Impacto del cateterismo derecho de ejercicio en el diagnóstico diferencial de la enfermedad tromboembólica pulmonar crónica / Value of exercise right heart catheterization in the differential diagnosis of chronic thromboembolic pulmonary disease

Introduction and objectives Chronic thromboembolic disease refers to the presence of chronic thrombotic pulmonary vascular thrombosis without pulmonary hypertension (PH) at rest but with exercise limitation after pulmonary embolism (PE). Our aim was to evaluate the hemodynamic response to exercise in these patients and its correlation with the values reached in cardiopulmonary exercise testing. Methods We included symptomatic patients with persistent pulmonary thrombosis after PE. We excluded patients with left heart disease or significant PH (mean pulmonary arterial pressure [mPAP] >25mmHg, pulmonary vascular resistance >3 WU, and pulmonary capillary wedge pressure [PCWP] >15mmHg). Cardiopulmonary exercise testing and exercise right heart catheterization were performed. Exercise-induced precapillary PH was defined as mPAP/CO slope >3 and PCWP/CO slope <2mmHg/l/min. The hemodynamic response and the values obtained in cardiopulmonary exercise testing were compared between patients with and without exercise-induced precapillary PH. Results We studied 36 patients; 4 were excluded due to incomplete hemodynamic data. Out of the 32 patients analyzed; 3 developed a pathological increase in PCWP. Among the remaining 29 patients (mean age, 49.4±13.7 years, 34.5% women), 13 showed exercise-induced PH. Resting mPAP was higher in those who developed exercise-induced PH (23.3±5.4 vs 19.0±3.8mmHg; P=.012), although CO was similar in the 2 groups. Patients with exercise-induced PH exhibited data of ventilatory inefficiency with reduced values of end-tidal CO2 pressure at the anaerobic threshold (32.8±3.0 vs 36.2±3.3mmHg; P=.021) and a higher Ve/VCO2 slope (34.2±4.8 vs 30.7±5.0; P=.049). Conclusions Exercise limitation and ventilatory inefficiency could be attributable to exercise-induced precapillary PH in a subgroup of patients with persistent pulmonary thrombosis and dyspnea (AU)

Introdución y objetivos La enfermedad tromboembólica crónica se define como la trombosis crónica de la vasculatura pulmonar y disnea, sin hipertensión pulmonar (HP) en reposo tras una embolia de pulmón. El estudio evaluó la hemodinámica al esfuerzo en estos pacientes y su relación con la ergoespirometría. Métodos Se incluyó a pacientes sintomáticos con trombosis pulmonar crónica tras una embolia de pulmón. Se excluyó a los pacientes con cardiopatía izquierda o HP significativa en reposo (presión arterial pulmonar media [PAPm] >25mmHg, resistencia vascular pulmonar >3 UW y presión capilar pulmonar [PCP] >15mmHg). Se realizó una ergoespirometría y un cateterismo derecho de ejercicio. La HP precapilar al ejercicio se definió como las pendientes PAPm/gasto cardiaco >3 y PCP/gasto cardiaco <2mmHg/l/min. Se comparó la respuesta hemodinámica y ergoespirométrica entre pacientes con y sin HP precapilar al ejercicio. Resultados Se estudió a 36 pacientes, excluyéndose 4 por calidad subóptima en el registro hemodinámico. Tres pacientes presentaron una elevación patológica de la PCP. De los 29 restantes (edad, 49,4±13,7 años; el 34,5% mujeres), en 13 se halló HP precapilar al ejercicio. La PAPm basal fue mayor en aquellos con HP al ejercicio (23,3±5,4 frente a 19,0±3,8mmHg; p=0,012), con similar gasto cardiaco. Aquellos con HP al ejercicio exhibieron valores reducidos de la presión de CO2 exahalada en el umbral anaeróbico (32,8±3,0 frente a 36,2±3,3mmHg; p=0,021) y mayor pendiente Ve/VCO2 (34,2±4,8 frente a 30,7±5,0; p=0,049). Conclusiones La HP precapilar al ejercicio se asocia con limitación funcional e ineficiencia ventilatoria en un subgrupo de pacientes con trombosis arterial pulmonar crónica y disnea persistente (AU)

Simplified risk stratification based on cardiopulmonary exercise test: A Spanish two-center experience.

