The Function of microRNAs in Pulmonary Embolism: Review and Research Outlook

Pulmonary embolism (PE) is a common pathologic condition that frequently occurs in patients with deep venous thrombosis. Severe PE may critically suppress cardiopulmonary function, thereby threatening the life of patients. Chronic pulmonary hypertension caused by PE may lead to deterioration of respiratory dysfunction, resulting in complete disability. MicroRNAs (miRNAs) are a group of abundantly expressed non-coding RNAs that exert multiple functions in regulating the transcriptome via post-transcriptional targeting of mRNAs. Specifically, miRNAs bind to target mRNAs in a matching mechanism between the miRNA seed sequence and mRNA 3ʹ UTR, thus modulating the transcript stability or subsequent translation activity by RNA-induced silencing complex. Current studies have reported the function of miRNAs as biomarkers of PE, revealing their mechanism, function, and targetome in venous thrombophilia. This review summarizes the literature on miRNA functions and downstream mechanisms in PE. We conclude that various related miRNAs play important roles in PE and have great potential as treatment targets. For clinical application, we propose that miRNA biomarkers combined with traditional biomarkers or miRNA signatures generated from microchips may serve as a great predictive tool for PE occurrence and prognosis. Further, therapies targeting miRNAs or their upstream/downstream molecules need to be developed more quickly to keep up with the progress of routine treatments, such as anticoagulation, thrombolysis, or surgery.

COVID-19 as a cause of chronic pulmonary hypertension: pathophysiological rationale and potential of instrumental investigations

Coronavirus disease 2019 (COVID-19) is a poorly understood and dangerous medical problem. COVID-19-related pulmonary vessels involvement is a complex set of interrelated pathophysiological processes associated with vascular endothelial dysfunction and accompanied by thrombosis of various localization, vasomotor disorders, severe respiratory failure, as well as pulmonary embolism (PE) resulting in chronic thromboembolic pulmonary hypertension (CTEPH). According to computed tomographic pulmonary angiography, the incidence of PE in patients with COVID-19 ranges from 23 to 30%. The aim of this work was to focus the doctors' attention on the risk of pulmonary hypertension in patients after COVID-19.Despite the ability of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) to infect various organs and systems, the main and most serious complications are pulmonary infiltration, acute respiratory distress syndrome, acute respiratory failure and PE, which in some cases becomes the triggering mechanism for CTEPH development. The literature review presents data on main pathological abnormalities developing in target organs during COVID-19 and playing an important role in increasing the CTEPH risk. The paper describes the main methods of instrumental investigations of CTEPH and an algorithm for its use in COVID-19 survivors.The revealed data demonstrated that the absence of obvious signs of pulmonary hypertension/CTEPH, the cardiopulmonary system abnormalities cannot be ruled out. Therefore, it seems appropriate to actively follow up COVID-19 survivors. A thoroughly, purposefully collected anamnesis, pulmonary function tests and stress echocardiography in an ambiguous clinical situation will play a leading role as they identify cardiopulmonary disorders and provide the doctor with basic information for further planning of patient management.

INFERIOR VENA CAVA FILTER RETRIEVAL 23 MONTH AFTER IMPLANTATION WITH STANDARD SNARE LOOP TECHNIQUE : CASE REPORT

1. Introduction. Pulmonary embolism (PE ) and Deep vein thrombosis (DVT ) continues to be a cause of signicant morbidity and mortality which is also third 1 leading cardiovascular cause of death . If not treated properly it also leads to chronic pulmonary hypertension and cor pulmonale . Once DVT is diagnosed treatmet is required and consist of oral anticoagulation and inferior vena cava interruption via lter placement in patients with contraindication for anticoagulation treatment. In 2003 ,the U.S .Food and Drug Administration (FDA ) cleared retrievable inferior vena cave lters (rIVCFs) for clinical use , after that its uses exponentially increases . In parallel with these trends ,there has been growing awareness of device –related complication including fracture , penetration to adjuscent structure , migration , thrombosis and some time embolisation of fractured segment in heart that leads to cardiac 2 3 peforation , arrhythmia and death . In response , the FDA released safety communication in 2010 and 2014 advocating immediate retrieval of 4 lter once mechanical prophylaxis was no longer uses .However retrieval of lter remained rare with rates reported as low as 8.5 %. . Once lter remain in place for long duration, normal standard snare retrieval technique usually not work and alternative techniques like , Sling technique , 5 Excimer laser and Endobronchial forcep supported methods can be used . But prolong duration of lter implantion always associated with less chance of lter retrieval and associated with multiple complication .

