Patient-Reported Long-Term Outcome of Balloon Pulmonary Angioplasty for Inoperable CTEPH.

BACKGROUND: Balloon pulmonary angioplasty (BPA) is a promising interventional treatment for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Evidence in favor of BPA is growing, but long-term data remain scarce. The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) is validated for the assessment of patients with pulmonary hypertension within three domains: symptoms, activity, and quality of life (QoL). The aim of the present study was to evaluate the long-term effects of BPA on these domains in patients with inoperable CTEPH. METHODS: Between March 2014 and August 2019, technically inoperable patients with target lesions for BPA were included in this prospective, observational study. CAMPHOR scores were compared between baseline (before the first BPA) and 6 months after the last intervention and also for scores assessed at annual follow-ups. RESULTS: A total of 152 patients had completed a full series of BPA interventions and a 28 (interquartile range [IQR]: 26-32) week follow-up. Further follow-up assessments including the CAMPHOR score were performed 96 (IQR: 70-117) weeks, 178 (IQR: 156-200) weeks, and 250 (IQR: 237-275) weeks after the last intervention. From baseline to the last follow-up, CAMPHOR scores for symptoms, activity, and QoL improved from 9 (IQR: 6-14) to 3 (IQR: 0-9) (p < 0.001), 8 (IQR: 5-12) to 4 (IQR: 2-8) (p < 0.001), and 5 (IQR: 2-9) to 1 (IQR: 0-5) (p < 0.001). CONCLUSION: BPA leads to long-lasting, significant improvement of symptoms, physical capacity, and QoL in inoperable CTEPH patients.

Pregnancy-associated plasma protein A - a new indicator of pulmonary vascular remodeling in chronic thromboembolic pulmonary hypertension?

BACKGROUND: In 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). METHODS: The 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. RESULTS: The 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. CONCLUSION: PAPP-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.

Galectin-3, GDF-15, and sST2 for the assessment of disease severity and therapy response in patients suffering from inoperable chronic thromboembolic pulmonary hypertension.

PURPOSE: This study examined sST2, GDF-15, and galectin-3 as indicators of disease severity and therapy response in chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: This study included 57 inoperable CTEPH patients who underwent balloon pulmonary angioplasty and 25 controls without cardiovascular disease. Biomarker levels were examined in relation to advanced hemodynamic impairment [tertile with worst right atrial pressure (RAP) and cardiac index], hemodynamic therapy response [normalized hemodynamics (meanPAP ≤25 mmHg, PVR ≤3 WU and RAP ≤6 mmHg) or a reduction of meanPAP ≥25%; PVR ≥ 35%, RAP ≥25%]. RESULTS: GDF-15 [820 (556-1315) pg/ml vs. 370 (314-516) pg/ml; p < 0.001] and sST2 [53.7 (45.3-74.1) ng/ml vs. 48.7 (35.5-57.0) ng/ml; p = 0.02] were higher in CTEPH patients than in controls. At baseline, a GDF-15 level ≥1443 pg/ml (AUC 0.88; OR 31.4) and a sST2 level ≥65 ng/ml (AUC 0.80; OR 10.9) were associated with advanced hemodynamic impairment. At follow-up GDF-15 ≤ 958 pg/ml (AUC = 0.74, OR 18) identified patients with optimal hemodynamic therapy response and ≤760 pg/ml (AUC = 0.79, OR 14). CONCLUSION: GDF-15 and sST2 levels are higher in CTEPH and identified patients with advanced hemodynamic impairment. Further, decreased GDF-15 levels at follow-up were associated with hemodynamic therapy response. The diagnostic strength was not superior to NT-proBNP.

Development of renal function during staged balloon pulmonary angioplasty for inoperable chronic thromboembolic pulmonary hypertension.

