Pulmonary Hypertension Research Articles

Perspectives on Sotatercept in Pulmonary Arterial Hypertension.

Sotatercept acts as a type IIA-Fc activin receptor, thereby scavenging free activin from its physiological membrane receptor. Through this type of action, sotaterpect leads to a rebalancing of the proliferation and antiproliferation pathways of pulmonary smooth muscle cells in response to bone morphogenic protein (BMP). Although sotatercept has been approved as the fourth pillar of therapy for group 1 pulmonary arterial hypertension (PAH) in the United States and Europe, several studies are ongoing to broaden the application of the drug to non-Group 1 PAH. We provide an overview of the clinical and preclinical evidence of targeting the activation pathway by sotatercept in the treatment of PAH. We also discuss other potential applications of sotatercept in the context of pulmonary hypertension other than PAH group 1.

Comparison of pulmonary arterial risk assessment tools to predict mortality or morbidity in treatment naive and previously diagnosed patients

Abstract Background Pulmonary arterial hypertension (PAH) risk stratification (1-year prediction of risk) is crucial and should be the most accurate to ensure appropriate aggressiveness of the treatment choices. According to the European guidelines, several risk tools can be used both at baseline and/or follow-up assessment. Yet, a comparison of risk tools performances only in treatment-naïve or only previously diagnosed patients is still missing. Aims To compare the available risk assessment tools performances to predict 1-year mortality but also 1-year clinical worsening in treatment-naïve and previously diagnosed PAH patients. Methods Eight PAH trials (AMBITION, ARIES1, ARIES2, FREEDOM, GRIPHON, PATTENT, PHIRST and SERAPHIN) provided by the FDA were harmonized and treatment-naïve patients were separated from previously diagnosed patients. Outcomes were 1-year mortality and 1-year clinical worsening (i.e., morbidity) either from baseline assessment or at follow-up. Kaplan-Meier and log-rank tests were performed for each of the following risk tools: European 4-strata, REVEAL2.0, REVEAL Lite, noninvasive FRENCH. In each subgroup, their C-indices were calculated and compared using a total of 100 bootstrap samples from the original data, providing a robust method for comparing across the different tools. Results Among the 4,122 patients included, 1,701 (41%) were treatment-naïve and 2,411 (59%) were previously diagnosed patients. Compared to treatment naïve patients, previously diagnosed patients were younger (p<0.001), with lower level of natriuretic peptide (p=0.013), higher 6MWD (p<0.001) and higher mPAP (p<0.001). At 1-year, the mortality rate was the same in the 2 subgroups (5.6% 5.1%, p=0.05) but clinical worsening occurred more often among previously diagnosed patients (19% vs 8.4%, p<0.001). Each of the risk tools were able to predict both 1-year mortality or morbidity in each subgroup, especially among previously diagnosed or at follow-up, with fair to good C-index (Figure 1). Forrest plots of 95%CI for the C-index differences among the 100 bootstrap samples showed that REVEAL 2.0 was the best performer, followed by REVEAL Lite (Figure 2). Conclusions In this large dataset, we showed that all PAH risk tools were able to predict not only 1-year mortality but also 1-year morbidity, both in treatment naïve and previously diagnosed patients. REVEAL 2.0 depicted the higher C-index.Figure 1.C-index for PAH risk toolsFigure 2.Forrest plots of 95%CI

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

Scoring system for early detection in pulmonary hypertension type I based on clinical presentation, electrocardiography, and chest X-ray at RSUD dr. Saiful Anwar

Background: In Indonesia, pulmonary hypertension prevalence is 1:10.000 population. Due to its atypical symptoms, often PH patients come as a late presenters thus they have a worse prognosis. The golden standard to diagnose is Right Heart Catheterization (RHC) which is not widely available. Objectives: To generate a scoring system based on clinical presentation, electrocardiogram, and chest x-ray for early detection. Methods: A hospital-based cross-sectional survey was conducted in RSUD dr. Saiful Anwar, East Java from July 2020 – November 2023 with data from the medical record in which all variables are obtained at one period. Data were analyzed using bivariate analysis, multiple logistic regression, and Area Under Curve (AUC) from Receiver Operating Characteristic (ROC). Results: A total of 244 patients who were above 18 years old were conducted RHC at RSUD dr. Saiful Anwar East Java. We found a total score of 12 consisting of Dyspnea on Effort (DOE) score 2, Palpitation score 1, Increasaed P2 score 2, Increased JVP (Jugular vein pressure) score 2, RV (Right Ventricular) Heaves score 2, Right bundle branch block (RBBB) score 1, and Cardiomegaly (CTR >50%) score 2. With a 2 x 2 table, we found that a score of ⩾5 is likely for pulmonary hypertension diagnosis. Conclusion: Our study is a predictive model with a scoring system that has good sensitivity and specificity in selected populations where one of its limitations is sampling bias thus cannot yet be applied to the general population and needs further research for validation. Keyword: congenital heart disease, pulmonary hypertension, scoring for early detection

Long-standing response to calcium channel blocker therapy on patients with various types of pulmonary hypertension: a systematic review and meta analysis

