Клинические и морфологические аспекты рецидивов миксом сердца

Aim: to conduct a one-center retrospective research of heart myxoma relapses in a large group of patients. Materials and methods. Since 1992 to 2016 115 surgical removal of sporadic cardiac myxoma was performed (44 male, 71 female).Results. Two (1.7%) patients had recurrence of sporadic myxoma of the left atrium. One patient had the tumor returned due to inadequate removal of the tumor. Myxoma was removed without excising the place of fi xation to the interatrial septum. The second patient possibly had recurrence of myxoma due to the conservation of a small tumor fragment in another part of the interatrial septum that was not diagnosed during the removal of the primary tumor. Conclusion. Recurrence of sporadic myxoma of the left atrium is rare. The reasons for the recurrence may be different but usually it is due to non-radical removal of the tumor. The results of our research show that even removal of the myxoma together with the interatrial septum does not fully guarantee the prevention of recurrence. The recurrence of sporadic cardiac myxoma is possibly associated with minor formations that are not diagnosed during surgery. We cannot exclude the possibility of forming myxoma denovo also. Цель. Провести одноцентровое ретроспективное исследование рецидивов миксомы сердца в значительной группе пациентов.Материалы и методы. В ФГБУ «НМИЦ трансплантологии и искусственных органов имени академика В.И. Шумакова» в период с 1992-го по 2016 год у 115 пациентов (44 мужчины, 71 женщина) со спорадическими миксомами сердца была выполнена хирургическая резекция опухоли.Результаты. Рецидив спорадической миксомы левого предсердия произошел у двух (1,7%) пациентов. У одного пациента возврат опухоли произошел из-за неадекватной резекции опухоли. Миксому удалили без иссечения места фиксации к межпредсердной перегородке. У второго пациента рецидив миксомы, возможно, был связан с сохранением небольшого фрагмента опухоли в другой части МПП, который не был диагностирован во время удаления первичной опухоли.Заключение. Рецидив спорадической миксомы левого предсердия встречается редко. Причины возврата опухоли могут быть различными, но обычно это происходит из-за нерадикальной резекции опухоли. Результаты нашего исследования показали, что удаление миксомы даже вместе с межпредсердной перегородкой полностью не гарантирует профилактику рецидива. Повторное возникновение спорадических миксом сердца, возможно, связано с не диагностированным во время операции дополнительным образованием незначительного размера. Нельзя также исключить возможность образования миксомы de novo.

