No-reflow phenomenon and reperfusion injury. Mechanisms and treatment

Currently, one of the key methods of treating a patient with ST-elevation myocardial infarction is to restore blood flow to the infarct-related artery as quickly, completely and steadily as possible. However, in some cases, it is not possible to achieve adequate myocardial reperfusion, despite the restoration of coronary blood flow. This phenomenon was named no-reflow. Due to the lack of a unified approach to the diagnosis of no-reflow, its occurrence varies widely – from 2 to 44 %. Failure to achieve adequate myocardial perfusion leads to a higher mortality rate – from 7.4 to 30.3 %, as well as to more aggressive remodeling of the myocardium. For a long time, distal embolization in percutaneous coronary intervention was considered one of the leading mechanisms. However, the routine use of protective devices did not show a pronounced effect on the outcome and prognosis, although it is justified in certain clinical situations. Ischemic injury directly plays a significant role due to overload of cardiomyocytes with calcium, cellular edema, necrosis and apoptosis, which is significantly aggravated by myocardial reperfusion and forms obstruction at the level of the microcirculatory bed. More data is being accumulated about immune-mediated injury through activation of cellular immunity, intense inflammation and thrombosis in situ. Despite the success in the animal experiment, the clinical use of certain groups of drugs showed an ambiguous results. According to the latest recommendations European Society of Cardiology / European Association for Cardio-Thoracic Surgery (ESC / EACTS) 2018, GPIIb / IIIa platelet receptor inhibitors are recommended in the case of no-reflow. Besides this, according to the literature nicorandil and sodium nitroprusside, as well as IL-1β antagonists, seem to be promising. As a non-drug therapy, selective intracoronary hypothermia also has shown its effectiveness and safety in a pilot study. To date, it is clear that the no-reflow phenomenon is a manifestation of a complex cascade of reactions, including ischemic, reperfusion and immune-related injury, as well as distal embolization. Considering its significant contribution to the frequency of adverse outcomes and late complications, it seems necessary to introduce unified approaches to the diagnosis, prevention and treatment of no-reflow, which requires high-quality clinical studies

Сопоставление рентгенологической и патоморфологической картины легких у пациентов с COVID-19

Aim. Compare radiological patterns of COVID-19 pneumonia with pulmonary histology in deceased patients.Materials and methods. The analysis of recent lifetime CT studies of deceased patients was performed with the identification of all existing and leading CT symptoms, including “ground glass”, “crazy paving”, consolidation, as well as the symptom complex (pattern) of organizing pneumonia. Based on the CT symptoms, we selected the target points for taking the specimens by 3-D reconstructions. At the autopsy the lungs were entirely fixed into the front and then marked on CT sections cut from 1 to 3 pieces that were placed in paraffin and processed according to the standard technique, stained with hematoxylin and eosin and fuchsin-facelina. The specimens were analyzed by identifying all available histology changes and selecting the leading one.Results. 45 targeted pieces of lung tissue were obtained from 14 deceased COVID-19 patients (7 men/ 7 women), with an average age of 77.1 ± 12.9 (49–90 years). In deceased patients with the presence of the "ground glass" symptom, in most cases (57.1%) revealed an increase in intra-alveolar cellularity, hyaline membranes, desquamation of the alveolar epithelium and infiltration of the interalveolar septum by lymphocytes, which corresponds to the exudative phase of diffuse alveolar damage (DAP). Mosaic histological changes with alternation of filled alveoli (intraalveolar edema, clusters of red blood cells, macrophages, lymphocytes) and air alveoli were detected from the areas of “crazy paving” zones. Several cases demonstrated interstitial edema and lymphoid infiltration of interalveolar partitions of different severity without their thickening. Areas of consolidation were histologically represented by extensive intraalveolar hemorrhages and / or typical zones of hemorrhagic infarcts in 45.5% of cases. Perilobular consolidation, subpleural cords, symptoms of “halo” and “reverse halo”, which we considered as part of the symptom complex of organizing pneumonia in 43% of cases, morphologically corresponded to organizing pneumonia (the proliferative phase of DAP), as well as to distelectases.Conclusion. Comparison of CT patters and post-mortem pulmonary histology in COVID-19 deceased patients demonstrated that CT symptoms and patterns correspond to certain morphological changes of different phases of DAP.Цель исследования: сопоставить рентгенологические паттерны COVID-19 с гистологическими изменениями у умерших.Материал и методы. Проведен анализ последних прижизненных КТ-исследований умерших пациентов с выделением всех имеющихся и ведущего КТ-симптомов, включая “матовое стекло”, “булыжная мостовая”, консолидация, а также симптомокомплекс (паттерн) организующейся пневмонии. На основании выделенных КТ-симптомов были выбраны прицельные точки взятия материала при помощи построения трехмерных реконструкций. На аутопсии фиксированные целиком легкие разрезались фронтально, далее из обозначенных на компьютерной томограмме участков вырезали от 1 до 3 кусочков, которые заливались в парафин и обрабатывались по общепринятой методике с последующей окраской срезов толщи- ной 3–5 мкм гематоксилином и эозином, пикрофуксин-фукселином. Анализ материала проводили путем выявления всех имеющихся патоморфологических изменений с выделением ведущего из них.Результаты. Были получены 45 прицельно взятых кусочков ткани легкого от 14 умерших (7 мужчин/ 7 женщин), средний возраст 77,1 ± 12,9 (49–90) года. У умерших пациентов с наличием симптома “матово- го стекла” при КТ в большинстве случаев (57,1%) были выявлены увеличение числа клеток в просветах альвеол (внутриальвеолярная клеточность), гиалиновые мембраны, десквамация альвеолярного эпителия и инфильтрация лимфоцитами межальвеолярных перегородок, что может соответствовать признакам экссудативной фазы диффузного альвеолярного повреждения (ДАП). Из участков, обозначенных как зоны “булыжной мостовой”, были выявлены мозаичные гистологические изменения с чередованием заполненных альвеол (внутриальвеолярный отек, скопления эритроцитов, макрофагов, лимфоцитов) и воздушных альвеол, местами при наличии интерстициального отека и лимфоидной инфильтрации межальвеолярных перегородок разной степени выраженности без их утолщения. Участки консолидации гистологически были представлены обширными внутриальвеолярными кровоизлияниями и/или типичными зонами геморрагических инфарктов в 45,5% случаев. Перилобулярная консолидация, субплевральные тяжи, симптомы “ободка” и “обратного ободка”, которые мы расценивали в рамках симптомокомплекса организующейся пневмонии, на компьютерной томограмме в 43% случаев морфологически соответствовали организующейся пневмонии (пролиферативная фаза ДАП), а также дистелектазам.Заключение. При попытке рентгенопатоморфологического сопоставления у пациентов с COVID-19 с поражением легких нами было показано, что различные симптомы и паттерны при КТ соответствуют определенным морфологическим изменениям в различные фазы ДАП