Abstract Background It is widely acknowledged that the extended use of calcium channel blocker (CCBs) therapy in patients diagnosed with Idiopathic Pulmonary Arterial Hypertension (IPAH), Heritable Pulmonary Arterial Hypertension (HPAH), or Drug- or Toxin-Associated Pulmonary Arterial Hypertension (DPAH) who exhibit a positive acute vasoreactivity test (VdT+) provides benefits to patients. However, this practice is supported by a limited body of evidence in the scientific literature, mainly derived from expert consensus and/or small-scale studies, retrospective analyses, and registries, as per the European Society of Cardiology (ESC) guidelines. Objectives We performed a meta-analysis to evaluate the long-standing response to CCBs in patients diagnosed with various forms of pulmonary hypertension. Design We conducted searches in PubMed, Embase, and Cochrane to select both randomised and non-randomised studies. The primary outcomes of interest identified were Mean Pulmonary Artery Pressure (mPAP), 6-minute walk distance (6MWD), Cardiac Index (CI), Mean Right Atrial Pressure (mRAP), and Mixed venous oxygen saturation (SvO₂) measured at the beginning and end of the studies. Additionally, we performed subgroup analyses for all outcomes based on age groups: ≤18 years and >18 years. Statistical analysis was carried out using OpenMeta[Analyst] 12.11.14, and heterogeneity was assessed using I² statistics. Results We identified 7 non-randomised studies comprising a total of 131 patients with an average follow-up duration of 2.74 (1.3) years. The following are the mean values observed for individual outcomes: mPAP (33.1 mmHg; 95% CI [31.6, 34.6]; p < 0.001; I²=0%), 6MWD (470.1 m; 95% CI [452.6, 487.7]; I²=0%), Cardiac index (3.8 L/min/m²; 95% CI [3.6, 4.0]; I²=0%), mRAP (4.2 mmHg; 95% CI [3.6, 4.8]; I²=0%) and SvO₂ (73.9%; 95% CI [72.5, 75.3]; I²=0%) in patients with positive acute vasoreactivity test (VdT+) treated long-term with CCBs. Additionally, at study initiation, we found the following means: mPAP (51.2 mmHg; 95% CI [49.3, 53.0]; I²=0%), 6MWD (428.4 m; 95% CI [410.3, 446.6]; I²=0%), Cardiac index (2.8 L/min/m²; 95% CI [2.7, 2.9]; I²=0%), mRAP (6.4 mmHg; 95% CI [5.6, 7.2]; I²=0%), and SvO₂ (68.5%; 95% CI [66.5, 70.5]; I²=0%). Conclusion The findings from this meta-analysis suggest that in VdT+ patients, the means of certain haemodynamic parameters with long-standing use of CCBs are similar or nearly similar to those of patients without any subtype of PAH. These results align with current guidelines and reinforce their level of evidence.

Idiopathic pulmonary arterial hypertension, associated with connective tissue disease and comorbidities: prognostic differences? Results the Spanish Registry of pulmonary hypertension (REHAP Registry)

Abstract Introduction Idiopathic pulmonary arterial hypertension (iPAH) and associated with connective tissue disease (PAH-SSc) are the most frequent groups of pulmonary arterial hypertension (PAH) but their long-term survival is usually unequal. Comorbidities, increasing in frequency in these patients, show prognostic influences but it is not known whether these differ in both groups of patients. Methods We collected patients diagnosed with iPAH, heritable, associated with drug or toxine exposure and PAH-SSc between 2014 and 2023 from the Spanish Registry of Pulmonary Hypertension. Patients are classifies into iPAH and PAH-SSc. We analyzed baseline characteristics and the distribution of the different comorbidities in the two groups. Survival analyses estimated by Kaplan-Meier analysis using the log-rank test were done according to PAH etiology and comorbidities and Cox proportional hazard analyses were performed to determine the effects of baseline characteristics on survival. Results Seven hundred and fifty-seven patients were selected for this study. The characteristics of the patients are shown in Table 1. Patients with PAH-SSc compared to iPAH were older (62 vs 56 years), more female (81.8% vs 62.4%), had a more favorable hemodynamic profile, TAPSE/sPAP ratio and lower NT-proBNP levels. No differences were found in functional class or 6MWT. We found a higher proportion of patients in a low and intermediate risk profile, according to ESC, in patients with PAH-SSC as opposed to PAHi (46.8/50.9% vs. 29.3/64.5%; p<0.001). Regarding comorbidities, history of smoking (27.1 vs 54%; p<0-001), obesity (17.1 vs 20.7%; p<0.001) and diabetes (9.4 vs 22.1%; p<0.001) are less frequent in PAH-SSc than in iPAH. There are no differences in the rest of the comorbidities studied in the two groups of patients. In a survival analysis, we found no differences between patients with iPAH and PAH-SSc at 7-year follow-up. Patients with ≥ 3 comorbidities had statistically significantly higher mortality (p<0.001) compared to those with 0 or 1-2 comorbidities in both etiologies. There were no differences between 0 and 1-2 comorbidities. (Figure 1). Variables associated with mortality were male sex (HR 1.9, 95% CI 1,28 – 2.8), age (HR 1.04, 95% CI 1.02 – 1.06), the intermediate risk profile (HR 2.64, 95% CI 1.62 – 4.32) and high risk profile (HR 9.97, 95% CI 4.36 – 18.47), but not etiology. The presence of connective tissue diseases, were not associated with increased mortality. Conclusions Patients with PAH-SSc show lower comorbidities, better hemodynamic profile, RV-PA coupling and risk profile than those with iPAH. Comorbidity has a great relevance in survival but without differences according to etiology. The presence of male sex, age, the intermediate and high risk profile is associated with worse survival, but not the connective tissue diseases.

