Residual Pulmonary Hypertension Research Articles

Impact of sex on outcome after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension

The impact of sex on long-term outcomes after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (PH) remains unclear. We therefore examined the early and long-term outcome after PEA to determine whether sex had an impact on the risk of residual PH and need for targeted PH medical therapy. Retrospective study of 401 consecutive patients undergoing PEA at our institution between August2005 and March2020 was performed. Primary outcome was the need for targeted PH medical therapy postoperatively. Secondary outcomes included survival and measures of hemodynamic improvement. Females (N =203, 51%) were more likely to have preoperative home oxygen therapy (29.6% vs 11.6%, p<0.01), and to present with segmental and subsegmental disease compared to males (49.2% vs 21.2%, p<0.01). Despite similar preoperative values, females had higher postoperative pulmonary vascular resistance (final total pulmonary vascular resistance after PEA, 437Dynes∙s∙cm-5 vs 324 Dynes∙s∙cm-5 in males, p<0.01). Although survival at 10 years was not significantly different between sexes (73% in females vs 84% in males, p=0.08), freedom from targeted PH medical therapy was lower in females (72.9% vs 89.9% in males at 5 years, p<0.001). Female sex remained an independent factor affecting the need for targeted PH medical therapy after PEA in multivariate analysis (HR 2.03, 95%CI 1.03-3.98, p=0.04). Although outcomes are excellent for both sexes, females had greater need for targeted PH medical therapy in the long-term. Early reassessment and long-term follow-up of these patients are important. Further investigations into possible mechanisms to explain the differences are warranted.

Predictors of procedural complications in balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension

BackgroundBalloon pulmonary angioplasty (BPA) is an effective treatment for inoperable chronic thromboembolic pulmonary hypertension, with good results reported for residual pulmonary hypertension (PH) after pulmonary endarterectomy (PEA). However, BPA is associated with complications, such as pulmonary artery perforation and vascular injury, which can lead to critical pulmonary hemorrhage requiring embolization and mechanical ventilation. Furthermore, the risk factors for occurrence of complications in BPA are unclear; therefore, this study aimed to evaluate predictors of procedural complications in BPA. MethodsIn this retrospective study, we collected clinical data (patient characteristics, details of medical therapy, hemodynamic parameters, and details of the BPA procedure) from 321 consecutive sessions involving 81 patients who underwent BPA. Procedural complications were evaluated as endpoints. ResultsBPA for residual PH after PEA was performed in 141 sessions (43.9 %), which involved 37 patients. Procedural complications were observed in 79 sessions (24.6 %), including severe pulmonary hemorrhage requiring embolization in 29 sessions (9.0 % of all sessions). No patients experienced severe complications requiring intubation with mechanical ventilation or extracorporeal membrane oxygenation. Age ≥ 75 years and mean pulmonary artery pressure ≥ 30 mmHg were independent predictors of procedural complications. Residual PH after PEA was a significant predictor of severe pulmonary hemorrhage requiring embolization (adjusted odds ratio, 3.048; 95 % confidence interval, 1.042–8.914, p = 0.042). ConclusionsOlder age, high pulmonary artery pressure, and residual PH after PEA increase the risk of severe pulmonary hemorrhage requiring embolization in BPA.

Hemodynamic Effects of Ketone Bodies in Patients With Pulmonary Hypertension.

Background Pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) are debilitating diseases with a high mortality. Despite emerging treatments, pulmonary vascular resistance frequently remains elevated. However, the ketone body 3-hydroxybutyrate (3-OHB) may reduce pulmonary vascular resistance in these patients. Hence, the aim was to assess the hemodynamic effects of 3-OHB in patients with PAH or CTEPH. Methods and Results We enrolled patients with PAH (n=10) or CTEPH (n=10) and residual pulmonary hypertension. They received 3-OHB infusion and placebo (saline) for 2 hours in a randomized crossover study. Invasive hemodynamic and echocardiography measurements were performed. Furthermore, we investigated the effects of 3-OHB on the right ventricle of isolated hearts and isolated pulmonary arteries from Sprague-Dawley rats. Ketone body infusion increased circulating 3-OHB levels from 0.5±0.5 to 3.4±0.7 mmol/L (P<0.001). Cardiac output improved by 1.2±0.1 L/min (27±3%, P<0.001), and right ventricular annular systolic velocity increased by 1.4±0.4 cm/s (13±4%, P=0.002). Pulmonary vascular resistance decreased by 1.3±0.3 Wood units (18%±4%, P<0.001) with no significant difference in response between patients with PAH and CTEPH. In the rat studies, 3-OHB administration was associated with decreased pulmonary arterial tension compared with saline administration (maximal relative tension difference: 12±2%, P<0.001) and had no effect on right ventricular systolic pressures (P=0.63), whereas pressures rose at a slower pace (dP/dtmax, P=0.02). Conclusions In patients with PAH or CTEPH, ketone body infusion improves cardiac output and decreases pulmonary vascular resistance. Experimental rat studies support that ketone bodies relax pulmonary arteries. Long-term studies are warranted to assess the clinical role of hyperketonemia. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04615754.

