Pulmonary Vascular Obstruction Research Articles

Predictors of Residual Pulmonary Vascular Obstruction after Acute Pulmonary Embolism Based on Patient Variables and Treatment Modality.

Background: Residual Pulmonary Vascular Obstruction (RPVO) is an area of increasing focus in patients with acute pulmonary embolism (PE) due to its association with long-term morbidity and mortality. The predictive factors and the effect catheter-directed therapies (CDT) have on RPVO are still under investigation. Methods: This is a single-center retrospective review between April 2017 and July 2021. Patients with intermediate risk of PE were included. Patient variables associated with RPVO were analyzed and the degree of clot burden was quantified using the Qanadli score. Results: A total of 551 patients with acute PE were identified, 288 were intermediate risk and 53 had RPVO based on CT or V/Q scan three months post-PE. Baseline clot burden was higher in patients who received CDT compared to those who received anticoagulation alone (Qanadli score 45.88% vs. 31.94% p < 0.05). In univariate analysis, treatment with CDT showed a HR of 0.32 (95% CI 0.21-0.50, p < 0.001) when compared with anticoagulation alone. Patient variables including intermediate-high risk, sPESI ≥ 1, elevated biomarkers, RV dysfunction on imaging, malignancy, history of or concurrent DVT were also significantly associated with development of RPVO in univariate analysis. In multivariable analysis, only baseline Qanadli score (HR 13.88, 95% CI 1.42-135.39, p = 0.02) and concurrent DVT (HR 2.53, 95% CI 1.01-6.40, p = 0.04) were significantly associated with the development of RPVO. Conclusions: Catheter-directed therapy may be associated with a reduced risk of RPVO at 3 months; however, quantitative clot burden scores, such as the Qanadli score, may be stronger predictors of the risk of developing RPVO at 3 months. Further prospective studies are required.

Establishing a risk prediction model for residual pulmonary vascular obstruction after regular anticoagulant therapy for non-high-risk pulmonary embolism

Establishing a risk prediction model for residual pulmonary vascular obstruction after regular anticoagulant therapy for non-high-risk pulmonary embolism

Exercise Capacity Following Pulmonary Embolism in Children and Adolescents

BackgroundSelf-reported physical activity following pediatric pulmonary embolism(PE) is reduced after diagnosis. However, objectively measured exercise capacity and mechanisms of exercise pathophysiology following PE are unknown. Research QuestionDoes exercise capacity one year after acute PE in children differ from controls? Study Design and MethodsOur case-control study compared exercise capacity and responses to maximal exercise in PE survivors with controls. We also investigated the association of low exercise capacity following PE with prespecified clinical/radiological features at PE diagnosis and elucidated the cause of functional limitations. The primary study outcome was exercise capacity defined by peak oxygen uptake (peak VO2) as a percent of predicted on cardiopulmonary exercise testing (CPET), with <80% predicted peak VO2 considered abnormal/low. Ventilatory inefficiency was defined as VE/VCO2 slope >30 and abnormal stroke volume augmentation as oxygen pulse <10 mL O2.min -1 at peak exercise. Logistic regression was performed to assess the association of prespecified variables with low peak VO2. ResultsWe compared 25 consecutive pediatric PE survivors who completed CPET one-year post-diagnosis with 25 controls who underwent CPET within the same period and were otherwise healthy. Exercise capacity was reduced in 8 of the 25 PE survivors (32%) at one-year post-diagnosis vs. 2 of the 25 control participants (8%) (p:0.034). PE survivors with low exercise capacity demonstrated elevated VE/VCO2 slope (p: 0.01) and a decreased oxygen pulse at peak exercise (p:0.001) consistent with cardiovascular limitation. In univariable analysis, PE category, pulmonary vascular obstruction by Qanadli index, or RV dysfunction at diagnosis was not associated with low exercise capacity. InterpretationAbnormal exercise capacity of cardiopulmonary origin occurred in 1 of 3 pediatric PE survivors despite anticoagulation and irrespective of PE severity, degree of pulmonary vascular obstruction, or RV dysfunction at diagnosis. Cardiorespiratory fitness should be formally considered to develop rehabilitation interventions following pediatric PE.