Magnetic resonance lymphangiography abnormalities as extracardiac biomarkers of pulmonary hypertension and functional phenotype in Fontan-Kreutzer univentricular circulation.

Lymphatic abnormalities have been documented on magnetic resonance lymphangiography in patients with functionally univentricular circulation. The aim of this study is to evaluate associations between findings on magnetic resonance lymphangiography, cardiac catheterisation and functional phenotype in patients with Fontan-Kreutzer circulation. Between January 2017 and October 2019, seven patients with Fontan-Kreutzer circulation (16.57 ± 7.10 years) were enrolled following ethical committee approval and attainment of informed consent. Clinical data, consecutive magnetic resonance imaging and cardiac catheterisation findings were reviewed. Qualitative lymphatic abnormality types were defined as: 1 - Little or none; 2 - Localised to the supraclavicular region; 3 - Extending into the mediastinum; and 4 - Extending into the lung. Pulmonary hypertension was defined as a transpulmonary gradient > 6 mmHg. Quantitative data were assessed using Mann-Whitney U tests, and p < 0.05 was considered statistically significant. Patients with lymphatic abnormalities categorised type 1 or 2 and transpulmonary gradient ≤ 6 mmHg had a normal functional phenotype, while those with type 3 or 4 and transpulmonary gradient > 6 mmHg had a failing functional phenotype. Magnetic resonance lymphangiography in patients with Fontan-Kreutzer circulation and pulmonary hypertension revealed lymphatic abnormalities types 3-4, indicative of a failing functional phenotype compared to patients without pulmonary hypertension. If validated in larger studies, these results suggest the potential utility of this extracardiac biomarker for improving risk stratification. Integration of lymphangiography and transpulmonary gradient with functional class, atrioventricular valve function, and ejection fraction allowed for the categorisation of three distinct functional phenotypes, which may be valuable for future analyses.

The optimal cut-off value for the one-minute sit-to-stand test to determine functional impairment in patients with pulmonary hypertension

Abstract Introduction Pulmonary hypertension (PH) often leads to reduced functional capacity, commonly assessed by the six-minute walk test (6MWT). The 1-min sit-to-stand test (1-min STST) is a shorter test with smaller space requirements. Despite its potential utility, to our knowledge no studies have determined the optimal cut-off value for the 1-min STST in patients with PH. Aim This study aimed to assess the optimal cut-off value for the 1-min STST by utilizing three established 6MWT thresholds (165m, 320m, and 440m) recommended in current European PH guidelines published by Humbert et al. (1). Methods A receiver operating characteristics (ROC) curve analysis was conducted to identify a threshold for the 1-min STST, aligning with the three 6MWT cut-offs. Clinical parameters and health-related quality of life (HRQoL) assessed through the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) questionnaire were evaluated. Results A total number of 114 patients with PH (mean age 66±14 years, 57% female) were included in the analysis. Patients performed a mean number of 17±7 repetitions in the 1-min STST and achieved a mean 6MWT distance of 351±137m. The &amp;lt;165m 6MWT threshold revealed the highest area under the curve (AUC=0.90; 95%-CI 0.84-0.97). The optimal cut-off for the 1-min STST was 14.5 repetitions, exhibiting 69% sensitivity and 100% specificity. Patients below this threshold demonstrated significantly worse clinical parameters and reported worse HRQoL (p&amp;lt;0.001), as shown in Table 1. Conclusion A 1-min STST cut-off of 14.5 repetitions identified PH patients with functional impairment, suggesting its potential utility for risk stratification.

Long-acting CRF2 receptor agonist COR-1389 improves cardiopulmonary function parameters in monocrotaline-induced pulmonary hypertension and right heart failure rat model

