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The clinical classification of pulmonary hypertension (PH) has guided diagnosis and treatment of patients with PH for several decades. Discoveries relating to underlying mechanisms, pathobiology, and responses to treatments for PH have informed the evolution in this clinical classification to describe the heterogeneity in PH phenotypes. In more recent years, advances in imaging, computational science, and multi-omic approaches have yielded new insights into potential phenotypes and sub-phenotypes within the existing clinical classification. Identification of novel phenotypes in pulmonary arterial hypertension (PAH) with unique molecular profiles, for example, could lead to new precision therapies. Recent phenotyping studies have also identified groups of patients with PAH that more closely resemble patients with left heart disease (group 2 PH) and lung disease (group 3 PH), which has important prognostic and therapeutic implications. Within group 2 and group 3 PH, novel phenotypes have emerged that reflect a persistent and severe pulmonary vasculopathy that is associated with worse prognosis but still distinct from PAH. In group 4 PH (chronic thromboembolic pulmonary disease) and sarcoidosis (group 5 PH) the current approach to patient phenotyping integrates clinical, hemodynamic and imaging characteristics to guide treatment but applications of multi-omic approaches to sub-phenotyping in these areas are sparse. The next iteration of the PH clinical classification is likely to reflect several emerging PH phenotypes and improve the next generation of prognostication tools, clinical trial design, and improve treatment selection in clinical practice.
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Pulmonary hypertension (PH) continues to present significant challenges to the medical community, both in terms of diagnosis and treatment. The advent of the updated 2022 European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines has introduced pivotal changes that reflect the rapidly advancing understanding of this complex disease. These changes include a revised definition of PH, updates to the classification system, and treatment algorithm. While these guidelines offer a critical framework for the management of PH, they have also sparked new discussions and questions. The 5th French Pulmonary Hypertension Network Meeting (Le Kremlin-Bicêtre, France, 2023), addressed these emergent questions and fostering a deeper understanding of the disease's multifaceted nature. These discussions were not limited to theoretical advancements but extended into the practical realms of patient management, highlighting the challenges and opportunities in applying the latest guidelines to clinical practice.
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BACKGROUND: Exercise hemodynamics are recommended for early detection of pulmonary arterial hypertension (PAH) and have been suggested to be predictive of future development of PAH in high-risk populations such as bone morphogenetic protein receptor type 2 (BMPR2) mutation carriers. However, the optimal exercise hemodynamic screening parameter remains to be determined. Recent data suggest that pulmonary vascular distensibility coefficient (α) may serve as a useful parameter for early detection of PAH. RESEARCH QUESTION: What is the value of exercise hemodynamics, including α, for predicting the occurrence of PAH during long-term follow-up in BMPR2 mutation carriers? STUDY DESIGN AND METHODS: 52 asymptomatic BMPR2 mutation carriers who underwent symptom-limited exercise hemodynamic assessment were followed for a median of 10 years. The impact of hemodynamics at rest and exercise, presence of exercise PH and α on occurrence of PAH during long-term follow-up was assessed. RESULTS: During long-term follow-up 5 patients developed PAH. Patients who developed PAH had a significantly lower α (0.8±0.4%/mmHg) than patients without PAH (1.8±0.8%/mmHg, p=0.008). α was the only hemodynamic parameter that predicted the occurrence of PAH during long-term follow-up at regression analysis. At receiver operating characteristic analysis α ≤1.5%/mmHg predicted PAH occurrence with a specificity of 75% and sensitivity of 100%. INTERPRETATION: α is markedly reduced prior to development of PAH in BMPR2 mutation carriers and may serve as a useful parameter in the setting of early disease detection. Given the low event rate, caution is warranted in interpreting these results, highlighting the need for validation studies.
