Inoperable chronic thromboembolic pulmonary hypertension: Evolution of prognosis over 10 years of new emerging therapies.

Therapies for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) include balloon pulmonary angioplasty (BPA) and PH-specific medical therapy. This study compares survival and its predictors before and after the introduction of BPA. BPA was independently associated with survival; however, there was no difference in overall survival between the two cohorts.

Blood Biomarkers Predict 10-Year Clinical Outcomes in Adult Patients With Congenital Heart Disease.

Background: The adult congenital heart disease (ACHD) population is growing and risk prediction is important to predict adverse outcome and consult patients during their lifecourse. Objectives: This study aims to describe the long-term prognostic value of blood biomarkers in ACHD. Methods: In this prospective observational cohort study, 602 patients with moderate or complex ACHD were included (median age 32.5 years [IQR: 24.7-41.2], 42% female, 90% New York Heart Association I). N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitive-troponin T, growth differentiation factor 15, high-sensitive-C-reactive protein, suppression of tumorigenicity-2 and galectin-3, as well as full blood count, renal function, LDL, and HDL were measured. Cox models were applied to relate the selected biomarkers with the primary end point of all-cause mortality and secondary end point of mortality or heart failure. Standardized HRs adjusted for relevant prognostic factors, including age, sex, and complexity of diagnosis, were reported. Results: Abnormal biomarker levels were present in 424 (70.4%) patients. During a median follow-up of 10.1 years, 41 (6.8%) patients died and 81 (13.5%) developed heart failure. Associations were observed between the primary and secondary end point and red cell distribution width, NT-proBNP, and growth differentiation factor 15. In a multibiomarker model, only NT-proBNP remained associated with mortality (HR: 2.74; 95% CI: 2.01-3.74). NT-proBNP significantly improved the C-statistic of the clinical prediction model (0.85-0.92). Based on NT-proBNP alone, low-risk patients could be identified. Patients with NT-proBNP <76 ng/L showed a 10-year heart failure-free survival of 98.5%. Conclusions: Blood biomarkers have prognostic value in ACHD. NT-proBNP improves risk prediction and is able to identify low-risk patients. Its routine use should be implemented in ACHD.

Prognostic value of the electrocardiogram in patients with bicuspid aortic valve disease.

BACKGROUND: Identifying bicuspid aortic valve (BAV) patients at risk for cardiac events remains challenging and the role of the electrocardiogram (ECG) has not yet been described. Therefore, this study aims to describe ECG parameters in BAV patients, and investigate their prognostic value. METHODS: In this single-center prospective study patients with BAV without a prior aortic valve replacement (AVR) were included. Transthoracic echocardiogram and 12­lead resting-ECG were obtained. Associations between ECG parameters and the composite endpoint of all-cause mortality and AVR were assessed using Cox-proportional hazard analysis. RESULTS: 120 patients with BAV were included (median age 30 years, 61% male). Median aortic jet velocity was 2.4 m/s [IQR: 1.7-3.4] and 5 patients (4%) had severe aortic regurgitation. All patients were in sinus rhythm. Any ECG abnormality was present in 57 patients (48%). Median PR-interval was 156 [IQR: 138-170] msec. A deviating QRS axis was found in 17 patients (14%) and Cornell criteria for LVH were fulfilled in 20 patients (17%). Repolarization abnormalities were present in 12 patients (10%). Median follow-up duration was 7.0 [6.3-9.8] years, during which 23 patients underwent AVR and 2 patients died. After adjusting for age, a longer PR-interval was associated with worse intervention-free survival (HR 1.02, 95% CI: 1.01-1.04). CONCLUSION: Almost half of the patients with BAV had abnormalities on their ECG. Moreover, the PR-interval may be an interesting prognostic marker for intervention-free survival in BAV patients.

Bioactive adrenomedullin as a marker of congestion and disease progression in patients with a systemic right ventricle.