Abstract Background Pulmonary hypertension (PH) associated with right heart failure (RHF) poses a significant therapeutic challenge. Short term studies have shown that urocortin-2 (UCN-2) administration, either intravenously or subcutaneously, can ameliorate cardiac and/or pulmonary parameters in human heart failure (HF) and in animal models of PH and RHF. Purpose This study aimed to evaluate the potential benefits of COR-1389, a long-acting CRF2 receptor agonist, on cardiopulmonary function and adverse remodeling in a rat model of monocrotaline (MCT)-induced PH and RHF. Method Monocrotaline (40 mg/kg) was administered subcutaneously in rats on Day-0 to induce PH and RHF, while the control group received vehicle. After 14 days, MCT-injected rats were evenly allocated into two groups based on echocardiography parameters of accelerated time/ejection time ratio and tricuspid annular plane systolic excursion (TAPSE), before receiving either COR-1389 (100 ug/kg) or its vehicle subcutaneously every 4 days for 14 days. On Day-28, echocardiography was repeated in all groups, followed by right heart catheterization to directly measure pulmonary hemodynamics. Heart and lung samples were prepared for histological analysis. Results By Day-28, MCT-treated rats exhibited significantly elevated mean pulmonary arterial pressure (mPAP) and right ventricular (RV) mass (Fulton Index/BW), along with decreased RV function (increased TAPSE) and reduced cardiac output (CO) compared to control rats. These changes were accompanied by severe tissue remodeling, including increased vascular muscularization (alpha-smooth muscle actin content) and pulmonary arterial wall thickening, RV fibrosis, and cardiomyocyte hypertrophy. Following 14 days of curative treatment, MCT+COR-1389 compared to MCT, significantly decreased mPAP and RV mass (Fulton Index/BW), while RV function improved (reduced TAPSE) and CO was increased. Moreover, COR-1389 attenuated adverse pulmonary vascular remodeling (reduced muscularization and arterial wall thickening), RV fibrosis, and cardiomyocyte hypertrophy, consistent with its hemodynamic effects. Conclusions Chronic CRF2 agonism with COR-1389 improved dysregulated cardiac and pulmonary function and structure in the MCT rat model, suggesting its potential for the treatment of PH and RHF.

Does the presence of severe pulmonary hypertension affect survival at 5 years follow-up in patients who underwent TAVI for severe aortic stenosis?

Abstract Background Pulmonary hypertension (PH) is common in patients with severe aortic stenosis (AS) and is associated with increased mortality after transcatheter aortic valve implantation (TAVI) as well as surgical aortic valve replacement (SAVR). Preprocedural systolic pulmonary artery pressure (sPAP) often improves after TAVI because the most common type of PH is postcapillary PH secondary to left-sided heart disease, which potentially improves after treatment for AS. However, there are limited data regarding the prognostic impact on outcomes after TAVI and their predictors. Purpose The aim of this study is to compare survival at 5 years between patients with severe PH against those who did not have severe PH who underwent TAVI. Methods Between January 2012 until December 2022, we carried out a retrospective study of all patients who underwent TAVI at our hospital. Severe PH was defined as the presence of sPAP &amp;gt;40mmHg on echocardiography. Patients with aortic regurgitation and mixed aortic valve disease were excluded. Co-morbid pulmonary disease was defined as the presence of any significant pulmonary disease including COPD and Asthma. Co-morbid neurological disease was defined as the presence of any significant neurological disease including CVA/ TIA. Diabetes mellitus was defined as per WHO and included patients who were diet, medication and insulin controlled. Survival status and date of death were ascertained from our electronic health records. Counts and incidence rates of clinical outcomes at 5-year follow-up were computed from Kaplan-Meier analysis (See Figure 1). A Cox proportional hazards model was used to compute HRs and 95% CIs for the study outcomes. Results Of the 274 patients available for analysis, 115 (14%) patients had severe PH. The mean age was 84 years in both cohorts whilst patients in the severe PH cohort were frailer by Katz Index Score. Death occurred in 67 patients out of 115 patients who had severe PH and in 87 out of 158 patients who did not have severe PH after a median follow-up time of 4.1 years (58% vs 55%; adjusted HR: 1.04; 95% CI: 0.71-1.51; P = 0.86). Conclusion Our data shows that presence of severe pulmonary hypertension in severe aortic disease patients who had undergone TAVI did not affect survival at 5 years follow up compared to patients without severe pulmonary hypertension undergoing TAVI. Determining predictors of mortality in this high-risk cohort is likely to be complex and multifactorial, owing to the severe multi-comorbidity precluding them from SAVR.

Exercise Doppler echocardiography to detect early changes in the right ventricular-pulmonary circulation unit after pulmonary embolism