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INTRODUCTION: Long-term outcome data are limited for non-achalasia esophageal motility disorders treated by peroral endoscopy myotomy (POEM) as a separate group. We investigated a subset of symptomatic patients with hypercontractile esophagus (Jackhammer esophagus). METHODS: Forty two patients (mean age 60.9 years; 57% female, mean Eckardt score 6.2 ± 2.1) treated by primary peroral myotomy for symptomatic Jackhammer esophagus 2012-2018 in seven European centers were retrospectively analyzed; myotomy included the lower esophageal sphincter but did not extend more than 1 cm into the cardia in contrast to POEM for achalasia. Manometry data were re-reviewed by an independent expert. The main outcome was the failure rate defined by retreatment or an Eckardt score >3 after at least two years following POEM. RESULTS: Despite 100% technical success (mean intervention time 107 ± 48.9 min, mean myotomy length 16.2 ± 3.7 cm), the 2-year success rate was 64.3% in the entire group. In a subgroup analysis, POEM failure rates were significantly different between Jackhammer-patients without (n = 22), and with esophagogastric junction outflow obstruction (EGJOO, n = 20) (13.6% % vs. 60%, p = 0.003) at a follow-up of 46.5 ± 19.0 months. Adverse events occurred in nine cases (21.4%). 14 (33.3%) patients were retreated, two with surgical fundoplication due to reflux. Including retreatments, an improvement in symptom severity was found in 33 (78.6%) at the end of follow-up (Eckardt score ≤3, mean Eckardt change 4.34, p < 0.001). EGJOO (p = 0.01) and frequency of hypercontractile swallows (p = 0.02) were predictors of POEM failure. The development of a pseudodiverticulum was observed in four cases within the subgroup of EGJOO. CONCLUSIONS: Patients with symptomatic Jackhammer without EGJOO benefit from POEM in long-term follow-up. Treatment of Jackhammer with EGJOO, however, remains challenging and probably requires full sphincter myotomy and future studies which should address the pathogenesis of this variant and alternative strategies.
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BACKGROUND: Plasma asymmetric dimethylarginine (ADMA) is elevated in pulmonary arterial hypertension (PAH) and is associated with unfavorable outcomes. OBJECTIVES: The aim of this study was to assess changes in ADMA plasma levels for monitoring disease progression and outcomes during PAH-specific therapy. METHODS: ADMA was measured at baseline and after at least 6 months of follow-up using enzyme-linked immunosorbent assay and high-performance liquid chromatography. Changes in ADMA were analyzed in relation to changes in established PAH markers, including hemodynamic status, N-terminal pro-brain natriuretic peptide (NT-proBNP) and risk assessment scores. Impact on survival was assessed using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: Between 2008 and 2019, ADMA samples were collected prospectively from 215 patients with PAH. Change in ADMA plasma level was a predictor of disease progression and survival. ΔADMA (median -0.03 µmol/L; 95% CI: -0.145 to 0.0135) was correlated with change in mean pulmonary arterial pressure (P < 0.005; rS = 0.287) but was not significantly correlated with ΔNT-proBNP (P = 0.056; rS = 0.135). Patients with decreased ADMA plasma levels at follow-up had better 3-year and 5-year survival rates (88% and 80%, respectively, vs 72% and 53% in those without decreases in ADMA) (P < 0.005; pulmonary hypertension-related mortality or lung transplantation). Patients with decreases in both ADMA and NT-proBNP had better survival rates compared with patients in whom only 1 parameter improved (P < 0.005). ΔADMA was a significant predictor of survival in Cox regression analysis and also when corrected for ΔNT-proBNP (HRs: 1.27 and 1.35, respectively; P < 0.005). CONCLUSIONS: ADMA and NT-proBNP provide synergistic prognostic information for patients with PAH. ADMA could be used as an objective and distinct biomarker for monitoring treatment response in PAH.