Outcome of moderate-severe tricuspid regurgitation after pulmonary endarterectomy or balloon pulmonary angioplasty

Introduction and objectivesThe management of persistent moderate-severe tricuspid regurgitation (TR) in patients with chronic thromboembolic pulmonary hypertension after treatment with pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA) is not well defined. This study aimed to analyze the progression and predictors of significant persistent postintervention TR and its prognostic impact. MethodsThis single-center observational study included 72 patients undergoing PEA and 20 who completed a BPA program with a previous diagnosis of chronic thromboembolic pulmonary hypertension and moderate-to-severe TR. ResultsThe postintervention prevalence of moderate-to-severe TR was 29%, with no difference between the PEA- or BPA-treated groups (30.6% vs 25% P=.78). Compared with patients with absent-mild postprocedure TR, those with persistent TR had higher mean pulmonary arterial pressure (40.2±1.9 vs 28.5±1.3mmHg P <.001), pulmonary vascular resistance (472 [347-710] vs 282 [196-408] dyn.s/cm5; P <.001), and right atrial area (23.0 [21-31] vs 16.0 [14.0-20.0] P <.001). The variables independently associated with persistent TR were pulmonary vascular resistance> 400 dyn.s/cm5 and postprocedure right atrial area> 22cm2. No preintervention predictors were identified. The variables associated with increased 3-year mortality were residual TR and mean pulmonary arterial pressure> 30mmHg. ConclusionsResidual moderate-to-severe TR following PEA-PBA was associated with persistently high afterload and unfavorable postintervention right chamber remodeling. Moderate-to-severe TR and residual pulmonary hypertension were associated with a worse 3-year prognosis.

Impact of residual pulmonary hypertension on long-term outcomes after pulmonary endarterectomy in the modern era.

Residual pulmonary hypertension (PH) negatively impacts long-term results following pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH). We sought to reveal whether modern PH therapy with PH-targeted medicine and balloon pulmonary angioplasty (BPA) improved long-term results of residual PH after PEA. Long-term findings of 80 patients who survived PEA between 2011 and 2019 were retrospectively investigated. One month after PEA, 30 patients developed residual PH defined as mean pulmonary artery pressure (mPAP) ≥25 mmHg, of whom 23 were treated by PH-targeted medicine and 9 by BPA. Patients with residual PH acquired considerably better functional status and exercise capacity after PEA, however, exhibited significantly worse survival rates than those without. Eleven patients died during follow-up: 8 patients with residual PH and 3 controls. Among patients with residual PH, the deceased had a significantly lower %decrease in mPAP from 1 month to 1 year following PEA (7.4 [-32.6 to 8.0] % vs. 10.4 [3.7-27.8] %, p = 0.03) and higher mPAP at 1 year following PEA (39.5 [33.25-42.5] vs. 27 [26-34] mmHg, p < 0.01) despite PH-targeted medicine than the survived. No patients passed away from right heart failure, and there was no difference between the groups in CTEPH-related mortality. Modern PH therapy was used to address the majority of residual PH. Long-term survival after PEA was negatively impacted by residual PH, but it appeared that long-term mortality was also correlated with unrelieved residual PH despite PH-targeted medicine. Modern PH therapy may have enhanced functional status and excercise capacity, and averted fatal right heart failure.