A simplified 4-strata risk stratification approach based on three variables is widespread in pulmonary arterial hypertension (PAH) at follow-up. This study aimed to assess the impact of replacing the 6-min walk test (6MWT) with the peak 02 uptake evaluated by the cardiopulmonary exercise test (CPET) on risk stratification by this scale. We included 180 prevalent patients with PAH from two reference hospitals in Spain, followed up between 2006 and 2022. Patients were included if all the variables of interest were available within a 3-month period on the Spanish Registry of Pulmonary Arterial Hypertension (REHAP): functional class (FC); NT-proBNP; 6MWT; and CPET. The original 4-strata model (NT-proBNP, 6MWT, FC) identified most patients at low or intermediate-low risk (36.7% and 51.1%, respectively). Notably, the modified scale (NT-proBNP, CPET, FC) improved the identification of patients at intermediate-high risk up to 18.9%, and at high risk up to 1.1% in comparison with the previous 12.2% and 0.0% in the original scale. This new model increased the number of patients correctly classified into higher-risk strata (positive NRI of 0.06), as well as classified more patients without events in lower-risk strata (negative NRI of 0.04). The proposed score showed a slightly superior prognostic capacity compared with the original model (Harrel's C-index 0.717 vs. 0.709). Using O2 uptake instead of distance walked in the 6MWT improves the identification of high-risk patients using the 4-strata scale. This change could have relevant prognostic implications and lead to changes in the specific treatment of PAH.

Triple vasodilator therapy in pulmonary arterial hypertension associated with congenital heart disease.

OBJECTIVE: This study assessed the long-term effects of triple therapy with prostanoids on patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD), as there is limited information on the safety and efficacy of this treatment approach. METHODS: A retrospective cohort study was conducted on patients with PAH-CHD who were actively followed up at our centre. All patients were already receiving dual combination therapy at maximum doses. Clinical characteristics, including functional class (FC), 6-minute walking test distance (6MWTD) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, were documented before initiating triple therapy and annually for a 2-year follow-up period. RESULTS: A total of 60 patients were included in the study, with a median age of 41 years and 68% being women. Of these, 32 had Eisenmenger syndrome, 9 had coincidental shunts, 18 had postoperative PAH and 1 had a significant left-to-right shunt. After 1 year of triple combination initiation, a significant improvement in 6MWTD was observed (406 vs 450; p=0.0027), which was maintained at the 2-year follow-up. FC improved in 79% of patients at 1 year and remained stable in 76% at 2 years. NT-proBNP levels decreased significantly by 2 years, with an average reduction of 199 ng/L. Side effects were experienced by 33.3% of patients but were mostly mild and manageable. Subgroup analysis showed greater benefits in patients without Eisenmenger syndrome and those with pre-tricuspid defects. CONCLUSIONS: Triple therapy with prostanoids is safe and effective for patients with PAH-CHD, improving FC, 6MWTD and NT-proBNP levels over 2 years. The treatment is particularly beneficial for patients with pre-tricuspid defects and non-Eisenmenger PAH-CHD.

Value of exercise right heart catheterization in the differential diagnosis of chronic thromboembolic pulmonary disease.

INTRODUCTION AND OBJECTIVES: Chronic thromboembolic disease refers to the presence of chronic thrombotic pulmonary vascular thrombosis without pulmonary hypertension (PH) at rest but with exercise limitation after pulmonary embolism (PE). Our aim was to evaluate the hemodynamic response to exercise in these patients and its correlation with the values reached in cardiopulmonary exercise testing. METHODS: We included symptomatic patients with persistent pulmonary thrombosis after PE. We excluded patients with left heart disease or significant PH (mean pulmonary arterial pressure [mPAP] >25mmHg, pulmonary vascular resistance >3 WU, and pulmonary capillary wedge pressure [PCWP] >15mmHg). Cardiopulmonary exercise testing and exercise right heart catheterization were performed. Exercise-induced precapillary PH was defined as mPAP/CO slope >3 and PCWP/CO slope <2mmHg/l/min. The hemodynamic response and the values obtained in cardiopulmonary exercise testing were compared between patients with and without exercise-induced precapillary PH. RESULTS: We studied 36 patients; 4 were excluded due to incomplete hemodynamic data. Out of the 32 patients analyzed; 3 developed a pathological increase in PCWP. Among the remaining 29 patients (mean age, 49.4±13.7 years, 34.5% women), 13 showed exercise-induced PH. Resting mPAP was higher in those who developed exercise-induced PH (23.3±5.4 vs 19.0±3.8mmHg; P=.012), although CO was similar in the 2 groups. Patients with exercise-induced PH exhibited data of ventilatory inefficiency with reduced values of end-tidal CO2 pressure at the anaerobic threshold (32.8±3.0 vs 36.2±3.3mmHg; P=.021) and a higher Ve/VCO2 slope (34.2±4.8 vs 30.7±5.0; P=.049). CONCLUSIONS: Exercise limitation and ventilatory inefficiency could be attributable to exercise-induced precapillary PH in a subgroup of patients with persistent pulmonary thrombosis and dyspnea.

