Pulmonary Artery Research Articles

Prognostic value of right ventricular-pulmonary arterial coupling indices in patients with moderate to severe mitral stenosis

Abstract Background Right ventricular-pulmonary arterial (RV-PA) coupling represents the relationship of RV contractility and RV afterload. The ability of RV to adapt to changes in RV afterload (i.e. increased pulmonary arterial (PA) loading) has prognostic implications in various cardiovascular diseases such as heart failure and pulmonary arterial hypertension. RV-PA uncoupling occurs when RV contractility cannot match RV afterload, resulting in right heart dysfunction. However, RV-PA coupling has not been investigated in mitral stenosis patients. Purpose To evaluate the prognostic significance of various non-invasive RV-PA coupling parameters (TAPSE/PASP and RVFWLS/PASP) in patients with moderate to severe mitral stenosis. Methods This was a single-center retrospective study of 237 patients with moderate or severe mitral stenosis enrolled between January 2010 to December 2022. Baseline clinical and echocardiographic parameters were collected. RV free wall longitudinal strain (RVFWLS) was subsequently analyzed using TOMTEC software. Echocardiography-derived RV-PA coupling parameters were collected, including TAPSE/PASP and RVFWLS/PASP. The primary endpoint was a composite outcome of all-cause mortality, heart failure hospitalization and valve intervention (percutaneous transvenous mitral commissurotomy and surgical intervention). RV parameters were analyzed separately to avoid collinearity. Results A total of 237 patients were included in the study. The patients had a mean age was 66.56 ± 13.61 years-old and were predominantly female (67.9%). The median follow-up duration was 4.54 years (IQR 1.44 – 6.44). Mean left ventricular ejection fraction (LVEF) was 56.86 ± 10.51%, mean TAPSE 18.29 ± 5.36 mm and mean RVFWLS was -23.60 ± 7.96 %. In separate multivariable Cox regression models after adjustment for age , sex and mitral stenosis severity, TAPSE/PASP ratio < 0.36mm/mmHg (HR 2.025 , 95% CI 1.395-2.939, p < 0.001 ) and RVFWLS/PASP ratio ≥ - 0.5%/mm Hg (HR 2.031 95% CI 1.404 – 2.938 , p< 0.001) remained independently associated with mortality , heart failure hospitalization and valve intervention. Conclusion TAPSE/PASP and RVFWLS/PASP were independently associated with all-cause mortality, heart failure hospitalization and valve intervention in patients with moderate to severe mitral stenosis.

Pulmonary artery pulsatility index evaluation in intermediate-to-high and high-risk pulmonary embolism patients underwent transcatheter intervention

Abstract Background The clinical impact of pulmonary embolism (PE) transcatheter intervention on the right ventricular function and its potential role as procedural outcomes has to be defined. Methods Consecutive patients who underwent pulmonary transcatheter intervention between 2021 and 2023 were included in an observational fashion. Data about clinical characteristics, PE risk stratification, pre and post-interventional pulmonary artery pressure (PAP) and Pulmonary Artery Pulsatility Index (PAPi) were collected. The primary endpoint was a composite of in-hospital death or repeated intervention. Results 49 patients were included, mostly female gender (61.2%), with a mean age of 67±12,9 years old, 79.6% with > 1 PE risk factor, and 55% of them stratified as high-risk (HR) PE. 34.6% of the patients were treated with transcatheter thrombolysis (all in the intermediate-to-high-risk cohort), 20% with FlowTriever device, 53.4% with Indigo Cath8 or Lightning 12 device, 8.1% of the procedure was performed under ECMO support. All patients classified in intermediate-to-high risk (IHR) survived, and the mean PAP was reduced (33.4±10.9 to 24.3±7.1 mmHg p<0.01), as well as PAPi (2,3±0.35 to 1.68±0.26 p<0.01). 22% of the patients In IHR experienced the primary endpoint, in these populations, the mean PAP (pre 33±4.1 vs post 30.5±4.6 p=0.58) and PAPi (pre 1.35±.0.6 vs post 1.4±0.6 p=0.39) did not change significantly. On the other side, those who survived without events had a slight significative reduction in mean PAP (pre 32±6.7 vs post 24.6±4.3 p<0.02) while the PAPi significantly increased (1.2±0.6 vs 1.8±0.2 p<0.01). In the HR population, a delta PAPi > 0.45 demonstrated a 65.7% sensitivity and 75% Specificity for the primary outcome AUC 0.83 at ROC curve analysis. Conclusion Pulmonary Thrombus aspiration significantly changes the PAP and PAPi in patients with acute PE. While in IHR patients the overperforming PAPi seems to normalize, in HR patients it increases and may be a marker of procedural success and right ventricle recovery.

The effects of targeting mild hypercapnia on right ventricular function after out-of-hospital cardiac arrest. A sub-study of the TAME trial.

Abstract Background The Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest (TAME) trial found similar neurological outcomes between mild hypercapnia and normocapnia in resuscitated out-of- hospital cardiac arrest (OHCA) patients. Hypercapnic acidosis can cause pulmonary vasoconstriction and aggravate right ventricular dysfunction, which is common and associated with worsened outcomes after OHCA. Purpose We investigated the effects of targeting mild hypercapnia on right ventricular function. Methods Single-centre, pre-planned and prospective sub-study. Comatose OHCA patients were randomised to targeted mild hypercapnia (PaCO2 =6.7–7.3 kPa) or targeted normocapnia (PaCO 2 =4.7- 6.0 kPa) for 24 hours. Transthoracic echocardiography was performed at baseline, during intervention and 48 hours after randomisation. Serial right heart catherisation (RHC) was performed if available. Results A total of 137 patients were randomised, 111 were evaluated with echocardiography and 52 and 59 randomised to mild hypercapnia and normocapnia, respectively. 84 patients received RHC; 41 and 43 in the hypercapnia and normocapnia-group, respectively. Overall, the median age was 64 years, 80 % were male and median time to ROSC was 22 minutes. Baseline characteristics did not differ significantly between treatments groups (p >0.05). Targeting mild hypercapnia was associated with lower tidal volumes, respiratory frequencies and respiratory acidosis (P-group < 0.05). Positive end-expiratory pressure, right atrial pressure, pulmonary vascular resistance index and pulmonary capillary wedge pressure were similar between groups (P-group > 0.05). Median time to echocardiography after randomisation was 21 (IQR 14-23) and 17 (IQR 9-22) hours in the hypercapnia and normocapnia-group, respectively. Tricuspid annular plane systolic excursion (TAPSE) was similar between treatment-groups at baseline and higher in the hypercapnia-group during the intervention with a median of 21 mm (IQR 18-23) versus 16 mm (IQR 13-21), p = 0.002. S', fractional area change (FAC) and the ratio of TAPSE to the pulmonary artery systolic pressure (PASP) were all higher in the hypercapnia-group during the intervention. Overall, median left ventricular ejection fraction was 45 % (IQR 38-55) without treatment group differences (p=0.2). Both invasive and echocardiographic assessment found increased cardiac index and stroke volumes in the hypercapnia-group (p <0.05). Right ventricular stroke work index (RVSWI) was consistently higher in the hypercapnia-group throughout the intervention (P-group < 0.001), while the pulmonary artery pulsatility index did not differ (P-group >0.05). Conclusions In patients resuscitated from OHCA, targeting mild hypercapnia compared to normocapnia was associated with increased TAPSE, S', FAC, TAPSE:PASP, RVSWI and cardiac index. Contrary to our prior concern these results indicate improved right ventricular function while targeting mild hypercapnia.