СВЯЗЬ ЭФФЕКТА QUILTY С ОСТРЫМ ОТТОРЖЕНИЕМ ТРАНСПЛАНТИРОВАННОГО СЕРДЦА

Introduction. The Quilty Effect (lymphoid-cellular infiltration of the endocardium) is a frequent finding in biopsies of the transplanted heart. The role of this phenomenon in the rejection of the transplanted heart remains unclear. Aim. Retrospective analysis of endomyocardial biopsies of the transplanted heart and assessment of the relationship between acute cellular rejection and Quilty Effect. Methods and results. 112 endomyocardial biopsies with Quilty Effect were identified out of 883 studied biopsies during the period from January 2010 to June 2014. The frequency of Quilty damage occurrence in acute cellular rejection is significantly higher than in its absence (17.7% and 5.6%; р < 0.001). The combination of acute cellular rejection with acute antibodymediated rejection significantly increases the frequency of Quilty damage (р = 0.039). Isolated acute antibodymediated rejection of the transplanted heart does not affect the frequency of Quilty Effect occurrence and is not a direct etiologic and pathogenetic factor of this phenomenon. In the absence of acute cellular rejection, Quilty Effect is a predictor of its later development. Mild acute cellular rejection in conjunction with the Quilty Effect causes the risk of more severe degree of rejection. Quilty Effect type B occurs much less frequently than type A (1.9% and 10.8%; р = 0.001) and is observed primarily in acute cellular rejection of grade G2R (р = 0.001); the frequency of these morphological types at various periods after heart transplant was not significantly different (р > 0.05). Conclusion. The Quilty Effect is a kind of manifestation of acute cellular rejection of the transplanted heart when immunosuppressive therapy with calcineurin inhibitors is used. Введение. Эффект Quilty (лимфоидно-клеточная инфильтрация эндокарда) является нередкой находкой в биоптатах трансплантированного сердца. Остается неясным, какую роль играет этот феномен в отторжении трансплантированного сердца. Цель. Ретроспективный анализ эндомиокардиальных биоптатов трансплантированного сердца и оценка взаимосвязи острого клеточного отторжения с эффектом Quilty. Методы и результаты. В период с января 2010 г. по июнь 2014 г. было выявлено 112 эндомиокардиальных биоптатов с эффектом Quiltу из 883 изученных биоптатов. Установлено, что частота возникновения Quilty-повреждения при остром клеточном отторжении значительно выше, чем при его отсутствии (соответственно 17,7 и 5,6%; р < 0,001). Сочетание острого клеточного с острым антителоопосредованным отторжением существенно увеличивает частоту Quilty повреждения (р = 0,039). Изолированное острое антителоопосредованное отторжение трансплантированного сердца не влияет на частоту появления эффекта Quilty и не является непосредственным этиологическим и патогенетическим фактором этого феномена. При отсутствии острого клеточного отторжения эффект Quilty является предиктором его более позднего развития. При легкой степени острого клеточного отторжения в сочетании с эффектом Quilty существует риск более тяжелой степени отторжения. Эффект Quilty типа В встречается существенно реже типа А (1,9 и 10,8%; р = 0,001) и наблюдается преимущественно при остром клеточном отторжении степени G2R (р = 0,001); частота этих морфологических типов в различные сроки после трансплантации сердца значимо не отличается (р > 0,05). Заключение. Эффект Quilty является своеобразным проявлением острого клеточного отторжения трансплантированного сердца при иммуносупрессивной терапии ингибиторами кальциневрина.

ДИАГНОСТИЧЕСКОЕ ЗНАЧЕНИЕ ТРОМБОЦИТАРНОГО ФАКТОРА РОСТА PDGF-BB И ST2 ПРИ ОТТОРЖЕНИИ ТРАНСПЛАНТИРОВАННОГО СЕРДЦА