Abstract Introduction After pulmonary embolism (PE), patients frequently complain about reduced exercise capacity and dyspnea on exertion, even without pulmonary hypertension (PH). The underlying condition is often chronic thromboembolic disease, which is caused by residual pulmonary obstruction with preserved resting pulmonary haemodynamics. The symptoms are the consequences of the increased dead space ventilation, exercise-induced PH and right ventricular (RV) dysfunction. We aimed to assess the pathologic differences in the echocardiographic parameters of the RV- pulmonary circulation unit among patients with previous PE and the healthy control group. Furthermore, an objective was to compare the hemodynamic response to stress after different treatment strategies (thrombolysis vs. heparin administration). Methods 21 patients after PE (mean age 58,5±12,1 years; 53% men) have been included in the study. All of them were effectively anticoagulated for at least three months, and none had any signs of PH on echocardiography at rest. The control group included 20 healthy volunteers (mean age 56,9±11,5 years; 55% men). Each patient underwent resting and exercise stress echocardiography on a semi-recumbent bicycle ergometer according to a standardised protocol until the maximally tolerated workload. Echocardiography was performed at rest, at 50 Watt workload and during peak stress. The measurements focused on the RV's systolic function (TAPSE), the estimated pulmonary artery systolic pressure (PASP), and the Doppler measurements in the RV and left ventricular outflow tracts. Pulmonary vascular resistance (PVR) and RV-pulmonary artery coupling (RV-PA) were calculated from the echocardiographic parameters. Results The post-PE group had significantly higher PASP (39,2 ±16,6 vs. 27,7±12,5 mmHg; p&amp;lt;0,05) and PVR (1,5±0,4 vs. 1,1±0,3 Wood Units; p&amp;lt;0,05) at peak stress, than the controls. 55% of post-PE patients remained symptomatic, but there were no significant differences between the symptomatic and asymptomatic groups regarding TAPSE, PASP, RV-PA coupling and PVR. 30% of post-PE patients had thrombolysis. In the patients where thrombolysis was performed, the coupling at peak stress was significantly higher than in heparin-treated patients (1,4±0,1 vs 0,9±0,4 mm/mmHg, p&amp;lt;0,05). Conclusion Post-PE patients without resting PH have higher PVR and PASP than the healthy control group, even after at least 3 months of adequate therapy. Post-PE patients treated with thrombolysis may have more preserved RV-PA coupling than the heparin-treated patients.

CS585, a novel prostacyclin receptor agonist, demonstrates sustained efficacy in vivo in the prevention of thrombosis

Abstract Background Uncontrolled platelet activity resulting from cardiovascular disease can lead to occlusive thrombi, culminating in myocardial infarction or stroke. Despite major advances in anti-platelet therapeutics, many patients remain at risk. Although prostacyclin (IP) receptor agonists are currently used for the treatment of pulmonary arterial hypertension (PAH), activation of the IP receptor has been shown to decrease platelet reactivity. However, engaging the IP receptor as a therapeutic target was previously considered unviable due to the lack of a sustained effect of current IP agonists in the blood. The development of an IP agonist with sustained effects in the blood would represent a novel prevention strategy in targeting platelet hyperreactivity and thrombosis. Purpose Assess the stability profile of CS585, an IV and orally bioavailable IP agonist, compared to FDA-approved IP agonists iloprost and selexipag, with regards to sustained activity in vivo in the blood in limiting platelet activation and thrombosis. Methods Using ex vivo and in vivo mouse models, we assessed the timeframe of effect of CS585, iloprost and selexipag in blood. Blood was drawn from wild-type mice 24 hours following a single IV dose of CS585, iloprost or selexipag. Platelet adhesion and blood clotting were measured using perfusion flow chamber at arterial shear and total thrombus activation system (T-TAS), respectively. In vivo, platelets and fibrin were labelled 24 hours post IV or oral administration of CS585, iloprost or selexipag, and accumulation at the site of injury was measured using the cremaster arteriole injury thrombosis assay. Results Blood drawn from mice administered CS585 was observed to show a decrease in platelet adhesion and clot formation in the perfusion flow chamber and T-TAS assays. The effects of iloprost and selexipag are no longer observed at 24 hours post-administration. Administration of CS585 resulted in sustained inhibition of platelet accumulation and fibrin formation in the laser-induced cremaster arteriole thrombosis assay up to 18 hours post-administration. In mice administered iloprost, a decrease in thrombus formation was observed 10 minutes post-administration, but thrombus size returned to vehicle levels by 4 hours. Selexipag-dosed mice demonstrated inhibition of thrombus formation up to 4 hours, but effects were no longer observed at 18 hours. Conclusions CS585, a novel IP agonist, inhibits platelet activation and clot formation up to 24 hours post-administration. In both in vivo and ex vivo models, we demonstrate the sustained effects of CS585. In contrast, current FDA-approved IP agonists do not possess an effect profile sufficient to target the IP receptor in blood. By overcoming the sustainability challenge facing IP agonists, CS585 represents a novel approach to anti-platelet treatment of thrombotic diseases, which could include thrombosis, VTE, secondary prevention after MI and stroke, and PAH.

Cardiopulmonary exercise testing in long-term calcium channel blockers responders, does it normalize in the same way as pulmonary vascular resistance?