Right ventricular outflow tract arrhythmias in patients with obstructive sleep apnea- electrophysiological insights

Abstract Background Obstructive sleep apnea (OSA) was associated with atrial fibrillation and heart failure. Furthermore, the arrhythmic sudden death during sleep in patients with OSA raises serious concerns. Non-ischemic ventricular arrhythmias arise frequently from the right ventricular outflow tract (RVOT). The involvement of obstructive sleep apnea in the genesis of arrhythmia (premature ventricular contraction or tachycardia) originating specifically in the RVOT is not yet coherently established. Purpose This study aims to demonstrate the possible relationship between untreated obstructive sleep apnea and the occurrence of RVOT arrhythmia and to follow the electrophysiological features and outcomes after radiofrequency catheter ablation (RFA) in patients carrying this double burden. Methods One-hundred-twelve (112) consecutive asymptomatic and symptomatic patients admitted with RVOT arrhythmia ((PVCs and VTs) underwent a sleep study (polysomnography). Apnea was set out as the cessation of breathing and hypopnea was defined as shallow, slow, and restricted breathing occurring in episodes of ten seconds or more. The patients had normal left and right ventricle ejection fractions and no structural cardiovascular disease or other known extracardiac arrhythmia predisposing conditions. No significantly elevated systolic pressure in the pulmonary artery was assessed at echocardiography. Every patient was investigated by electrophysiologic study (EPS) and RFA of the clinical ventricular arrhythmia was immediately performed. Practicing and former professional athletes were excluded. Results Seventy-eight (69 %) of the included patients had an apnea-hypopnea index > 10/h. The included patients had the following characteristics: mean age 52 ± 8 years, 62% males, 81% had a BMI >30kg/m². The cardiac electrophysiologic study did not induce sustained VTs. The distribution of the PVCs and non-sustained VTs evidenced a predilection for the superior, septal and anterior (68%) and also superior and anterolateral aspects of the RVOT (23%). Radiofrequency catheter ablation (RFA) guided by activation mapping, precocity (the site of earliest activation > 30 ms before the setting of the QRS complex) and pace-mapping were performed in all patients. Immediate success was obtained in 98 patients (88%). After a mean follow-up of 24± 6 months, 28 patients (28%) from the success arm had a recurrence of the PVCs or the non-sustained VTs, 22 patients (22%) with and 6 patients (6%) without sleep apnea. Conclusions RVOT arrhythmia genesis and relapse after successful RFA seem highly associated with sleep apnea. Furthermore, patients with sleep apnea are more prone to have recurrent arrhythmias after radiofrequency catheter ablation in the absence of appropriate control of OSA.

Vascular thrombosis and relapse-associated factors in Behcet's syndrome: a comprehensive analysis of 136 patients

Abstract Background Vascular thrombosis in Behçet syndrome (BS) is frequent and associated with high morbidity and mortality rates. Purpose To investigate BS patients presenting with a thrombotic event (TE) and identify the factors associated with relapse. Methods We retrospectively conducted a single-center, descriptive, and analytic study, from 2000 to 2022, enrolling all BS patients presenting TE, including venous thrombosis (VT) and/or arterial thrombosis (AT). Results TE was observed in 136/531 patients (25%), mostly men (83%), aged 29 ± 9 years (11-50) at BS onset. TE was the initial presentation of BS (32%) or occurred after a median of 4 years [0;25]. It included VT (92.5%), AT (18%), and both (13%). VT mostly consisted of DVT in the lower extremities (60%), vena cava (30%), and cerebral (15%) veins. It involved one (55%), two (27%), and multiple (16%) veins (Figure 1). AT mainly affected the pulmonary (42%), femoral (21%), coronary (17%), cerebral (8%) arteries, and aorta (8%). Arterial aneurysms were common (18%), especially in the pulmonary arteries (11%). Intracardiac thrombosis was also visualized (10%). Noncardiovascular manifestations mainly included aphthous ulcers (96%), pseudofolliculitis (36%), ocular lesions (41%), and arthralgias (22%). Hemostasis parameters were within normal ranges. Patients were treated with colchicine (98%), corticoids (98%), and immunosuppressants (80%). Anticoagulation and anti-platelet aggregation were administered in 90% and 15% of the cases, respectively. Six patients underwent vascular surgery. Post-thrombotic syndrome was noted in 14% of the patients. Relapse was common (25%), mainly occurring in men (81%), of younger age (24 ± 6) at first TE. Relapse consisted of one (55%), two (32%), or multiple episodes (13%). It occurred in the same vascular system initially affected (69%), a different one (12%), and both at the same time (19%). Multivariable analysis revealed TE at onset (OR= 2.99, 95% CI[1.14 ; 7.82], p=0.02), arterial thrombosis (OR= 2.91, 95% CI[1.10 ; 8.40], p=0.04), and arterial aneurysms (OR= 2.58, 95% CI [1.09 ; 8.45], p=0.02) as factors significantly associated with TE relapse (Figure 2). Conclusion Our study highlights several particularities of TE in BS, with TE at onset, arterial thrombosis, and arterial aneurysms emerging as significant relapse factors.