Aim: to determine the association between plasma concentrations of biomarkers (sCD40L, PDGF-BB, PlGF-1, ST2) with histochemical and immunohistochemical signs of heart rejection.Materials and methods. The study included 98 heart recipients aged from 12 to 69 (mean age 43 ± 14) years, of which 78 men. In 68 patients dilated cardiomyopathy was diagnosed, 30 recipients were diagnosed with coronary heart disease. The concentrations of placental growth factor (PlGF-1), platelet-derived growth factor (PDGF-BB), soluble CD40 ligand (sCD40L) were measured using xMAP technology. The concentrations of ST2 cardiac biomarker were measured by ELISA.Results. No correlation was found between the levels of biomarkers (sCD40L, PDGF-BB, PlGF-1, ST2) and gender, age and diagnosis. The rejection was diagnosed via biopsy in 49 biopsies taken from 37 recipients. 1A rejection was found in 25 patients (34 biopsies), 1B rejection was identifi ed in 2 patients (3 biopsies), 3A rejection was diagnosed in 4 patients. Immunohistochemical signs of humoral rejection were identifi ed in 3 patients. The combination of acute cellular and humoral rejection was found in 4 patients (5 biopsies). The PDGFBB level was measured at the same day as the biopsy was taken, and it was shown to be signifi cantly higher in patients with rejection (p = 0.02). Rejection frequency was signifi cantly higher in patients with high PDGF-BB level (≥2473.7 pg/ml, RR = 1.64 ± 0.23; 95% CI [1.03–2.61]). Rejection frequency increased to 2.11 ± 0.34 [95% CI [1.08–4.11]] in recipients with ST2 and PDGF-BB concentration higher than the median value. The highest predictive value for heart rejection can be reached by a panel of three biomarkers: sCD40L, PlGF-1 and ST2 (RR = 2.51 ± 0.38; 95% CI [1.18–5.3]).Conclusion. PDGF-BB has moderate predictive value for heart rejection. The highest predictive value for heart rejection was reached by a panel of three biomarkers: sCD40L, PlGF-1 and ST2.Цель: определить связь концентрации биомаркеров sCD40L, PDGF-BB, PlGF-1, ST2 в плазме крови реципиентов сердца с наличием и выраженностью гистохимических и иммуногистохимических признаков отторжения сердечного трансплантата.Материалы и методы. В исследование включены 98 пациентов с трансплантированным сердцем в возрасте от 12 до 69 (43 ± 14) лет, из них 78 мужчин. У 68 реципиентов до трансплантации сердца была диагностирована дилатационная кардиомиопатия, у 30 – ишемическая болезнь сердца. Концентрацию плацентарного фактора роста (PlGF-1), фактора роста тромбоцитов (PDGF-BB), растворимой формы лиганда CD40 (sCD40L) измеряли с использованием мультиплексной технологии; концентрацию стимулирующего фактора роста ST2 – с помощью иммуноферментного анализа.Результаты. Концентрация каждого биомаркера не зависела от пола, возраста и диагноза до трансплантации. У 37 пациентов (по результатам 49 биопсий) были диагностированы признаки отторжения. Гистохимические признаки острого клеточного отторжения – у 30 реципиентов (в 41 биоптате): 1А – у 25 пациентов (в 34 биоптатах), 1В – у двух пациентов (в трех биоптатах), 3А – у четырех пациентов. Иммуногистохимические признаки антителоопосредованного отторжения выявлены у трех пациентов. Сочетание острого клеточного и гуморального отторжения обнаружено у четырех пациентов (в пяти биоптатах). Концентрация PDGF-BB, измеренная в день эндомиокардиальной биопсии, была достоверно выше у пациентов с отторжением (p = 0,02). У реципиентов сердца с уровнем PDGF-BB выше медианы (2473,7 пг/мл) риск отторжения был в 1,64 раза выше, чем у пациентов с уровнем ниже медианы. У реципиентов с концентрацией и ST2, и PDGF-BB, превышающей значения медианы, относительный риск отторжения возрастал до 2,11 ± 0,34 [95% ДИ 1,08–4,11]. Наибольшей диагностической значимостью в отношении отторжения трансплантата обладала панель из трех биомаркеров (sCD40L, PlGF-1, ST2): RR = 2,51 ± 0,38 [95% ДИ 1,18–5,3].Заключение. PDGF-BB обладает умеренной прогностической значимостью в отношении отторжения трансплантированного сердца. Наибольшей диагностической значимостью обладает панель из трех биомаркеров: sCD40L, PlGF-1, ST2

