Thromboembolic Pulmonary Hypertension Research Articles

Induced Ablation of Prmt1 in Endothelial Cells Causes Endothelial Dysfunction Associated with Pulmonary Thromboembolic Hypertension

Endothelial cells (ECs) play vital roles in regulation of vascular homeostasis, vascular tone, leukocyte traffcking, and barrier function to ensure pulmonary function. Endothelial dysfunction is a key factor for the progression of pulmonary pathogenesis. Protein arginine methyltransferase 1 (Prmt1) catalyzes asymmetric di-methylation of substrates on arginine residues and is implicated in a variety of cellular processes, including cardiovascular function. In the current study, we examined the role of Prmt1 in endothelial function by using tamoxifen-inducible EC-specific Prmt1 ablation (KO) mice. EC-specific Prmt1 ablation in adult mice (KO) for 8 weeks led to lethality, concurrent with pulmonary hypertension and thromboembolism. The lung bulk RNA sequencing and single EC RNA sequencing analyses revealed that Prmt1 ablation increased inflammation, endothelial junction disruption, apoptosis, and fibrosis. Comprehensive analysis through bulk RNA and single cell RNA sequencing revealed that Prmt1 ablation in ECs triggers homeostatic disturbance accompanied by inflammation and endothelial dysfunction, associated with hyperactivation of NFkB and Stat signaling. In conclusion, the current study suggests that Prmt1 plays a key role in pulmonary endothelial function and vascular homeostasis via the suppression of NFkB-induced endothelial dysfunction. The National Research Foundation Grant funded by the Korean Government (MIST) (NRF-2022R1A2B5B02001482). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Pulmonary Thromboendarterectomy for Chronic Pulmonary Thromboembolism

Pulmonary embolism in terms of causes of mortality is the third most common cause, when talking about cardiovascular diseases, yet most undiagnosed or misdiagnosed one. Among causes of pulmonary thromboembolism protein C deficiency is a rare one and idiopathic most common entity. In general population the incidence of severe protein C deficiency is about 1 in 500,000-750,000 people. We present a case of chronic pulmonary thromboembolism in young female of 23 years. She presented with history of dyspnea, dry cough and bilateral DVT of legs. On pulmonary CT diagnosis of massive pulmonary thrombus was made and her pulmonary thromboendarterectomy was done in our center. Conclusion: All patients with chronic pulmonary thromboembolic hypertension should be assessed for operability by proper referral to an experienced CTEPH (chronic thromboembolic pulmonary hypertension) team to determine if they are viable candidate for PEA (pulmonary endarterectomy). PEA is standard and recommended operative technique for treatment of CTEPH. Keywords: pulmonary endarterectomy, pulmonary embolism, protein C deviciency

Risk stratification and long-term outcome of patients receiving in-hospital medical emergency team critical care: experience from Austria's largest medical center.

We aimed to investigate predictors for long-term survival of in-hospital patients with medical emergency team (MET) consultation with or without in-hospital cardiac arrest (IHCA) in Austria's largest medical center. Data of patients, who needed an intervention of a MET between 01/2014 and 03/2020 were reviewed for this retrospective analysis. In total, 708 MET calls were analyzed. The minimum follow-up was 7 months, the maximum 6.2 years. The main MET indications were circulatory failure (63%) followed by respiratory failure (27.1%), and bleeding events (3.5%). IHCA with subsequent cardiopulmonary resuscitation (CPR) was experienced by 425 (60%) patients. Of those, 274 (64%) reached return of spontaneous circulation (ROSC), and 221 (52%) survived the first 24-hours (median survival: 146 days) and 22.1% the first year. After adjustment for potential confounders, age (P<0.001), time to ROSC (P<0.001), a non-shockable rhythm (P=0.041), chronic kidney disease (CKD, P=0.041), peak lactate levels (P<0.001), and C-reactive protein (P=0.001) were associated with long-term all-cause mortality in IHCA patients in Cox regression analysis. The 283 MET calls (40%) which were due to other reasons than IHCA were associated with a much better 24-hours (93%) and 1-year survival (61.8%). Beside age (P<0.001), the main risk factors associated with mortality in MET patients without IHCA were comorbidities such as chronic obstructive pulmonary disease (COPD, P=0.008), CKD (P=0.001), pulmonary hypertension/chronic thromboembolic pulmonary hypertension (PH/CTEPH, P=0.024), and cancer (P=0.040). Patients triggering MET calls have an increased mortality, especially those with IHCA. Predictors of mortality comprise age, comorbidities, and cardiac arrest-related parameters. A better characterization of MET call populations and their outcome might help to improve clinical decision making.