Metabolic alterations in human pulmonary artery smooth muscle cells treated with PDGF-BB.

Metabolic abnormalities are considered to play a key regulatory role in vascular remodeling of pulmonary arterial hypertension. However, to date, there is a paucity of research documenting the changes in metabolome profiles within the supernatants of pulmonary artery smooth muscle cells (PASMC) during their transition from a contractile to a synthetic phenotype. CCK-8 and Edu staining assays were used to evaluate the cell viability and proliferation of human PASMCs. IncuCyte ZOOM imaging system was used to continuously and automatically detect the migration of the PASMCs. A targeted metabolomics profiling was performed to quantitatively analyze 121 metabolites in the supernatant. Orthogonal partial least squares discriminant analysis was used to discriminate between PDGF-BB-induced PASMCs and controls. Metabolite set enrichment analysis was adapted to exploit the most disturbed metabolic pathways. Human PASMCs exhibited a transformation from contractile phenotype to synthetic phenotype after PDGF-BB induction, along with a significant increase in cell viability, proliferation, and migration. Metabolites in the supernatants of PASMCs treated with or without PDGF-BB were well profiled. Eleven metabolites were found to be significantly upregulated, whereas seven metabolites were downregulated in the supernatants of PASMCs induced by PDGF-BB compared to the vehicle-treated cells. Fourteen pathways were involved, and pyruvate metabolism pathway was ranked first with the highest enrichment impact followed by glycolysis/gluconeogenesis and pyrimidine metabolism. Significant and extensive metabolic abnormalities occurred during the phenotypic transformation of PASMCs. Disturbance of pyruvate metabolism pathway might contribute to pulmonary vascular remodeling.

Endarterectomy in CTEPH: hemodynamic improvement and RV-PA coupling

Abstract Introduction Pulmonary artery endarterectomy (PAE) remains the gold standard in treating chronic thromboembolic pulmonary hypertension (CTEPH). Reducing the thrombotic burden and mechanical obstruction of the pulmonary artery (PA) leads to significant hemodynamic improvement, allowing for favorable right ventricular (RV) remodeling. Methods Single center retrospective study, including 30 pts submitted to PEA over a 7-year period. Hemodynamic assessment was performed by right heart catheterization (RHC) before PEA, immediately after and at 6-month follow-up (FUP). Echocardiographic assessment of RV function was acquired at baseline and 6m FUP. Mean absolute differences were calculated before and after PEA. Differences between groups were assessed with ANOVA analysis and ROC curve analysis allowed us to define a cut-off point in mPAP reduction to predict favorable RV remodeling. Results We included 30 pts with a mean age of 57,9 ± 13 years old and slight predominance of female sex (57%). Regarding risk assessment with the 4 strata tool at baseline, 23% of pts were high risk, 20% intermediate high, 27% intermediate low and 6% at low risk. Pulmonary hemodynamics improved immediately after PEA, as indicated by a mean reduction of 28,3 ±17 mmHg in mPAP; 44,4±27,6mmHg in sPAP; 8±3,4 Wu in PVR and an increase in CO of 0,5±1 l/min. This improvement was sustained at 6-m post PEA assessment, with a mean reduction of 31,5 ±26,7 mmHg in mPAP; 48,3±41,2mmHg in sPAP; 6,3±6,2Wu in PVR and a 0,5±1 l/min increase in CO. Regarding RV remodeling at 6m post PEA, an increase of 0.15±0.2mm/mmHg in TAPSE/PSAP ratio and 3±2,8cm/s in Tricuspid S’ were recorded. RV/PA uncoupling, defined as TAPSE/PSAP <0,31 mm/mmHg, was evident in 73% of pts at baseline, 25% of which recovered at 6m follow-up. There were no significant differences between groups, according to the 4 strata risk assessment at baseline, regarding pulmonary hemodynamics and RV remodeling. Through ROC curve analysis, we were able to define a cut-off point of 37mmHg in immediate mPAP post-op reduction to predict RV-RA coupling normalization at 6-m FUP (sensitivity 70%, specificity 89%). Conclusions PEA remains a cornerstone of CTEPH treatment. It’s impact on improving pulmonary hemodynamics is immediate and maintained at 6-month FUP. This improvement may be expected regardless of risk assessment at baseline. Reducing RV afterload allows favorable remodeling and an immediate post operative reduction of mPAP > 37mmHg may predict normalization of RV-PA coupling.

Prognostic role of right ventricular-pulmonary artery coupling assessed by TAPSE/PASP ratio in patients with heart failure and mildly reduced ejection fraction

Abstract Background The development of right ventricular (RV)-pulmonary arterial (PA) coupling has resulted in a novel and comprehensive index for evaluating RV function in relation to the underlying RV afterload. In patients with heart failure (HF), it is acknowledged that RV-PA uncoupling are features that are associated with poor outcome. The RV-PA coupling index can be readily assessed non-invasively using the ratio of two standard echocardiographic measurements: tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP). However, few studies have defined the prognostic impact of the TAPSE/PASP ratio in patients with HF and mildly reduced EF (HFmrEF). Methods From the prospective cohort study of 1,410 hospitalized HF patients (age 68+/-15, men 62%) between August 2015 and September 2019, this study enrolled 191 HFmrEF (i.e., left ventricular ejection fraction (LVEF) 41–49%) patients whose TAPSE and PASP were measured during hospitalization and discharged alive. We studied the prognostic impact of TAPSE/PASP ratio on HFmrEF patients using by cut-off value obtained from receiver operating characteristic (ROC) analysis. The primary and secondary endpoints was defined as the all-cause death and HF re-hospitalization after discharge, respectively. Results During median follow-up of 38 [23–52] months, 48 patients (25%) died. The deceased patients had a significantly older (median 75 vs. 71 years, p<0.05), higher rate of ischemic heart disease (50% vs. 23%, p<0.05), elevated brain natriuretic peptide levels (325 vs. 159 pg/ml, p<0.05) and lower rate of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (65% vs. 80%, p<0.05) at discharge. In the ROC analysis, the cut-off value of TAPSE/PASP ratio for mortality was 0.46. Patients with TAPSE/PASP ≤0.46 had a significantly higher all-cause mortality (log-rank p<0.05) and had a tendency of higher rate of HF re-hospitalization than patients with TAPSE/PASP >0.46 (log-rank p=0.06) (Figure). Using multivariate analysis, the lower TAPSE/PASP ratio had an independent predictive value of prognosis in patients with HFmrEF (hazard ratio 2.16, 95% confidence interval; 1.08–3.92, p<0.05) (Table). Conclusion The TAPSE/PASP ratio has a significant prognostic value in patients with HFmrEF. The RV-PA uncoupling assessed by TAPSE/PASP ratio might be useful for risk assessment in patients with HFmrEF.