Does pulmonary embolism guideline increase the pulmonary vascular obstruction index and help to elucidate the severity of pulmonary embolism?

According to Chinese Thoracic Society (CTS) guidelines, patients with pulmonary embolism (PE) can be stratified into low-risk, intermediate-low, intermediate-high, and high-risk groups based on the severity and comorbidity assessment. For low-risk PE patients, anticoagulant therapy can be given in outpatient department. Patients at high risk for PE may require thrombolytic therapy; however, this risk stratification is not included in comparing the pulmonary vascular obstruction index (PVOI) assessment. In practice, this severity and comorbidity assessment often leads people to believe that PE severity is positively correlated with PVOI assessment, i.e., the larger the thrombus, the higher the risk stratification, and the smaller the thrombus, the lower the risk stratification. Herein, we investigated the relationship between PVOI and risk stratification and prognosis in PE patients. We found that although some patients had a greater PVOI, they were low-risk patients according to the PE severity. Moreover, even though some patients had small PVOI, they were intermediate-risk and high-risk patients, and their PVOI did not correlate with the severity of PE. Therefore, we recommend that the PE guidelines add a classification of the degree of thrombus occlusion to the risk group, as this could reduce misconceptions about the severity and comorbidity assessment of PE.

Intensive Care Treatment of Pulmonary Embolism: An Update Based on the Revised AWMF S2k Guideline.

Acute pulmonary embolism (PE) remains a significant cause of morbidity and requires prompt diagnosis and management. The prognosis of affected patients depends on the clinical severity. Therefore, risk stratification is imperative for therapeutic decision-making. Patients with high-risk PE need intensive care. These include patients who have successfully survived resuscitation, with obstructive shock or persistent haemodynamic instability. Bedside diagnostics by means of sonographic procedures are of outstanding importance in this high-risk population. In addition to the treatment of hypoxaemia with noninvasive and invasive techniques, the focus is on drug-based haemodynamic stabilisation and usually requires the elimination or reduction of pulmonary vascular thrombotic obstruction by thrombolysis. In the event of a contraindication to thrombolysis or failure of thrombolysis, various catheter-based procedures for thrombus extraction and local thrombolysis are available today and represent an increasing alternative to surgical embolectomy. Mechanical circulatory support systems can bridge the gap between circulatory arrest or refractory shock and definitive stabilisation but are reserved for centres with the appropriate expertise. Therapeutic strategies for patients with intermediate- to high-risk PE in terms of reduced-dose thrombolytic therapy or catheter-based procedures need to be further evaluated in prospective clinical trials.

Impact of reperfusion therapies on clot resolution and long-term outcomes in patients with pulmonary embolism

ObjectiveMajor progress in reperfusion strategies has substantially improved the short-term outcomes of patients with pulmonary embolism (PE), however, up to 50% of patients report persistent dyspnea after acute PE. MethodsA retrospective study of the PE response team registry and included patients with repeat imaging at 3 to 12 months. The primary outcome was to determine the incidence of residual pulmonary vascular obstruction following acute PE. Secondary outcomes included the development of PE recurrence, right ventricular (RV) dysfunction, chronic thromboembolic pulmonary hypertension, readmission, and mortality at 12 months. ResultsA total of 382 patients were included, and 107 patients received reperfusion therapies followed by anticoagulation. Patients who received reperfusion therapies including systemic thrombolysis, catheter-directed thrombolysis, and mechanical thrombectomy presented with a higher vascular obstructive index (47% vs 28%; P < .001) and signs of right heart strain on echocardiogram (81% vs 43%; P < .001) at the time of diagnosis. A higher absolute reduction in vascular obstructive index (45% vs 26%; 95% confidence interval, 14.0-25.6; P < .001), greater improvement in RV function (82% vs 65%; P = .021), and lower 12-month mortality rate (2% vs 7%; P = .038) and readmission rate (33% vs 46%; P = .031) were observed in the reperfusion group. No statistically significant differences were found between groups in the development of chronic thromboembolic pulmonary hypertension (8% vs 5%; P = .488) and PE recurrence (8% vs 6%; P = .646). ConclusionsWe observed a favorable survival and greater improvement in clot resolution and RV function in patients treated with reperfusion therapies.