Antiproliferative effect of selexipag active metabolite MRE-269 on pulmonary arterial smooth muscle cells from patients with chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a group 4 pulmonary hypertension (PH) characterized by nonresolving thromboembolism in the central pulmonary artery and vascular occlusion in the proximal and distal pulmonary artery. Medical therapy is chosen for patients who are ineligible for pulmonary endarterectomy or balloon pulmonary angioplasty or who have symptomatic residual PH after surgery or intervention. Selexipag, an oral prostacyclin receptor agonist and potent vasodilator, was approved for CTEPH in Japan in 2021. To evaluate the pharmacological effect of selexipag on vascular occlusion in CTEPH, we examined how its active metabolite MRE-269 affects platelet-derived growth factor-stimulated pulmonary arterial smooth muscle cells (PASMCs) from CTEPH patients. MRE-269 showed a more potent antiproliferative effect on PASMCs from CTEPH patients than on those from normal subjects. DNA-binding protein inhibitor (ID) genes ID1 and ID3 were found by RNA sequencing and real-time quantitative polymerase chain reaction to be expressed at lower levels in PASMCs from CTEPH patients than in those from normal subjects and were upregulated by MRE-269 treatment. ID1 and ID3 upregulation by MRE-269 was blocked by co-incubation with a prostacyclin receptor antagonist, and ID1 knockdown by small interfering RNA transfection attenuated the antiproliferative effect of MRE-269. ID signaling may be involved in the antiproliferative effect of MRE-269 on PASMCs. This is the first study to demonstrate the pharmacological effects on PASMCs from CTEPH patients of a drug approved for the treatment of CTEPH. Both the vasodilatory and the antiproliferative effect of MRE-269 may contribute to the efficacy of selexipag in CTEPH.

Repeat pulmonary thromboendarterectomy outcomes: A 15-year single-center retrospective review

ObjectiveChronic thromboembolic pulmonary hypertension is potentially curable via pulmonary thromboendarterectomy. A minority of patients experience recurrence of their symptoms and are eligible for repeat pulmonary thromboendarterectomy. However, little data exist regarding risk factors and outcomes for this patient population. MethodsWe performed a retrospective review of the University of California San Diego chronic thromboembolic pulmonary hypertension quality improvement database, including all patients who underwent pulmonary thromboendarterectomy from December 2005 to December 2020. Of the 2019 cases performed during this period, 46 were repeat pulmonary thromboendarterectomy procedures. Demographics, preoperative and postoperative hemodynamics, and surgical complications were compared between the repeat pulmonary thromboendarterectomy group and 1008 first pulmonary thromboendarterectomy group. ResultsRepeat pulmonary thromboendarterectomy recipients were more likely to be younger, to have an identified hypercoagulable state, and to have higher preoperative right atrial pressure. Etiologies of recurrent disease include incomplete initial endarterectomy, discontinuation of anticoagulation (noncompliance or for medical reasons), and anticoagulation treatment failure. Patients who received repeat pulmonary thromboendarterectomy had significant hemodynamic improvement, but less pronounced compared with patients who received first pulmonary thromboendarterectomy. Repeat pulmonary thromboendarterectomy was associated with an increased risk of postoperative bleeding, reperfusion lung injury, residual pulmonary hypertension, and increased ventilator, intensive care unit, and hospital days. However, hospital mortality was similar between the groups (2.2% vs 1.9%). ConclusionsThis is the largest reported series of repeat pulmonary thromboendarterectomy surgery. Despite an increase in postoperative complications, this study demonstrates that repeat pulmonary thromboendarterectomy surgery can result in significant hemodynamic improvement with acceptable surgical mortality in an experienced center.