ОТТОРЖЕНИЕ СЕРДЕЧНОГО ТРАНСПЛАНТАТА И НЕИНВАЗИВНЫЕ ПОКАЗАТЕЛИ ФУНКЦИОНАЛЬНОГО СОСТОЯНИЯ СТЕНКИ ОБЩЕЙ СОННОЙ АРТЕРИИ

Allograft rejection would entail an increase in certain blood biomarkers and active substances derived from activated inflammatory cells which could influence entire vascular endothelial function and deteriorate arterial wall stiffness. We propose that carotid wall functional indices measured with non-invasive ultrasound could we valuable markers of the subclinical cardiac allograft rejection. Aim. Our goal was to analyze the clinical utility of functional common carotid wall (CCW) variables measured with high-resolution Doppler ultrasound as a non-invasive screening tool for allograft rejection in cardiac transplant patients (pts). Methods. One hundred and seventy one pts included 93 cardiac recipients, 30 dilated cardiomyopathy waiting list pts, and 48 stable coronary artery disease (SCAD) pts without decompensated heart failure were included. Along with resistive index (Ri), pulsative index (Pi), and CCW intima-media thickness (IMT), CCW rigidity index (iRIG) was estimated using empirical equation. Non-invasive evaluation was performed in cardiac transplant recipients prior the endomyo- cardial biopsy. Results. Neither of Ri, Pi, or CCW IMT were different in studied subgroups. iRIG was signifi- cantly lower in SCAD pts when compared to the dilated cardiomyopathy subgroup. The later had similar values with cardiac transplant recipients without rejection. Antibody-mediated and cellular rejection were found in 22 (23.7%) and 17 (18.3%) cardiac recipients, respectively. Mean iRIG in pts without rejection was significantly lower in comparison to antibody-mediated rejection and cell-mediated (5514.7 ± 2404.0 vs 11856.1 ± 6643.5 and 16071.9 ± 10029.1 cm/sec2, respectively, p = 0.001). Area under ROC for iRIG was 0.90 ± 0.03 units2. Analysis showed that iRIG values above estimated treshold 7172 cm/sec2 suggested relative risk of any type of rejection 17.7 (95%CI = 6.3–49.9) sensitivity 80.5%, specificity – 81.1%, negative predictive value – 84.3%. Conclusions. Increased carotid wall stiffness is found in patients with both antibody-mediated and cellular car- diac allograft rejection. Non-invasive measurement of carotid artery wall rigidity index with triplex ultrasound is a simple screening tool for risk stratification. Having a functional marker would enable preventive measures to be taken at the early stages. Введение. Отторжение сердечного трансплантата может сопровождаться повышением содержания в крови определенных биомаркеров, которые могут оказывать влияние на эластические свойства сте- нок артерий. Согласно нашей гипотезе, показатели функционального состояния общей сонной арте- рии (ОСА) могут быть использованы в качестве неинвазивных маркеров при скрининге отторжения трансплантированного сердца (ТС). Цель исследования. Изучить возможность применения методов ультрасонографической оценки функционального состояния стенки ОСА для неинвазивного скри- нинга отторжения сердечного трансплантата. Методы. В исследование включен 171 больной, из них 93 реципиента ТС, 30 больных дилятационной кардиомиопатией (ДКМП) с терминальной сердечной недостаточностью (СН) и 48 больных ИБС без декомпенсации СН. При помощи ультрасонографичес- кого исследования у обследуемых больных определялись резистивный индекс (Ri), пульсативный ин- декс (Pi), толщина комплекса интима–медиа (ТИМ) ОСА и индекс ригидности ОСА(iRIG), рассчиты- ваемый по эмпирической формуле. Неинвазивные исследования у пациентов после ТС проводились до выполнения эндомиокардиальной биопсии (ЭМБ). Результаты. Средние значения Ri, Pi и ТИМ ОСА в исследуемых подгруппах не отличались. Значения показателя iRIG у больных ИБС были достоверно ниже, чем у больных ДКМП и реципиентов без признаков отторжения (в последних двух подгруппах достоверных различий не выявлено). Признаки гуморального (ГО) и клеточного отторжения (КО) по результатам ЭМБ были выявлены у 22 (23,7%) и 17 (18,3%) реципиентов соответственно. Средние значения показателя iRIG у реципиентов без отторжения трансплантата были достоверно ниже по сравнению с пациентами с признаками ГО и КО (5514,7 ± 2404,0 против 11856,1 ± 6643,5 и 16071,9 ± 10029,1 см/сек2 соответственно, p = 0,001). Площадь под кривой ROC для показателя iRIG была 0,90 ± 0,03 ед2. Анализ показал, что у лиц со значениями показателя iRIG, превышающими расчетное поро- говое значение 7172 см/сек2, относительный риск выявления отторжения при проведении ЭМБ состав- ляет 17,7 (95% ДИ = 6,3–49,9); чувствительность показателя в качестве неинвазивного маркера оттор- жения составляет 80,5%, специфичность – 81,1%, негативная предсказательная значимость – 84,3%. Выводы. У реципиентов сердечного трансплантата с признаками отторжения повышается ригидность стенки ОСА. Определение значения показателя ригидности ОСА при помощи неинвазивного ультра- сонографического исследования может быть использовано в качестве доступного метода скрининга отторжения ТС.

Recurrence of cardiac myxoma. Clinical and morphological aspects

Aim: to conduct a one-center retrospective research of heart myxoma relapses in a large group of patients. Materials and methods. Since 1992 to 2016 115 surgical removal of sporadic cardiac myxoma was performed (44 male, 71 female).Results. Two (1.7%) patients had recurrence of sporadic myxoma of the left atrium. One patient had the tumor returned due to inadequate removal of the tumor. Myxoma was removed without excising the place of fi xation to the interatrial septum. The second patient possibly had recurrence of myxoma due to the conservation of a small tumor fragment in another part of the interatrial septum that was not diagnosed during the removal of the primary tumor. Conclusion. Recurrence of sporadic myxoma of the left atrium is rare. The reasons for the recurrence may be different but usually it is due to non-radical removal of the tumor. The results of our research show that even removal of the myxoma together with the interatrial septum does not fully guarantee the prevention of recurrence. The recurrence of sporadic cardiac myxoma is possibly associated with minor formations that are not diagnosed during surgery. We cannot exclude the possibility of forming myxoma denovo also