Abstract Background and aims Long-term calcium channel blockers (CCB) responders represent &amp;lt;10% of pulmonary arterial hypertension (PAH) patients and are known to have an excellent prognosis on high dose CCB. The few reports of lung histology of these patients suggest a predominant muscular thickening of the precapillary arterioles. Nevertheless, the classic intimal proliferation characteristic of PAH has also been reported, although to a lesser extent. Hence, we hypothesized that long-term CCB responders are likely to exhibit some degree of ventilatory inefficiency as a result of their impaired alveolo-capillary membrane. In this study, we aimed to evaluate the exercise performance of a contemporary cohort of long-term responders to CCB in terms of both exercise capacity and ventilatory efficiency, and whether there are differences depending on the haemodynamic severity. Methods We evaluated all long-term CCB responders with regular follow-up at our institution between 1996 to 2024 with at least one cardiopulmonary exercise test (CPET) and a right heart catheterization (RHC) within a three-year period, provided they had remained clinically stable without changes in pulmonary vasodilator treatment. Patients with additional PAH specific treatment were excluded. For data analysis purposes, the population was divided into 2 groups according to pulmonary vascular resistance (PVR). The cut-off point for PVR was set at ≥3. Results Twenty-four patients (91,6% female) with complete data were retrospectively enrolled. Baseline characteristics were as follows: median age 45.5 years (59-33) median mean pulmonary artery pressure of 26 mmHg (29-24) and median PVR of 3 WU (3-2.6). Regarding the whole cohort, peak oxygen consumption (pVO2) revealed mild impairment of functional capacity (mean pVO2: 1281 ± 245 ml/kg – 75 ± 15% of predicted). Ventilatory efficiency parameters were also mildy affected with low end-tidal carbon dioxide pressure at the anaerobic threshold (PETCO2@AT) (33.7±3.6mmHg), and increased minute ventilation (VE)/carbon dioxide output (VCO2) slope (33.5±4.5). The subgroup analysis depending on PVR showed no significant differences between groups in terms of pVO2 (1291.9 ±240 Vs. 1150 ±350 ml/kg, p:0.29 / 79%±16 vs 67%±12, p:0.8), VE/VCO2 slope (33 Vs. 34, p:0.21), or PETC02@AT (35 Vs. 33 mmHg, p:0.25). All CPET parameters by subgroups are displayed in Table 1. Conclusions Long-term CCB responders exhibit mildly reduced functional capacity. Moreover, they often fail to normalize the ventilatory efficiency parameters in most of the cases, even when PVR reaches close to normal values, suggesting persistent endothelial impairment.Results according to PVR

The importance of comorbidities in idiopathic and associated with connective tissue disease pulmonary arterial hypertension: from the Spanish Registry of Pulmonary Hypertension (REHAP Registry)

Abstract Introduction Comorbidities play a major role in the prognosis of patients with pulmonary arterial hypertension (PAH). These comorbidities are present in more than 80% of patients diagnosed in the last years with idiopathic PAH (iPAH) and their presence is associated with increased morbidity and mortality although its influence on PAH associated with connective tissue disease (PAH-SSc) is unknown. We studied the impact of comorbidities on iPAH and PAH-SSc in the Spanish population. Methods We collected patients diagnosed with iPAH, heritable, associated with drug or toxine exposure and PAH-SSc between 2014 and 2023 from the Spanish Registry of Pulmonary Hypertension. Patients are classified into: no comorbidities, 1-2 comorbidities and ≥3 comorbidities. We analyzed the impact of comorbidities in baseline characteristics, exercise capacity and hemodynamic profile, as well as in the risk profile and initial treatment. Survival analyses estimated by Kaplan-Meier analysis using the log-rank test and Cox proportional hazard analyses were performed to determine the effects of baseline characteristics on survival. Results 757 patients were selected for this study. The characteristics of the patients are shown in Table 1. As the number of comorbidities increases (0/1-2/≥3) we found higher age (49/59/67 years; p&amp;lt;0.001), higher percentage of male sex (12.9/29.9/43.4%; p&amp;lt;0.001) and higher FC III at diagnosis (42.7/46.9/59.6%; p=0.013). We observed a shorter distance in 6MWD, higher NT-proBNP levels, lower DLCO and a less unfavorable hemodynamic profile (PAPm, PAWP, CI and PVR). The most frequent comorbidities were a history of smoking (46.4%), followed by arterial hypertension (41.5%), obesity (24.6%) and chronic kidney disease (19.2%). Diabetes mellitus, although less frequent, reached more than 55% in patients with ≥3 comorbidities (p&amp;lt;0.001). The presence of ≥ 3 comorbidities was more frequent in iPAH than PAH-SSc (p&amp;lt;0,001). Intermediate risk profile was the most common (58.4%) and this reached 68.7% in those with ≥3 comorbidities due to a lower number of patients in a low-risk profile (p&amp;lt;0.001). A statistically significant lower survival (p&amp;lt;0.001) was observed in patients with ≥ 3 comorbidities; however, we found no differences between 0 and 1-2 comorbidities at 7-year follow-up (Figure 1). Variables associated with mortality were male sex (HR 1.88, 95% CI 1,26 – 2.8), age (HR 1.04, 95% CI 1.02 – 1.06) and the presence of ≥3 comorbidities (HR 1.49, 95% CI 0.98 – 2.27), not the presence of connective tissue diseases, which were not associated with increased mortality in our study. Conclusions The presence of comorbidities in iPAH and PAH-SSc is very frequent in the Spanish population. They are associated with a worse clinical profile, risk profile, lower use of oral double theraphy and prostacyclins. The presence of ≥3 comorbidities is associated with worse survival, not the presence of 1-2 comorbidities or connective tissue disease.