Distal vessel pulmonary thromboendarterectomy: Results from a single institution

Chronic thromboembolic pulmonary hypertension (CTEPH) is primarily managed by pulmonary thromboendarterectomy (PTE). As advanced surgical techniques permit resection at the segmental and subsegmental level, PTE can now be curative for CTEPH mostly involving the distal pulmonary arteries. Between January 2017 and June 2021, consecutive patients undergoing PTE were categorized according to the most proximal level of chronic thrombus resection: Level I (main pulmonary artery), Level II (lobar), Level III (segmental) and Level IV (subsegmental). Proximal disease patients (any Level I or II) were compared to distal disease (Level III or IV bilaterally) patients. Demographics, medical history, preoperative pulmonary hemodynamics, and immediate postoperative outcomes were obtained for each group. During the study period, 794 patients underwent PTE, 563 with proximal disease and 231 with distal disease. Patients with distal disease more frequently had a history of an indwelling intravenous device, splenectomy, upper extremity thrombosis or use thyroid replacement and less often had prior lower extremity thrombosis or hypercoagulable state. Despite more use of PAH-targeted medications in the distal disease group (63.2% vs 50.1%, p < 0.001), preoperative hemodynamics were similar. Both patient groups exhibited significant improvements in pulmonary hemodynamics postoperatively with comparable in-hospital mortality rates. Compared to proximal disease, a lower percentage of patients with distal disease showed residual pulmonary hypertension (3.1% vs 6.9%, p=0.039) and airway hemorrhage (3.0% vs 6.6%, p=0.047) postoperatively. Thromboendarterectomy for distal (segmental and subsegmental) CTEPH is technically feasible and may result in favorable pulmonary hemodynamic outcomes, without increased mortality or morbidity.

Evolución y pronóstico de la insuficiencia tricuspídea moderada-grave tras tromboendarterectomía pulmonar o angioplastia de arterias pulmonares

Introduction and objectivesThe management of persistent moderate-severe tricuspid regurgitation (TR) in patients with chronic thromboembolic pulmonary hypertension after treatment with pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA) is not well defined. This study aimed to analyze the progression and predictors of significant persistent postintervention TR and its prognostic impact. MethodsThis single-center observational study included 72 patients undergoing PEA and 20 who completed a BPA program with a previous diagnosis of chronic thromboembolic pulmonary hypertension and moderate-to-severe TR. ResultsThe postintervention prevalence of moderate-to-severe TR was 29%, with no difference between the PEA- or BPA-treated groups (30.6% vs 25% P=.78). Compared with patients with absent-mild postprocedure TR, those with persistent TR had higher mean pulmonary arterial pressure (40.2±1.9 vs 28.5±1.3mmHg P <.001), pulmonary vascular resistance (472 [347-710] vs 282 [196-408] dyn.s/cm5; P <.001), and right atrial area (23.0 [21-31] vs 16.0 [14.0-20.0] P <.001). The variables independently associated with persistent TR were pulmonary vascular resistance> 400 dyn.s/cm5 and postprocedure right atrial area> 22cm2. No preintervention predictors were identified. The variables associated with increased 3-year mortality were residual TR and mean pulmonary arterial pressure> 30mmHg. ConclusionsResidual moderate-to-severe TR following PEA-PBA was associated with persistently high afterload and unfavorable postintervention right chamber remodeling. Moderate-to-severe TR and residual pulmonary hypertension were associated with a worse 3-year prognosis.

Efficacy and safety of guide extension catheter in balloon pulmonary angioplasty for treatment of complex lesions in chronic thromboembolic pulmonary hypertension.

Balloon pulmonary angioplasty (BPA) is used for treatment of inoperable chronic thromboembolic pulmonary hypertension (CTEPH) and residual pulmonary hypertension after pulmonary endarterectomy (PEA) to improve hemodynamics, right ventricular function, and exercise capacity. However, the effectiveness and safety of guide extension catheters for BPA treatment in patients with CTEPH have not been demonstrated. We retrospectively analyzed 91 lesions in 55 sessions of 28 patients with CTEPH who underwent BPA using a guide extension catheter. The purpose (backup, coaxial, and extension), efficacy, and safety of the guide extension catheters were explored. The efficacy of the guide extension catheter was assessed based on the success of the procedures and safety was evaluated based on procedure-related complications. Regarding the intended use, a guide extension catheter was used to strengthen the backup force of the guiding catheter in 52% of cases, extend the tip of the catheter in 38% of cases, and maintain the coaxiality of the guiding catheter in 10% of cases. Procedural success was achieved in 92.7% of 55 sessions and in 95.6% of 91 lesions. Complex lesions had a lower success rate than simple lesions (p = 0.04). Regarding safety concerns, complications were observed in 5 of 55 sessions (9.1%) and 6 of 91 lesions (6.6%). Only one case of pulmonary artery dissection using a guide extension catheter was reported. Except for this one case, extension catheter-related complications were not observed. A guide extension catheter can be used safely in BPA procedures with anatomically complex pulmonary artery branches and complex lesions by increasing backup support.

