлені можливості щодо поліпшення результативного показника діяльності підприємства, відображеного в економіко-математичній моделі. Доведено, що збільшення витрат на розвиток ресурсу праці й витрат на адміністративнозбутову діяльність підвищують рівень доходу підприємства, а зростання матеріальних витрат і витрат на основні виробничі фонди надають негативного впливу на ефективність функціонування, а отже, і розвиток суб’єктів господарювання. Також встановлено, що найбільш крупні резерви підвищення рівня доходу підприємств готельно-ресторанного господарства закладені у витратах на ОВФ і адміністративно-збутову діяльність. Практичне значення. Запропоновану методологію дослідження використано у прогнозуванні та плануванні результатів діяльності підприємств. Перспективи подальших досліджень полягають у встановленні трендів і формуванні ефективного механізму сталого економічного розвитку підприємств готельно-ресторанного господарства

THE VALUE OF INTEGRATED PULMONARY INDEX IN ASSESSMENT OF POSTOPERATIVE PERIOD AFTER OFF-PUMP CORONARY ARTERY BYPASS GRAFTING

Forty patients after elective off-pump coronary artery bypass grafting (OPCAB) were enrolled into a prospective observational study and monitored using SpO2, EtCO2, pulse rate and respiratory rate. In addition, the Integrated Pulmonary Index (IPI, CapnostreamTM 20p, Covidien) was registered prior tracheal extubation and at 2, 6, 12, and 18 hrs after extubation. The hemodynamics was monitored using continuous non-invasive cardiac index (esCCO, Nihon Kohden) and left ventricular ejection fraction (EF) before and after the intervention. The value of IPI registered during the respiratory support correlated with cardiac index (p = 0.04). In the subgroup of the patients with IPI below 8 at 2 hrs after extubation, we found lower ejection fraction (p = 0.007). In addition, the IPI value ≤ 9 was a predictor of complicated early postoperative period (AUC = 0,7; p = 0, 04). Thus, IPI reflects the hemodynamic status and the course of postoperative stay after OPCAB

Pulmonary Hypertension-Associated Right Ventricular Cardiomyocyte Remodelling Reduces Treprostinil Function

(1) Pulmonary hypertension (PH)-associated right ventricular (RV) failure is linked to a reduction in pulmonary vasodilators. Treprostinil has shown effectiveness in PAH patients with cardiac decompensation, hinting at potential cardiac benefits. We investigated treprostinil’s synergy with isoprenaline in RV and LV cardiomyocytes. We hypothesised that disease-related RV structural changes in cardiomyocytes would reduce contractile responses and cAMP/PKA signalling activity. (2) We induced PH in male Sprague Dawley rats using monocrotaline and isolated their ventricular cardiomyocytes. The effect of in vitro treprostinil and isoprenaline stimulation on contraction was assessed. FRET microscopy was used to study PKA activity associated with treprostinil stimulation in AKAR3-NES FRET-based biosensor-expressing cells. (3) RV cells exhibited maladaptive remodelling with hypertrophy, impaired contractility, and calcium transients compared to control and LV cardiomyocytes. Combining treprostinil and isoprenaline failed to enhance inotropy in PH RV cardiomyocytes. PH RV cardiomyocytes displayed an aberrant contractile behaviour, which the combination treatment could not rectify. Finally, we observed decreased PKA activity in treprostinil-treated PH RV cardiomyocytes. (4) PH-associated RV cardiomyocyte remodelling reduced treprostinil sensitivity, inotropic support, and impaired relaxation. Overall, this study highlights the complexity of RV dysfunction in advanced PH and suggests the need for alternative therapeutic strategies

Pulmonary Hypertension-Associated Right Ventricular Cardiomyocyte Remodelling Reduces Treprostinil Function

(1) Pulmonary hypertension (PH)-associated right ventricular (RV) failure is linked to a reduction in pulmonary vasodilators. Treprostinil has shown effectiveness in PAH patients with cardiac decompensation, hinting at potential cardiac benefits. We investigated treprostinil’s synergy with isoprenaline in RV and LV cardiomyocytes. We hypothesised that disease-related RV structural changes in cardiomyocytes would reduce contractile responses and cAMP/PKA signalling activity. (2) We induced PH in male Sprague Dawley rats using monocrotaline and isolated their ventricular cardiomyocytes. The effect of in vitro treprostinil and isoprenaline stimulation on contraction was assessed. FRET microscopy was used to study PKA activity associated with treprostinil stimulation in AKAR3-NES FRET-based biosensor-expressing cells. (3) RV cells exhibited maladaptive remodelling with hypertrophy, impaired contractility, and calcium transients compared to control and LV cardiomyocytes. Combining treprostinil and isoprenaline failed to enhance inotropy in PH RV cardiomyocytes. PH RV cardiomyocytes displayed an aberrant contractile behaviour, which the combination treatment could not rectify. Finally, we observed decreased PKA activity in treprostinil-treated PH RV cardiomyocytes. (4) PH-associated RV cardiomyocyte remodelling reduced treprostinil sensitivity, inotropic support, and impaired relaxation. Overall, this study highlights the complexity of RV dysfunction in advanced PH and suggests the need for alternative therapeutic strategies