Balloon pulmonary angioplasty (BPA), for chronic thromboembolic pulmonary hypertension, improves pulmonary and systemic hemodynamics. The kidney might benefit from this effect. However, staged BPA therapy comes along with repetitive administration of contrast agent. This study examined the overall effect of BPA therapy on renal function. This study included consecutive patients who underwent BPA treatment and completed a 6-month follow-up between March 2014 and March 2017. Biomarker-based evaluation of renal function was performed at baseline, consecutively prior to and after each BPA and at 6-month follow-up. The 51 patients underwent an average of 5 (±2) BPA sessions. In this course, patients received 133 (±48; 21-300) mL of contrast agent per session and 691 (±24; 240-1410) mL during the whole sequence. Acute kidney injury occurred after 6 (2.3%) procedures. The creatinine [80.1 (IQR 67.8-96.8) µmol/L vs. 77.4 (IQR 66.9-91.5) µmol/L, p = .02] and urea level [13.7 (IQR10.7-16.6) mmol/L vs. 12.5 (IQR 10.0-15.5) mmol/L, p = .02] decreased from baseline to the 6-month follow-up. The estimated glomerular filtration rate (eGFR) [79 (IQR 59-94) mL/min/m2 vs. 79.6 (IQR 67.1-95.0) mL/min/m2, p = .11] did not change. The Chronic kidney disease (CKD) stages at baseline were: G1:15; G2:23; G3a:10; G3b:2; G4:1; G5:0. Among patients with a CKD-stage ≥2, analysis revealed an increase of eGFR, decrease of creatinine and urea from baseline to 6-month follow-up. Among those patients, the baseline-CKD-stage improved in 14 (41.2%) patients. BPA therapy improves pulmonary and systemic hemodynamics, with positive effects on renal function. Repetitive administration of contrast agent seems not to be harmful regarding renal function.

Balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension: the initial German experience.

Balloon pulmonary angioplasty (BPA) is an emerging treatment for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH).We report on a prospective series of 56 consecutive patients who underwent 266 BPA interventions (median, five per patient) at two German institutions. All patients underwent a comprehensive diagnostic work-up including right heart catheterisation at baseline and 24 weeks after their last intervention.BPA resulted in improvements in WHO functional class, 6 min walk distance (mean change, +33 m), right ventricular function and haemodynamics, including a decline in mean pulmonary artery pressure by 18% and in pulmonary vascular resistance by 26%. Procedure-related adverse events occurred in 9.4% of the interventions. The most common complications were related to pulmonary vascular injury and consecutive pulmonary bleeding. Most of these events were asymptomatic and self-limiting, but one patient died from pulmonary bleeding, resulting in a mortality rate of 1.8%.BPA resulted in haemodynamic and clinical improvements but was also associated with a considerable number of complications, including one fatal pulmonary bleeding. As the effects of BPA on survival are unknown, randomised controlled outcome trials comparing BPA with approved medical therapies in patients with inoperable CTEPH are required to allow for appropriate risk-benefit assessments.

Riociguat and balloon pulmonary angioplasty improve prognosis in patients with inoperable chronic thromboembolic pulmonary Hypertension.

BACKGROUND: The combination of riociguat and interventional balloon pulmonary angioplasty (BPA) is currently used to treat patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). The aim of the present study was to evaluate the impact of this combination therapy on the prognosis of inoperable CTEPH patients by comparing the long-term survival rates of patients undergoing combination therapy with riociguat and BPA with those of inoperable patients from the first international CTEPH registry who did not receive specific treatment. METHODS: Between March 2014 and August 2019, 138 technically inoperable patients were included in the present prospective, observational cohort study when they were treated with riociguat and BPA at a single CTEPH referral center. Long-term survival of this cohort was compared using propensity score matching with that of inoperable patients recruited between 2007 and 2009 in the first international CTEPH registry. Kaplan-Meier methods were used to evaluate differences in outcomes. RESULTS: Whereas the survival rate in the historical group was 84.6% in the first year, 76.6% in the second, 68.5% in the third, and 58.5% in the fifth year after diagnosis, implementation of riociguat/BPA led to survival rates of 100%, 96.7%, 92.9%, and 90% in the respective follow-up periods. In a comparison of 83 well-matched pairs from the 2 cohorts, survival was markedly better in the group treated with riociguat and BPA than in the historical cohort (HR = 0.145, 95% CI 0.05, 0.421). CONCLUSION: The combination of riociguat and BPA for the treatment of inoperable CTEPH is associated with excellent 5-year survival rates.

Complications of balloon pulmonary angioplasty for inoperable chronic thromboembolic pulmonary hypertension: Impact on the outcome.