Impairment of cognitive functions in patients with chronic thromboembolic pulmonary hypertension before and after surgical treatment

To study cognitive functions in patients with chronic thromboembolic pulmonary hypertension (CTEPH) before and in the long-term after pulmonary thromboendarterectomy and to study factors that negatively affect cognitive status. One hundred and twenty-four patients with CTEPH were examined before and 6 months after surgery with an assessment of cognitive impairment using the Mini-Mental State Examination (MMSE). Multivariate regression analysis was used to identify factors affecting the MMSE indicators before and in the long-term postoperative periods. Initially, patients with CTEPH had a total MMSE score 23.8±1.1. Six months after surgery, the score was 26.1±1.9 (p<0.001). A history of stroke, disability, stress (loss of spouse), and a high Charleson comorbidity index were independent factors affecting MMSE score before surgery. After surgery, the total MMSE score was influenced by a history of stroke, stress (loss of spouse), residual pulmonary hypertension and atrial fibrillation in the early postoperative period. Cognitive impairment in the form of mild dementia was observed in patients with CTEPH before surgery. Six months after the operation, an improvement in cognitive status was revealed, which corresponded to moderate cognitive impairment. At the same time, no complete recovery of cognitive functions was recorded. Patients with CTEPH still experienced the greatest difficulties in the following areas: concentration and counting, memory. A history of stroke, disability, stress (loss of spouse), and a high comorbidity index are associated with a decrease in MMSE scores before surgery. Six months after surgery, MMSE score was affected by a history of stroke, stress (loss of spouse), residual pulmonary hypertension and atrial fibrillation in the early postoperative period.

Utility of cardiac magnetic resonance feature tracking strain assessment in chronic thromboembolic pulmonary hypertension for prediction of REVEAL 2.0 high risk status.

Chronic thromboembolic pulmonary hypertension may be cured by pulmonary endarterectomy(PEA). Thromboembolic disease distribution/PEA success primarily determines prognosis but risk scoring criteria may be adjunctive. Right ventriculoarterial (RV-PA) and ventriculoatrial (RV-right atrium [RA]) coupling may be evaluated by cardiac MRI (CMR) feature tracking deformation/strain assessment. We characterized biatrial and biventricular CMR feature tracking(FT) strain parameters following PEAand tested the ability of CMR FT to identify REVEAL 2.0 high-risk status. We undertook a retrospective single-center cross-sectional study of patients (n = 57) who underwent PEA (2015-2020). All underwent pre and postoperative catheterization and CMR. Pulmonary arterial hypertension validated risk scores were calculated. Significant postoperative improvements were observed in mean pulmonary artery pressure(mPAP) (pre-op 45 ± 11 mmHg vs. post-op 26 ± 11 mmHg; p < 0.001) and PVR however a large proportion had residual pulmonary hypertension (45%; mPAP ≥25 mmHg). PEA augmented left heart filling with left ventricular end diastolic volume index and left atrial volume index increment. Left ventricular ejection fraction was unchanged postoperatively but LV global longitudinal strain improved (pre-op median -14.2% vs. post-op -16.0%; p < 0.001). Right ventricular (RV) geometry and function also improved with reduction in RV mass. Most had uncoupled RV-PA relationships which recovered (pre-op right ventricular free wall longitudinal strain -13.2 ± 4.8%, RV stroke volume/right ventricular end systolic volume ratio 0.78 ± 0.53 vs. post-op -16.8 ± 4.2%, 1.32 ± 0.55; both p < 0.001). Postoperatively, there were sixREVEAL 2.0 high-risk patients, best predicted by impaired RA strain which was superior to traditional volumetric parameters (area under the curve [AUC] 0.99 vs.RVEF AUC 0.88). CMR deformation/strain evaluation can offer insights into coupling recovery; RA strain may be an expeditious surrogate for the more laborious REVEAL 2.0 score.