BACKGROUND: Adults with a systemic right ventricle (sRV) are at a high risk for heart failure (HF) hospitalization and mortality. Bioactive adrenomedullin (bio-ADM) has been proposed as a marker of congestion and prognosis in patients with cardiovascular disease. We aimed to evaluate the association between bio-ADM and mortality and HF events in sRV patients. METHODS: Plasma bio-ADM was measured by a novel immunoassay in plasma of 85 sRV patients. A composite endpoint of all-cause mortality and HF events was used as outcome. HF events were defined as onset or progression of HF signs or symptoms requiring hospitalization, initiation or intensification of therapy. Multivariable Cox regression analyses were performed to evaluate the association between bio-ADM and outcome. RESULTS: The mean age of the patients was 37 ± 9 years and 65% were male. Patients with higher plasma bio-ADM concentrations were more often treated with diuretics (p = 0.007), possibly because of signs and/or symptoms of congestion. During a median follow-up of 10.2 years, 33.7% of the patients reached the endpoint. After adjustment for age and N-terminal pro B-type natriuretic peptide (NT-pro BNP), higher bio-ADM levels were associated with a higher risk of the composite endpoint (hazard ratio: 2.09 [95%-confidence interval: 1.15-3.78]). Bio-ADM improved risk prediction when added to NT-proBNP and age (C-statistic improved from 0.748 to 0.776 [p = 0.03]). CONCLUSIONS: Bio-ADM can be considered as a marker of congestion and independent predictor of death and HF events in adult patients with a sRV. Moreover, in terms of risk prediction, it has added value to NT-proBNP.

Blood and Imaging Biomarkers in the Long-term Follow-up of Bicuspid Aortic Valve Patients.

Background: Bicuspid aortic valve (BAV) is a common congenital heart defect. Patients with BAV are at risk for long-term complications such as valve stenosis and regurgitation. This study aimed to investigate sex differences in blood and imaging biomarkers and to describe the long-term prognostic value of blood and echocardiographic biomarkers. Methods: Patients were included from 2 prospective observational cohort studies; they underwent venous blood sampling and transthoracic echocardiography including speckle tracking. Analyzed blood biomarkers were red-cell distribution width (RDW), creatinine, C-reactive protein (CRP), troponin T, N-terminal pro B-type natriuretic peptide (NT-proBNP), and transforming growth factor-beta (TGF-ß). Sex differences were analyzed at baseline. Associations between biomarkers and arrhythmia-free and intervention-free survival were determined by Cox regression, adjusted for age and sex. Results: A total of 182 patients with BAV were included: median age 34; interquartile range [IQR]: 23-46 years; 55.5% male. CRP, NT-proBNP, and RDW were higher in women, whereas creatinine, troponin T and TGF-ß were higher among men. After a median follow-up time of 6.9 (IQR: 6.5-9.9) years, arrhythmia-free and intervention-free survival was, 81.0% and 73.1%, respectively. NT-proBNP was associated with both arrhythmia-free and intervention-free survival (hazard ratio [HR], 1.94, P = 0.005 and HR, 2.06, P = 0.002, respectively). On echocardiography higher left atrial (LA) size, left ventricular end-diastolic diameter (LVEDD), left ventricular (LV) mass index and E/e' ratio were associated with lower arrhythmia-free survival, whereas higher LA size, LV mass index, aortic valve peak velocity, and aortic regurgitation were associated with lower intervention-free survival. Conclusions: Differences were observed in blood biomarkers between men and women with BAV. Besides LV systolic parameters, diastolic LV function and NT-proBNP should have a more prominent role as prognostic markers in clinical care.

Contexte: La bicuspide valvulaire aortique (BVA) est une anomalie cardiaque congénitale fréquente. Les patients atteints d'une BVA présentent des risques de complications à long terme, comme la sténose valvulaire ou la régurgitation valvulaire. Cette étude visait 1) à évaluer les différences entre les sexes en ce qui concerne les biomarqueurs sanguins et les biomarqueurs à l'imagerie; et 2) à décrire la valeur pronostique à long terme des biomarqueurs sanguins et échocardiographiques. Méthodologie: Des patients de 2 études de cohortes observationnelles prospectives ont été inclus dans l'analyse. Des échantillons de sang veineux ont été prélevés, et des échocardiographies transthoraciques, y compris le suivi des marqueurs acoustiques, ont été effectuées. Les biomarqueurs sanguins analysés étaient les suivants : indice de distribution des globules rouges (IDR), créatinine, protéine C-réactive (CRP), troponine T, propeptide natriurétique de type B N-terminal (NT-proBNP) et facteur de croissance transformant ß (TGF-ß). Les différences entre les sexes ont été analysées au départ. Les liens entre les biomarqueurs et la survie sans arythmie et sans intervention ont été déterminés par la régression de Cox, avec correction en fonction de l'âge et du sexe. Résultats: Cent quatre-vingt-deux patients présentant une BVA étaient inclus (âge médian de 34 [écart interquartile : 23-46] ans, 55,5 % hommes). La CRP, la NT-proBNP et l'IDR étaient plus élevées chez les femmes, alors que la créatinine, la troponine T et le TGF-ß étaient plus élevés chez les hommes. Après une période de suivi médiane de 6,9 (écart interquartile : 6,5-9,9) ans, les taux de survie sans arythmie et sans intervention étaient respectivement de 81,0 % et de 73,1 %. La NT-proBNP a été associée à la survie sans arythmie (rapport des risques instantanés [RRI] : 1,94, p = 0,005) et à la survie sans intervention (RRI : 2,06, p = 0,002). À l'échocardiographie, des valeurs élevées pour la taille de l'oreillette gauche, le diamètre télédiastolique du ventricule gauche (VG), l'indice de masse du VG et le rapport E/e' étaient associées à un faible taux de survie sans arythmie, alors que des valeurs élevées pour la taille de l'oreillette gauche, l'indice de masse du VG, la vitesse maximale aortique et la régurgitation aortique étaient associées à un faible taux de survie sans intervention. Conclusions: Les biomarqueurs sanguins variaient en fonction du sexe des personnes présentant une BVA. Outre les paramètres systoliques du VG, la fonction VG diastolique et la NT-proBNP devraient être davantage utilisées comme marqueurs pronostiques en soins cliniques.