Seven Additional Patients with SOX17 Related Pulmonary Arterial Hypertension and Review of the Literature.

Pulmonary arterial hypertension (PAH) is an infrequent disorder characterized by high blood pressure in the pulmonary arteries. It may lead to premature death or the requirement for lung and/or heart transplantation. Genetics plays an important and increasing role in the diagnosis of PAH. Here, we report seven additional patients with variants in SOX17 and a review of sixty previously described patients in the literature. Patients described in this study suffered with additional conditions including large septal defects, as described by other groups. Collectively, sixty-seven PAH patients have been reported so far with variants in SOX17, including missense and loss-of-function (LoF) variants. The majority of the loss-of-function variants found in SOX17 were detected in the last exon of the gene. Meanwhile, most missense variants were located within exon one, suggesting a probable tolerated change at the amino terminal part of the protein. In addition, we reported two idiopathic PAH patients presenting with the same variant previously detected in five patients by other studies, suggesting a possible hot spot. Research conducted on PAH associated with congenital heart disease (CHD) indicated that variants in SOX17 might be particularly prevalent in this subgroup, as two out of our seven additional patients presented with CHD. Further research is still necessary to clarify the precise association between the biological pathway of SOX17 and the development of PAH.

Evolución y pronóstico de la insuficiencia tricuspídea moderada-grave tras tromboendarterectomía pulmonar o angioplastia de arterias pulmonares / Outcome of moderate-severe tricuspid regurgitation after pulmonary endarterectomy or balloon pulmonary angioplasty

Introducción y objetivos: No está definido el abordaje de la insuficiencia tricuspídea (IT) funcional moderada-grave en los pacientes con hipertensión pulmonar tromboembólica crónica tras la tromboendarterectomía pulmonar (TEA) o angioplastia con balón de las arterias pulmonares (ABAP). El objetivo de este estudio es analizar la evolución y los predictores de IT residual tras el procedimiento, así como su impacto pronóstico. Métodos: Estudio observacional unicéntrico. Se incluyó a 72 pacientes sometidos a TEA y 20 que completaron el programa de ABAP con diagnóstico de hipertensión pulmonar tromboembólica crónica y presentaban IT moderada-grave antes del procedimiento intervencionista. Resultados: La prevalencia de IT moderada-grave tras el procedimiento fue del 29%, sin diferencias entre los tratados con TEA o ABAP (el 30,6 frente al 25%; p=0,78). En el grupo con IT persistente se hallaron mayores presión arterial pulmonar media (40,2± 1,9 frente a 28,5±1,3mmHg; p<0,001), resistencia vascular pulmonar (472 [347-710] frente a 282 [196-408] dyn·s/cm5; p <0,001) y área de la aurícula derecha (23,0 [21-31] frente a 16,0 [14,0-20,0]; p <0,001) tras el procedimiento comparado con el de pacientes con IT ausente-ligera. La resistencia vascular pulmonar> 400dyn.s/cm5 y el área de la aurícula derecha> 22 cm2 tras el procedimiento se asociaron de manera independiente con la persistencia de la IT, pero no se identificaron predictores antes de la intervención. La IT moderada-grave residual y la presión pulmonar media> 30mmHg se asociaron con mayor mortalidad en 3 años de seguimiento. Conclusiones: La IT moderada-grave residual posterior a TEA o ABAP se asoció con la persistencia de una mayor poscarga y un persistente remodelado desfavorable de las cámaras cardiacas derechas tras el procedimiento. La IT moderada-grave y la hipertensión pulmonar residual se asociaron con un peor pronóstico a 3 años. (AU)

Introduction and objectives: The 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. Methods: This 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. Results: The 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. Conclusions: Residual 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. (AU)

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

INTRODUCTION AND OBJECTIVES: The 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. METHODS: This 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. RESULTS: The 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. CONCLUSIONS: Residual 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.