Continuous heart monitoring to evaluate treatment effects in pulmonary hypertension

Abstract Background The treatment of pulmonary hypertension (PH) has improved rapidly in recent years, and there is increasing evidence to support the role of early intervention. However, studies demonstrate that timely intervention is often still lagging which affects clinical outcomes in patients with PH. Purpose To assess treatment effects after escalation of specific PH treatments using continuous heart monitoring via a Reveal LINQ loop recorder. Methods The patients change in heart rate variability (HRV), heart rate (HR), and physical activity were assessed before and after treatment escalation. Treatment escalation was defined as an additional PAH drug, pulmonary endarterectomy (PEA), percutaneous balloon angioplasty (PBA), or bilateral lung transplantation (BLTX). Results In this prospective study, 41 patients (27 with PAH and 14 with chronic thromboembolic pulmonary hypertension) were enrolled. Among them, 15 patients (36.6%) underwent PH treatment escalation. Prior to escalation, patients were monitored for a median of 100 (range: 68–100) days and after therapy escalation for a median duration of 165 (range: 89–308) days. In the escalation group, a significant increase in HRV (Figure), physical activity indexed by daytime HR was observed, while a significant decrease was seen in nighttime HR assessed at baseline and after treatment escalation. These changes were found both in the PAH and CTEPH group. In parallel a significant improvement in WHO functional class, 6-minute walking distance, and N-terminal pro-b-type natriuretic peptide (NT-proBNP) was observed. Conclusions This is the first study to demonstrate a direct association between specific PH therapies and changes in HRV, HR nighttime and physical activity in patients with PAH and CTEPH. Continuous monitoring allows for an early intervention with supplementary treatment for PH. This is especially relevant considering the increasing availability of wearables that allow for a convenient measurement of relevant prognostic parameters in PH.

Types of pulmonary hypertension and prognosis in COVID-19: 18-months analysis of BNP-PL national database

Abstract Introduction The COVID-19 pandemic significantly increased mortality in the group of patients (pts) with pulmonary hypertension (PH). However, there is no data whether specific types of this disease, such as PAH associated with connective tissue diseases, were more likely to have a poor prognosis. Aim To assess mortality in the course of COVID-19 among pts diagnosed with PH, treated under the Polish ministry therapeutic program and registered in the national BNP-PL database, according to the type of PH. Methods We analyzed the records of the complete population of Polish pts treated under the National Drug Program of PH (PAH and CTEPH) and registered in the national database of BNP-PL from 01 March 2020 to 31 August 2022. The clinical severity of COVID-19 course and mortality were reviewed. Clinical characteristics of infected and deceased patients were compared in relation to the type of PH. Results The analysis included 143 pts with SARS-CoV-2 infection (mean age 61 ± 15 years; 60% female). Mortality rate was 24% (34/143, including 20 out-of-hospital deaths) vs. 2.6% for estimated in the general population. The highest mortality was observed in the group of pts with idiopathic PAH (33%), slightly lower among pts with connective tissue diseases [CTD] (29%). Patients with congenital heart diseases had a fairly good prognosis [CHD] (81% recovered), and the best survival was recorded in those with CTEPH (84%). CTD and IPAH were found to represent "high-risk" subset with mortality risk ~ 32% vs. ~ 17% in others (p=0.032). Etiologic categories had significant trend for different COVID-19 outcomes according to chi2 test for trend (p=0.039). Conclusions The SARS-CoV-2 infection in pulmonary hypertension pts was related to high mortality, with pts with IPAH had the worst prognosis, folloved by pts with CTD who might already have had lung involvement. Interestingly, the best survival was recorded in one of the oldest group - patients with CTEPH. This may be related to the chronic anticoagulant treatment used in this group, as significant disorders of coagulation pathways have been observed in SARS-CoV-2 infection.

Long-term follow-up after catheter ablation of atrial fibrillation and atrial tachycardia in patients with pulmonary hypertension

Abstract Introduction Catheter ablation of atrial fibrillation and atrial tachycardia (AF / AT) is established treatment in selected population. Only limited data, including long-term results, exist in patients with pulmonary hypertension (PH). Recently published prospective multicentric trial showed that more extensive radiofrequency catheter ablation of the bi-atrial arrhythmogenic substrate instead of clinical arrhythmia ablation alone is not beneficial in terms of arrhythmia recurrence in patients with AF / AT and PH. Now, we present the results of an extended, long-term follow-up from one of the study centres. Methods Patients with combined post- and pre-capillary or isolated pre-capillary PH and AF / AT indicated to catheter ablation were enrolled and randomised 1:1 into two parallel treatment arms. Patients underwent either clinical arrhythmia ablation only (Limited ablation group) or clinical arrhythmia plus substrate-based ablation (Extended ablation group). The primary endpoint was arrhythmia recurrence &amp;gt;30 s without antiarrhythmic drugs after the 3-month blanking period. Results A total of 52 patients (median age 71 years (IQR 62-75); 27 males) were enrolled. The presumable clinical arrhythmia was AF in 20 and AT in 32 patients, including typical AFL in 22 patients. Limited and extended ablation group included 28 and 24 patients, respectively. During the extended follow-up period of median 31 (IQR: 18; 46) months, the primary endpoint occurred in 17 patients (71 %) vs. 13 patients (46 %) in the Extended vs. Limited ablation group (p = 0.096). In parallel, overall mortality was comparable between groups (9 [38 %] vs. 11 [39 %]). Only 2 patients had recurrence of AFL during the extended follow-up. However, new different arrhythmia was documented in another 7 patients after the AFL ablation. Conclusion In PH patients, recurrence of AF / AT after a catheter ablation is frequent and the recurrence rate increases with the duration of follow-up. Ablation strategy seems to have no impact on arrhythmia free survival. Patients with typical atrial flutter have significantly higher chance to maintain sinus rhythm after a catheter ablation compared to AF or other AT.