Prognostic value of tricuspid valve regurgitation in patients with pulmonary arterial hypertension and CTEPH: A longitudinal study.

Aims: The prognostic value of functional tricuspid valve regurgitation (TR) in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (CTEPH) remains undetermined. This study primarily aims to quantify the prognostic role of TR in relation to right ventricle (RV) dysfunction on clinical outcomes and secondarily the evolution of TR and RV dysfunction over time. Methods: Adult PAH or CTEPH patients diagnosed by right heart catheterization were included. Exclusion criteria were prevalent patients and age < 18 years.The primary endpoint was a composite of death or lung transplantation. Longitudinal evolution of TR and RV dysfunction were modelled with generalized mixed-effect models, which were inserted in a cox model under the joint-modelling framework in order to investigate the association of TR and RV dysfunction with the endpoint. Results: We included 76 PAH and 44 CTEPH patients (median age:59, females:62 %), with a mean follow-up of 3.2 ± 2.1 years. 31 patients reached the endpoint (2 transplant, 29 mortality). On average the probability of moderate-to-severe TR decreased during follow-up, whereas the probability of moderate-to-severe RV dysfunction remained stable. The cumulative effect of moderate-to-severe TR (HRper day 1.01 95 %CI[1.00-1.01],P < 0.001) and moderate-to-severe RV dysfunction (HRper day: 1.01 95 %CI[1.00-1.01],P < 0.001) was associated with the endpoint in univariable joint-models. In a multivariable joint-model with both the evolutions of TR and RV dysfunction only TR remained significant (HR per day: 1.01 95 %CI[1.00-1.01],P < 0.001). Conclusion: Persistent moderate-to-severe tricuspid valve regurgitation during follow-up predicts adverse outcomes and might be a better predictor of lung transplantation and mortality compared to right ventricle dysfunction.

Heart rate: an accessible risk indicator in adult congenital heart disease.

BACKGROUND: Higher resting heart rate has been described as a risk factor for adverse outcome in healthy individuals and cardiovascular patients. The aim of this study was to evaluate resting heart rate as risk factor in adult congenital heart disease (ACHD). METHODS: In this prospective observational cohort study, patients with moderate or complex ACHD were included at routine outpatient visit. Standard 12-lead ECGs were obtained in rest. Heart rate was obtained from the ECG automatically by the Modular ECG Analysis System (MEANS). The primary endpoint was all-cause mortality and the secondary endpoint was a composite of all-cause mortality and heart failure. Survival was derived using the Kaplan-Meier estimator. Subgroups based on heart rate tertiles were compared by the log-rank test. Cox proportional hazards models were adjusted for clinical factors including age, sex and diagnosis (moderate vs complex ACHD). RESULTS: A total of 556 patients were included (median age 32 years (IQR 24-41), 57.6% male). Mean heart rate was 69±13 bpm. Negative chronotropic medication was used by 74 (13.3%) patients. During a median follow-up of 10.1 (IQR 9.6-10.5) years, 36 patients (6.5%) died and 83 (14.9%) reached the secondary endpoint. Patients with higher heart rates had significantly lower survival and heart failure-free survival. After adjusting for clinical factors, heart rate remained associated with mortality (HR 1.57 per 10 bpm, 95% CI 1.26 to 1.96) and mortality or heart failure (HR 1.33 per 10 bpm, 95% CI 1.13 to 1.57). CONCLUSION: Higher heart rate is associated with lower survival and heart failure-free survival in ACHD.

