Real-World Treatment Patterns and Burden of Chronic Thromboembolic Pulmonary Hypertension Patients across Consultation Settings in the USA.

Balloon Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension in Patients With Chronic Obstructive Pulmonary Disease: A Note of Caution.

Descriptive patterns of severe chronic pulmonary hypertension by chest radiography

Nailfold capillary density is lower in patients with pulmonary arterial hypertension (PAH). It is unclear whether this observation signifies a unique systemic manifestation of PAH, or reflects microcirculatory dysfunction secondary to pulmonary hypertension (PH). Capillary density and loop dimensions were measured by nailfold-capillaroscopy (NC) in 30 PAH (23 idiopathic, or iPAH, 7 hereditary, or hPAH), 17 chronic thromboembolic PH (CTEPH) patients and 48 controls. NC-Measurements were repeated after pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA) in CTEPH patients. We examined whether NC-measurements were related to markers of disease severity and predictive of time to clinical worsening (TTCW) as tested by univariate linear/logistic regression and cox-regression analysis, respectively. Capillary density was significantly lower in PAH (7.5 ± 1.1, p < 0.001) and in CTEPH (8.4 ± 1.5, p < 0.001) compared to asymptomatic controls (10.3 ± 1.0 capillaries/mm). Capillary density was similar in iPAH and hPAH and unrelated to hemodynamics in either PAH or CTEPH. A lower capillary density was predictive of clinical worsening in PAH (p 0.05). After normalization of pulmonary artery pressures by PEA or BPA, capillary density remained reduced in CTEPH patients. Capillary loop apex, capillary and venous- and arterial limb diameter were increased in patients with PAH and CTEPH compared to controls. Nailfold capillary density is reduced to a similar extent in iPAH, hPAH and CTEPH. Normalization of hemodynamics by PEA or BPA does not lead to a restoration of capillary density in CTEPH. Capillary dimensions were increased in both patients with PAH and CTEPH. Lower capillary density was predictive of clinical worsening in PAH. Our findings indicate that a loss of peripheral capillaries is not specific to PAH and is not related to the hemodynamic disturbance per se, but that shared mechanisms may account for a simultaneous development of a systemic microangiopathy and pulmonary vascular remodeling.

Learning curve and analysis of curative effects after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension.

Over 7 decades after Isaac Starr declared that “ weakness of the right side of the heart … seems less important … in the dynamics of congestive failure, [1][1]” the right ventricle (RV) has finally been afforded its due respect in many disease states. However, the definition and assessment

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BackgroundIn chronic thromboembolic pulmonary hypertension (CTEPH) impaired pulmonary hemodynamics lead to right heart failure. Natriuretic peptides reflect hemodynamic disease severity. Pregnancy-associated plasma protein-A (PAPP-A) might address another aspect of CTEPH - chronic tissue injury and inflammation. This study assessed dynamics of PAPP-A in CTEPH patients who undergo therapy with pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA).MethodsThe study included a total of 125 CTEPH patients scheduled for treatment (55 PEA/ 70 BPA) and a control group of 58 patients with pulmonary hypertension other than CTEPH. Biomarker measurement was performed at baseline and follow-up in the CTEPH cohort, prior to each BPA in the BPA cohort and once in the control group.ResultsThe median PAPP-A level was slightly higher (p = 0.05) in CTEPH patients [13.8 (11.0–18.6) mU/L], than in the control group [12.6 (8.6–16.5) mU/L], without a difference between the BPA and PEA group (p = 0.437) and without a correlation to mean pulmonary artery pressure (p = 0.188), pulmonary vascular resistance (p = 0.893), cardiac index (p = 0.821) and right atrial pressure (p = 0.596). PEA and BPA therapy decreased the mean pulmonary artery pressure (p < 0.001) and pulmonary vascular resistance (p < 0.001) and improved the WHO-functional-class (baseline: I:0/II:25/III:80/IV:20 vs. follow-up: I:55/II:58/III:10/IV:2). PAPP-A levels decreased after PEA [13.5 (9.5–17.5) vs. 11.3 (9.8–13.6) mU/L; p = 0.003) and BPA treatment [14.3 (11.2–18.9) vs. 11.1 (9.7–13.3) mU/L; p < 0.001). The decrease of PAPP-A levels is delayed in comparison to N-terminal pro-B-type natriuretic peptide.ConclusionPAPP-A is overexpressed in CTEPH and decrease significantly after surgical or interventional therapy, however without association to hemodynamics. Further investigation is needed to define the underlying mechanism of PAPP-A expression and changes after therapy in CTEPH.

Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the leading causes of severe pulmonary hypertension (PH). The disease is still underdiagnosed, and the true prevalence is unknown. CTEPH is characterized by intraluminal non-resolving thrombus organization and fibrous stenosis, or complete obliteration of pulmonary arteries, promoted by progressive remodeling of the pulmonary vasculature. One consequence of this is an increase in pulmonary vascular resistance and pressure, resulting in PH and progressive right heart failure, leading to death if left untreated.Endovascular disobliteration by pulmonary endarterectomy (PEA) is the preferred treatment for CTEPH patients. PEA surgery is the only technique that can potentially cure CTEPH disease, especially in patients with fresh or organized thrombi of the proximal branches of pulmonary arteries. However, not all patients are eligible for PEA surgery. Recent research has provided evidence suggesting balloon pulmonary angioplasty (BPA) and targeted medical therapy as additional promising available treatments options for inoperable CTEPH and recurrent/persistent PH after PEA surgery.Studies on BPA have shown it to improve pulmonary hemodynamics, symptoms, exercise capacity and RV function in inoperable CTEPH. Subsequently, BPA has developed into an essential component of the modern era of CTEPH treatment. Large randomized controlled trials have demonstrated varying significant improvements with targeted medical therapy in technically inoperable CTEPH patients. Thus, treatment of CTEPH requires a comprehensive multidisciplinary assessment, including an experienced PEA surgeon, PH specialist, BPA interventionist and CTEPH-trained radiologist at expert centers. In this comprehensive review, we address the latest developments in the fast-evolving field of CTEPH. These include advancements in imaging modalities and developments in operative and interventional techniques, which have widened the range of patients who may benefit from these procedures. The efficacy and safety of targeted medical therapies in CTEPH patients are also discussed. As the treatment options for CTEPH improve, hybrid management involving multiple treatments in the same patient may become a viable option in the near future.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, morbid, potentially curable subtype of pulmonary hypertension that negatively impacts health-related quality of life (HRQoL). Little is known about differences in HRQoL and hospitalization between CTEPH patients and idiopathic pulmonary arterial hypertension (IPAH) patients. Using multivariable linear regression and mixed effects models, we examined differences in HRQoL assessed by emPHasis-10 (E10) and SF-12 between CTEPH and IPAH patients in the Pulmonary Hypertension Association Registry, a prospective multicenter cohort of patients newly evaluated at a Pulmonary Hypertension Care Center. Multivariable negative binomial regression models were used to estimate incidence rate ratios (IRR) for hospitalization amongst the two groups. We included 461 IPAH patients and 169 CTEPH patients. Twenty-one percent of CTEPH patients underwent pulmonary thromboendarterectomy (PTE) before the end of follow-up. At baseline, patients with CTEPH had significantly worse HRQoL (higher E10 scores) (ß 2.83, SE 1.11, p = 0.01); however, differences did not persist over time. CTEPH patients had higher rates of hospitalization (excluding the hospitalization for PTE) compared to IPAH patients after adjusting for age, sex, body mass index, WHO functional class and six-minute walk distance (IRR 1.66, 95%CI 1.04–2.65, p = 0.03). CTEPH patients who underwent PTE had improved HRQoL as compared to those who were medically managed, but patients who underwent PTE were younger, had higher cardiac outputs and greater six-minute walk distances. In this large, prospective, multicenter cohort, CTEPH patients had significantly worse baseline HRQoL and higher rates of hospitalizations than those with IPAH. CTEPH patients who underwent PTE had significant improvements in HRQoL.

Recent Advances in the Understanding of Thrombosis.

Chronic thromboembolic pulmonary hypertension (CTEPH) is the only potentially curable form of precapillary pulmonary hypertension. Although pulmonary endarterectomy (PEA) is the preferred management strategy, a significant number of CTEPH patients will have an inoperable disease. As drug therapy is not expected to offer relief from the mechanical component of the disease, the novel technique of balloon pulmonary angioplasty (BPA) has provided a new therapeutic option for patients with inoperable CTEPH. This review will discuss the contemporary use of BPA technique in inoperable CTEPH patients highlighting the effectiveness and safety of this therapeutic option. Data supporting the role of BPA in inoperable CTEPH are limited to observational studies. However, these observational studies report consistent findings that BPA results in marked improvements in pulmonary hemodynamics and exercise capacity indicating its efficacy and safety as a treatment strategy in inoperable CTEPH patients. Summarizing, BPA is an emerging treatment option providing marked improvements in parameters affecting the outcome of CTEPH patients, but multicenter studies are needed to confirm the safety and the long-term efficacy of the procedure, before BPA can be recommended as an established treatment for CTEPH.