Pulmonary endarterectomy and balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension: The Singapore experience

Pulmonary endarterectomy and balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension: The Singapore experience

How to deal with chronic thromboembolic pulmonary arterial hypertension (CTEPH) during the COVID-19 pandemic: Too many gray zones to be considered

How to deal with chronic thromboembolic pulmonary arterial hypertension (CTEPH) during the COVID-19 pandemic: Too many gray zones to be considered

351: Early Systolic Notching Occurs in Thromboembolic Pulmonary Hypertension, Not Unique to Acute PE

351: Early Systolic Notching Occurs in Thromboembolic Pulmonary Hypertension, Not Unique to Acute PE

Efficacy of Ventilation Perfusion Lung Scanning and Computed Tomography Pulmonary Angiography for Chronic Thrombo-Embolic Pulmonary Hypertension

Introduction: The diagnostic approach for patients with suspected Chronic Thrombo-Embolic Pulmonary Hypertension (CTEPH) is a combination of clinical and pre-test probability assessment, and diagnostic imaging of computed tomography pulmonary angiogram (CTPA) or lung ventilation and perfusion scintigraphy (V/Q). There is a paucity of literature, particularly for Southeast Asia (SEA) populations, regarding the efficacy of these imaging approaches. This study investigated the sensitivity and specificity of V/Q and CTPA in the diagnosis of CTEPH. Methods: A retrospective analysis was undertaken on 133 consecutive patients presenting for pulmonary hypertension (PH). The population included 42 males, 91 females, 683 V/Q images and 6288 CTPA images for patients in the age range 18 to 93 years (mean 66). All data was retrospectively analysed by two nuclear medicine physicians and classified as findings consistent with CTEPH or inconsistent with CTEPH. These classifications were independently and collectively correlated with a final diagnosis of CTEPH or no CTEPH. Results: The accuracy, sensitivity, and specificity of V/Q for detection of CTEPH was 83.5%, 57.5% and 97.7% respectively, with a positive predictive value (PPV) of 93.1% and a negative predictive value (NPV) of 80.8% when only high probability reports were considered CTEPH positive. The accuracy, sensitivity, and specificity of V/Q for detection of CTEPH was 96.2%, 97.9% and 95.4% respectively, with a PPV of 92.0% and a NPV of 98.8% when both high probability and intermediate probability reports were considered CTEPH positive. The accuracy, sensitivity and specificity of CTPA for detection of CTEPH were 70.7%, 19.2% and 98.8% respectively, with 90% PPV and 69.1% NPV. All 47 CTEPH studies were reported as having abnormal lung perfusion. Conclusion: This investigation has shown that V/Q is a more valuable diagnostic imaging tool in detecting CTEPH than CTPA. In suspected CTEPH, a high/intermediate V/Q report is consistent with a positive diagnosis. This is an important finding as CTEPH is a potentially treatable condition.