One-year prognostic value of right ventricular to pulmonary arterial coupling in patients hospitalized for acute coronary syndrome: insights from the ADDICT-ICCU study

Abstract Background Tricuspid annular plane systolic excursion over systolic pulmonary artery pressure (TAPSE/sPAP) assessed by echocardiography is a good non-invasive approach for right ventricular to pulmonary artery (RV-PA) coupling assessment. Although the prognostic value of this ratio is well known in many cardiovascular diseases, its prognostic value in acute coronary syndrome (ACS) is not established. Purpose To assess one-year prognostic value of TAPSE/sPAP among patients hospitalised for ACS. Methods In the prospective multicentric ADDICT-ICCU study, all consecutive patients hospitalized for ACS (either Non ST-Elevation Myocardial Infarction or ST-Elevation Myocardial Infarction) over two weeks in April 2021 at 39 centres across France were included. The TAPSE/sPAP ratio was measured using the first echocardiography performed within the first 24 hours of hospitalisation. The primary composite outcome was one-year major adverse cardiovascular event (MACE) including: all-cause death or urgent hospitalisation for acute cardiovascular reason (acute heart failure, urgent myocardial revascularisation). C-tree analysis was used to find the optimal TAPSE/sPAP cut-off to predict the primary outcome. Results Among the 772 ACS patients (age 64±12 years, 74% males) included, 113 (15%) experienced 1-year MACE. The best cut-off for TAPSE/sPAP to predict 1-year MACE was 0.67 mm/mmHg. Patients with TAPSE/sPAP ≤0.67 mm/mmHg were more likely older (p<0.001), with previous atrial fibrillation (p<0.001), a higher length of hospitalization in ICCU (p<0.001), a higher NTproBNP (p=0.001) and a worse LVEF value (p<0.001). At one-year, all-cause death occurred in 27 (14%) patients with TAPSE/sPAP ≤0.67, compared to 7 (2.5%) with TAPSE/sPAP>0.67 (p<0.001), and 32 (16%) patients with TAPSE/sPAP ≤0.67 were hospitalised for acute cardiovascular reason against 20 (7%) with TAPSE/sPAP >0.67 (p=0.006). After adjustment for all traditional prognosticators, TAPSE/sPAP <0.67 mm/mmHg remained independently associated with the primary outcome (Table1): model 1 (comorbidities): HR 2.82, 95%CI[2.92-4.38], p<0.001, model 2 (echocardiography): HR=2.38, 95%CI [1,40-4,03], p<0.001). Patients with TAPSE/sPAP ≤0.67 mm/mmHg had worse event-free survival for the primary outcome: HR=2.92, 95%CI[1.98-4.29], p<0.001). Conclusion TAPSE/sPAP, a noninvasive approach for RV-PA coupling, was independently associated with 1-year MACE in patients hospitalised for ACS, even after adjustment with traditional prognosticators, including LVEF.Fig2.Multivariable Cox analysis

CMR-derived pulmonary artery to aorta ratio as a predictor of adverse outcome in patients with cardiac transthyretin amyloidosis

Abstract Introduction Cardiac transthyretin amyloidosis (ATTR) represents a heart failure phenotype often accompanied by pulmonary hypertension. The pulmonary artery to aorta ratio (PA/Ao), as assessed on cardiac computed tomography or cardiac magnetic resonance (CMR), has demonstrated to indicate risk for adverse events in a variety of cardiovascular diseases, particularly in heart failure and pulmonary hypertension. However, its prognostic value in cardiac ATTR remains unknown. Aim We aimed to investigate the prognostic value of the PA/Ao ratio in patients with cardiac ATTR. Methods Data of consecutive patients diagnosed with cardiac ATTR undergoing CMR were prospectively collected. PA/Ao ratios were measured from CMRs using axial images (Figure 1A). Adverse outcome, defined as heart failure related hospitalizations and/or mortality, was recorded during follow-up. Results Among the 190 confirmed cardiac ATTR patients (mean age 76±11 years, 79% males), encompassing hereditary transthyretin (vATTR, n=22) and senile (wtATTR, n=168) types, the median pulmonary artery diameter was 28mm (IQR 25-31) and the median ascending aorta diameter was 35mm (IQR 33-39). Over the median follow-up period of 28 months (IQR 11-50 months), 84 (44%) patients experienced an adverse event. Kaplan Meier curves demonstrated an increased risk for adverse outcome in patients with PA/Ao ratios above the median of ≥0.8 (p<0.001 by log rank test, see Figure 1B). In univariate analysis, a high PA/Ao ratio was associated with adverse outcome (HR=10.3, 95% CI=2.59–41.1, p<0.001). When adjusted for age, sex, body mass index and right ventricular function, the PA/Ao ratio remained significantly related to adverse outcome (adj. HR=10.8, 95% CI=1.76–65.8, p=0.010). Conclusion A PA/Ao ratio ≥0.8 on CMR is associated with heart failure hospitalization and death in patients with cardiac ATTR. This threshold, notably lower than the commonly reported ≥1.0 in other patient populations, holds promise for future risk stratification.