Changes in Pulmonary Vascular Resistance and Obstruction Score Following Acute Pulmonary Embolism in Pigs.

To investigate the contribution of mechanical obstruction and pulmonary vasoconstriction to pulmonary vascular resistance (PVR) in acute pulmonary embolism (PE) in pigs. Controlled, animal study. Tertiary university hospital, animal research laboratory. Female Danish slaughter pigs (n = 12, ~60 kg). None. PE was induced by infusion of autologous blood clots in pigs. CT pulmonary angiograms were performed at baseline, after PE (first experimental day [PEd0]) and the following 2 days (second experimental day [PEd1] and third experimental day [PEd2]), and clot burden quantified by a modified Qanadli Obstruction Score. Hemodynamics were evaluated with left and right heart catheterization and systemic invasive pressures each day before, under, and after treatment with the pulmonary vasodilators sildenafil (0.1 mg/kg) and oxygen (Fio2 40%). PE increased PVR (baseline vs. PEd0: 178 ± 54 vs. 526 ± 160 dynes; p < 0.0001) and obstruction score (baseline vs. PEd0: 0% vs. 45% ± 13%; p < 0.0001). PVR decreased toward baseline at day 1 (baseline vs. PEd1: 178 ± 54 vs. 219 ± 48; p = 0.16) and day 2 (baseline vs. PEd2: 178 ± 54 vs. 201 ± 50; p = 0.51). Obstruction score decreased only slightly at day 1 (PEd0 vs. PEd1: 45% ± 12% vs. 43% ± 14%; p = 0.04) and remained elevated throughout the study (PEd1 vs. PEd2: 43% ± 14% vs. 42% ± 17%; p = 0.74). Sildenafil and oxygen in combination decreased PVR at day 0 (-284 ± 154 dynes; p = 0.0064) but had no effects at day 1 (-8 ± 27 dynes; p = 0.4827) or day 2 (-18 ± 32 dynes; p = 0.0923). Pulmonary vasoconstriction, and not mechanical obstruction, was the predominant cause of increased PVR in acute PE in pigs. PVR rapidly declined over the first 2 days after onset despite a persistent mechanical obstruction of the pulmonary circulation from emboli. The findings suggest that treatment with pulmonary vasodilators might only be effective in the acute phase of PE thereby limiting the window for such therapy.

Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension

Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A–D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH; however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA–CREB–BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.

Patients with CTEPH and mild hemodynamic severity of disease improve to a similar level of exercise capacity after pulmonary endarterectomy compared to patients with severe hemodynamic disease.

The correlation between hemodynamics and degree of pulmonary vascular obstruction (PVO) is known to be poor in chronic thromboembolic pulmonary hypertension(CTEPH), which makes the selection of patients eligible for pulmonary endarterectomy (PEA) challenging. It can be postulated that patients with similar PVO but different hemodynamic severity have different postoperative hemodynamics and exercise capacity. Therefore, we aimed to assess the effects of PEA on hemodynamics and exercise physiology in mild and severe CTEPH patients. We retrospectively studied 18 CTEPH patients with a mild hemodynamic profile (mean pulmonary arterial pressure[mPAP] between 25 and 30 mmHg at rest) and CTEPH patients with a more severe hemodynamic profile (mPAP > 30 mmHg), matched by age, gender, and PVO. Cardiopulmonary exercise testing parameters were evaluated at baseline and 18 months following PEA. At baseline, exercise capacity, defined as oxygen uptake, was less severely impaired in the mild CTEPH group compared to the severe CTEPH group. After PEA, in the mild CTEPH group, ventilatory efficiency and oxygen pulse improved significantly (p < 0.05), however, the change in ventilatory efficiency and oxygen pulse was smaller compared to the severe CTEPH group. Only in the severe CTEPH group exercise capacity improved significantly (p < 0.001). Hence, in the present study, postoperative hemodynamic outcome and the CPET-determined recovery of exercise capacity in mild CTEPH patients did not differ from a matched group of severe CTEPH patients.