BACKGROUND: Balloon pulmonary angioplasty (BPA) is an emerging interventional treatment for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) that targets subsegmental branches of the pulmonary artery. As the reported complication rates are high, the aim of the present study was to evaluate the effects of certain complications on the outcome after treatment. METHODS: From March 2014 to December 2019, a total of 235 patients with inoperable CTEPH underwent BPA. Of these patients, 140 were included who completed a follow-up examination 6 months after the last intervention; another 2 patients deceased due to complications of BPA. RESULTS: A high baseline pulmonary vascular resistance (PVR) >6.6 WU correlated with a higher rate of complications (mostly pulmonary artery perforations). Wire perforation during BPA did not correlate with worse outcome in terms of PVR reduction. The complication rate per intervention decreased from 21% to 14% during the 5 year period of the study. CONCLUSIONS: Complications are frequently observed in BPA, but the mortality rate is very low in expert centers. Importantly, the occurrence of complications does not portend a worse outcome.

Transradial Closure of a Large Ascending Aortic Pseudoaneurysm With a Duct Occluder II - A Case Report.

Pseudoaneurysm of the ascending aorta is a rare but potentially life-threatening complication of cardiothoracic surgery. Re-operation is associated with a high mortality risk; therefore, percutaneous endovascular closure techniques with different closure devices have been repeatedly reported over the last 15 years. Previous endovascular procedures were performed using a transfemoral or transbrachial approach. We report a case of transradial ascending aortic pseudoaneurysm closure in a patient deemed unsuitable for surgery.

Cardiac biomarkers as indicators of right ventricular dysfunction and recovery in chronic thromboembolic pulmonary hypertension patients after balloon pulmonary angioplasty therapy - a cardiac magnetic resonance imaging cohort study.

BACKGROUND: In chronic thromboembolic pulmonary hypertension, right heart failure determines outcome. Balloon pulmonary angioplasty therapy allows right heart recovery, which can be monitored by cardiac magnetic resonance imaging. This study evaluates whether cardiac biomarkers (NT-proBNP, MR-proANP, sST2, and PAPP-A) are associated with cardiac magnetic resonance imaging findings prior to and after balloon pulmonary angioplasty therapy. METHODS: This observational cohort study enrolled 22 chronic thromboembolic pulmonary hypertension patients who underwent balloon pulmonary angioplasty therapy and completed a six-month follow-up including cardiac magnetic resonance imaging. Biomarker levels were compared with findings for right heart morphology and function derived from cardiac magnetic resonance imaging. RESULTS: Pulmonary hemodynamics improved after balloon pulmonary angioplasty therapy [pulmonary vascular resistance: 7.7 (6.0-9.0) vs. 4.7 (3.5-5.5) wood units, p < 0.001; mean pulmonary artery pressure 41 (38-47) vs. 32 (28-37) mmHg, p < 0.001]. Cardiac magnetic resonance imaging findings indicated right heart maladaptation at baseline and recovery after therapy [right ventricular end-diastolic volume 192 (141-229) ml vs. 143 (128-172) ml, p = 0.002; right ventricular end-systolic volume 131 (73-157) ml vs. 77 (61-99) ml (p < 0.001); right ventricular ejection fraction (RVEF) 34 (28-41) % vs. 52 (41-54) %; p < 0.001]. Biomarker level cut-offs [NT-proBNP 347 ng/L (area under the curve (AUC) 0.91), MR-proANP 230 pg/L (AUC 0.78), PAPP-A 14.5 mU/L (AUC 0.81), and sST2 48.0 ng/ml (AUC 0.88)] indicated a RVEF ≤ 35% at baseline. The dynamics of NT-proBNP (rs = -0.79; p < 0.001), MR-proANP (rs = -0.80; p < 0.001), and sST2 (rs = -0.49; p = 0.02) correlated inversely with the improvement in RVEF after therapy. A relative decrease of NT-proBNP < 53% (AUC 0.86) and MR-proANP < 24% (AUC 0.82) indicated a limited RVEF response. CONCLUSIONS: In chronic thromboembolic pulmonary hypertension patients, cardiac magnetic resonance imaging findings illustrate right heart failure and recovery after balloon pulmonary angioplasty therapy. Cardiac biomarker levels correlate with right heart parameters at baseline and their dynamics after therapy.

