Pulmonary Hypertension Research Articles

Smartphone Apps for Pulmonary Hypertension: Systematic Search and Content Evaluation.

Pulmonary hypertension (PH) is a chronic and complex condition, requiring consistent management and education. The widespread use of smartphones has opened possibilities for mobile health apps to support both patients and health care professionals in monitoring and managing PH more effectively. This study aimed to identify and assess the quality of free smartphone apps for PH targeted at either patients or health care professionals. A systematic search was conducted on freely available apps for patients with PH and health care professionals, accessed from a Spanish IP address, on Android (Google Play) and iOS (App Store) platforms. Searches were performed in October 2022 and 2023. Apps were independently analyzed by two reviewers, focusing on general characteristics. Quality assessment was based on the Mobile Application Rating Scale (MARS) framework, and Mann-Whitney U tests compared mean MARS scores against specific variables. In the overall study, 21 apps were identified. In the 2022 search, 19 apps were listed (9 iOS, 7 Android, 3 available on both platforms). In the subsequent 2023 search, 16 apps were identified (6 Android, 7 iOS, 3 available on both platforms). Of those identified in 2022, 14 remained available in 2023, with only 7 updated since 2022. In addition, 12 apps targeted patients or the general population, while 9 targeted health care professionals; none involved patients in the development or design. Conversely, 13 apps involving health care professionals were identified. There were 10 apps that received pharmaceutical industry funding. The primary goal for 81% (17/21) of the apps was to disseminate general information about PH. The overall mean MARS quality was acceptable in 2022 and 2023, with mean ratings of 3.1 (SD 0.6) and 3.3 (SD 0.5), respectively. The functionality category achieved the highest scores in both years, indicating ease of use and intuitive navigation. In contrast, the subjective quality domain consistently received the lowest ratings in the MARS assessment across both years. None of the apps underwent clinical testing themselves; however, 2 incorporated tools or algorithms derived from trials. The overall quality of iOS apps statistically outperformed that of Android apps in both years (P<.05). Furthermore, the involvement of health care professionals in app development was associated with enhanced quality, a trend observed in both years (P=.003 for both years). This review of mobile health apps for PH reveals their emergent development stage, with generally acceptable quality but lacking refinement. It highlights the critical role of health care professionals in app development, as they contribute significantly to quality and reliability. Despite this, a notable stagnation in app quality and functionality improvement over 2 years points to a need for continuous innovation and clinical validation for effective clinical integration. This research advocates for future app developers to actively engage with health care professionals, integrate patient insights, and mandate rigorous clinical validation for PH management.

Sequelae of Acute Pulmonary Embolism: From Post-Pulmonary Embolism Functional Impairment to Chronic Thromboembolic Disease.

Among survivors of acute pulmonary embolism (PE), roughly half report persistent dyspnea, impaired functional status, and decreased quality of life. Post-pulmonary embolism syndrome (PPES) is a broad condition which has been increasingly recognized in recent years and may be due to post-pulmonary embolism functional impairment, chronic thromboembolic disease, or the most severe long-term complication of PE, chronic thromboembolic pulmonary hypertension. Despite guideline recommendations for appropriate follow-up for post-pulmonary embolism patients, PPES remains underrecognized and diagnostic testing underutilized. Patients with symptoms suggestive of PPES at follow-up should undergo a transthoracic echocardiogram to screen for the presence of pulmonary hypertension; additional testing, such as a ventilation/perfusion scan, right heart catheterization, and cardiopulmonary exercise testing may be indicated. The pathophysiology of post-pulmonary embolism syndrome is complex and heterogeneous. In chronic thromboembolic pulmonary hypertension, the pathophysiology reflects persistent pulmonary arterial thrombi and a progressive small vessel vasculopathy. In patients with chronic thromboembolic disease or chronic thromboembolic pulmonary hypertension, medical therapy, balloon pulmonary angioplasty, or pulmonary thromboendarterectomy should be considered, and in cases of chronic thromboembolic pulmonary hypertension, pulmonary thromboendarterectomy significantly improves mortality. In all causes of post-pulmonary embolism syndrome, rehabilitation is a safe treatment option that may improve quality of life.

Use of Lower-Leg Bathing to Facilitate Exercise Therapy in a Patient With Severe Pulmonary Arterial Hypertension: A Case Report

Use of Lower-Leg Bathing to Facilitate Exercise Therapy in a Patient With Severe Pulmonary Arterial Hypertension: A Case Report

Idiopathic pulmonary hypertension in an adult with patent foramen ovale

The article is devoted to the clinical case of combined idiopathic pulmonary hypertension with an open foramen ovale of the atrial septum in a young man of 21 years old with progressive decrease in lung ventilation function. The relationship of pulmonary arterial hypertension with an open foramen ovale of the atrial septum is nearly not described in the literature, as it is rarely found in clinical practice. According to the classification, pulmonary hypertension is divided into idiopathic (primary), secondary and pulmonary hypertension caused by other causes. In the pathogenesis of any PAH, an important role belongs to a complex of vascular changes. Verification of vascular changes is carried out histologically. Variants of idiopathic pulmonary hypertension are plexiform and thrombotic arteriopathy, veno-occlusive disease, capillary hemangiomatosis. An open foramen ovale as a structural anomaly of the adult heart (a vestige of embryonic blood circulation) causes a variety of hemodynamic disorders that can affect the pathogenesis of pulmonary hypertension. Because of this, preclinical observation of a combination of plexiform and thrombotic arteriopathy with a patent foramen ovale of the interatrial septum in a young man of 21 years old and an attempt to determine the role of an open oval window in the progression of pulmonary hypertension and its effect on treatment is of interest. The diagnosis of idiopathic pulmonary hypertension was made based on the clinical picture, laboratory parameters, echocardiography and histological examination of pulmonary vessels. The article discusses the importance of a patent foramen ovale in the pathogenesis of idiopathic pulmonary hypertension.