Chronic Thromboembolic Pulmonary Hypertension after Pulmonary Embolism in SARS-CoV-2

Introduction: Chronic thromboembolic pulmonary disease (CTEPD) consists of persistent pulmonary vascular obstruction on imaging and involves long-term functional limitations, with or without chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to evaluate the incidence and risk factors of both persistent pulmonary vascular defects and CTEPH after hospitalization in patients with COVID-19 and PE during a 2-year follow-up. Methods: A prospective observational study was carried out in a tertiary hospital center. Patients were hospitalized between March 2020 and December 2021 with a diagnosis of PE during SARS-CoV-2 infection. Patients received anticoagulant treatment for at least 3 months and were followed up for 2 years. Between the third and fourth months after discharge, all patients were evaluated for the presence of residual thrombotic defects by CTPA and/or perfusion pulmonary scintigraphy. Clinical findings, lung function tests with DLCO, exercise capacity, and echocardiograms were also assessed. Results: Of the 133 patients included, 18% had persistent thrombotic defects on lung imaging at follow-up. The incidence of CTEPD was 0.75% at 2 years of follow-up. Patients with persistent defects were significantly older, had a higher prevalence of systemic arterial hypertension, higher D-dimer and NT-proBNP levels, and more severe PE at diagnosis. Furthermore, there was a higher prevalence of right ventricular dysfunction on echocardiogram at diagnosis of PE (25.0% vs. 2.7%, p = 0.006). This was the only variable independently related to persistent defects in multivariate analyses (OR: 8.13 [95% CI: 1.82–36.32], p = 0.006). Conclusion: The persistence of thrombotic defects after PE is a common finding after SARS-CoV-2 infection, affecting 18% of the population. However, the incidence of CTEPH appears to be lower (0.75%) in COVID-19-related PE compared to that previously observed in PE unrelated to COVID-19.

Residual Pulmonary Vascular Obstruction Following Mechanical Thrombectomy for Submassive Pulmonary Embolism: A Single-Center Analysis

BackgroundResidual pulmonary vascular obstruction (RPVO) following pulmonary embolism (PE) is associated with residual dyspnea, recurrent venous thromboembolism, and chronic thromboembolic pulmonary hypertension. Historically, acute PE treated with anticoagulation alone results in high rates of significant RPVO. Contemporary treatment of submassive PE often involves catheter-based interventions, including mechanical thrombectomy (MT), although their relation to RPVO is not characterized. In this study, we aimed to evaluate the rate of ≥10% RPVO in patients treated with MT. MethodsTwenty consecutive patients with submassive PE in a single center underwent MT and subsequent planar ventilation/perfusion scintigraphy scan at a median of 4 months after thrombectomy. A quantitative perfusion score was calculated for each planar ventilation/perfusion scintigraphy study to provide a % perfusion defect. Complete hemodynamic data were collected during the procedure and Miller score was calculated using prepulmonary and postpulmonary angiography. Echocardiographic data were collected prior to, 24 to 48 hours after, and 30 days after the procedure. ResultsFour of 20 patients (20%) had ≥10% RPVO at a median of 4 months follow-up. Following MT, the mean Miller score decreased from 24.5 ± 2.9 to 15.8 ± 3.3 (P < .001) and mean pulmonary artery pressure decreased from 36.1 ± 4.8 mm Hg to 26.8 ± 5.4 mm Hg (P < .001). Right ventricle–to–left ventricle ratio decreased from 1.44 ± 0.2 to 1.05 ± 0.24 by 24 to 48 hours (P < .001) and 0.85 ± 0.1 at 30 days (P < .001) and right ventricular systolic pressure decreased from 63.2 ± 10 mm Hg to 42.1 ± 9.8 mm Hg at 24 to 48 hours (P < .001) and 31.9 ± 10.4 at 30 days (P < .001). ConclusionsIn this prospective study of patients with submassive PE treated with MT, favorable rates of RPVO were noted in comparison to prior studies of anticoagulation alone along with expected acute hemodynamic and echocardiographic improvements. While this study was small in scope, the results suggest the potential for long-term benefits of MT in acute PE in addition to the acute benefits previously described.