Norepinephrine and dobutamine improve cardiac index equally by supporting opposite sides of the heart in an experimental model of chronic pulmonary hypertension

Background Pulmonary hypertension is a significant risk factor in patients undergoing surgery. The combined effects of general anaesthesia and positive pressure ventilation can aggravate this condition and cause increased pulmonary blood pressures, reduced systemic blood pressures and ventricular contractility. Although perioperative use of inotropic support or vasopressors is almost mandatory for these patients, preference is disputed. In this study, we investigated the effects of norepinephrine and dobutamine and their ability to improve the arterio-ventricular relationship and haemodynamics in pigs suffering from chronic pulmonary hypertension. Method Pulmonary hypertension was induced in five pigs by banding the pulmonary artery at 2–3 weeks of age. Six pigs served as controls. After 16 weeks of pulmonary artery banding, the animals were re-examined under general anaesthesia using biventricular conductance catheters and a pulmonary artery catheter. After baseline measurements, the animals were exposed to both norepinephrine and dobutamine infusions in incremental doses, with a stabilising period in between the infusions. The hypothesis of differences between norepinephrine and dobutamine with incremental doses was tested using repeated two-way ANOVA and Bonferroni multiple comparisons post-test. Results At baseline, pulmonary artery-banded animals had increased right ventricular pressure (+ 39%, p = 0.04), lower cardiac index (− 23% p = 0.04), lower systolic blood pressure (− 13%, p = 0.02) and reduced left ventricular end-diastolic volume (− 33%, p = 0.02). When incremental doses of norepinephrine and dobutamine were administered, the right ventricular arterio-ventricular coupling was improved only by dobutamine (p < 0.05). Norepinephrine increased both left ventricular end-diastolic volume and left ventricular contractility to a greater extent (p < 0.05) in pulmonary artery-banded animals. While the cardiac index was improved equally by norepinephrine and dobutamine treatments in pulmonary artery-banded animals, norepinephrine had a significantly greater effect on mean arterial pressure (p < 0.05) and diastolic arterial pressure (p < 0.05). Conclusion While norepinephrine and dobutamine improved cardiac index equally, it was obtained in different manners. Dobutamine significantly improved the right ventricular function and the arterio-ventricular coupling. Norepinephrine increased systemic resistance, thereby improving arterial pressures and left ventricular systolic function by maintaining left ventricular end-diastolic volume.

Norepinephrine and dobutamine improve cardiac index equally by supporting opposite sides of the heart in an experimental model of chronic pulmonary hypertension

Background: Pulmonary hypertension is a significant risk factor in patients undergoing surgery. The combined effects of general anaesthesia and positive pressure ventilation can aggravate this condition and cause increased pulmonary blood pressures, reduced systemic blood pressures and ventricular contractility. Although perioperative use of inotropic support or vasopressors is almost mandatory for these patients, preference is disputed. In this study, we investigated the effects of norepinephrine and dobutamine and their ability to improve the arterio-ventricular relationship and haemodynamics in pigs suffering from chronic pulmonary hypertension.Method: Pulmonary hypertension was induced in five pigs by banding the pulmonary artery at 2–3 weeks of age. Six pigs served as controls. After 16 weeks of pulmonary artery banding, the animals were re-examined under general anaesthesia using biventricular conductance catheters and a pulmonary artery catheter. After baseline measurements, the animals were exposed to both norepinephrine and dobutamine infusions in incremental doses, with a stabilizing period in between the infusions. The hypothesis of differences between norepinephrine and dobutamine with incremental doses was tested using repeated two-way ANOVA and Bonferroni multiple comparisons post-test. Results: At baseline, pulmonary artery banded animals had increased right ventricular pressure (+39%, p=0.04), lower cardiac index (-23% p=0.04), lower systolic blood pressure (-13%, p=0.02) and reduced left ventricular end-diastolic volume (-33%, p=0.02). When incremental doses of norepinephrine and dobutamine were administered, the right ventricular arterio-ventricular coupling was improved only by dobutamine (p<0.05). Norepinephrine increased both left ventricular end-diastolic volume and left ventricular contractility to a greater extent (p<0.05) in pulmonary artery banded animals. While the cardiac index was improved equally by norepinephrine and dobutamine treatments in pulmonary artery banded animals, norepinephrine had a significantly greater effect on mean arterial pressure (p<0.05) and diastolic arterial pressure (p<0.05).Conclusion: While norepinephrine and dobutamine improved cardiac index equally, it was obtained in different manners. Dobutamine significantly improved the right ventricular function and the arterio-ventricular coupling. Norepinephrine increased systemic resistance, thereby improving arterial pressures and left ventricular systolic function by maintaining left ventricular end-diastolic volume.

Mechanisms Contributing to the Dysregulation of miRNA-124 in Pulmonary Hypertension