Exercise postcapillary pulmonary hypertension in patients with chronic thromboembolism. Role of multimodal resting and exercise assessment

Abstract Introduction Chronic thromboembolic pulmonary disease refers to the presence of thrombotic material after a pulmonary embolism (PE), exercise limitation and the absence of resting pulmonary hypertension (PH) but impaired right ventricular and pulmonary vascular reserve during exercise causing exercise precapillary PH (exprecapPH). However, in some patients, PH arises from an abnormal increase in pulmonary arterial wedge pressure (PAWP) with exercise in relation to underlying diastolic dysfunction, with thrombotic material not playing a substantial role. Whether these patients present distinct non-invasive and resting invasive parameters remains largely unknown. Purpose To compare the different exercise hemodynamic profiles of patients with chronic thromboembolism to identify clinical, echocardiographic, functional and hemodynamic parameters associated with exercise postcapillary PH (expostcapPH). Methods Data come from a prospective cohort of 71 symptomatic patients with perfusion defects in lung scintigraphy and computed tomographic confirmation of chronic thrombi despite anticoagulation ≥3 months after PE without or mild resting PH, undergoing exercise cardiac catheterization via supine cycle ergometry. A multipoint mean pulmonary artery pressure (mPAP)/cardiac output (CO) and mean PAWP/CO slope were calculated. Simultaneous stress echocardiography was available in 43 patients. Cardiopulmonary exercise test (CPET) was performed 24 hours before catheterization. Results Mean age was 53±13.9 years, 46 (64.8%) were males. 37 patients showed normal exercise hemodynamics, while 26 developed exprecapPH and 8 expostcapPH. Mean mPAP/CO slope was 3.1±1.6 mmHg/L/min, mean PAWP/CO slope 1.5±0.9 mmHg/L/min. Patients with expostcapPH were older, had a higher body mass index and hypertension. Comparison of hemodynamics, CPET and resting echocardiography is depicted in the table. Patients with expostcapPH, similar to those without exercise PH, had significantly lower resting pulmonary pressures and pulmonary vascular resistance than those with exprecapPH. These differences remained at peak exercise; however, while resting PAWP did not differ between groups, a significant increase in PAWP was unmasked in patients with expostcapPH compared to the other groups, and accordingly a significant difference in the PAWP/CO slope. Regarding CPET, patients with expostcapPH had higher baseline systolic blood pressure and lower functional capacity (VO2 max, VO2 at VT1, O2 pulse, OUES). Resting TAPSE/PASP was higher in patients with expostcapPH compared to those with exprecapPH. Conclusions Patients with chronic thromboembolism and expostcapPH exhibit distinct clinical features and have lower functional capacity, while resting PAWP did not allow differentiation between groups. Further studies are warranted to delineate characteristic elements of patients with underlying diastolic dysfunction due to its distinct prognosis and treatment.

Transcatheter closure of atrial septal defect (ASD) in adult and paediatric population without transoesophageal echocardiography/general anaesthesia

Abstract Background Transcatheter device closure is the preferred therapeutic option for ostium secundum atrial septal defect(OS-ASD). Standard practice is to perform it under transoesophageal echocardiography(TEE) guidance. However, TEE is performed under general anaesthesia (GA) and leads to increases in cost, procedural duration, ICU stay, total hospital stays, risk of oesophageal injury and complications of GA. Transthoracic echocardiography(TTE) is an excellent alternative and prior studies have shown it to be a safe alternative in paediatric population. In current study we analysed safety and efficacy of TTE-guided device closure of OS-ASD in all comer population irrespective of age, weight, defect size. Methods The study enrolled all patients who underwent device closure of OS-ASD between March 2017 and December 2023. All procedures were performed under LA for adults and conscious sedation for children. The device was placed under fluoroscopy guidance and position were confirmed on TTE. Procedural success, device, defect size ratio, procedural time, fluoroscopy time, complications, intensive care unit/hospital stay duration were analysed and compared with our own experience of 125 patients with TEE-guided closures before switching to complete TTE-guided procedure(before 2017). Results 340 patients underwent TTE-guided device closure of ASD. Procedure success was 97.4% with acceptable risk of major complications. Three(0.8%) had embolization into pulmonary artery, successfully operated surgically. Two had tamponade requiring drainage. In 9 patients, device could not be deployed despite multiple attempts and approaches. All of these had defect size of > 34mm and deficient IVC rim along with shorter (other than aortic) rim. Findings were compared with our own previous experience of TOE guided closure (practised before 2017). Compared to TOE group, TTE group had significantly lower total procedural duration (75±4 vs. 28 ±1 min; p < 0.01), intensive care unit stay (24±10 vs. 10.5±1 h; p < 0.01), and hospital (48±12 vs. 25.5±4h; p < 0.01) stay duration. Fluoroscopic time was similar in both. There was no mortality in either group. Major complications were comparable, TTE-guided group had less post-procedure complications of vomiting and headache. Additional findings of less pre-procedure fasting duration and early commencement of post procedure oral intake were noted in TTE group. Conclusion TTE-guided device closure of OS-ASD is a safe and feasible in all-comer population in experienced hands. It can definitely negate the use of TEE except in very poor echo window. The added advantages include utilization of physiological variations in PV/LV pressure during cough, Valsalva manoeuvres in awake patients. It definitely reduces the procedural duration, cost of procedure and dependence on GA and trained transoesophageal echocardiographer.

Novel CMR-assessed right ventricular-pulmonary artery coupling index independently associates with exercise capacity and clinical risk in pulmonary arterial hypertension

Abstract Background We defined a novel noninvasive right ventricle (RV)–pulmonary artery (PA) coupling index as the ratio of cardiovascular magnetic resonance (CMR)-assessed RV direct flow (RVDF) and PA pulse wave velocity (PWV), and investigated its associations with exercise capacity and clinical risk in pulmonary arterial hypertension (PAH). Method 43 PAH patients (mean age 46±12 years, M:F 7:36) and 60 healthy volunteers (mean age 46±13 years, M:F 11:48) underwent CMR and cardiopulmonary exercise test (CPET) within one week. From cine CMR, RV ejection fraction (EF) and RV end-diastolic volume (RVEDV) were calculated using volumetric analysis; and tricuspid annular plane systolic excursion (TAPSE), feature tracking. PAPWV was the ratio of early systolic DPA flow and DPA area measured from instantaneous phase and magnitude through plane 2D flow CMR images across the pulmonary trunk, respectively. RVDF was the 4D flow CMR-assessed blood volume entering and exiting the RV in one cardiac cycle, indexed to RVEDV. RV-PA coupling was RVDF/PAPWV. Based on CPET-assessed peak oxygen consumption (PVO2), all 103 participants were stratified into two groups: PVO2>15 ml/kg/min; and PVO2≤15 ml/kg/min. Based on the REVEAL (Registry to Evaluate Early and Long-term PAH Disease Management) 2.0 score, the 43 PAH patients were stratified into low risk (score ≤6) and intermediate to high risk (score >6) groups. Results RVDF/PAPWV was significantly lower in PAH vs. controls (7.9 vs. 20.4 %/(m/s), P<0.001); and in PAH patients with intermediate to high risk vs. low risk (4.6 vs. 9.4 %/(m/s), P=0.001). On multivariable analyses, RVDF/PAPWV was an independent predictor of PVO2≤15 ml/kg/min (=0.302, P=0.001) among all participants, and of REVEAL 2.0 score >6 (=0.621, P=0.009) among PAH patients. Compared to RVEF and TAPSE, RVDF/PAPWV had numerically higher discrimination (p values non-significant based on Delong test) for PVO2≤15 ml/kg/min (AUC=0.914 vs. 0.872, 0.843); and among PAH patients, REVEAL 2.0 score >6 (AUC=0.851 vs. 0.723 and 0.728) (Figure). Conclusion CMR-derived noninvasive RVDF/PAPWV independently associates with exercise capacity and PAH clinical risk, supporting its utility as an imaging marker of disease progression and therapeutic response.