Reduced fibrin clot permeability on admission and elevated E-selectin at 3 months as novel risk factors of residual pulmonary vascular obstruction in patients with acute pulmonary embolism

BackgroundResidual pulmonary vascular obstruction (RPVO) is common following pulmonary embolism (PE) but its association with fibrin clot properties is poorly understood. We investigated whether prothrombotic state and hypofibrinolysis markers can identify patients with RPVO.MethodsIn 79 normotensive noncancer patients (aged 56 ± 13.3 years) with acute PE, we determined fibrin clot permeability (Ks), clot lysis time (CLT), endogenous thrombin potential (ETP), fibrinolysis proteins, oxidative stress markers, and E-selectin on admission before initiation of anticoagulant therapy, after 5–7 days, and 3 months of anticoagulation. RPVO was diagnosed using computed tomography angiography 3–6 months since PE.ResultsPatients with RPVO (n = 23, 29.1%) had at baseline higher simplified Pulmonary Embolism Severity Index (sPESI) (P = 0.004), higher N-terminal brain natriuretic propeptide (P = 0.006) and higher D-dimer (P = 0.044). Patients with versus without RPVO had lower Ks (P < 0.001) and longer CLT (P < 0.05), both at baseline and 5–7 days since admission, but not at 3 months. Patients with RPVO showed 40.6% higher E-selectin (P < 0.001) solely at 3 months. By multivariable logistic regression, baseline Ks (odds ratio [OR] 0.010, 95% confidence interval [CI] 0.001–0.837, P = 0.042, per 10− 9 cm2), baseline D-dimer (OR 1.105, 95% CI 1.000-1.221, P = 0.049, per 100 ng/ml), and E-selectin levels after 3 months (OR 3.874, 95% CI 1.239–12.116, P = 0.020, per 1 ng/ml) were associated with RPVO.ConclusionsRPVO patients despite anticoagulation characterize with the formation of denser fibrin clots on admission and higher E-selectin at 3 months. Those parameters could be the potential novel RPVO risk factors that warrant further evaluation in an independent cohort.Graphical

PB0444 Residual Pulmonary Vascular Obstruction is Associated with Prothrombotic Fibrin Clot Phenotype in Patients Following Pulmonary Embolism

PB0444 Residual Pulmonary Vascular Obstruction is Associated with Prothrombotic Fibrin Clot Phenotype in Patients Following Pulmonary Embolism

To Study the Correlation of Clinical Severity and Cytokine Storm in COVID-19 Pulmonary Embolism Patients by Using Computed Tomography Pulmonary Angiography (CTPA) Qanadli Clot Burden Scoring System.

Pulmonary embolism (PE) is a fatal form of venous thromboembolism (VTE), with an overall untreated mortality of up to 30%. Greater than 50% of patients with lower extremity proximal DVT have concurrent PE at presentation. VTE has been seen in up to one-third of patients with COVID-19 infections requiring intensive care unit (ICU) admission.The objective of this study is to determine the correlation between CT pulmonary angiography, pulmonary embolism clot burden, and the Qanadli scoring system with clinically severe COVID-19 pneumonia and cytokine storm. 153 COVID-19 hospitalized patients who underwent CT pulmonary angiography (CTPA) for likelyPE on pretest probability modified Wells criteriawere enrolled. COVID-19 pneumonia was classified as URTI (upper respiratory tract infection), mild, severe, and critical COVID pneumonia. For data analysis, we categorized into two groups: (1) the non-severe group included URTI and mild pneumonia, and (2) the severe group included severe and critical pneumonia. We used the Qanadli scoring system to assess the PE percentages of pulmonary vascular obstruction using CTPA. Results: 41.8% (64) of COVID-19 patients were diagnosed with pulmonary embolism (PE) on CTPA. The majority of 51.6% of pulmonary vascular occlusions using the Qanadli scoring system for pulmonary embolism were at segmental arterial levels. Out of 104 COVID-19 cytokine storm patients, 45 (43%)were associated with pulmonary embolism. Overall, a 25% (16) mortality rate wasobserved in COVID-19 patients with pulmonary embolism. The pathogenesis of hypercoagulability in COVID-19 may include direct endothelial cell invasion by the virus, microvascular inflammation, endothelial exocytosis, and endotheliitis. A meta-analysis of 71 studies to investigate the occurrence of PE on CTPA in COVID-19 patients found 48.6% in ICU settingsand 65.3% of patients have clots in the peripheral pulmonary vasculature. There is a significant correlation between pulmonary embolism and high clot burdenQanadli CTPA scores, as well as between the severity of COVID-19 pneumonia and mortality. The association between critically ill COVID-19 pneumonia and pulmonary embolism may result in higher mortality and a poor prognostic marker.