Chronic pulmonary hypertension (PH) is a fatal disease characterized by the persistent activation of pulmonary vascular cells that exhibit aberrant expression of genes including miRNAs. We and others reported that decreased levels of mature microRNA-124 (miR-124) plays an important role in modulating the activated phenotype of pulmonary vascular cells and HDAC inhibitors (HDACi) can restore the levels of mature miR-124 and reverse the persistently activated phenotype of PH vascular cells. In this study, we sought to determine the mechanisms contributing to reduced levels of miRNAs, as well as how HDACi restores the levels of reduced miRNA in PH vascular cells. We found that pulmonary artery fibroblasts isolated from IPAH patients (PH-Fibs) exhibit reduced levels of mature miR-124 and several other miRNAs including let-7i, miR-224, and miR-210, and that these reduced levels can be restored by HDACi. Using miR-124 expression in human PH-Fibs as a model, we determined that reduced miR-124 gene transcription, not decreased expression of miRNA processing genes, is responsible for reduced levels of mature miR-124 in human PH-Fibs. Using both DNase I Sensitivity and chromatin immunoprecipitation assays, we found that the miR-124-1 gene exhibits a more condensed chromatin structure in human PH-Fibs, compared to corresponding controls. HDACi relaxed miR-124-1 chromatin structure, evidenced by increased levels of the open chromatin mark H3K27Ac, but decreased levels of closed chromatin mark H3K27Me3. Most importantly, the delivery of histone acetyltransferase (HAT) via CRISPR-dCas9-HAT and guiding RNAs to the promoter of the miR-124-1 gene increased miR-124-1 gene transcription. Thus, our data indicate epigenetic events play important role in controlling miR-124 and likely other miRNA levels and epigenetic regulators such as HDACs appear to be promising therapeutic targets for chronic PH.

Multicentre prospective observational study exploring the predictive value of functional echocardiographic indices for early identification of preterm neonates at risk of developing chronic pulmonary hypertension secondary to chronic neonatal lung disease

IntroductionAlthough chronic pulmonary hypertension (cPH) secondary to chronic neonatal lung disease is associated with increased mortality and respiratory and neurodevelopmental morbidities, late diagnosis (typically ≥36 weeks postmenstrual age, PMA) and the use of qualitative echocardiographic diagnostic criterion (flat interventricular septum in systole) remain significant limitations in clinical care. Our objective in this study is to evaluate the utility of relevant quantitative echocardiographic indices to identify cPH in preterm neonates, early in postnatal course and to develop a diagnostic test based on the best combination of markers.Methods and analysisIn this ongoing international prospective multicentre observational diagnostic accuracy study, we aim to recruit 350 neonates born <27 weeks PMA and/or birth weight <1000 g and perform echocardiograms in the third week of age and at 32 weeks PMA (early diagnostic assessments, EDA) in addition to the standard diagnostic assessment (SDA) for cPH at 36 weeks PMA. Predefined echocardiographic markers under investigation will be measured at each EDA and examined to create a scoring system to identify neonates who subsequently meet the primary outcome of cPH/death at SDA. Diagnostic test characteristics will be defined for each EDA. Pulmonary artery acceleration time and tricuspid annular plane systolic excursion are the primary markers of interest.Ethics and disseminationEthics approval has been received by the Mount Sinai Hospital Research Ethics Board (REB) (#16-0111-E), Sunnybrook Health Sciences Centre REB (#228-2016), NHS Health Research Authority (IRAS 266498), University of Iowa Human Subjects Office/Institutional Review Board (201903736), Rotunda Hospital Research and Ethics Committee (REC-2019-008), and UBC Children’s and Women’s REB (H19-02738), and is under review at Boston Children’s Hospital Institutional Review Board. Study results will be disseminated to participating families in lay format, presented to the scientific community at paediatric and critical care conferences and published in relevant peer-reviewed journals.Trail registration numberNCT04402645.

Survey of practices in relation to chronic pulmonary hypertension in neonates in the Canadian Neonatal Network and the National Institute of Child Health and Human Development Neonatal Research Network

Current knowledge gaps pertaining to diagnosis and management of neonatal chronic pulmonary hypertension (cPH) may result in significant variability in clinical practice. The objective of the study is to understand cPH management practices in neonatal intensive care units affiliated with the Canadian Neonatal Network (CNN) and National Institute of Child Health and Human Development Neonatal Research Network (NRN). A 32-question survey seeking practice details for cPH evaluation, diagnostic criteria, conservative measures, pharmacotherapeutics, and follow-up was e-mailed to a designated physician at each center. Responses were described as frequency (percentage) and compared between CNN and NRN, where appropriate. Overall response rate was 67% (CNN 20/28 (71%), NRN 9/15 (60%)). While 8 (28%) centers had standardized management protocols, 17 (59%) routinely evaluate high-risk patients; moderate-severe chronic lung disease being the commonest indication. While interventricular septal flattening on echocardiography was the commonest listed diagnostic criterion, several adjunctive indices were also identified. Asymptomatic neonates with cPH were managed expectantly (routine care) in 50% of sites, and using various conservative measures in others. Pulmonary vasodilators were prescribed for symptomatic cases, with 60% of sites using them early (86% reporting any use). Seventy-five percent of sites use inhaled nitric oxide and sildenafil citrate as first- and second-line agents, respectively. Use of standard protocols, cardiac catheterization, and conservative measures for asymptomatic cases was more common in NRN units ( p < 0.05). While there is relative homogeneity in patient identification and diagnostic criteria used for neonatal cPH, significant interunit inconsistencies still exists in routine evaluation, use of additional investigations, management of asymptomatic cases, frequency and type of conservative measures, and choice of pulmonary vasodilators.