Perioperative Extracorporeal Membrane Oxygenation-Based Protocol for Massive Acute Pulmonary Embolism

Purpose At our institution, since 2012, we have applied a protocol using perioperative veno-arterial extracorporeal membrane oxygenation (v-a ECMO) support in all patients with acute massive pulmonary embolism, in order to reduce the impact of hemodynamic instability. In this study, we present the results of perioperative ECMO-therapy in these high-risk surgical patients. Methods We retrospectively reviewed all patients who underwent embolectomy due to massive acute pulmonary embolism at our institution between 11/2012 and 10/2018. In these patients, v-a ECMO was implanted percutaneously in the femoral vessels before the beginning of the anaesthesia, if it had not already been implanted before. At the end of operation, cardiopulmonary bypass support was switched again to v-a ECMO support, which was continued perioperatively at the intensive care unit. Results During the study period, 20 patients (median age 64 years, 75% male patients, 10% cardiac redos) underwent pulmonary embolectomy for acute massive embolism. Among these patients, preoperatively, 7 (35%) patients showed concomitant chronic thromboembolic pulmonary artery hypertension (CTEPH), 11 (55%) patients required mechanical ventilation, 14 (70%) patients required v-a ECMO support for cardiogenic shock and 11 (55%) patients had undergone thrombolysis. Median time under preoperative ECMO support amounted to 2 days. V-a ECMO was implanted before beginning of the anaesthesia in the remaining 6 (30%) patients. Intraoperatively, cardiopulmonary and cross clamp times amounted to a median of 127 and 53 minutes, respectively. Seven (35%) patients underwent pulmonary endarterectomy for concomitant CTEPH. V-a ECMO was continued after the end of the operation in all patients and weaned successfully after a median of 5 days. Twelve (60%) patients were extubated before ECMO weaning. Six (30%) patients required prolonged ventilation and underwent tracheostomy. Three (15%) patients required rethoracotomy for bleeding and 5 (25%) patients required new dialysis treatment. One (5%) patient showed lung reperfusion injury. Two (10%) patients died in-hospital of sepsis. Conclusion Ourv-a ECMO based protocol for massive acute pulmonary embolectomy led to stabilization of preoperative compromised haemodynamic. Postoperative ECMO provided good postoperative results in high risk patients.

To evaluate the results of balloon pulmonary angioplasty in patients with chronic distal pulmonary thromboembolic disease and pulmonary hypertension

To evaluate the results of balloon pulmonary angioplasty in patients with chronic distal pulmonary thromboembolic disease and pulmonary hypertension

Soluble guanylate cyclase stimulators and phosphodiesterase-5 inhibitors in therapy of some groups of pulmonary hypertension

Pulmonary hypertension (PH) is a large group of diseases characterized by pulmonary artery pressure (PAP) > 25 mm Hg. Currently, specific medications are available for several groups of PH only. These are prostacyclin analogues, soluble guanylate cyclase (sGC) stimulators (sGCS), phosphodiesterase-5 inhibitors (iPDE-5), and endothelin receptor antagonists. Modern evidence-based pharmacological treatment of PH and therapeutic algorithm have been described in this review. Particular attention was paid to mechanisms of dysregulation of vascular tone including nitric oxide (NO-sGC-cGMP) pathway that is a target for sGCS and iPDE-5. A new class of sGCS principally differs from iPDE-5 and is very important for clinical practice. Safety, availability and benefit of switching from iPDE-5 to riociguat was investigated in the RESPITE trial. Results of main clinical trials of efficacy and safety of riociguat in patients with pulmonary arterial hypertension and thromboembolic PH were also discussed in this review.

Recurrent Pulmonary Embolism and Pulmonary Hypertension in a Patient with β-Thalassemia Intermedia

Patients with β-thalassemia intermedia are at increased risk of thromboembolic events and multifactorial pulmonary arterial hypertension. A pro-thrombotic state, including decreased levels of natural anticoagulant proteins and chronic platelet activation, has been shown in these patients, in particular after splenectomy. We report the case of a 54-year-old splenectomized β-thalassemic patient with a history of unprovoked deep venous (femoro-politeal) thrombosis, complicated by a pulmonary embolism event at the age of 37, recurrent episodes of superficial vein thrombosis of the lower limbs with leg ulcers, and a progressive severe pulmonary arterial hypertension, related to recurrences of pulmonary embolism, despite long-term, well conducted oral anticoagulant treatment (vitamin K antagonists and apixaban). After the performance of a right heart catheterization, pulmonary endarterectomy was not considered indicated in this patient because of the distal localization of thrombi. Aspirin treatment was added to vitamin K antagonists. Riociguat and ambrisentan therapy induced an improvement of both symptoms and echocardiographic picture over 12-mo follow-up. Splenectomized thalassemic patients are at high risk of thromboembolic events, and pulmonary hypertension, despite common, is yet a poorly understood complication. Clear recommendations on the management of such condition are lacking due to the limited data regarding the use of vasodilators, anticoagulants (vitamin K antagonists, heparins, direct oral anticoagulants) and antiplatelet agents.