Oxygenation index and NT-proBNP as predictors of pulmonary hypertension and ventilation/perfusion mismatch in acute pulmonary embolism.

The magnitude of pulmonary artery pressure (PAP) and the extent of ventilation/perfusion (V/Q) mismatch are essential for assessing the prognosis of acute pulmonary embolism (APE). We aimed to develop a model for predicting the status of the pulmonary circulation and arterial gas exchange functions using serum levels of cardiac biomarkers and arterial oxygenation index (OI) values. This single-center, retrospective observational cohort study included 224 patients with APE. Multivariate linear regression and Poisson regression were used to test the statistical association between cardiac biomarkers, OI, PAP, and V/Q mismatch. Diagnostic efficiency was calculated from a receiver operating characteristic (ROC) curve. Serum levels of troponin I (TNI), N-terminal pro-brain natriuretic peptide (NT-proBNP), and arterial OI magnitude significantly correlated with PAP and V/Q mismatches (P < 0.05). Multivariate linear regression showed that NT-proBNP serum levels (β = 0.002, P < 0.001) and OI values (β = -0.022, P = 0.001) significantly influenced PAP. Arterial OI (β = -0.039, P < 0.001) had a significant influence on the percentage of pulmonary vascular obstruction (PVO) as determined by perfusion scanning. Poisson regression showed that OI (odds ratio: 0.995, p < 0.001) was a predictor of the number of lung segments with V/Q mismatches. ROC area under the curve (AUC) values of NT-proBNP and OI predicting pulmonary hypertension were 0.716 and 0.730, respectively, and for V/Q mismatch scanning, the results were 0.601 and 0.634, respectively. Arterial OI and serum levels of cardiac biomarkers may be used as indicators of pulmonary hypertension and V/Q mismatch.

Residual pulmonary vascular obstruction and recurrence after acute pulmonary embolism: a systematic review and meta-analysis of individual participant data

We aimed to assess the relationship between residual pulmonary vascular obstruction (RPVO) on planar lung scan after completion of at least 3 months of anticoagulant therapy for acute pulmonary embolism (PE) and the risk of recurrent venous thromboembolism (VTE) or death due to PE one year after treatment discontinuation. The systematic review was registered with the International Prospective Registry of Systematic Reviews (PROSPERO: CRD42017081080). The primary outcome measure was to generate a pooled estimate of the rate of recurrent VTE at one year in patient with RPVO diagnosed on planar lung scan after discontinuation of at least 3 months of anticoagulant treatment for an acute PE. Individual data were obtained for 809 patients. RPVO (ie, obstruction >0%) was found in 407 patients (50.3%) after a median of 6.6 months of anticoagulant therapy for a first acute PE. Recurrent VTE or death due to PE occurred in 114 patients (14.1%), for an annual risk of 6.4% (95% confidence interval, 4.7%-8.6%). Out of the 114 recurrent events, 63 occurred within one year after discontinuation of anticoagulant therapy corresponding to a risk of 8.1% (6.4%-9.8%) at 1 year. The risk of recurrent VTE at one year was 5.8% (4.4-7.2) in participants with RPVO <5%, vs 11.7% (9.5-13.8) in participants with RPVO ≥5%. RPVO is a significant predictor of the risk of recurrent venous thromboembolism. However, the risk of recurrent events remains too high in patients without residual perfusion defect for it to be used as a stand-alone test to decide on anticoagulation discontinuation.