Novel Loss-of-Function KCNA5 Variants in Pulmonary Arterial Hypertension.

Reduced expression and/or activity of Kv1.5 channels (encoded by KCNA5) is a common hallmark in human or experimental pulmonary arterial hypertension (PAH). Likewise, genetic variants in KCNA5 have been found in patients with PAH, but their functional consequences and potential impact on the disease are largely unknown. Herein, this study aimed to characterize the functional consequences of seven KCNA5 variants found in a cohort of patients with PAH. Potassium currents were recorded by patch-clamp technique in HEK293 cells transfected with wild-type or mutant Kv1.5 cDNA. Flow cytometry, Western blot, and confocal microscopy techniques were used for measuring protein expression and cell apoptosis in HEK293 and human pulmonary artery smooth muscle cells. KCNA5 variants (namely, Arg184Pro and Gly384Arg) found in patients with PAH resulted in a clear loss of potassium channel function as assessed by electrophysiological and molecular modeling analyses. The Arg184Pro variant also resulted in a pronounced reduction of Kv1.5 expression. Transfection with Arg184Pro or Gly384Arg variants decreased apoptosis of human pulmonary artery smooth muscle cells compared with the wild-type cells, demonstrating that KCNA5 dysfunction in both variants affects cell viability. Thus, in addition to affecting channel activity, both variants were associated with impaired apoptosis, a crucial process linked to the disease. The estimated prevalence of dysfunctional KCNA5 variants in the PAH population analyzed was around 1%. The data indicate that some KCNA5 variants found in patients with PAH have critical consequences for channel function, supporting the idea that KCNA5 pathogenic variants may be a causative or contributing factor for PAH.

Novel Molecular Mechanisms Involved in the Medical Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a severe condition with a high mortality rate despite advances in diagnostic and therapeutic strategies. In recent years, significant scientific progress has been made in the understanding of the underlying pathobiological mechanisms. Since current available treatments mainly target pulmonary vasodilation, but lack an effect on the pathological changes that develop in the pulmonary vasculature, there is need to develop novel therapeutic compounds aimed at antagonizing the pulmonary vascular remodeling. This review presents the main molecular mechanisms involved in the pathobiology of PAH, discusses the new molecular compounds currently being developed for the medical treatment of PAH and assesses their potential future role in the therapeutic algorithms of PAH.

Effectiveness and Safety of Balloon Pulmonary Angioplasty for the Treatment of Patients with Persistent Pulmonary Hypertension after Pulmonary Endarterectomy.

(1) Background: Pulmonary endarterectomy (PEA) is the "gold standard" treatment for operable patients with chronic thromboembolic pulmonary hypertension (CTEPH). Persistent pulmonary hypertension (PH) after PEA confers a worse prognosis. Balloon pulmonary angioplasty (BPA) could represent a useful therapy in this setting, but evidence about its effectiveness and safety in patients with previous PEA is limited. (2) Methods: A total of 14 patients with persistent PH after PEA were treated with BPA in a single PH center. Hemodynamic and clinical effects of BPA and complications of the procedure were retrospectively collected. (3) Results: After BPA, the mean pulmonary arterial pressure fell from 50.7 ± 15.3 mmHg to 38.0 ± 7.9 mmHg (25.0% decrease; 95% confidence interval (CI) 14.0-35.5%; p = 0.01). Pulmonary vascular resistances were reduced from 8.5 ± 3.6 WU to 5.3 ± 2.2 WU (37.6% decrease; 95% CI 18.8-56.5%; p = 0.01). WHO functional class was also improved with BPA. Severe BPA-related complications were infrequent and no periprocedural deaths were observed. (4) Conclusions: BPA is an effective and safe therapy for patients with CTEPH and persistent PH after PEA.

Usefulness of genetics for clinical reclassification and refinement of prognostic stratification in pulmonary arterial hypertension.