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Arginina , Biomarcadores , Progresión de la Enfermedad , Péptido Natriurético Encefálico , Fragmentos de Péptidos , Hipertensión Arterial Pulmonar , Humanos , Péptido Natriurético Encefálico/sangre , Arginina/análogos & derivados , Arginina/sangre , Femenino , Masculino , Fragmentos de Péptidos/sangre , Persona de Mediana Edad , Biomarcadores/sangre , Hipertensión Arterial Pulmonar/sangre , Hipertensión Arterial Pulmonar/fisiopatología , Estudios Prospectivos , Adulto , Pronóstico , Anciano , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/fisiopatologíaRESUMEN
AIMS: A common feature of various forms of pulmonary hypertension (PH) is progressive decline of pulmonary arterial compliance (CPA), which correlates with reduced survival. In this acute study, we evaluated feasibility, safety and haemodynamic performance of the Aria pulmonary endovascular device in patients with PH associated with left heart disease (PH-LHD) and chronic lung disease (PH-CLD). METHODS AND RESULTS: Eight patients with PH-LHD and 10 patients with PH-CLD were included in this study. The device was placed in the main pulmonary artery via the right femoral vein and was connected by a catheter to a gas-filled reservoir outside the body. During systole, gas shifts from the balloon to the reservoir, leading to deflation of the balloon. In diastole, the gas returns from the reservoir to the balloon, leading to balloon inflation and enhancing diastolic blood flow to the distal pulmonary capillary bed. Haemodynamics were assessed at baseline, and again with device off, device on and device off. The primary safety endpoint was the incidence of serious adverse events through 30 days after the procedure. No complications or investigational device-related serious adverse events occurred. Device activation in PH-LHD and PH-CLD patients decreased pulmonary arterial pulse pressure by 5.6 ± 4.2 mmHg (-12%; p = 0.003) and 4.2 ± 2.2 mmHg (-11%; p < 0.001), increased CPA by 0.4 ± 0.2 ml/mmHg (+23%; p = 0.004) and 0.4 ± 0.3 ml/mmHg (+25%; p = 0.001), and increased right ventricular-to-pulmonary vascular (RV-PV) coupling by 0.24 ± 0.18 (+40%; p = 0.012) and 0.11 ± 0.07 (+21%; p = 0.001), respectively. CONCLUSIONS: Temporary implantation of the Aria endovascular device was feasible and safe. Device activation resulted in acute improvement of CPA and RV-PV coupling.
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Hipertensión Pulmonar , Humanos , Masculino , Femenino , Hipertensión Pulmonar/fisiopatología , Persona de Mediana Edad , Anciano , Resultado del Tratamiento , Hemodinámica/fisiología , Estudios de Factibilidad , Arteria Pulmonar/fisiopatología , Procedimientos Endovasculares/métodos , Diseño de EquipoRESUMEN
Background: Percutaneous cholangioscopy (PerC) offers an alternative for patients with an inaccessible biliary tree. This systematic review and meta-analysis aimed to evaluate the performance of this technique. Methods: A search in Medline, Cochrane and ClinicalTrials.gov databases was performed for studies assessing PerC up to October 2022. The primary outcome was diagnostic success, defined as successful stone identification or stricture workup. Secondary outcomes included therapeutic success (stone extraction, stenting) and complication rate. A subgroup analysis compared previous-generation and modern cholangioscopes. We performed meta-analyses using a random-effects model and the results were reported as percentages with 95% confidence interval (CI). Results: Fourteen studies (682 patients) were eligible for analysis. The rate of diagnostic success was 98.7% (95%CI 97.6-99.8%; I2=31.19%) and therapeutic success was 88.6% (95%CI 82.8-94.3%; I2=74.92%). Adverse events were recorded in 17.1% (95%CI 10.7-23.5%; I2=77.56%), of which 15.9% (95%CI 9.8-21.9%; I2=75.98%) were minor and 0.6% (95%CI 0.1-1.2%; I2=0%) major. The Spyglass system showed null heterogeneity for all outcomes; compared with older-generation endoscopes it offered comparable diagnostic success, but yielded significantly superior therapeutic success (96.1%, 95%CI 90-100%; I2=0% vs. 86.4%, 95%CI 79.2-93.6%; I2=81.41%; P=0.02]. Conclusion: PerC, especially using currently available cholangioscopes, is associated with high diagnostic and therapeutic success.