Frequency and predictors for chronic thromboembolic pulmonary hypertension after a first unprovoked pulmonary embolism: Results from PADIS studies

BackgroundChronic thromboembolic pulmonary hypertension (CTEPH) is a life‐threatening complication of a pulmonary embolism (PE) whose incidence and predictors are not precisely determined. ObjectiveTo determine the frequency and predictors for CTEPH after a first unprovoked PE. Patients/MethodsIn a randomized trial comparing an additional 18‐month warfarin versus placebo in patients after a first unprovoked PE initially treated with vitamin K antagonist for 6 months, we applied recommended CTEPH screening strategies through an 8‐year follow‐up to determine cumulative incidence of CTEPH. CTEPH predictors were estimated using Cox models. Pulmonary vascular obstruction (PVO) and systolic pulmonary arterial pressure (sPAP) at PE diagnosis and 6 months were studied by receiver operating curves analysis. All CTEPH cases and whether they were incident or prevalent were adjudicated. ResultsDuring a median follow‐up of 8.7 years, nine CTEPH cases were diagnosed among 371 patients, with a cumulative incidence of 2.8% (95% confidence interval [CI] 0.95–4.64), and of 1.31% (95% CI 0.01–2.60) after exclusion of five cases adjudicated as prevalent. At PE diagnosis, PVO > 45% and sPAP > 56 mmHg were associated with CTEPH with a hazard ratio (HR) of 33.00 (95% CI 1.64–667.00, p = .02) and 12.50 (95% CI 2.10–74.80, p < .01), respectively. Age > 65 years, lupus anticoagulant antibodies and non‐O blood groups were also predictive of CTEPH. PVO > 14% and sPAP > 34 mmHg at 6 months were associated with CTEPH (HR 63.90 [95% CI 3.11–1310.00, p < .01]and HR 17.2 [95% CI 2.75–108, p < .01]). ConclusionAfter a first unprovoked PE, CTEPH cumulative incidence was 2.8% during an 8‐year follow‐up. PVO and sPAP at PE diagnosis and at 6 months were the main predictors for CTEPH diagnosis.

Abstract 12004: Mitochondrial Fission Mediator MiD49 Regulates Proliferation via MYO1C in Pulmonary Arterial Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by pulmonary vascular obstruction that is partially due to hyperproliferation of apoptosis-resistant pulmonary arterial smooth muscle cells (PASMC). This “pseudoneoplastic phenotype” of PAH PASMC is due, in part, to excessive mitochondrial fission caused by activation of dynamin related protein-1 (Drp-1) and its binding partner MiD49. The mechanism by which MiD49 regulates the proliferation of PASMC is not completely understood. Here we investigate the possibility that MiD49 promotes cellular proliferation by regulating a non-filamentaous class-1 myosin protein, MYO1C. Hypothesis: MiD49 regulates cell proliferation via a MYO1C-dependent mechanism, which is pathologically upregulated in PAH. Methods: MiD49 and MYO1C expression was compared between normal (n=4) vs PAH (n=5) human PASMC using western blot analysis. The colocalization was visualized using super-resolution confocal microscopy. The effects of manipulating MYO1C on cell proliferation and apoptosis were assessed by flowcytometry. Results: MiD49 and MYO1C are upregulated and colocalized in PAH PASMC. The expression of MYO1C positively correlated with MiD49 in PAH. Silencing MiD49 downregulated MYO1C expression whilst augmenting MiD49 upregulated MYO1C. Silencing MYO1C, however, does not affect MiD49 expression, proving that MYO1C is downstream of MiD49. The downregulation of MYO1C by MiD49 silencing is rescued by a proteasomal blockade, MG132. Downregulating MYO1C using siRNA inhibited proliferation, prevented ERK1/2 activation, and induced apoptosis in PAH PASMC. Conclusion: Increased proliferation and apoptosis resistance of PAH PASMC are in part due to the dysregulation of MiD49-MYO1C pathway. Targeting this pathway may have therapeutic implications against PAH.