Plasma fibrin clot structure and thromboembolism: clinical implications.

Fibrin formed as a result of fibrinogen polymerization is the main protein component of a clot in a test tube and intravascular thrombi in vivo. Fibrin clot structure characterized by fiber diameter and pore size differs between healthy persons and those with thromboembolic diseases, in part due to the quality and quantity of fibrinogen and the magnitude of thrombin generation. A key measure of plasma clot structure is its permeability, reflected by the Darcy constant (Ks). Reduced Ks is a typical feature of the prothrombotic fibrin clot phenotype, which is associated with faster formation of denser fibrin mesh, relatively resistant to lysis. Low Ks has been reported in patients with prior or acute myocardial infarction (MI), stroke, or venous thromboembolism (encompassing deep vein thrombosis [DVT] and pulmonary embolism [PE]), as well as in those with prothrombotic conditions (eg, in several thrombophilic states) and in the presence of cardiovascular risk factors (eg, obesity). Antithrombotic and anticoagulant agents, along with statins, have been shown to increase Ks. Growing evidence indicates associations between the properties of plasma fibrin clots and morphology of intravascular thrombi in patients with MI. Recently, reduced Ks has been shown to predict recurrent thromboembolic episodes in patients with a history of stroke, PE, DVT, and their serious complications, including postthrombotic syndrome and thromboembolic pulmonary hypertension. We discuss the current evidence for the significance of clot density measured in vitro as a prognostic marker in a number of clinical conditions associated with elevated thromboembolic risk.

Consensus Statement on Chronic Thromboembolic Disease, Prophylaxis and Special Situations / Abridged Version

Chronic thromboembolic disease refers to a set of conditions that manifest over time after acute pulmonary embolism (PE). In most cases, this episode is associated with acute deep vein thrombosis (DVT). These conditions include chronic pulmonary thromboembolic hypertension (CTEPH), post-thrombotic syndrome (PTS) and chronic venous insufficiency (CVI). (1) A timely diagnosis and treatment may modify the prognosis of this entity during the course of its free progression. (2) Damage caused by DVT may lead to valve dysfunction in the deep venous system. (3) Both CTEPH, PTS and CVI are associated with gradual impairment in the quality of life of those affected. Hence, it is important to postulate prophylaxis strategies in a patient at risk of suffering from a DVT-PE event.

Prothrombotic Fibrin Clot Phenotype in Patients with Deep Vein Thrombosis and Pulmonary Embolism: A New Risk Factor for Recurrence.

Prothrombotic fibrin clot phenotype, involving faster formation of dense meshwork composed of thinner and highly branched fibers that are relatively resistant to plasmin-induced lysis, has been reported in patients with not only myocardial infarction or stroke, but also venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT), and/or pulmonary embolism (PE). Prothrombotic fibrin clot phenotype, in particular prolonged clot lysis time, is considered a novel risk factor for VTE as well as venous thrombosis at unusual location, for example, cerebral sinus venous thrombosis, retinal vein obstruction, and Budd-Chiari syndrome. Growing evidence from observational studies indicates that abnormal fibrin clot properties can predict recurrent DVT and PE and they are involved in serious complications of VTE, for example, thromboembolic pulmonary hypertension and postthrombotic syndrome. The purpose of this article is to review our current understanding of the role of fibrin clot structure and function in venous thrombosis with emphasis on clinical issues ranging from prognosis to therapy.