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Pulmonary hypertension (PH) refers to a pathologic elevation of the mean pulmonary artery pressure (mPAP) and is associated with increased morbidity and mortality in a wide range of medical conditions. These conditions are classified according to similarities in pathophysiology and management in addition to their invasive hemodynamic profiles. The 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension present the newest clinical classification system and includes significant updates to the hemodynamic definitions. Pulmonary hypertension is now hemodynamically defined as an mPAP > 20 mmHg, reduced from the previous threshold of ≥25 mmHg, due to important insights from both normative and prognostic data. Pulmonary vascular resistance has been extended into the definition of pre-capillary pulmonary hypertension, with an updated threshold of >2 Wood Units (WU), to help differentiate pulmonary vascular disease from other causes of increased mPAP. Exercise pulmonary hypertension has been reintroduced into the hemodynamic definitions and is defined by an mPAP/cardiac output slope of >3 mmHg/L/min between rest and exercise. While these new hemodynamic thresholds will have a significant impact on the diagnosis of pulmonary hypertension, no evidence-based treatments are available for patients with mPAP between 21-24 mmHg and/or PVR between 2-3 WU or with exercise PH. This review highlights the evidence underlying these major changes and their implications on the diagnosis and management of patients with pulmonary hypertension.
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BACKGROUND: Nowadays, large benign lateral spreading lesions (LSLs) and sessile polyps in the colorectum are mostly resected by endoscopic mucosal resection (EMR). A major drawback of EMR is the polyp recurrence rate of up to 20%. Snare tip soft coagulation (STSC) is considered an effective technique to reduce recurrence rates. However, clinical trials on STSC have mainly been conducted in expert referral centers. In these studies, polyp recurrence was assessed optically, and additional adjunctive techniques were excluded. In the current trial, we will evaluate the efficacy and safety of STSC in daily practice, by allowing adjunctive techniques during EMR and the use of both optical and histological polyp recurrence to assess recurrences during follow-up. METHODS: The RESPECT study is a multicenter, parallel-group, international single blinded randomized controlled superiority trial performed in the Netherlands and Germany. A total of 306 patients undergoing piecemeal EMR for LSLs or sessile colorectal polyps sized 20-60 mm will be randomized during the procedure after endoscopic complete polyp resection to the intervention or control group. Post-EMR defects allocated to the intervention group will be treated with thermal ablation with STSC of the entire resection margin. Primary outcome will be polyp recurrence by optical and histological confirmation at the first surveillance colonoscopy after 6 months. Secondary outcomes include technical success and complication rates. DISCUSSION: The RESPECT study will evaluate if STSC is effective in reducing recurrence rates after piecemeal EMR of large colorectal lesions in daily clinical practice performed by expert and non-expert endoscopists. Moreover, endoscopists will be allowed to use adjunctive techniques to remove remaining adenomatous tissue during the procedure. Finally, adenomatous polyp recurrence during follow-up will be defined by histologic identification. TRIAL REGISTRATION: ClinicalTrials.gov NCT05121805. Registered on 16 November 2021. Start recruitment: 17 March 2022. Planned completion of recruitment: 31 April 2025.
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Adenoma , Pólipos del Colon , Neoplasias Colorrectales , Resección Endoscópica de la Mucosa , Humanos , Resección Endoscópica de la Mucosa/efectos adversos , Recurrencia Local de Neoplasia/prevención & control , Neoplasias Colorrectales/cirugía , Neoplasias Colorrectales/patología , Adenoma/cirugía , Adenoma/patología , Colonoscopía/efectos adversos , Colonoscopía/métodos , Pólipos del Colon/cirugía , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
This manuscript on real-world evidence (RWE) in pulmonary hypertension (PH) incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative Real-World Evidence Working Group. We aim to strengthen the research community's understanding of RWE in PH to facilitate clinical research advances and ultimately improve patient care. Herein, we review real-world data (RWD) sources, discuss challenges and opportunities when using RWD sources to study PH populations, and identify resources needed to support the generation of meaningful RWE for the global PH community.