Pulmonary Endarterectomy for Chronic Thromboembolic Pulmonary Hypertension: A Systematic Review of the Most Updated Literature

Pulmonary endarterectomy (PEA) is the treatment of choice in case of chronic thromboembolic pulmonary hypertension (CTEPH). PEA is performed by an increasing number of surgeons; however, the reported outcomes are limited to a few registries or to individual centers' experiences. This systematic review focuses on pre-operative evaluation, intra-operative procedure and post-operative results in patients submitted to PEA for CTEPH. The literature included was searched using a formal strategy, combining the terms "pulmonary endarterectomy" AND "chronic pulmonary hypertension" and focusing on studies published in the last 5 years (2017-2022) to give a comprehensive overview on the most updated literature. The selection of the adequate surgical candidate is a crucial point, and the decision should always be performed by expert multidisciplinary teams composed of surgeons, pulmonologists and radiologists. In all the included studies, the surgical procedure was performed through a median sternotomy with intermittent deep hypothermic circulatory arrest under cardiopulmonary bypass. In case of residual pulmonary hypertension, alternative combined treatments should be considered (balloon angioplasty and/or medical therapy until lung transplantation in highly selected cases). Short- and long-term outcomes, although not homogenous across the different studies, are acceptable in highly experienced CTEPH centers.

Airway Hemorrhage Complicating Pulmonary Thromboendarterectomy: Risk Factors and Outcomes

BackgroundAirway hemorrhage is a known complication of pulmonary thromboendarterectomy (PTE) in patients with chronic thromboembolic pulmonary hypertension. Predisposing factors for postoperative airway hemorrhage have not been well described. The aims of this study were to determine the incidence and outcomes of airway hemorrhage after PTE and to identify potential risk factors. MethodsThis was a retrospective chart review of subjects undergoing PTE between 2015 and 2019. Postoperative airway hemorrhage was defined as significant endobronchial bleeding requiring withholding anticoagulation, bronchial blocker placement, and/or extracorporeal membrane oxygenation (ECMO). ResultsOf 877 subjects who underwent PTE, 58 subjects (6.6%) developed postoperative airway hemorrhage. Subjects with hemorrhage were more likely to be women (60% vs 45%, P = .03), to be older (57.8 vs 54.0 years, P = .04), and to have a higher incidence of preoperative hemoptysis (19.0% vs 7.6%, P = .006) compared with control subjects (subjects without airway hemorrhage). Those with hemorrhage had significantly higher preoperative right atrial pressure (P = .002) and pulmonary vascular resistance (P < .001) and a higher incidence of residual pulmonary hypertension (P = .005). Airway hemorrhage management included ECMO with bronchial blocker (n = 2), bronchial blocker without ECMO (n = 26), or withholding anticoagulation alone until bleeding subsided (n = 30). Mortality was significantly higher in those with airway hemorrhage compared with control subjects (13.8% vs 1.2%, P < .001). ConclusionsThe incidence of postoperative airway hemorrhage is low but associated with significant mortality. Older age, female sex, preoperative hemoptysis, and worse preoperative pulmonary hypertension were associated with an increased risk of developing postoperative airway hemorrhage.

Abstract 10395: Atherosclerotic Lesion in Chronic Thromboembolic Pulmonary Hypertension is Associated With Prolonged Symptom Duration

Background: The cause of atherosclerotic lesions in the pulmonary artery of patients with chronic thromboembolic pulmonary hypertension (CTEPH) remains unclear. We aimed to discuss the clinical characteristics of CTEPH patients with atherosclerotic lesions and further explore the unique metabolic pathway of atherosclerosis in the pulmonary artery. Methods: Following detailed pathological examination of the pulmonary endarterectomy (PEA) specimen, CTEPH patients were divided into two age- and sex-matched groups, those with and without atherosclerotic lesion (n=25 each), and their clinical characteristics were compared. Untargeted metabolomics were used to determine the different metabolites in the proximal lesions of the pulmonary artery. Results: 27.2% (25/92) of all PEA specimens were found with atherosclerotic lesions. Patients with atherosclerotic lesions were more likely to have a history of symptomatic embolism than those without atherosclerotic lesion (88% vs. 56%, P=0.012), including pulmonary embolism and deep venous thrombosis. Patients with atherosclerotic lesions were found to have longer symptom duration (8.0±6.5 vs. 4.7±4.2, P=0.039) and a lower rate of residual pulmonary hypertension after PEA than those without atherosclerotic lesion (40% vs. 56%). However, the existence of atherosclerotic lesion was not associated with pre-operative hemodynamic parameters and cardiac function. Metabolomic profiling revealed that the formation of atherosclerotic lesion in CTEPH is closely related to glycine, serine and threonine metabolic axes involved in cellular aging and energy metabolism. Conclusions: The occurrence of atherosclerotic lesions in the pulmonary artery of CTEPH was associated with symptomatic thromboembolic history and extended symptom duration. The results suggested a new link between atherosclerotic lesions and aberrant amino acid metabolism in the context of CTEPH. Further investigations focused on atherosclerotic lesion and pulmonary vascular remodeling may provide novel insight into the pathophysiology and new therapeutic strategies for CTEPH.