Optical coherence tomography improves the results of balloon pulmonary angioplasty in inoperable chronic thrombo-embolic pulmonary hypertension.

Optical coherence tomography improves the results of balloon pulmonary angioplasty in inoperable chronic thrombo-embolic pulmonary hypertension.

The role of tissue factor and autophagy in pulmonary vascular remodeling in a rat model for chronic thromboembolic pulmonary hypertension.

BackgroundFew reports have examined tissue factor (TF) and autophagy expression in chronic pulmonary thromboembolic hypertension (CTEPH) animal models. Objectives: To investigate the role of tissue factor (TF), autophagy and their interactions during chronic thromboembolic pulmonary hypertension (CTEPH) pathogenesis in a rat model.MethodsAutologous blood clots were repeatedly injected into the left jugular vein of rats with injecting endogenous fibrinolysis inhibitor tranexamic acid (TXA). Mean pulmonary arterial pressure (mPAP), histopathology and TF, Beclin-1 and microtubule-associated protein 1 light chain (LC3) expression levels were detected.ResultsThe mPAP and vessel wall area/total area (WA/TA) ratio in the experiment group increased significantly (P < 0.05). TF mRNA and protein expression levels in the experiment group increased significantly (P < 0.05). Beclin-1 and LC3B mRNA and protein expression levels were lower in the experiment group (P < 0.05). The mPAP had a positive correlation with WA/TA ratio (r = 0.955, P < 0.05). Beclin-1 and LC3B protein expression had a negative correlation with the WA/TA ratio (r = -0.963, P < 0.05, r = -0.965, P < 0.05, respectively). TF protein expression had a negative correlation with both Beclin-1 and LC3B protein expression (r = -0.995, P <0.05, r = -0972, P < 0.05, respectively).ConclusionsA rat model of CTEPH can be established by repeatedly introducing autologous blood clots into the pulmonary artery with injecting TXA. TF and autophagy may play a key role during CTEPH pathogenesis, especially in vascular remodeling.

Use of Technetium-99m-Labelled Sodium Diphosphate Decahydrate to Assess Right Ventricle Dysfunction in Patients with Pulmonary Embolism

The objective of this study was to identify the signs of the right ventricular dysfunction in patients with non-massive pulmonary artery thromboembolism (PE) using radionuclide gated blood pool SPECT (GBPS). The study included 55 patients: 40 with PE, and 15 - control group. Radionuclide studies included perfusion-ventilation scintigraphy and GBPS. GBPS results suggest that the signs of right ventricular dysfunction in PE are: the reduction in its stroke volume, as well as reduction in the peak filling and ejection rate. GBPS results allow distinguishing acute thromboembolism and chronic post-thromboembolic pulmonary hypertension.

Assessing pulmonary hypertensive vascular disease in childhood. Data from the Spanish registry.

There is a lack of knowledge regarding the epidemiology, clinical characterization, and survival in pediatric pulmonary hypertension. To describe the epidemiology, outcomes, and risk factors for mortality in pediatric pulmonary hypertension in Spain. We analyzed data from the Spanish Registry for Pediatric Pulmonary Hypertension. From January 2009 to June 2012, a total of 225 patients diagnosed with pulmonary hypertension in 1998 or after were collected from 21 referral and nonreferral centers. We included all Nice etiologies, estimated incidence and prevalence of pulmonary hypertension in the Spanish pediatric population, and analyzed risk factors for mortality (Nice etiologic group, clinical and hemodynamic variables). Patients were classified as follows: group I, pulmonary arterial hypertension (n = 142; 61%); group II, left heart disease (n = 31; 14%); group III, respiratory disease (n = 41; 18%); group IV, thromboembolic pulmonary hypertension (n = 2; 1%); or group V, mostly inherited metabolic diseases (n = 10; 4.5%). Of the patients studied, 31% had multifactorial pulmonary hypertension. Mean age at diagnosis was 4.3 ± 4.9 years (50% < 2 yr). Survival rates at 1 and 3 years were 80 and 74% for the whole cohort, and 89 and 85% for patients with pulmonary arterial hypertension. Independent risk factors for mortality included an etiologic group other than pulmonary arterial hypertension (P < 0.001), age at diagnosis younger than 2 years old (P < 0.001), advanced functional class at diagnosis (P < 0.001), and high right atrial pressure at diagnosis (P = 0.002). In moderate to severe pediatric pulmonary hypertension, the prognosis is better in pulmonary arterial hypertension than in other Nice categories. In pediatric pulmonary hypertension age at diagnosis younger than 2 years is a risk factor for mortality, in addition to the previously established risk factors.