May right heart failure cause pulmonary congestion in pulmonary arterial hypertension?

Abstract Aims Recent studies have shown that lung ultrasound-assessed pulmonary congestion is worse in heart failure when pulmonary vascular resistance (PVR) is increased, suggesting a paradoxical relationship between right heart failure and increased lung water content. Accordingly, we wondered if lung ultrasound would reveal otherwise clinically silent pulmonary congestion in patients with pulmonary arterial hypertension (PAH). Methods and results All patients referred for suspicion of PAH in a tertiary center from January 2020 to December 2022 underwent a complete diagnostic work-up including echocardiography, lung ultrasound and right heart catheterization. Pulmonary congestion was identified by lung ultrasound B-lines using an 8-site scan. The study enrolled 102 patients with idiopathic PAH (mean age 53±13; 71% female). WHO functional classes I, II and III were found respectively in 2, 52 and 46% of them. The N-terminal-pro-brain natriuretic peptide (NT-proBNP) was 377 pg/mL [interquartile range, IQR 218, 906]. B-lines were identified in 77 out of 102 patients (75%), with a median of 3 [IQR: 1-5]. At univariable analysis B-lines were positively correlated to male sex, age, NT-proBNP, systolic PA pressure (sPAP), right atrial pressure (RAP), PVR, left ventricular end-diastolic volume and tricuspid annulus plane systolic excursion (TAPSE), and negatively to cardiac output and stroke volume. At multivariable analysis, RAP (p<0.001; Fig 1), TAPSE/sPAP (p=0.001), and NT-proBNP (p=0.04) were independent predictors of B-lines. Conclusion Lung ultrasound commonly discloses pulmonary congestion in PAH. This finding is related to right ventricle to pulmonary artery uncoupling, and may tentatively be explained by increased central venous pressure impeding lymphatic outflow.Figure 1

Unravel novel therapeutic targets in heart failure and associated pulmonary hypertension

Abstract Background Heart Failure (HF) is a complex clinical syndrome with poor prognosis. Pulmonary hypertension (PH) often complicates HF but can hardly be addressed therapeutically. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with HF. Whether SGLT2i positively impact on HF-associated PH is poorly understood. Omics offer great promise in the discovery of novel biomarkers and therapeutic targets for HF and PH. Aims We investigated novel markers associated with HF and PH, as well as how these biomarkers vary in response to HF-modyfing therapies, including SGLT2i. We also explored the impact of SGLT2i, compared with conventional anti-HF therapy, on HF-associated PH and right ventricular function. Methods Seventy-four patients with HF and reduced ejection fraction (HFrEF) with/without diabetes were divided into a gliflozin (G)-group receiving 10 mg/day empagliflozin or dapagliflozin, and a control (C)-group receiving conventional anti-HF therapy. Resting echocardiography, analyses on senescence markers [leucocyte telomere length (LTL), mitochondrial DNA copy number (mtDNAcn)], as well as measurement of two microRNAs (miRNA-21 and miRNA-92, recently implicated in response to treatment in HFpEF patients), were performed. Shotgun proteomic analyses were conducted on peripheral blood mononuclear cells. Results Compared to group C, group G had a significantly higher ejection fraction (EF, 42±13 vs 33±8, p=0.001), reduced left ventricular filling pressures (11±3 vs 15±5, p=0.001), reduced pulmonary artery systolic pressure (PAPs, 31±11 vs 46±15, p=0.001), better right ventricular-pulmonary artery coupling index (0.64±0.31 vs 0.44±0.22, p=0.002), increased LTL (Figure 1 A), higher mtDNAcn (Figure 1 B), reduced miRNA-21 levels (Figure 1 C) and no significant changes of miRNA-92 (Figure 1 D). Functional proteomic analysis showed that, compared with the C-group, the protein cargo from the G-group was able to trigger several biological pathways, showing a significant activation of T lymphocytes immune response (p-value=9.67x10-06, z-score=2.21) chemotaxis of monocytes (p-value=9.39x10-07, z-score=2.0), leukocytes (p-value=9.67x10-10, z-score=2.0)and phagocytes (p-value)=3.10x10-10, z-score=2.03) (Figure 2). Compared with the C-group, the G-group showed a downregulation of activin signaling pathway (z-score=-2.12), which is a novel therapeutic target in pulmonary arterial hypertension (PAH). Conclusions In HF patients, SGLT2i therapy is associated with improved left ventricular function and improved pulmonary hemodynamics. Activin is overactive in HF patients and its serum levels may be reduced by SGLT2i. SGLT2i may preserve LTL and mtDNA-cn as well as modulate the expression of specific miRNA implied in the regulation of endothelial function. SGLT2i may represent an additional therapeutic tool in patients with HF-associated PH, an area with no approved treatment options beyond traditional HF therapy.Figure 1:genomic analysesFigure 2:proteomic analyses

Right ventricular myocardial work: a step forward for the assessment of right ventricular to pulmonary artery coupling

