Diagnosis and Treatment Patterns of Chronic Thromboembolic Pulmonary Hypertension in Russia, Kazakhstan, Turkey, Lebanon, and Saudi Arabia: A Registry Study.

BACKGROUND: Patients with chronic thromboembolic pulmonary hypertension (CTEPH) in countries with limited resources have, to date, been poorly represented in registries. OBJECTIVE: This work assesses the epidemiology, diagnosis, hemodynamic and functional parameters, and treatment of CTEPH in Russia, Kazakhstan, Turkey, Lebanon, and Saudi Arabia. METHODS: A prospective, cohort, phase IV, observational registry with 3-year follow-up (n = 212) in patients aged ≥ 18 years diagnosed with CTEPH was created. Clinical, hemodynamic, and functional parameters were obtained at an initial visit, follow-up visits, and a final visit at the end of 3 years' observation or end of follow-up. Data were recorded on electronic case report forms. Parameters evaluated included 6-minute walking distance (6MWD), use of pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA), pulmonary hypertension (PH)-targeted therapy, and survival. All statistical analyses were exploratory and descriptive, and were performed in the overall population. RESULTS: The most common symptoms were typical of those expected for CTEPH. Almost 90% of patients underwent right heart catheterization at diagnosis or initial study visit. In total, 66 patients (31%) underwent PEA before the initial visit; 95 patients (45%) were considered operable, 115 (54%) were inoperable, and two (1%) had no operability data. Only 26 patients (12%) had been assessed for BPA at their initial visit. PH-targeted therapy was documented at diagnosis for 77 patients (36%), most commonly a phosphodiesterase type 5 inhibitor (23%). Use of PH-targeted therapy increased to 142 patients (67%) at the initial visit, remaining similar after 3 years. Use of riociguat increased from 6% of patients at diagnosis to 38% at 3 years. Between baseline and end of observation, results for patients with paired data showed an increase in 6MWD. Survival at the end of observation was 88%. CONCLUSIONS: These data highlight the current diagnosis and management of CTEPH in the participating countries. They show that early CTEPH diagnosis remains challenging, and use of off-label PH-targeted therapy is common. CLINICALTRIALS: gov: NCT02637050; registered December 2015.

Elderly Patients with Idiopathic Pulmonary Hypertension: Clinical Characteristics, Survival, and Risk Stratification in a Single-Center Prospective Registry.

INTRODUCTION: The predictive value of the risk stratification scales in elderly patients with IPAH might differ from that in younger patients. It is unknown whether young and older IPAH patients have the same survival dependence on PAH-specific therapy numbers. The aim of this study was to evaluate the prognostic relevance of risk stratification scales and PAH medication numbers in elderly IPAH patients in comparison with young IPAH patients. MATERIALS AND METHODS: A total of 119 patients from a prospective single-center PAH registry were divided into group I < 60 years old (n = 89) and group II ≥ 60 years old (n = 30). ESC/ERS, REVEAL, and REVEAL 2.0 risk stratification scores were assessed at baseline, as well as H2FpEF score and survival at follow-up. RESULTS: During a mean follow-up period of 2.9 years (1.63; 6.0), 42 (35.3%) patients died; at 1, 2, 3, 5, 7, and 10 years, survival was 95%, 88.6%, 78.5%, 61.7%, 48.5%, and 33.7%, respectively. No survival differences were observed between the two groups, despite the use of monotherapy in the elderly patients. The best predictive REVEAL value in elderly patients (IPAH patients ≥ 60 years) was AUC 0.73 (0.56-0.91), p = 0.03; and in patients with LHD comorbidities in the entire cohort, it was AUC 0.73 (0.59-0.87), p < 0.009. Factors independently associated with death in the entire cohort were CKD (p = 0.01, HR 0.2), the right-to-left ventricle dimension ratio (p = 0.0047, HR 5.97), and NT-proBNP > 1400 pg/mL (p = 0.008, HR 3.18). CONCLUSION: Risk stratification in the elderly IPAH patients requires a fundamentally different approach than that of younger patients, taking into account the initial limitations in physical performance and comorbidities that interfere with current assessment scores. The REVEAL score reliably stratifies patients at any age and LHD comorbidities. The initial monotherapy seems to be reasonable in patients over 60 years. Selection tools for initial combination PAH therapy in older IPAH patients with comorbidities need to be validated in prospective observational studies.