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Chronic pancreatitis (CP) is an ongoing inflammatory disease with most patients developing pancreatic calculi during their course of disease. Extracorporeal shock wave lithotripsy (ESWL) is a first-line treatment option in patients with large lumen obstructing pancreatic duct (PD) stones. In patients with CP and PD dilatation, digital single-operator pancreatoscopy (DSOP)-guided lithotripsy seems to be an appealing option to ESWL and surgery. DSOP-guided lithotripsy for the treatment of large symptomatic PD-stones has been demonstrated to be safe, technically, and clinically effective, and should be regarded as an alternative endoscopic treatment of certain patients.
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Litotricia , Enfermedades Pancreáticas , Pancreatitis Crónica , Humanos , Enfermedades Pancreáticas/cirugía , Pancreatitis Crónica/etiología , Pancreatitis Crónica/terapia , Endoscopios Gastrointestinales , Conductos Pancreáticos/cirugíaRESUMEN
Pulmonary arterial hypertension (PAH) is a rare and progressive disease characterised by remodelling of the pulmonary arteries and progressive narrowing of the pulmonary vasculature. This leads to a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure and, if left untreated, to right ventricular failure and death. A correct diagnosis requires a complete work-up including right heart catheterisation performed in a specialised centre. Although our knowledge of the epidemiology, pathology and pathophysiology of the disease, as well as the development of innovative therapies, has progressed in recent decades, PAH remains a serious clinical condition. Current treatments for the disease target the three specific pathways of endothelial dysfunction that characterise PAH: the endothelin, nitric oxide and prostacyclin pathways. The current treatment algorithm is based on the assessment of severity using a multiparametric risk stratification approach at the time of diagnosis (baseline) and at regular follow-up visits. It recommends the initiation of combination therapy in PAH patients without cardiopulmonary comorbidities. The choice of therapy (dual or triple) depends on the initial severity of the condition. The main treatment goal is to achieve low-risk status. Further escalation of treatment is required if low-risk status is not achieved at subsequent follow-up assessments. In the most severe patients, who are already on maximal medical therapy, lung transplantation may be indicated. Recent advances in understanding the pathophysiology of the disease have led to the development of promising emerging therapies targeting dysfunctional pathways beyond endothelial dysfunction, including the TGF-ß and PDGF pathways.
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BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by obstruction of major pulmonary arteries with organized thrombi. Clinical risk factors for pulmonary hypertension due to left heart disease including metabolic syndrome, left-sided valvular heart disease, and ischemic heart disease are common in CTEPH patients. OBJECTIVES: The authors sought to investigate prevalence and prognostic implications of elevated left ventricular filling pressures (LVFP) in CTEPH. METHODS: A total of 593 consecutive CTEPH patients undergoing a first diagnostic right and left heart catheterization were included in this study. Mean pulmonary arterial wedge pressure (mPAWP) and left ventricular end-diastolic pressure (LVEDP) were utilized for assessment of LVFP. Two cutoffs were applied to identify patients with elevated LVFP: 1) for the primary analysis mPAWP and/or LVEDP >15 mm Hg, as recommended by the current pulmonary hypertension guidelines; and 2) for the secondary analysis mPAWP and/or LVEDP >11 mm Hg, representing the upper limit of normal. Clinical and echocardiographic features, and long-term mortality were assessed. RESULTS: LVFP was >15 mm Hg in 63 (10.6%) and >11 mm Hg in 222 patients (37.4%). Univariable logistic regression analysis identified age, systemic hypertension, diabetes, atrial fibrillation, calcific aortic valve stenosis, mitral regurgitation, and left atrial volume as significant predictors of elevated LVFP. Atrial fibrillation, calcific aortic valve stenosis, mitral regurgitation, and left atrial volume remained independent determinants of LVFP in adjusted analysis. At follow-up, higher LVFPs were measured in patients who had meanwhile undergone pulmonary endarterectomy (P = 0.002). LVFP >15 mm Hg (P = 0.021) and >11 mm Hg (P = 0.006) were both associated with worse long-term survival. CONCLUSIONS: Elevated LVFP is common, appears to be due to comorbid left heart disease, and predicts prognosis in CTEPH.