Balloon Pulmonary Angioplasty in the Management of Chronic Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH), which is classified as group 4 pulmonary hypertension (PH) in the 2015 European Society of Cardiology/European Respiratory Society guidelines for the diagnosis and treatment of PH, is regarded as a complication of pulmonary embolism and is caused by the transformation of incompletely resolved thrombi into fibrous tissue that occludes the pulmonary arteries. The current established reference standard curative therapy for CTEPH is pulmonary endarterectomy (PEA), which provides good long-term outcomes with a low mortality rate. For patients with inoperable disease with inaccessible lesions and risk factors for surgery or patients who are diagnosed with residual or recurrent PH after PEA, medical therapy with riociguat is recommended. Balloon pulmonary angioplasty (BPA) is an emerging alternative treatment option for patients with inoperable disease or those with residual or recurrent PH after PEA. BPA has been reported to improve hemodynamics, cardiac function, exercise capacity, and symptoms, as well as PEA. A detailed assessment of thromboembolic lesions in pulmonary arteries by using multiple imaging techniques and treatment strategies with multiple staged procedures based on the patient's condition is important for safe and effective BPA. However, this new technique may still induce life-threatening complications, such as reperfusion pulmonary edema, wire perforation, vessel dissection, and vessel rupture. Meticulous attention to technique is mandatory to minimize serious complications owing to the nature of the anatomic territory involved. The authors summarize the current roles, goals, and complications of BPA in patients with CTEPH and demonstrate ways to formulate an effective and safe treatment strategy. The future perspective of BPA is also discussed. Online supplemental material is available for this article. ©RSNA, 2022.

Riociguat inhibits ultra-large VWF string formation on pulmonary artery endothelial cells from chronic thromboembolic pulmonary hypertension patients.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by elevated pulmonary arterial pressure and organized thrombi within pulmonary arteries. Riociguat is a soluble guanylate cyclase stimulator and is approved for patients with inoperable CTEPH or residual pulmonary hypertension after pulmonary endarterectomy (PEA). Previous work suggested that riociguat treatment is associated with an increased risk of bleeding, although the mechanism is unclear. The aim of this study is to assess how riociguat affects primary hemostasis by studying its effect on the interaction between platelets and endothelial cells derived from CTEPH patients. Pulmonary artery endothelial cells (PAECs) were isolated from thrombus-free regions of PEA material. Purified PAECs were cultured in flow chambers and were stimulated with 0.1 and 1 µM riociguat for 24 h before flow experiments. After stimulation with histamine, PAECs were exposed to platelets under shear stress. Platelet adhesion and expression of von Willebrand Factor (VWF) were evaluated to assess the role of riociguat in hemostasis. Under dynamic conditions, 0.1 and 1.0 µM of riociguat suppressed platelet adhesion on the surface of PAECs. Although riociguat did not affect intracellular expression and secretion of VWF, PAECs stimulated with riociguat produced fewer VWF strings than unstimulated PAECs. Flow cytometry suggested that decreased VWF string formation upon riociguat treatment may be associated with suppressed cell surface expression of P-selectin, a protein that stabilizes VWF anchoring on the endothelial surface. In conclusion, Riociguat inhibits VWF string elongation and platelet adhesion on the surface of CTEPH-PAECs, possibly by reduced P-selectin cell surface expression.

Long-term outcomes of combined pulmonary endarterectomy and additional balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension.