Surgical treatment of chronic thromboembolic pulmonary hypertension in combination with a left anterior descending artery myocardial bridge: A case report.

Pulmonary thromboendarterectomy is a potentially curative option for most patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, a special group of patients with CTEPH requires simultaneous cardiac procedures. We report a rare case of successful surgical treatment of a CTEPH patient with a left anterior descending artery myocardial bridge. Despite the complexity of performing pulmonary thromboendarterectomy (PTE), the issue concerning the method of revascularization of the artery in the case of the left anterior descending artery myocardial bridge is controversial. PTE and supracoronary myotomy were performed. In our case, the optimal surgery method for the left anterior descending artery myocardial bridge was chosen intraoperatively based on the depth and length of the myocardial bridge. The patient's significant functional improvement after surgery and hemodynamic normalization were confirmed at the follow-up assessment. This case demonstrates rare but potentially dangerous pathologies that can be treated with minimal adverse effects.

Circulating Small Extracellular Vesicles Profiling and Thrombin Generation as Potential Markers of Thrombotic Risk in Glioma Patients.

Introduction: Patients with glioma (GM) are at a high risk of venous thromboembolism (VTE). The role of microvesiculation in the cancer-associated thrombosis mechanisms has been previously demonstrated. This study aimed to evaluate the relative abundance of extracellular vesicles (EVs) and thrombin generation (TG) in combination with standard laboratory tests in patients with newly diagnosed GM as potential prognostic markers in VTE. Materials and Methods: In the present study, 11 patients with newly diagnosed GM and 10 healthy volunteers were analyzed. EVs were counted and their cellular origin was determined (CytoFlex B4-R2-V2, Beckman Coulter, United States), as well as thrombin generation test (TGT) (Diagnostica Stago SAS, France) was performed. Results: In patients with GM, the relative abundance of the CD41 + EVs (platelet-derived)-and CD105 + EVs (endothelial-derived) was significantly higher than in the control group (44.3 [40.5; 52.4] vs. 27.2 [22.9; 31.0]%, p = 0.002, and 5.4 [4.8; 7.8] vs. 1.9 [1.5; 2.8]%, p = 0.0003, respectively). The D-dimer level was higher in patients with GM compared with the control group (0.46 [0.38; 1.85] vs. 0.36 [0.27; 0.40] µg/ml FEU, p = 0.03, respectively). There was a trend toward an increase in the peak thrombin and velocity index (VI) in the GM group (p = 0.06). During the follow-up period, two patients (18%) developed thrombosis, had tumor sizes of more than 5 cm, thrombocytopenia, increased VI, and D-dimer. Conclusion: Analysis of platelet-derived EVs, platelet count, and TGT in combination with D-dimer assessment could improve the stratification of patients prone to VTE, which needs to be confirmed in a larger sample.

Case Report: Multiple Causes of Cardiac Death After the First Infusion of Atezolizumab: Histopathological and Immunohistochemical Findings.

Immune checkpoint inhibitors are promising agents for anticancer therapy. But despite their high efficacy in the treatment of solid tumors, there is still a problem with immune-related adverse events, especially cardiovascular complications with a very high mortality rate. Myocarditis or ischemic heart disease progression is not the only possible cause of cardiovascular death in patients treated with checkpoint inhibitors. We report a case of a patient with mucinous carcinoma of the lung, with a previous history of hypertension and moderate left ventricular dysfunction. The patient was prescribed atezolizumab, but the first atezolizumab infusion resulted in the patient cardiovascular death. Postmortem histopathological evaluation of myocardium revealed several possible reasons for hemodynamic instability: tumor embolism of the coronary arteries, micrometastases of mucinous carcinoma in the myocardium, and myocarditis diagnosed by both Dallas and immunohistochemistry criteria. In addition, testing for expression of PD-L1 detected the high levels of membranous and cytoplasmic PD-L1 protein even in the myocardium area free from tumor cells. The present clinical case demonstrates a problem of cardiovascular death in patients treated with checkpoint inhibitors and actualizes the need for future research of potential risk factors for cardiovascular complications.

Dual-energy computed tomography-angiography in the evaluation and management of significant multiple pulmonary vein stenoses following atrial fibrillation ablation.

A 58-year-old male patient with multi-vessel pulmonary vein (PV) stenosis following atrial fibrillation ablation was referred to a specialized pulmonary hypertension clinic. Chest dual-energy computed tomography (CT)-angiography allowed precise diagnosis of two PVs occlusion and three PVs significant stenosis. Iodine maps showed perfusion deficiency and its value for each stenosis, determining the sequence of multiple PV interventions. We suggest iodine CT mapping is a useful tool in the definition of PV stenosis severity and planning staged angioplasty.