Quantification of the pulmonary vascular obstruction index on ventilation/perfusion lung scintigraphy: Comparison of a segmental visual scoring to the Meyer score.

Quantifying the pulmonary vascular obstruction index (PVOI) is essential for the management of patients with pulmonary embolism or chronic thromboembolic pulmonary hypertension (CTEPH). The reference method for quantifying the PVOI with planar lung ventilation/perfusion (V/Q) scintigraphy is the Meyer score, which was validated using pulmonary angiography as a reference standard. However, it is complex to use in daily practice. In contrast, a rapid and fast quantification method consists in estimating the PVOI based on the number of segmental perfusion defects. However, the accuracy of this method has never been evaluated. In this study, we aimed to compare PVOI quantification on planar V/Q scintigraphy assessed by a segmental visual scoring (SVS) to the Meyer score. The eligible study population consisted of consecutive patients who underwent planar V/Q scan for CTEPH screening. A central review was performed by three nuclear medicine physicians. PVOI was assessed by summing the number of segmental perfusion defects or equivalent (2 sub-segments = 1 segment = 5%) and by Meyer's method. The two interpretations were performed 6 months apart. A Spearman rank correlation coefficient was calculated to evaluate correlation between the two measurement methods. An intra-class correlation (ICC) was calculated to assess agreement. A Bland et Altman plot analysis was used to evaluate agreement between the two measurements. A total of 226 V/Q scans were interpreted. Spearman rank correlation coefficient between SVS and Meyer was 0.963 (95%CI 0.952-0.971) for mismatched perfusion defects and 0.963 (95%CI 0.953-0.972) for perfusion defects regardless of ventilation. Intra-class correlation (ICC) for agreement was 0.978 (95%CI 0.972-0.983) for mismatched perfusion defects and 0.968 (95%CI 0.959-0.976) for perfusion defects regardless of ventilation. In Bland & Altmann analysis, the mean difference between the SVS method and the Meyer score was 0.42 and 0.61 for the mismatched or matched evaluation, respectively. Our study shows a high correlation, and low differences in PVOI quantification when using a segmental visual scoring (SVS) as compared to the Meyer score. The SVS has the great advantage to be easy and rapid to apply in daily practice.

Intrapulmonary shunt and alveolar dead space in a cohort of patients with acute COVID-19 pneumonitis and early recovery.

Pathological evidence suggests that coronavirus disease 2019 (COVID-19) pulmonary infection involves both alveolar damage (causing shunt) and diffuse microvascular thrombus formation (causing alveolar dead space). We propose that measuring respiratory gas exchange enables detection and quantification of these abnormalities. We aimed to measure shunt and alveolar dead space in moderate COVID-19 during acute illness and recovery. We studied 30 patients (22 males; mean±sd age 49.9±13.5 years) 3-15 days from symptom onset and again during recovery, 55±10 days later (n=17). Arterial blood (breathing ambient air) was collected while exhaled oxygen and carbon dioxide concentrations were measured, yielding alveolar-arterial differences for each gas (P A-aO2 and P a-ACO2 , respectively) from which shunt and alveolar dead space were computed. For acute COVID-19 patients, group mean (range) for P A-aO2 was 41.4 (-3.5-69.3) mmHg and for P a-ACO2 was 6.0 (-2.3-13.4) mmHg. Both shunt (% cardiac output) at 10.4% (0-22.0%) and alveolar dead space (% tidal volume) at 14.9% (0-32.3%) were elevated (normal: <5% and <10%, respectively), but not correlated (p=0.27). At recovery, shunt was 2.4% (0-6.1%) and alveolar dead space was 8.5% (0-22.4%) (both p<0.05 versus acute). Shunt was marginally elevated for two patients; however, five patients (30%) had elevated alveolar dead space. We speculate impaired pulmonary gas exchange in early COVID-19 pneumonitis arises from two concurrent, independent and variable processes (alveolar filling and pulmonary vascular obstruction). For most patients these resolve within weeks; however, high alveolar dead space in ∼30% of recovered patients suggests persistent pulmonary vascular pathology.