Treatment patterns of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) in Finland are unknown. Guidelines now recommend early escalation of treatment for PAH. We evaluated how well Finnish practice follows guidelines, and how treatment initiations and outcomes are related. The pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension patients in Finland cohort includes all PAH and CTEPH patients diagnosed between 2008 and 2020 in all Finnish university hospitals. Drug therapy was analysed in patients with medical/procedural history available, and changes in the 4-tier comparative, prospective registry of newly initiated therapies for pulmonary hypertension (COMPERA) 2.0 risk score were evaluated. PAH patients (n = 268) were initially treated with monotherapy (52%) or double therapy (24%). After year 2015, double therapy use increased to 39%. PAH treatment at 1 year after diagnosis included phosphodiesterase 5 inhibitors (71%), endothelin-receptor antagonist (48%), prostacyclin analogue (7%), calcium channel blocker (12%) and selexipag (1%). 35% achieved low risk at 1 year, increasing to 44% for patients diagnosed after 2015. Those remaining at intermediate-high (IH) or high risk (H) (28%) were not treated less aggressively than others but were older, had more comorbidities, and often history of smoking. CTEPH patients (n = 189) were treated with pulmonary endarterectomy (PEA) (27%), balloon pulmonary angioplasty (BPA) (11%) and medical therapy only (41%) within 1 year from diagnosis. 45% achieved low risk at 1 year. We present additional results on treatment of IH and H patients, patient characteristics preceding death, and treatment persistence. We found less treatment of PAH patients with double or triple therapies and of CTEPH patients with PEA and BPA than expected but with good results. Patients not reaching low or intermediate COMPERA 2.0 were old and had comorbidities.

Introduction Copeptin is the C-terminal fragment of the precursor protein of vasopressin. In acute pulmonary embolism, copeptin has been suggested to be a strong predictor of outcome and to provide additional predictive value to the established cardiac biomarkers high-sensitivity cardiac troponin and N-terminal pro-brain natriuretic peptide (NT-proBNP). Chronic thromboembolic pulmonary hypertension (CTEPH) is diagnosed in about 5% of patients who survive acute pulmonary embolism. Individualized risk stratification remains a challenge in the work-up of CTEPH patients. Purpose The current study investigated whether copeptin has the potential to aid the stratification of patients who have experienced pulmonary embolism and CTEPH patients. We examined the baseline (BL) levels and dynamics of copeptin during therapy in CTEPH patients who underwent balloon pulmonary angioplasty (BPA) or pulmonary endarterectomy (PEA). Moreover, the study compared copeptin levels between patients with or without therapy response. Methods The study included a total of 125 CTEPH patients scheduled for treatment. A total of 78 underwent staged BPA and 64 underwent PEA. In accordance with recent studies from our group, therapy success was defined as a decrease in meanPAP ≥25% and PVR ≥35% or a normalization below the thresholds defining pulmonary hypertension. Blood samples were collected at BL, prior to each BPA session in the BPA cohort, and at follow-up (FU) 6 months after BPA or 12 months after PEA. Copeptin was measured in thawed serum aliquots by an immunochemical method. Results The 78 patients in the BPA cohort underwent a mean of 6 BPA procedures each; there were a total of 413 interventions. The hemodynamic clinical and functional status the CTEPH patients improved after BPA and PEA therapy: meanPAP (BL: 43±9 mmHg vs. FU: 27±9 mmHg; p&amp;lt;0.001); PVR (BL: 7.6±3.4 WU vs. FU: 3.8±2.0 WU; p&amp;lt;0.001); RAP (BL: 7.9±5.8 mmHg vs. FU: 5.4±2.7 mmHg; p&amp;lt;0.001); WHO functional class [BL: I:0 / II:25 / III:80 / IV:20 vs. FU: I:56 / II:57 / III:10 / IV:2]; 6-minute-walk distance (BL: 405±99 m vs. FU: 456±112 m; p&amp;lt;0.001). The median serum levels of copeptin [BL 7.7 (4.6–14.2) pmol/L vs. FU 6.3 (3.9–12.5); p=0.009] and NT-proBNP [BL: 811 (157–1857) ng/L vs. FU: 142 (72–335) ng/L p&amp;lt;0.001] decreased significantly after therapy. The copeptin levels did not correlate with hemodynamics at BL: PVR (rrs=0.02; p=0.79) and meanPAP (rrs=0.03; p=0.75). The copeptin levels at BL (AUC=0.61) and the relative change (AUC=0.53) did not predict the endpoint of therapy response. Conclusions Copeptin levels are elevated in CTEPH patients compared with normal values in the literature. Although copeptin is known to provide additional value in the context of risk stratification in acute pulmonary embolism, it failed to provide additional diagnostic benefit in CTEPH in the current study. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): SFB 1213 area CP01