In Vitro Dedifferentiation of Melanocytes from Adult Epidermis

In previous work we described a novel culture technique using a cholera toxin and PMA-free medium (Mel-mix) for obtaining pure melanocyte cultures from human adult epidermis. In Mel-mix medium the cultured melanocytes are bipolar, unpigmented and highly proliferative. Further characterization of the cultured melanocytes revealed the disappearance of c-Kit and TRP-1 and induction of nestin expression, indicating that melanocytes dedifferentiated in this in vitro culture. Cholera toxin and PMA were able to induce c-Kit and TRP-1 protein expressions in the cells, reversing dedifferentiation. TRP-1 mRNA expression was induced in dedifferentiated melanocytes by UV-B irradiated keratinocyte supernatants, however direct UV-B irradiation of the cells resulted in further decrease of TRP-1 mRNA expression. These dedifferentiated, easily accessible cultured melanocytes provide a good model for studying melanocyte differentiation and possibly transdifferentiation. Because melanocytes in Mel-mix medium can be cultured with human serum as the only supplement, this culture system is also suitable for autologous cell transplantation

Impact of aspirin on takotsubo syndrome: a propensity score-based analysis of the InterTAK Registry

Aims: The aim of the present study was to investigate the impact of aspirin on prognosis in takotsubo syndrome (TTS). Methods and results: Patients from the International Takotsubo (InterTAK) Registry were categorized into two groups based on aspirin prescription at discharge. A comparison of clinical outcomes between groups was performed using an adjusted analysis with propensity score (PS) stratification; results from the unadjusted analysis were also reported to note the effect of the PS adjustment. Major adverse cardiac and cerebrovascular events (MACCE: a composite of death, myocardial infarction, TTS recurrence, stroke or transient ischaemic attack) were assessed at 30-day and 5-year follow-up. A total of 1533 TTS patients with known status regarding aspirin prescription at discharge were included. According to the adjusted analysis based on PS stratification, aspirin was not associated with a lower hazard of MACCE at 30-day [hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.50\u20133.04, P = 0.64] or 5-year follow-up (HR 1.11, 95% CI 0.78\u20131.58, P = 0.58). These results were confirmed by sensitivity analyses performed with alternative PS-based methods, i.e. covariate adjustment and inverse probability of treatment weighting. Conclusion: In the present study, no association was found between aspirin use in TTS patients and a reduced risk of MACCE at 30-day and 5-year follow-up. These findings should be confirmed in adequately powered randomized controlled trials. ClinicalTrials.gov Identifier: NCT01947621

CD133+ adult human retinal cells remain undifferentiated in Leukaemia Inhibitory Factor (LIF)