Mid-regional pro-atrial natriuretic peptide and copeptin as indicators of disease severity and therapy response in CTEPH.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) leads to right heart failure. Pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA) restore pulmonary haemodynamics and allow cardiac recovery. This study examined the relationship of copeptin and mid-regional pro-atrial natriuretic peptide (MR-proANP) levels to disease severity and therapy response. METHODS: This observational cohort study included 125 patients (55 PEA/70 BPA) who underwent treatment and completed a 6-/12-month follow-up. Biomarkers, measured at baseline, prior to every BPA and at follow-up, were compared to 1) severe disease at baseline (right atrial pressure (RAP) ≥8 mmHg and cardiac index ≤2.4 L·min-1·m-2) and 2) optimal therapy response (no persistent pulmonary hypertension combined with a normalised RAP (mean PAP ≤25 mmHg, pulmonary vascular resistance (PVR) ≤3 WU and RAP ≤6 mmHg) or a reduction in mean PAP ≥25%, PVR ≥35% and RAP ≥25%). RESULTS: Severely diseased patients had higher levels of MR-proANP (320 (246-527) pmol·L-1 versus 133 (82-215) pmol·L-1; p=0.001) and copeptin (12.7 (7.3-20.6) pmol·L-1 versus 6.8 (4.4-12.8) pmol·L-1; p=0.015) at baseline than the rest of the cohort. At baseline, MR-proANP (area under the curve (AUC) 0.91; cut-off value 227 pmol·L-1; OR 56, 95% CI 6.9-454.3) and copeptin (AUC 0.70; cut-off value 10.9 pmol·L-1; OR 1.5, 95% CI 1.2-1.9) identified severely diseased patients. After PEA/BPA, levels of MR-proANP (99 (58-145) pmol·L-1; p<0.001) and copeptin (6.3 (3.7-12.6) pmol·L-1; p=0.009) decreased and indicated optimal therapy response (MR-proANP <123 pmol·L-1 (AUC 0.70) and copeptin <10.1 pmol·L-1 (AUC 0.58)). CONCLUSION: MR-proANP and copeptin levels are affected in CTEPH and decrease after therapy. MR-proANP identifies a severe disease status and optimal therapy response.

Sequential treatment with riociguat and balloon pulmonary angioplasty for patients with inoperable chronic thromboembolic pulmonary hypertension.

Riociguat is the treatment of choice for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). We addressed here whether additional balloon pulmonary angioplasty (BPA) provides further benefits. A prospective series of 36 consecutive patients with inoperable CTEPH were treated with riociguat at least three months before BPA. All patients underwent diagnostic workup at baseline, before BPA treatments, and six months after final intervention. The main outcome measures were pulmonary hemodynamic parameters and World Health Organization (WHO) functional class (FC). Significant improvements in pulmonary hemodynamics and physical capacity were observed for riociguat treatment, and subsequent BPA interventions yielded further benefits. With targeted medication, WHO FC improved by at least one class in 13 (36.1%) patients ( P = 0.01). Hemodynamic assessment showed significant improvements in mean pulmonary arterial pressure (mPAP) (49 ± 12 mmHg vs. 43 ± 12 mmHg; P = 0.003) and PVR (956 ± 501 dyn·s·cm-5 vs. 517 ± 279 dyn·s·cm-5; P = 0.0001). Treatment with a combination of targeted medication and BPA resulted in WHO FC improvement in 34 (94.4%) patients. Hemodynamic assessment showed significant improvement in mPAP (43 ± 12 mmHg vs. 34 ± 14 mmHg; P = 0.0001) and PVR (517 ± 279 dyn·s·cm-5 vs. 360 ± 175 dyn·s·cm-5; P = 0.0001). These findings provide, for the first time, support for the therapeutic strategy recommended by current guidelines.

Dynamics of high-sensitivity cardiac troponin T during therapy with balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension.