The early and long-term outcomes after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) have been established by several high-volume centers, but the impact of postoperative residual pulmonary hypertension affecting postoperative clinical parameters remains unclear. This study aims to investigate the institutional surgical results of PEA and to evaluate the efficacy of additional balloon pulmonary angioplasty (BPA) for residual pulmonary hypertension. We retrospectively reviewed 222 patients (57.7 ± 12.9years old, 141 female) who underwent PEA for CTEPH at the National Cerebral and Cardiovascular Center between 2000 and 2020. The preoperative mean pulmonary artery pressure (mPAP) was 45.6 ± 9.7mmHg and pulmonary vascular resistance (PVR) was 1062 ± 451 dyne*sec/cm-5. Postoperative mPAP (23.4 ± 11mmHg, 204 patients, P < 0.001) and PVR (419 ± 291 dyne*sec/cm-5, 199 patients, P < 0.001) significantly improved after PEA. Since 2011, 62 patients (28%) underwent BPA after PEA for "catecholamine dependent" residual PH 1month after PEA in 14, "scheduled" BPA with residual PH 1year after PEA in 32, and 16 "symptomatic" patients without residual PH. Their mPAP had significantly improved by PEA (48.1 ± 7.7 to 32.0 ± 10.2mmHg, P < 0.001), and further improved (33.8 ± 11.1 to 26.5 ± 9.1mmHg, P < 0.001) after BPA. PEA provided immediate and substantial improvements in pulmonary hemodynamics and favorable long-term survival. In addition, postoperative BPA improved postoperative clinical parameters for eligible patients regardless of the presence of residual PH.

Long-term outcome prediction for chronic thromboembolic pulmonary hypertension after pulmonary endarterectomy.

The definitive treatment for chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA), which has good long-term outcomes. However, after surgery, a quarter of the patients still have residual pulmonary hypertension (RPH). In pulmonary hemodynamics, there are no unified criteria for RPH, even though the level may affect long-term survival. Between March 1997 and December 2021, 253 CTEPH patients were treated at our center with PEA. Patients were evaluated retrospectively and classified into early (1997-2014) and late (2015-2021) groups. The clinical characteristics and perioperative outcomes of the two groups were compared, and risk factor analysis for RPH and long-term survival for all cases was performed. There was no statistically significant difference in demographics between the two groups. However, the Early Group had a significantly higher rate of perioperative death (9.8% vs. 1.2%, p = .001), RPH (48.8% vs. 14.0%, p < .001), and reperfusion pulmonary edema (18.3% vs. 2.9%, p < .001). The median follow-up time was 66.0 months, and overall survival rates at 5, 10, 15, and 18 years after PEA were 91.2%, 83.9%, 64.5%, and 46.0%, respectively. Age and postoperative systolic pulmonary artery pressure (sPAP) were independently related to long-term outcomes in the multivariate Cox analyses. Patients with postoperative sPAP less than 46 mm Hg had a higher chance of survival. PEA improved CTEPH hemodynamics immediately and had a positive effect on long-term survival. Patients with postoperative sPAP ≥ 46 mm Hg indicate clinically significant RPH and have a lower long-term survival rate.

Update in approaches to pulmonary hypertension because of left heart disease.

Left heart disease is the most common cause of pulmonary hypertension. This review summarizes the current care of patients with pulmonary hypertension caused by left heart disease (PH-LHD) and discusses recent and active clinical trials in this patient population. The primary focus of interventions aimed at treating PH-LHD address the treatment of left heart disease. Significant advancements in the treatment of heart failure with preserved ejection fraction (HFpEF), a frequent cause of PH-LHD, are supported in the current literature. Patients with residual pulmonary hypertension despite optimal treatment of left heart disease have poor outcomes. Yet, interventions targeting the pulmonary vasculature in PH-LHD patients have not demonstrated significant benefits in studies to date. Current work focuses on differentiating isolated postcapillary pulmonary hypertension (IpcPH) from combined precapillary and postcapillary pulmonary hypertension (CpcPH) in a clinically consistent manner. It is hopeful that thorough phenotyping of PH-LHD patients will translate into effective treatment strategies addressing pulmonary vascular disease. Referral to centers of excellence, considerations for enrollment in clinical trials, and evaluation for transplant is recommended for patients with residual pulmonary hypertension despite optimal treatment of left heart disease, particularly those with CpcPH.