Abstract Background Right ventricular myocardial work (RVMW) is a novel method for non-invasive assessment of right ventricular (RV) function. By integrating RV global longitudinal strain as systolic function parameter, pulmonary systolic and diastolic pressures as afterload indices, and pulmonary and tricuspid valves timings, RVMW could provide a more comprehensive evaluation of RV function. Purpose The aim of this study was to assess patterns of RVMW indices in patients with preserved and impaired RV to pulmonary artery (PA) coupling (RVAC), as assessed by RV free wall longitudinal strain/pulmonary artery systolic pressure (RVFWLS/PASP) ratio. Methods We studied by echocardiography 158 consecutive patients with stable HF and left ventricular (LV) systolic dysfunction (LV ejection fraction < 50%). RVAC was assessed by RVFWLS/PASP and patients were grouped according to the median value. Four parameters of RVMW were obtained: RV global work index (RVGWI), RV global constructive work (RVGCW), RV global wasted work (RVGWW) and RV global work efficiency (RVGWE). Results According to RVFWLS/PASP ratio, patients were divided into two groups: A) preserved RVAC (RVFWLS/PASP ratio ≥ 0.51; N=84) and B) impaired RVAC (RVFWLS/PASP ratio < 0.51; N= 74). Both RVGWI (371±156 vs 384±207 mmHg%, P=NS) and RVGCW (449±171 vs 516±249 mmHg%, P=NS) did not significantly differ between the two groups (figure 1). However, group B (impaired RVAC) showed significantly greater RV wasted work (94±69 vs 44±30 mmHg%, P=0.0001) and significantly lower RV work efficiency (80±13 vs 88±8 %, P=0.0001) compared to group A (preserved RVAC, figure 2). Conclusions RVMW provided new insight in the RV function assessment, highlighting lower efficiency due to higher wasted work in RV to PA uncoupled patients.Figure 1Figure 2

A simple and reliable computed tomographic measure for the evaluation of right ventricle remodelling in acute PE: right ventricle apical angle

Abstract Background and aims In patients with acute pulmonary embolism (PE), right ventricular (RV) dysfunction as assessed by computed tomography (CT) and /or echocardiography has been considered to predict in-hospital and 30-day outcomes. In this study we proposed a novel CT measure for RV function, the apical angle (α1) between the RV free wall and the interventricular septum (IVS), and for the left ventricle (LV) function, the apical angle (α2) between the LV free wall and the IVS. We aimed to evaluate the predictive value of these angles to determine clinical and hemodynamic severity and in-hospital mortality (IHM) in acute PE patients. Methods The study population comprised retrospectively evaluated 536 patients (age 59+-16.2 years, female 55.3 %) with acute PE in whom diagnostic work-up and risk-based treatments have been performed in accordance with currently available acute PE Guidelines. The severity of pulmonary arterial (PA) obstruction (Qanadli score) and RV/LV ratio were assessed on CT, and RV function and non-invasive estimation of pulmonary arterial systolic pressures (PASP) were evaluted with echocardiography. The α1 was defined as the angle between the line from tricuspid medial annulus to the RV apex and second line from tricuspid lateral annulus to the RV apex, whereas α2 was defined as the angle between the line from mitral medial annulus to the LV apex and second line from mitral lateral annulus to the LV apex. Results Anticoagulant treatment only and intravenous tissue plasminogen activator were noted in 49.6 % and 17.9 % of patients, respectively. Ultrasound-assisted thrombolysis and rheolytic thrombectomy were also used in 25% and 7.5 % of patients, respectively. The IHM rate was 5.9 %. The increase in α1 was associated with a decrease in TAPSE/PASP ratio, and an increase in PESI score and a higher risk status (p=0.047, p<0.001, p=0.001 respectively), but α2 showed no relation to PE severity (p=0.78). The value of α1 in predicting in-hospital mortality was evaluated with a logistic regression analysis with a model including PESI score, RV/LV ratio and α1. PESI score and α1 significantly predicted IHM (p= <0.001 and 0.027, respectively. OR for a1 1.15, CI 95%[1.06-1.27]), but RV/LV ratio did not. In the receiver operating curve (ROC) analysis for IHM prediction, the cut-off value of 1.168 for α1/α2 ratio [area under the curve (AUC): 0.721; sensitivity:76.92 % and specificity: 65.8 %] and the cut-off value of 32.47 for α1 ( AUC: 0.718 ; sensitivity: 84.67 % and specificity: 59.5 %) provided higher prediction compared with cut-off value of 1.29 for RV/LV ratio ( AUC : 0.604 ; sensitivity 76.9 % and specificity 45.87 %). Conclusion Either α1 or α1/α2 ratio evaluation on CT seems to represent a simple and reliable approach in the assessment of RV acute remodelling in response to thrombo-obstructive pressure burden and for prediction of outcome in patients with acute PE.Alpha 1 angle of different risk groupsROC curve

Health care utilisation in patients with mild pulmonary hypertension - EVIDENCE-PAH UK study

Abstract Background ESC/ERS 2022 guidelines1, redefined precapillary pulmonary hypertension (PH) as patients with a mPAP>20mmHg,PVR>2WU and PAWP<15mmHg1.We and others identified patients with mildly elevated pulmonary artery(PA) pressures demonstrates a higher mortality2-4. It is important to understand healthcare resource utilisation(HRCU) in this newly defined group who now meet the thresholds for diagnosis, however, treatment options are limited. Purpose The EVIDENCE-PAH aims to describe mortality and hospitalisation outcomes, baseline demographics in mild elevations in PA pressure in a national cohort. We report preliminary analysis of HRCU from data obtained from NHS Hospital Episode Statistics(HES); inpatient admissions, outpatient(OP) and emergency attendances(AE). Method Retrospective analysis of all patients with a mPAP<25mmHg and a sample of patients with a mPAP≥25mmHg at index-right heart catheterisation(RHC), across all UK PH tertiary centres between 2009-2017 with hospitalisation data captured 24-months pre and post index-RHC. For analysis patients were categorised into 3 groups; normal haemodynamics(mPAP<21mmHg & PVR≤2WU), mild elevation in haemodynamics(mPAP<21mmHg & PVR>2WU, mPAP21-24mmHg with all PVR groups, mPAP>25mmHg & PVR≤3WU) and abnormal haemodynamics(mPAP>25mmHg & PVR>3WU). Results A total of 2413(82.3%) patients had complete records 24-months pre and post index-RHC; 561(23.2%), 1228(50.9%) and 624(25.9%) in the normal haemodynamic, mildly elevated haemodynamic and abnormal haemodynamic groups respectively. Figure 1, demonstrates HRCU; Unscheduled admissions are significantly higher in the abnormal haemodynamic group 24-months pre index-RHC compared to the normal/mild elevations in haemodynamic groups (p-value<0.05). There was reduction in unscheduled encounters 24-months post index-RHC in the normal/abnormal haemodynamic group. No significant difference identified in AE attendance and OP 24-months post across all haemodynamic groups. Total HRCU demonstrates a lower attendance 24-months post RHC in normal versus abnormal haemodynamic group (p-value<0.05). Multivariate analysis demonstrates unscheduled admissions 24-months pre/post index RHC, as an independent predictor of survival, adjusted for age, sex and haemodynamics (Figure 2;p-value<0.05). Conclusion Unscheduled admissions may act as a discriminator identifying advanced PH (abnormal haemodynamics), but not normal versus mild elevations in haemodynamics. Meanwhile AE and OP attendances fails to discriminate between normal and mild elevation in haemodynamics. Unscheduled admissions 24-months pre/post index RHC is an independent predictor of survival which may lend as a useful surrogate marker for mortality in the PH population as a whole. Although total HRCU appears high across haemodynamics groups referred to PH centre, in the 24-months post RHC HRCU increases in the mild/abnormal haemodynamic groups, this may represent ongoing unmet need in this group.