AIMS: Balloon pulmonary angioplasty (BPA) is an interventional treatment modality for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Therapy monitoring, based on non-invasive biomarkers, is a clinical challenge. This post-hoc study aimed to assess dynamics of high-sensitivity cardiac troponin T (hs-cTnT) as a marker for myocardial damage and its relation to N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels as a marker for cardiac wall stress. METHODS AND RESULTS: This study included 51 consecutive patients who underwent BPA treatment and completed a 6-month follow-up (6-MFU) between 3/2014 and 3/2017. Biomarker measurement was performed consecutively prior to each BPA and at 6-MFU. In total, the 51 patients underwent an average of 5 BPA procedures. The 6-month survival rate was 96.1%. The baseline (BL) meanPAP (39.5±12.1mmHg) and PVR (515.8±219.2dyn×sec×cm-5) decreased significantly within the 6-MFU (meanPAP: 32.6±12.6mmHg, P<0.001; PVR: 396.9±182.6dyn×sec×cm-5, P<0.001). At BL, the median hs-cTnT level was 11 (IQR 6-16) ng/L and the median NT-proBNP level was 820 (IQR 153-1872) ng/L. The levels of both biomarkers decreased steadily after every BPA, showing the first significant difference after the first procedure. Within the 6-MFU, hs-cTnT levels (7 [IQR 5-12] ng/L; P<0.001) and NT-proBNP levels (159 [IQR 84-464] ng/l; P<0.001) continued to decrease. The hs-cTnT levels correlated with the PVR (rrs = 0.42; p = 0.005), the meanPAP (rrs = 0.32; p = 0.029) and the NT-proBNP (rrs = 0.51; p<0.001) levels at BL. CONCLUSION: Non-invasive biomarker measurement provides valuable evidence for the decreasing impairment of myocardial function and structure during BPA therapy. Changes in hs-cTNT levels are suggestive for a reduction in ongoing myocardial damage.

N-terminal pro-B-type natriuretic peptide for monitoring after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension.

BACKGROUND: Balloon pulmonary angioplasty (BPA) is an emerging interventional treatment option for chronic thromboembolic pulmonary hypertension (CTEPH). The non-invasive monitoring of CTEPH patients is a clinical challenge. In this study we examined changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients undergoing BPA for inoperable CTEPH and related them to peri-procedural success. METHODS: In this study we analyzed a total of 51 consecutive patients who underwent BPA treatment and completed a 6-month follow-up (6-MFU) between March 2014 and March 2017. Serum samples for NT-proBNP measurement were collected before every BPA and at 6-MFU. RESULTS: The 51 patients underwent 265 interventions involving angioplasty of a total of 410 vessels. The 6-month survival rate was 96.1%. The baseline (BL) mean pulmonary artery pressure (PAP) was 39.5 ± 12.1 mm Hg, pulmonary vascular resistance (PVR) was 515.8 ± 219.2 dynes/s/cm5 and the median NT-proBNP level was 820 (153 to 1,871.5) ng/liter. At BL, World Health Organization functional class (FC) was ≥III in 96.1% of the patients, whereas, at 6-MFU, 11.8% were in WHO FC ≥III. At 6-MFU, mean PAP (32.6 ± 12.6 mm Hg; p < 0.001), PVR (396.9 ± 182.6 dynes/s/cm5; p < 0.001) and NT-proBNP (159.3 [84.4 to 464.3] ng/liter; p < 0.001) levels were reduced. The decrease in NT-proBNP levels correlated with the decrease in mean PAP (rrs = 0.43, p = 0.002) and PVR (rrs = 0.50, p = 0.001). A reduction in the NT-proBNP level of 46% indicated a decrease in mean PAP of ≥25% (area under the curve [AUC] = 0.71) and a reduction of 61% indicated a decrease in PVR of ≥35% (AUC 0.77). CONCLUSIONS: Our results demonstrate that NT-proBNP levels decrease after BPA, providing valuable evidence of procedural success. NT-proBNP measurement allows identification of patients who are BPA non-responders and may thus be a valuable adjunct in therapy monitoring.

Balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic disease.

Symptomatic patients with residual pulmonary perfusion defects or vascular lesions but no pulmonary hypertension at rest are diagnosed with chronic thromboembolic disease (CTED). Balloon pulmonary angioplasty (BPA) is an emerging treatment for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), but data regarding the safety and efficacy of BPA in patients with CTED are lacking. We report a prospective series of ten consecutive patients with CTED who underwent 35 BPA interventions (median of four per patient) at two German institutions. All patients underwent a comprehensive diagnostic workup at baseline and 24 weeks after their last intervention. BPA was safe, with one pulmonary vascular injury and subsequent self-limiting pulmonary bleeding as the only complication (2.9% of the interventions, 10% of the patients). After the procedures, World Health Organization functional class, 6-min walking distance, pulmonary vascular resistance, and pulmonary arterial compliance improved, and NT-proBNP concentrations declined in 9/10 patients. BPA may be a new treatment option for carefully selected patients with CTED. A larger, prospective, international registry is required to confirm these results.