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Fibrilación Atrial , Hipertensión Pulmonar , Hipertensión , Insuficiencia de la Válvula Mitral , Estenosis de la Válvula Mitral , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/epidemiología , Hipertensión Pulmonar/etiología , Función Ventricular Izquierda , Presión Esfenoidal Pulmonar , Presión VentricularRESUMEN
BACKGROUND: Digital single-operator pancreatoscopy (DSOP)-guided lithotripsy is a novel treatment modality for pancreatic endotherapy, with demonstrated technical success in retrospective series of between 88â% and 100â%. The aim of this prospective multicenter trial was to systematically evaluate DSOP in patients with chronic pancreatitis and symptomatic pancreatic duct stones. METHODS: Patients with symptomatic chronic pancreatitis and three or fewer stones ≥â5mm in the main pancreatic duct (MPD) of the pancreatic head or body were included. The primary end point was complete stone clearance (CSC) in three or fewer treatment sessions with DSOP. Current guidelines recommend extracorporeal shock wave lithotripsy (ESWL) for MPD stones >â5âmm. A performance goal was developed to show that the CSC rate of MPD stones using DSOP was above what has been previously reported for ESWL. Secondary end points were pain relief measured with the Izbicki pain score (IPS), number of interventions, and serious adverse events (SAEs). RESULTS: 40 chronic pancreatitis patients were included. CSC was achieved in 90â% of patients (36/40) on intention-to-treat analysis, after a mean (SD) of 1.36 (0.64) interventions (53 procedures in total). The mean (SD) baseline IPS decreased from 55.3 (46.2) to 10.9 (18.3). Overall pain relief was achieved in 82.4â% (28/34) after 6 months of follow-up, with complete pain relief in 61.8â% (21/34) and partial pain relief in 20.6â% (7/34). SAEs occurred in 12.5â% of patients (5/40), with all treated conservatively. CONCLUSION: DSOP-guided endotherapy is effective and safe for the treatment of symptomatic MPD stones in highly selected patients with chronic pancreatitis. It significantly reduces pain and could be considered as an alternative to standard ERCP techniques for MPD stone treatment in these patients.
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Cálculos , Litotricia , Enfermedades Pancreáticas , Pancreatitis Crónica , Humanos , Estudios Retrospectivos , Estudios Prospectivos , Resultado del Tratamiento , Enfermedades Pancreáticas/terapia , Enfermedades Pancreáticas/complicaciones , Pancreatitis Crónica/etiología , Cálculos/complicaciones , Litotricia/efectos adversos , Litotricia/métodos , Conductos Pancreáticos/diagnóstico por imagen , Dolor/etiología , Colangiopancreatografia Retrógrada Endoscópica/efectos adversos , Colangiopancreatografia Retrógrada Endoscópica/métodosRESUMEN
BACKGROUND : Motorized spiral enteroscopy (MSE) was recently introduced into clinical practice. The aim of the current study was to evaluate the feasibility and safety of MSE for biliopancreatic interventions in patients with surgically altered anatomy. METHODS : Patients with surgically altered anatomy receiving MSE-assisted ERCP at a single, endoscopy referral center were retrospectively enrolled between January 2016 and June 2021. RESULTS : 36 patients (14 female, 22 male), median age 67 years (range 43-88), with biliary (nâ=â35) and pancreatic (nâ=â1) indications for MSE-ERCP, were enrolled. The majority (75.0â%) had relevant comorbidities (American Society of Anesthesiologists class III). Surgical reconstruction included Roux-en-Y (nâ=â30) and Billroth II (nâ=â6). Technical success rates for enteroscopy, cannulation, and interventions were 86.1â%, 83.9â%, and 100â%, respectively. The overall MSE-ERCP success rate was 72.2â%. One major complication occurred (2.8â%; delayed post-sphincterotomy bleeding). CONCLUSIONS : This is the first study to demonstrate the feasibility and safety of MSE-assisted ERCP in postsurgical patients with altered anatomy at an expert center. These data justify further evaluation of this new technique, preferably in a prospective multicenter trial.