Sexual function is impaired in women and men with pulmonary hypertension.

BACKGROUND: Sexual health related quality of life (SHRQoL) is an important pillar of health related quality of life (HRQoL). The aim of this study was to investigate sexual functioning in men and women with pulmonary hypertension (PH). METHODS AND RESULTS: In this cross-sectional study, a total of 78 patients were included, 49 were diagnosed with pulmonary arterial hypertension and 29 with chronic thromboembolic pulmonary hypertension (median age 53 [IQR: 46-67 years], 66.7% female). All patients completed SHRQoL questionnaires; for women: ASEX, FSFI, and FSDS and for men: ASEX and IIEF. A PH-specific SHRQoL questionnaire was created based on 4 semi-structured interviews to investigate PH-specific barriers in sexuality. More than half of the patients experienced symptoms during sexual activity, mainly dyspnea (52.6%) and palpitations (32.1%). Sexual dysfunction was present, according to the FSFI-questionnaire, in 63.0% of women. All of the men experienced at least mild dysfunction in one of the domains of the IIEF and erectile dysfunction was present in 48.0%. Sexual dysfunction occurred more often in both men and women with PH than in the general population. PAH-specific medication was not associated with sexual dysfunction, nor was subcutaneous or intravenous pump therapy (OR 1.14, 95%-CI: 0.75-1.73). Diuretics were associated with sexual dysfunction in women (OR 4.01, 95%-CI: 1.04-15.41). Of all patients committed in a relationship, 69.0% would like to discuss sexuality with their healthcare provider. CONCLUSION: This study showed a high prevalence of sexual dysfunction in men and women with PH. It is important for healthcare providers to discuss sexuality with patients.

Role of the electrocardiogram in the risk stratification of pulmonary hypertension.

INTRODUCTION: The prognosis of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) remains dismal. Better risk prediction is needed. This study investigated the prognostic value of ECG characteristics. METHODS: In this single-centre prospective study, consecutive treatment-naïve patients with PAH or CTEPH were included at time of diagnosis. From the 12-lead ECG, obtained at baseline, the following parameters were collected: heart rate (HR), rhythm, QRS axis, conduction times, P-top amplitudes in II, R-top and S-wave amplitudes in V1 and V5 and repolarisation disorders. Associations between the ECG and transplant-free survival was assessed by Kaplan-Meier curves and Cox-proportional hazard regressions. RESULTS: In total, 140 patients were included (median age: 60.7 years, 63.6% female). The ECG was abnormal in 86.2%: sinus rhythm was not present in 9.3%, right QRS axis was observed in 47.8%, mean QRS duration was 101±17 ms. Only 42.5% of the patients had normal repolarisation, 34.5% had right ventricular strain and 14.4% non-specific repolarisation disorders. Over a median follow-up time of 3.49 (IQR: 1.37-6.42) years, 45 patients (32.5%) died or underwent lung transplantation. Transplant-free survival was worse in patients presenting with an abnormal ECG (64.0% vs 86.0%; p=0.037). The following ECG characteristics were associated with all-cause mortality or lung transplantation: heart rate (HR 1.02, 95% CI: 1.00 to 1.05), QRS duration >120 ms (HR 2.61, 95% CI: 1.01 to 6.71) and S-wave amplitude in V5 (HR 1.10, 95% CI: 1.04 to 1.17). CONCLUSION: Only 13.8% of patients with PAH and CTEPH presented with a normal ECG, which is associated with favourable outcome. The ECG provides additional prognostic value to current clinical parameters and should be considered in risk prediction.

The evolution of survival of pulmonary arterial hypertension over 15 years.