Temporal Requirement for the Protective Effect of Dietary Cholesterol against Alcohol-Induced Vasoconstriction.

Moderate-to-heavy episodic alcohol drinking resulting in 30-80 mM of ethanol in blood constricts cerebral arteries and constitutes a risk factor for cerebrovascular disease. Alcohol-induced constriction of cerebral arteries in vivo and ex vivo has been shown to be blunted by dietary cholesterol (CLR) in a rat model of a high-CLR diet. Such protection has been proposed to arise from the high-CLR diet-driven increase in blood CLR levels and accompanying buildup of CLR within the cerebral artery smooth muscle. Here we used a rat model of high-CLR feeding in vivo and pressurized cerebral arteries ex vivo to examine whether the degree and time-course of alcohol-induced constriction are related to blood CLR levels. We demonstrate that subjecting young (3 weeks-old, 50 g) male Sprague-Dawley rats to a high- CLR feeding up to 41 weeks, resulted in an age-dependent increase in total blood CLR levels, when compared to those of age-matched rats on isocaloric (control) chow. This increase was paralleled by a high-CLR diet-driven elevation of blood low-density lipoproteins whereas high-density lipoprotein levels matched those of age-matched, chow-fed controls. Alcohol-induced constriction was only blunted by high-CLR dietary intake when high-CLR chow was taken for up to 8-12 and 18-23 weeks. However, alcohol-constriciton was not blunted when high-CLR chow intake lasted for longer times, such as 28-32 and 38-41 weeks. Thus, alcohol-induced constriction of rat middle cerebral arteries did not critically depend on the total blood CLR levels. Alcohol-induced constriction seemed unrelated to the natural, progressive elevation of the total blood CLR level in control- or high-CLR-fed animals over time. Thus, neither the exogenously nor endogenously driven increases in blood CLR could predict cerebral artery susceptibility to alcohol-induced constriction. However, we identified a temporal requirement for the protective effect of dietary CLR against alcohol, that could be governed by the young age of the high- CLR chow recipients (3 weeks of age) and/or the short duration of high-CLR chow feeding lasting for up to 23 weeks.

Gestational Age-Dependent Interplay between Endocannabinoid Receptors and Alcohol in Fetal Cerebral Arteries.

Alcohol (ethanol) is one of the most widely consumed drugs. Alcohol consumption by pregnant women may result in a range of fetal abnormalities termed fetal alcohol spectrum disorders (FASDs). The cerebrovascular system is emerging as a critical target of alcohol in the developing brain. We recently showed that three episodes of prenatal alcohol exposure resulting in 80 mg/dL alcohol in maternal blood during mid-pregnancy up-regulated anandamide-induced dilation of fetal cerebral arteries. Moreover, ethanol dilated fetal cerebral arteries via cannabinoid (CB) receptors. Whether a critical role of fetal cerebral artery CB system in responses to alcohol was maintained throughout the gestation, remains unknow. MAIN METHODS: Pregnant baboons (second trimester equivalent) were subjected to three episodes of either alcohol or control drink infusion via gavage. Cerebral arteries from mothers and near-term female fetuses were in vitro pressurized for diameter monitoring. KEY FINDINGS: Near-term fetal and maternal arteries exhibited similar ability to develop myogenic tone, to constrict in presence of 60 mM KCl, and to respond to 10 µM anandamide. Fetal and maternal arteries largely failed to dilate in presence of 63 mM ethanol. No differences were detected between arteries from control and alcohol-exposed baboon donors. Therefore, previously observed ethanol-induced dilation of fetal cerebral arteries and up-regulation of CB components in response to fetal alcohol exposure during mid-pregnancy was transient and disappeared by near-term.

Large conductance voltage- and calcium-gated potassium channels (BK) in cerebral artery myocytes of perinatal fetal primates share several major characteristics with the adult phenotype.