INTRODUCTION AND OBJECTIVES: Risk stratification in pulmonary arterial hypertension (PAH) is essential to provide more aggressive treatment for patients at higher risk. Nevertheless, recently introduced simplified prognostic tools neglect the genetic background. Additionally, pulmonary veno-oclusive disease (PVOD) has never been considered in risk assessment strategies. METHODS: We analyzed consecutive patients in the Spanish registry of PAH (REHAP) genetically tested, between 2011 and 2022. We applied the 4-strata COMPERA 2.0 model, comparing these results with an amplified score including genetics. Cox regression models were compared using Harrel c-statistics. The application of the model was specifically tested in PVOD before inclusion. RESULTS: We identified 298 patients tested genetically among the group of idiopathic, familial, drug-induced PAH and PVOD patients in the REHAP registry. When we analyzed only patients with all available variables of interest at baseline (World Health Organization functional class, 6-minute walk test, B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide) and included in the 4-strata model (n=142), after a median follow-up of 58.2 months, 17.6% of patients died and 11.3% underwent lung transplant. The application of the 4-strata model in our population demonstrated a good prognostic capacity (Harrel c of 0.689), which was not improved by the introduction of genetics (c-index 0.690). This last model showed a tendency for a better identification of patients at intermediate-low and intermediate-high risk, and no differences between intermediate-high and high-risk strata. CONCLUSIONS: In this work, the addition of genetics to the COMPERA 4-strata model achieved a similar global prognostic capacity but changed the identification of different risk strata in a cohort of young genetically tested patients.

Balloon pulmonary angioplasty can be an effective and safe therapeutic option in non-surgical elderly patients.

Background: Advanced age, frailty, and age-related comorbidities are the major causes of pulmonary endarterectomy disqualification in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Balloon pulmonary angioplasty (BPA) is an attractive and less invasive therapy for elderly patients. However, information about the safety, procedure tolerance, and effectiveness of BPA in elderly patients is limited. Objective and methods: We aimed to analyze the safety, tolerance, and efficacy of BPA in CTEPH patients aged ≥70 years. This observational, descriptive, and retrospective series included consecutive patients aged ≥70 years, who underwent completed or interrupted BPA programs at a pulmonary hypertension reference center between May 2013 and May 2022. Results: We enrolled 155 patients in our institution's BPA program. Among these, 33 patients were aged ≥70 years (mean age, 76.4 years; women, 75.8%) and had finished or interrupted BPA programs. In this cohort, we performed 116 BPA procedures (average, 3.6 ± 1.8 sessions/patient). Among the 33 patients, 19 (57.6%) completed treatment for all lobes, while the BPA program was interrupted in the remaining 14 (42.4%). Among all 33 patients, BPA was associated with a significant reduction in mean pulmonary arterial pressure (39.2 ± 9.3 vs. 32.8 ± 8.8 mmHg; p < 0.001) and pulmonary vascular resistance (6.7 ± 3.1 vs. 4.4 ± 2.0 WU; p < 0.001), along with an improvement in the cardiac index (2.5 ± 0.6 vs. 2.8 ± 0.7 L/min/m2; p = 0.04) with significant reductions in the N-terminal prohormone of brain natriuretic peptide level (pre-BPA, 353 pg/mL [207-1,960 pg/mL] vs. post-BPA, 167 pg/mL [73-629 pg/mL]; p = 0.03). The patients' functional class improved, and pulmonary hypertension-targeting drug requirements were significantly reduced. The pulmonary injury appeared in 3.4% of the 116 procedures, of which 50% were of grade 2. No patient of ≥70 years had grade 5 pulmonary injury. One periprocedural mortality was recorded (3%), and the median follow-up period was 2.8 years. The survival rate of the entire cohort at 1 and 3 years was 90.5 and 82.8%, respectively. Conclusion: BPA is an effective and safe approach in patients aged ≥70 years. It significantly improves patients' functional class, hemodynamic, and biomarkers, and reduces their pulmonary hypertension-targeting medical therapy requirements. These successes were achieved even though a significant percentage of patients did not complete the therapy. The rates of procedural complications and periprocedural mortality were low. Survival at 1 and 3 years was good in comparison to that of younger patients undergoing BPA.