<p>Abstract</p> <p>Background</p> <p>CD133 is a cell surface marker of haematopoietic stem and progenitor cells. Leukaemia inhibitory factor (LIF), sustains proliferation and not differentiation of embryonic stem cells. We used CD133 to purify adult human retinal cells and aimed to determine what effect LIF had on these cultures and whether they still had the ability to generate neurospheres.</p> <p>Methods</p> <p>Retinal cell suspensions were derived from adult human post-mortem tissue with ethical approval. With magnetic automated cell sorting (MACS) CD133⁺retinal cells were enriched from post mortem adult human retina. CD133⁺retinal cell phenotype was analysed by flow cytometry and cultured cells were observed for proliferative capacity, neuropshere generation and differentiation with or without LIF supplementation.</p> <p>Results</p> <p>We demonstrated purification (to 95%) of CD133⁺cells from adult human postmortem retina. Proliferating cells were identified through BrdU incorporation and expression of the proliferation markers Ki67 and Cyclin D1. CD133⁺retinal cells differentiated whilst forming neurospheres containing appropriate lineage markers including glia, neurons and photoreceptors. LIF maintained CD133⁺retinal cells in a proliferative and relatively undifferentiated state (Ki67, Cyclin D1 expression) without significant neurosphere generation. Differentiation whilst forming neurospheres was re-established on LIF withdrawal.</p> <p>Conclusion</p> <p>These data support the evidence that CD133 expression characterises a population of cells within the resident adult human retina which have progenitor cell properties and that their turnover and differentiation is influenced by LIF. This may explain differences in retinal responses observed following disease or injury.</p

Cardiac arrest in takotsubo syndrome: Results from the InterTAK Registry

Aims: We aimed to evaluate the frequency, clinical features, and prognostic implications of cardiac arrest (CA) in takotsubo syndrome (TTS).Methods and results: We reviewed the records of patients with CA and known heart rhythm from the International Takotsubo Registry. The main outcomes were 60-day and 5-year mortality. In addition, predictors of mortality and predictors of CA during the acute TTS phase were assessed. Of 2098 patients, 103 patients with CA and known heart rhythm during CA were included. Compared with patients without CA, CA patients were more likely to be younger, male, and have apical TTS, atrial fibrillation (AF), neurologic comorbidities, physical triggers, and longer corrected QT-interval and lower left ventricular ejection fraction on admission. In all, 57.1% of patients with CA at admission had ventricular fibrillation/tachycardia, while 73.7% of patients with CA in the acute phase had asystole/pulseless electrical activity. Patients with CA showed higher 60-day (40.3% vs. 4.0%, P Conclusions: Cardiac arrest is relatively frequent in TTS and is associated with higher short- and long-term mortality. Clinical and electrocardiographic parameters independently predicted mortality after CA.</p

Prognostic impact of acute pulmonary triggers in patients with takotsubo syndrome: new insights from the International Takotsubo Registry

Aims Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes.Methods and results Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes.Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In-hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long-term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long-term mortality (hazard ratio 2.12, 95% confidence interval 1.33-3.38; P = 0.002).Conclusions The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome.Cardiolog

Ethnic comparison in takotsubo syndrome: novel insights from the International Takotsubo Registry

Background Ethnic disparities have been reported in cardiovascular disease. However, ethnic disparities in takotsubo syndrome (TTS) remain elusive. This study assessed differences in clinical characteristics between Japanese and European TTS patients and determined the impact of ethnicity on in-hospital outcomes.Methods TTS patients in Japan were enrolled from 10 hospitals and TTS patients in Europe were enrolled from 32 hospitals participating in the International Takotsubo Registry. Clinical characteristics and in-hospital outcomes were compared between Japanese and European patients.Results A total of 503 Japanese and 1670 European patients were included. Japanese patients were older (72.6 +/- 11.4 years vs. 68.0 +/- 12.0 years; p < 0.001) and more likely to be male (18.5 vs. 8.4%; p< 0.001) than European TTS patients. Physical triggering factors were more common (45.5 vs. 32.0%; p < 0.001), and emotional triggers less common (17.5 vs. 31.5%; p < 0.001), in Japanese patients than in European patients. Japanese patients were more likely to experience cardiogenic shock during the acute phase (15.5 vs. 9.0%; p < 0.001) and had a higher in-hospital mortality (8.2 vs. 3.2%; p< 0.001). However, ethnicity itself did not appear to have an impact on in-hospital mortality. Machine learning approach revealed that the presence of physical stressors was the most important prognostic factor in both Japanese and European TTS patients.Conclusion Differences in clinical characteristics and in-hospital outcomes between Japanese and European TTS patients exist. Ethnicity does not impact the outcome in TTS patients. The worse in-hospital outcome in Japanese patients, is mainly driven by the higher prevalence of physical triggers.Cardiolog