The prognosis of pulmonary arterial hypertension (PAH) remains dismal. Over the years, multiple therapeutic advances have been introduced. This study evaluates the evolution of PAH survival over the past 15 years. We included 293 consecutive adult patients diagnosed with PAH between 2005 and 2019 (median age: 61.8 years, 70.3% female). Patients were divided into three cohorts based on the time of diagnosis: 2005-2009, 2010-2014, and 2015-2019 (2005-2009: n = 56; 2010-2014: n = 111; 2015-2019: n = 126). Transplant-free survival was measured from the date of right heart catheterization until patients reached the composite endpoint of lung transplant or death. Multivariable cox-pulmonary hypertension regression was used to study the effect of the time of diagnosis. The final cox model was fitted in both younger and older patients to evaluate the difference between these groups. During a median follow-up time of 4.1 (interquartile range: 2.2-7.3) years, 9 patients underwent lung transplantation and 151 patients died. The median overall transplant-free survival was 6.2 (5.5-8.0) years. Patients older than 56 years at baseline who were diagnosed in 2005-2009 showed better survival compared to patients diagnosed in 2010-2014 and 2015-2019 with an adjusted hazard ratio of, respectively, 2.12 (1.11-4.03) and 2.83 (1.41-5.69). Patients younger than 56 years showed neither an improved nor deteriorated survival over time. In conclusion, survival in patients with PAH did not improve over time, despite more available therapeutic options. This might be partly due to the changed demographic characteristics of the PAH patients and a still important diagnostic delay.

Prognostic value of brain natriuretic peptides in patients with pulmonary arterial hypertension: A systematic review and meta-analysis.

BACKGROUND: Multiple biomarkers have been investigated in the risk stratification of patients with pulmonary arterial hypertension (PAH). This systematic review and meta-analysis is the first to investigate the prognostic value of (NT-pro)BNP in patients with PAH. METHODS: A systematic literature search was performed using MEDLINE, Embase, Web of Science, the Cochrane Library and Google scholar to identify studies on the prognostic value of baseline (NT-pro)BNP levels in PAH. Studies reporting hazard ratios (HR) for the endpoints mortality or lung transplant were included. A random effects meta-analysis was performed to calculate the pooled HR of (NT-pro)BNP levels at the time of diagnosis. To account for different transformations applied to (NT-pro)BNP, the HR was calculated for a 2-fold difference of the weighted mean (NT-pro)BNP level of 247 pmol/L, for studies reporting a HR based on a continuous (NT-pro)BNP measurement. RESULTS: Sixteen studies were included, representing 6999 patients (mean age 45.2-65.0 years, 97.3% PAH). Overall, 1460 patients reached the endpoint during a mean follow-up period between 1 and 10 years. Nine studies reported HRs based on cut-off values. The risk of mortality or lung transplant was increased for both elevated NT-proBNP and BNP with a pooled HR based on unadjusted HRs of 2.75 (95%-CI: 1.86-4.07) and 3.87 (95% CI 2.69-5.57) respectively. Six studies reported HRs for (NT-pro)BNP on a continues scale. A 2-fold difference of the weighted mean NT-proBNP resulted in an increased risk of mortality or lung transplant with a pooled HR of 1.17 (95%-CI: 1.03-1.32). CONCLUSIONS: Increased levels of (NT-pro)BNP are associated with a significantly increased risk of mortality or lung transplant in PAH patients.

The longitudinal use of EmPHasis-10 and CAMPHOR questionnaire health-related quality of life scores in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

BACKGROUND: Health-related quality of life (HRQoL) is impaired in patients with pulmonary hypertension (PH). The EmPHasis-10 and CAMPHOR questionnaires are developed to evaluate HRQoL specifically in patients with PH. Data on the longitudinal use of both questionnaires are still limited. We evaluated the longitudinal value of both questionnaires and established minimal clinically important differences (MCID). METHODS: Sixty-one treatment naïve pulmonary arterial hypertension or chronic thromboembolic patients were prospectively included. Patients were treated according to the current ESC/ERS guidelines. We compared EmPHasis-10 and CAMPHOR scores between baseline, 6 and 12 months of follow-up and evaluated the correlation between these scores and a 5-scale symptom severity score, 5-scale overall health score, NYHA-classification, 6 min walk test distance (6MWD), NT-proBNP and echocardiographic parameters. RESULTS: After one year of treatment a significant reduction in EmPHasis-10 score and CAMPHOR QoL and symptoms domain score was observed. Moderate to good correlations were observed between the questionnaires and the overall-health and symptom severity score and 6MWD. No relevant correlations were seen between the questionnaires and NT-pro-BNP and echocardiographic parameters. EmPHasis-10 scores showed strong correlations with all CAMPHOR domains. The MCID for the EmPHasis-10 questionnaire was -8. The MCIDs for the CAMPHOR domains were: activity -3, symptoms -4, QoL -3. CONCLUSION: The EmPHasis-10 and CAMPHOR questionnaires are valid tools for the longitudinal measurement of HRQoL in patients with PH. The much shorter EmPHasis-10 correlates well with the CAMPHOR domain scores and with the clinical endpoints and it may be easier to use in daily practice.