Efficacy and tolerability of triple sequential combination therapies with selexipag in patients with pulmonary arterial hypertension: insights from a single-centre study

Abstract Background and aims In this single-centre study we aimed to evaluate the efficacy and tolerability of prostacyclin receptor agonist selexipag in patients with pulmonary arterial hypertension (PAH). Methods The study included 110 out of the 1071 patients enrolled in the Evaluation of Pulmonary Hypertension Risk factors Associated with Survival study (EUPHRATES) and treated with selexipag added on background dual PAH therapies. The ESC/ERS 2022, SPAHR, French Registry, COMPERA 2.0 and REVEAL lite 2 models were used for risk predictions. Results Age (mean+SD) was 43.4+16.5 years and 84.5 % of patients were female. The PAH was idiopatic, and was associated with congenital heart disease (CHD), connective tissue disease (CTD) and drug in 47.2 %, 46.4 %, 5.5 % and 1 %, respectively. Background dual therapies, functional class (FC) was II, III and IV in 20 %, 65 %, and 15 % of patients. Six-minute walk distance (6MWD) was 314 + 134 m and serum N-terminal-pro-brain natriuretic peptide (NT-proBNP) level was 882+1732 ng/l. Tricuspid annular planary excursion (TAPSE) and tissue velocity (St), right atrial area and pulmonary arterial diameter were 2.02+0.48 cm,12.4+2.8 cm/sec,21.4+7.2 cm2 and 3.54+0.77 cm, respectively. Invasively evaluated pulmonary arterial mean pressure was 60.2±19.9 mm Hg, and pulmonary vascular resistance was 12.3±10.8 Wood units. COMPERA 2.0 1st, 2nd, 3rd and 4th risk strata were noted in 15.5 %, 31.8 %, 2.7 % and 10 %, and French Registry strata 0,1,2 and 3 were documented in 70 %, 14.5 %, 11 %, and 4.5 %, respectively. The SPAHR and REVEAL Lite 2 scores were 1.9+0.5 and 5.9+2.6, respectively. Background combinations were as follows; macitentan+tadalafil in 46.6 %, macitentan+sildenafil in13.6 %, macitentan+ riociguat in 6.8 %, bosentan +tadalafil in 8.7 %, bosentan+sildenafil in 16.5 %, bosentan+riociguat in 1 %, ambrisentan +tadalafil in 1.9 %, and ambrisentan+sildenafil in 2.9 % of patients. Maximally tolerable selexipag doses (ug)were 1600 bid in 21%, 1400 bid in 5 %, 1200 bid in 11%, 1000 bid in 17%, 800 bid in 12%, 600 bid in 9%, 400 bid in 14%, and 200 bid in 11%.Median follow-up period was 527( 278-831) days, and discontiuation rates of selexipag was 13.6 %. Headache, jaw-pain, diarrhoea, nausea, vomiting and flushing were main side effects. The changes in FC, 6MWD, Nt-pro-BNP and echocardiographic measures were not significant. French Registry score (p<0.001) and COMPERA 2.0 score (p<0.001) showed improvements, but SPAHR and REVEAL lite 2 did not. However, other PAH cohort compared with IPAH showed more pronounced improvements in REVEAL lite 2 and SPAHR scores. Clinical worsening and mortality rates were 23.6 % and 10.9 %, respectively. Survival for 1, 3 and 5 years were 95.8 %, 95.8 and 83.7 % in IPAH, and 92.6 %, 84.1 % and 78.8 % in other PAH patients. Conclusion Our results seem to be consistent with efficacy and tolerability of selexipag-included combinations in patients with PAH.

Echocardiographic profiles of patients with CPCPH and IPCPH in HFpEF: insights from the PHHF study

Abstract Background The 2022 ESC/ERS guidelines changed the definition of post-capillary pulmonary hypertension (pcPH) in heart failure (HF) by lowering the level of mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR). Yet, the echocardiographic profile of HF with preserved ejection fraction (PEF) patients according to their mPAP and RVP is not known. Objectives To investigate the echocardiographic profile of HFPEF patients according to their mPAP and RVP. Methods Stable HF patients with the need for right heart catheterization were enrolled from 2010 to 2018 and prospectively followed-up in this multicenter study. All patients had a right heart catheterization and an echocardiography within the 24 hours. PcPH was characterized by a pulmonary wedge pressure exceeding 20 mm Hg and mean mPAP greater than 20 mm Hg, from an isolated state when PVR was less than 2 Wood units (WU, IpcPH) to a combined form when PVR exceeded 2 WU (CpcPH). Results Out of 662 HF patients included in PHHF study, 268 (40%) were classified as having HFpEF (35% male, median age 71 yo). Compared to IpcPH patients, CpcPH patients had higher tricuspid regurgitation peak velocity (sPAP, 3.53 vs 3.00 m/s, p<0.01), lower S tricuspid tissue Doppler velocity (10 vs. 11 cm/s, p 0.01) and TAPSE (18 vs. 21 mm, p< 0.01) and lower TAPSE/sPAP ratio (0.3 vs. 0.4, p<0.01). There were no differences between groups regarding both right ventricle and right atrial diameter and area. Conclusion In HFpEF patients with PH, CpcPH patients had worse right ventricular function despite similar remodeling when compared to IpcPH patients