Background Although pulmonary endarterectomy (PEA) is an established surgical treatment for chronic thromboembolic pulmonary hypertension (CTEPH), a part of patients after PEA show residual pulmonary hypertension, leading to limited exercise capacity. Recently, several studies have indicated that balloon pulmonary angioplasty (BPA) improves hemodynamics, exercise capacity and prognosis in inoperable CTEPH patients. However, the effects of BPA in patients with residual pulmonary hypertension after PEA remain to be elucidated. Aim In the present study, we investigated comprehensive efficacy of BPA on hemodynamics, exercise capacity and right ventricular function in those with residual pulmonary hypertension after PEA. Methods From October 2010 to February 2019, 227 patients with CTEPH underwent PEA in our institution. Right heart catheterization after PEA (median follow up period from PEA to right heart catheterization 39 [10.5, 90] months) showed that 55 patients showed residual PH (mean pulmonary artery pressure (mPAP)≥25mmHg), and 38 of them referred to BPA (mean age 57 years old, male 8 (21%)) due to residual symptoms. In 29 out of 38 patients (76%) who completed BPA and underwent follow-up right heart catheterization, we examined hemodynamics, exercise capacity and right ventricular function before and after BPA. Follow-up examination was performed 3 months after last BPA session. Results In this study population (N=29), PEA significantly improved mPAP (47±7 to 38±10 mmHg), pulmonary vascular resistance (PVR, 14.6±4.6 to 9.2±4.6 WU) and right ventricular ejection fraction measured by magnetic resonance imaging (26.6±11.3 to 38.4±6.8%) (Figure). Median period from PEA to first BPA procedure was 42 [13.5, 94] months. Total session number during study period was 160 sessions, and mean session number of BPA was 5.5±1.5 per patient. Follow-up study revealed that BPA additionally improved mPAP (38±10 to 27±8 mmHg) and PVR (9.2±4.6 to 5.1±2.2 WU) (Figure). Similarly, 6-minute walk distance (393±125 to 452±125 m) and peak VO2 (16.4±3.8 to 18.1±4.6 ml/min/kg, p&amp;lt;0.05) were increased, and WHO functional class also significantly improved by BPA (I/II/III/IV, 0/21/8/ 0 to 1/27/1/0, p&amp;lt;0.01). In addition, right ventricular ejection fraction (38.4±6.8 to 44.2±7.1%) was increased after BPA (Figure). There were no procedure-related deaths and major lung injuries requiring oral intubation during study period. 3-year survival in patients after BPA was 100% (median follow-up period after last BPA session, 32 [18, 46] months). Conclusion In CTEPH patients with residual pulmonary hypertension after PEA, additional BPA significantly improved hemodynamics, right ventricular function, exercise capacity and residual symptoms without severe complications, leading to good prognosis. These results suggest that combination therapy of PEA and BPA could be an effective therapeutic option for post PEA patients with residual symptoms and exercise limitation. Figure 1 Funding Acknowledgement Type of funding source: None

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by unresolved thrombi in the pulmonary arteries and microvasculopathy in nonoccluded areas. If left untreated, progressive pulmonary hypertension will induce right heart failure and, finally, death. Currently, pulmonary endarterectomy (PEA) remains the only method that has the potential to cure CTEPH. Unfortunately, up to 40% of patients are ineligible for this procedure for various reasons. In recent years, refined balloon pulmonary angioplasty (BPA) has become an alternative option for inoperable CTEPH patients, and it may be another curative treatment in the future, particularly in combination with prior PEA. Nevertheless, 23% of patients still suffer from persistent PH after BPA. Given that CTEPH shares many similarities with idiopathic pulmonary arterial hypertension (PAH), targeted drugs developed for PAH are also attractive options for CTEPH, especially for inoperable or persistent/recurrent CTEPH patients. To date, riociguat, macitentan, and subcutaneous treprostinil are the only drugs proven by randomized control trials to be capable of improving the exercise capacity (6-min walking distance) of CTEPH patients. In this review, we summarize the achievements and unresolved problems of PAH-targeted therapy for CTEPH over the last decade.