Vmax as an Index of right ventricular function in pulmonary hypertension

Abstract Background For assessing right ventricular function in pulmonary hypertension (PH), the optimal approach is through the use of load-independent parameters. While pressure-volume (PV) loops are not feasible in clinical settings, the maximum velocity of the contractile element under no load, known as Vmax, serves as an alternative measure that could be derived only from right-heart catheterization (RHC). Objectives To determine Vmax in patients undergoing RHC and to evaluate its correlation with echocardiographic parameters. Methods 15 PH patients scheduled for risk stratification were subjected to RHC and echocardiography. The contractile velocity element (VCE) was calculated as VCE = 1 / (28.8 x P) x dP/dt, with P representing RV pressure in mm Hg and dP/dt its first derivative in mmHg/s. The P vs. VCE plot displays a peak VCE value, leading into a linear slope (red line, figure 1A) with Vmax as the zero-pressure intercept. Vmax was compared with 6 different echocardiographic parameters of RV function. Results They were six females and 9 males aging 61±6 y. Mean PH was 37,6±10,1 mm Hg and Vmax averaged 2,1±0,9 length/s (range from 0,8 to 4,4 length/s). Figure 1B illustrates 3 patients with deteriorated, mildly reduced and normal VCE. When compared to Vmax, tricuspid peak systolic tissue Doppler velocity and TAPSE shown the best correlation while RV fractional area change demonstrated the worse correlation (figure 2). Conclusion Vmax, an indicator of right ventricular systolic function that does not depend on load, can be obtained through right heart catheterization. Both tissue Doppler peak systolic velocity and tricuspid annular plane systolic excursion (TAPSE) have demonstrated a strong correlation with Vmax.Invasive pressureECHO parameters

Prognostic impact of cardiac events in asymptomatic mitral regurgitation

Abstract Background Mitral regurgitation (MR) is the most common valvular heart disease in adults and is associated with increased morbidity and mortality. Treatment recommendations of degenerative MR have been liberalized, however, the role of asymptomatic patients is still insufficiently defined. Purpose The purpose of this study were to evaluate the prevalence of cardiac events in a large asymptomatic MR cohort, based on health insurance data analysis, in comparison with healthy propensity score-matched general population and to define the prognostic impact of such cardiac events on ten-year survival. Methods We retrospectively analyzed health insurance claims data from Germany’s second largest health insurance fund, which maintains longitudinal data on outpatient and inpatient medical services for 8.7 million German residents. We included all patients with an outpatient diagnosis of MR (I34.0) in a minimum of two quarters during a calendar year and first recorded diagnosis between 2008 and 2011. To identify an asymptomatic MR cohort (study group), all patients with at least one complication attributable to MR / mitral valve intervention during the incidence quarter of MR were excluded. Ten-year outcomes were compared between study group vs. age- and sex-matched healthy control group. Cardiac events of interest were new congestive heart failure, new-onset atrial fibrillation, pulmonary hypertension, or cardiac decompensation. Results A total of 56.577 (62.7%) asymptomatic MR patients were identified from the whole cohort of 90.245 individuals with a newly diagnosed MR in the BARMER database. During a ten-year follow-up, 26.282 (46.5%) patients in the study group experienced at least one cardiac event vs. 11.763 (20.8%) individuals in the control group (OR: 3.31, 95%CI: 0.251-0.262, P&amp;lt;0.0001). The occurrence of at least one cardiac event (i.e., congestive heart failure, new-onset atrial fibrillation, pulmonary hypertension or cardiac decompensation) in the study group was associated with a significantly worse ten-year survival as compared to the control group. The risk of cardiac events was age- and sex-dependent, while female patients with an asymptomatic MR had a lower risk as compared to males in all age groups (OR: 0.38, 95%CI: -1.193- -0.754, P&amp;lt;0.0001). Only 1.530 (2.7%) patients underwent mitral valve (MV) intervention in the study group during ten-year follow-up. Conclusions Our study reveals high incidence of asymptomatic MR in a representative cohort of health insurance claims data in Germany. Every second patient with an asymptomatic MR experiences at least one cardiac event during a ten-year follow-up period that is associated with a significantly worse survival. The definition of asymptomatic MR cohort at risk of developing cardiac events may potentially improve early treatment strategies and lead to better outcome in the future.Abstract picture

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&amp;lt;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&amp;lt;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.