Large conductance voltage- and calcium-gated channels (BK) control fundamental processes, including smooth muscle contractility and artery diameter. We used a baboon (Papio spp) model of pregnancy that is similar to that of humans to characterize BK channels in the middle cerebral artery and its branches in near-term (165 dGa) primate fetuses and corresponding pregnant mothers. In cell-attached patches (K+pipette = 135 mM) on freshly isolated fetal cerebral artery myocytes, BK currents were identified by large conductance, and voltage- and paxilline-sensitive effects. Their calcium sensitivity was confirmed by a lower Vhalf (transmembrane voltage needed to reach half-maximal current) in inside-out patches at 30 versus 3 µM [Ca2+]free. Immunostaining against the BK channel-forming alpha subunit revealed qualitatively similar levels of BK alpha protein-corresponding fluorescence in fetal and maternal myocytes. Fetal and maternal BK currents recorded at 3 µM [Ca2+]free from excised membrane patches had similar unitary current amplitude, and Vhalf. However, subtle differences between fetal and maternal BK channel phenotypes were detected in macroscopic current activation kinetics. To assess BK function at the organ level, fetal and maternal artery branches were pressurized in vitro at 30 mmHg and probed with the selective BK channel blocker paxilline (1 µM). The degree of paxilline-induced constriction was similar in fetal and maternal arteries, yet the constriction of maternal arteries was achieved sooner. In conclusion, we present a first identification and characterization of fetal cerebral artery BK channels in myocytes from primates. Although differences in BK channels between fetal and maternal arteries exist, the similarities reported herein advance the idea that vascular myocyte BK channels are functional near-term, and thus may serve as pharmacological targets during the perinatal-neonatal period.

Corrigendum to "Topography Prediction of Helical Transmembrane Proteins by a New Modification of the Sliding Window Method".

[This corrects the article DOI: 10.1155/2014/921218.].

Statin therapy exacerbates alcohol-induced constriction of cerebral arteries via modulation of ethanol-induced BK channel inhibition in vascular smooth muscle.

Statins constitute the most commonly prescribed drugs to decrease cholesterol (CLR). CLR is an important modulator of alcohol-induced cerebral artery constriction (AICAC). Using rats on a high CLR diet (2% CLR) we set to determine whether atorvastatin administration (10mg/kg daily for 18-23weeks) modified AICAC. Middle cerebral arteries were pressurized in vitro at 60mmHg and AICAC was evoked by 50mM ethanol, that is within the range of blood alcohol detected in humans following moderate-to-heavy drinking. AICAC was evident in high CLR+atorvastatin group but not in high CLR diet+placebo. Statin exacerbation of AICAC persisted in de-endothelialized arteries, and was blunted by CLR enrichment in vitro. Fluorescence imaging of filipin-stained arteries showed that atorvastatin decreased vascular smooth muscle (VSM) CLR when compared to placebo, this difference being reduced by CLR enrichment in vitro. Voltage- and calcium-gated potassium channels of large conductance (BK) are known VSM targets of ethanol, with their beta1 subunit being necessary for ethanol-induced channel inhibition and resulting AICAC. Ethanol-induced BK inhibition in excised membrane patches from freshly isolated myocytes was exacerbated in the high CLR diet+atorvastatin group when compared to high CLR diet+placebo. Unexpectedly, atorvastatin decreased the amount and function of BK beta1 subunit as documented by immunofluorescence imaging and functional patch-clamp studies. Atorvastatin exacerbation of ethanol-induced BK inhibition disappeared upon artery CLR enrichment in vitro. Our study demonstrates for the first time statin's ability to exacerbate the vascular effect of a widely consumed drug of abuse, this exacerbation being driven by statin modulation of ethanol-induced BK channel inhibition in the VSM via CLR-mediated mechanism.

Topography prediction of helical transmembrane proteins by a new modification of the sliding window method.

Protein functions are specified by its three-dimensional structure, which is usually obtained by X-ray crystallography. Due to difficulty of handling membrane proteins experimentally to date the structure has only been determined for a very limited part of membrane proteins (<4%). Nevertheless, investigation of structure and functions of membrane proteins is important for medicine and pharmacology and, therefore, is of significant interest. Methods of computer modeling based on the data on the primary protein structure or the symbolic amino acid sequence have become an actual alternative to the experimental method of X-ray crystallography for investigating the structure of membrane proteins. Here we presented the results of the study of 35 transmembrane proteins, mainly GPCRs, using the novel method of cascade averaging of hydrophobicity function within the limits of a sliding window. The proposed method allowed revealing 139 transmembrane domains out of 140 (or 99.3%) identified by other methods. Also 236 transmembrane domain boundary positions out of 280 (or 84%) were predicted correctly by the proposed method with deviation from the predictions made by other methods that does not exceed the detection error of this method.