Optical Coherence Tomography in Thromboembolic Pulmonary Hypertension

La hipertensión arterial pulmonar es una enfermedad rara y progresiva que afecta principalmente a las arteriolas pulmonares (precapilar), independientemente de la etiología desencadenante. En España se estima que la prevalencia de hipertensión pulmonar y de hipertensión arterial pulmonar es de 19,2 y 16 casos por millón de habitantes, respectivamente. El diagnóstico de hipertensión arterial pulmonar se basa en criterios hemodinámicos (presión media de la arteria pulmonar ≥ 25 mmHg, presión de enclavamiento capilar pulmonar ≤ 15 mmHg, y resistencia vascular pulmonar > 3 unidades Wood) y por tanto requiere la realización de un cateterismo cardiaco derecho. En la práctica clínica se ha utilizado la terapia secuencial con un solo fármaco. Sin embargo, las recientes guías europeas recomiendan la terapia combinada de inicio en algunas situaciones. En esta revisión se realiza una actualización crítica de los conocimientos sobre esta enfermedad de acuerdo a las últimas guías y recomendaciones.Pulmonary arterial hypertension is a rare and progressive disease that mainly affects the pulmonary arterioles (precapillary), regardless of the triggering aetiology. The prevalence of pulmonary hypertension and pulmonary arterial hypertension in Spain is estimated at 19.2 and 16 cases per million inhabitants, respectively. The diagnosis of pulmonary arterial hypertension is based on haemodynamic criteria (mean pulmonary artery pressure ≥25 mmHg, pulmonary capillary wedge pressure ≤15 mmHg and pulmonary vascular resistance >3 Wood units) and therefore requires the implementation of right cardiac catheterisation. Sequential therapy with a single drug has been used in clinical practice. However, recent European guidelines recommend combined initial therapy in some situations. This review conducts a critical update of our knowledge of this disease according to the latest guidelines and recommendations.

Effects of exercise and vasodilators on cerebral tissue oxygenation in pulmonary hypertension.

Arterial and thromboembolic pulmonary hypertension (PH) lead to arterial hypoxaemia. To investigate whether cerebral tissue oxygenation (CTO) in patients with PH is reduced and whether this is associated with reduced exercise tolerance. 16 patients with PH (mean pulmonary arterial pressure ≥25 mmHg, 14 arterial, 2 chronic thromboembolic) and 15 controls underwent right heart catheterisation with monitoring of CTO at rest, during maximal bicycle exercise and during inhalation of oxygen and NO. The 6 min walk distance (6MWD) was measured. Median CTO in PH-patients at rest was 62 % (quartiles 53; 71), during exercise 60 % (53; 65); corresponding values in controls were 65 % (73; 73) (P = NS) and 68 % (66; 70) (p = .013 vs. PH). Inhalation of NO and oxygen improved CTO in PH. In multivariate regression analysis CTO at maximal exercise predicted the work load achieved when controlled for age, pulmonary vascular resistance and mixed venous oxygen saturation (R (2) = .419, p < .000); in addition, the 6MWD was predicted by CTO (adjusted R (2) = .511, p < .000). In PH-patients but not in controls CTO decreased during exercise. Since CTO was an independent predictor of the work load achieved and the 6MWD cerebral hypoxia may contribute to exercise limitation in PH. Clinicaltrials.gov: NCT01463514.