THE RELATIONSHIP OF QUILTY EFFECT TO ACUTE REJECTION OF THE TRANSPLANTED HEART

Introduction. The Quilty Effect (lymphoid-cellular infiltration of the endocardium) is a frequent finding in biopsies of the transplanted heart. The role of this phenomenon in the rejection of the transplanted heart remains unclear. Aim. Retrospective analysis of endomyocardial biopsies of the transplanted heart and assessment of the relationship between acute cellular rejection and Quilty Effect. Methods and results. 112 endomyocardial biopsies with Quilty Effect were identified out of 883 studied biopsies during the period from January 2010 to June 2014. The frequency of Quilty damage occurrence in acute cellular rejection is significantly higher than in its absence (17.7% and 5.6%; р < 0.001). The combination of acute cellular rejection with acute antibodymediated rejection significantly increases the frequency of Quilty damage (р = 0.039). Isolated acute antibodymediated rejection of the transplanted heart does not affect the frequency of Quilty Effect occurrence and is not a direct etiologic and pathogenetic factor of this phenomenon. In the absence of acute cellular rejection, Quilty Effect is a predictor of its later development. Mild acute cellular rejection in conjunction with the Quilty Effect causes the risk of more severe degree of rejection. Quilty Effect type B occurs much less frequently than type A (1.9% and 10.8%; р = 0.001) and is observed primarily in acute cellular rejection of grade G2R (р = 0.001); the frequency of these morphological types at various periods after heart transplant was not significantly different (р > 0.05). Conclusion. The Quilty Effect is a kind of manifestation of acute cellular rejection of the transplanted heart when immunosuppressive therapy with calcineurin inhibitors is used

CARDIAC TRANSPLANT REJECTION AND NON-INVASIVE COMON CAROTID ARTERY WALL FUNCTIONAL INDICES

Allograft rejection would entail an increase in certain blood biomarkers and active substances derived from activated inflammatory cells which could influence entire vascular endothelial function and deteriorate arterial wall stiffness. We propose that carotid wall functional indices measured with non-invasive ultrasound could we valuable markers of the subclinical cardiac allograft rejection. Aim. Our goal was to analyze the clinical utility of functional common carotid wall (CCW) variables measured with high-resolution Doppler ultrasound as a non-invasive screening tool for allograft rejection in cardiac transplant patients (pts). Methods. One hundred and seventy one pts included 93 cardiac recipients, 30 dilated cardiomyopathy waiting list pts, and 48 stable coronary artery disease (SCAD) pts without decompensated heart failure were included. Along with resistive index (Ri), pulsative index (Pi), and CCW intima-media thickness (IMT), CCW rigidity index (iRIG) was estimated using empirical equation. Non-invasive evaluation was performed in cardiac transplant recipients prior the endomyo- cardial biopsy. Results. Neither of Ri, Pi, or CCW IMT were different in studied subgroups. iRIG was signifi- cantly lower in SCAD pts when compared to the dilated cardiomyopathy subgroup. The later had similar values with cardiac transplant recipients without rejection. Antibody-mediated and cellular rejection were found in 22 (23.7%) and 17 (18.3%) cardiac recipients, respectively. Mean iRIG in pts without rejection was significantly lower in comparison to antibody-mediated rejection and cell-mediated (5514.7 ± 2404.0 vs 11856.1 ± 6643.5 and 16071.9 ± 10029.1 cm/sec2, respectively, p = 0.001). Area under ROC for iRIG was 0.90 ± 0.03 units2. Analysis showed that iRIG values above estimated treshold 7172 cm/sec2 suggested relative risk of any type of rejection 17.7 (95%CI = 6.3–49.9) sensitivity 80.5%, specificity – 81.1%, negative predictive value – 84.3%. Conclusions. Increased carotid wall stiffness is found in patients with both antibody-mediated and cellular car- diac allograft rejection. Non-invasive measurement of carotid artery wall rigidity index with triplex ultrasound is a simple screening tool for risk stratification. Having a functional marker would enable preventive measures to be taken at the early stages

Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial

Background: Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial. Methods: NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy. Findings: Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. Interpretation: Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted. Funding: Bayer and Janssen