Nr1d1 inhibition mitigates intermittent hypoxia-induced pulmonary hypertension via Dusp1-mediated Erk1/2 deactivation and mitochondrial fission attenuation

Intermittent hypoxia (IH) precipitates pulmonary vasoconstriction, culminating in the onset of pulmonary hypertension (PH) among individuals afflicted with sleep apnea. While Nuclear receptor subfamily 1 group D member 1 (Nr1d1) is progressively recognized as pivotal regulator of cellular physiology, the role in the pathogenesis of IH-induced PH remains largely uncharted. The expression of Nr1d1 was examined in IH-induced rodent PH and in IH-treated PASMCs. To elucidate the contribution of Nr1d1 to the development of IH-induced PH, we employed siRNA to modulate Nr1d1 expression in vitro and employed serotype 1 adeno-associated virus (AAV1) in vivo. Nr1d1 levels were elevated in IH-induced rodents PH lung tissues and IH-treated PASMCs. Knocking down Nr1d1 by AAV1 effectively inhibited PH progression in chronic IH-induced PH models. Mechanistic investigations identified dual specificity phosphatase 1 (Dusp1), as a direct target that Nr1d1 trans-repressed, mediating Nr1d1’s regulatory influence on Erk1/2/Drp1 signaling. Nr1d1 deficiency ameliorates mitochondrial dysfunction and fission by restoring Dusp1 dysregulation and Drp1 phosphorylation. Activation of Erk1/2 with PMA reversed the Dusp1-mediated regulation of Drp1 phosphorylation, indicating the involvement of the Erk1/2 pathway in Drp1 phosphorylation controlled by Dusp1. Meanwhile, intermittent hypoxia induced more severe PH in Dusp1 knockout mice compared with wild-type mice. Our data unveil a novel role for Nr1d1 in IH-induced PH pathogenesis and an undisclosed Nr1d1-Dusp1 axis in PASMCs mitochondrial fission regulation.

Integrated multi-omics analysis of the microbial profile characteristics associated with pulmonary arterial hypertension in congenital heart disease.

Dysregulation of immune and inflammatory cells around blood vessels and metabolic dysfunction are key mechanisms in the development of pulmonary arterial hypertension (PAH). The homeostasis of the human microbiome plays a crucial role in regulating immune responses and the progression of diseases. For pulmonary arterial hypertension associated with congenital heart disease involving body-lung shunt (PAH-CHD), the potential impact of the microbiome on the "gut-lung axis" remains underexplored. This study recruited 15 healthy individuals and 15 patients with pulmonary arterial hypertension due to congenital heart disease from Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences, and Kunming Children's Hospital. We performed differential analyses of metabolites and microbiota from both the gut and lower respiratory tract for these two groups. The goal was to investigate the "gut-lung axis" microbiome and metabolome profiles in children with PAH-CHD and to analyze the interrelationships between these profiles. Ultimately, we aim to propose the potential value of these profiles in aiding diagnosis. The results indicated that the gut and pulmonary microbiota of children with PAH-CHD are characterized by an increased abundance of beneficial symbionts, which are closely linked to changes in the metabolome. Metabolite functional enrichment analysis revealed energy metabolism reprogramming in the PAH-CHD group, with active metabolic pathways associated with bile acid secretion and carnitine homeostasis. Moreover, the differential expression of metabolites was correlated with right heart function and growth development.IMPORTANCEPrevious studies have primarily focused on the relationship between the gut microbiome and PAH. However, the impact of microbial homeostasis on the progression of PAH-CHD from the perspective of the gut-lung axis has not been adequately elucidated. Our study utilizes an integrated multi-omics approach to report on the differential characteristics of gut and lung microbiota between children with PAH-CHD and reference subjects. We found that microbiota influence the pathological changes and disease manifestations of PAH-CHD through their metabolic activity. Additionally, alterations in metabolites impact the microbial ecological structure. Our findings suggest that modulating the microbiome composition may have positive implications for maintaining and regulating the immune environment and pathological progression of PAH-CHD.

The Role of Early Child Nutrition in Pulmonary Hypertension—A Narrative Review

Pulmonary hypertension is a complex condition that has distinct characteristics in pediatric populations. This review explores the important role of early childhood nutrition in the growth, progression, and management of pediatric pulmonary hypertension. Nutritional deficiencies, including those of vitamins C, D, and iron, are closely linked to worse outcomes in children with this disease, emphasizing the importance of early intervention to prevent malnutrition and promote growth. Emerging research revealed that promising nutrients like resveratrol, along with modulation of the gut and respiratory microbiomes, may offer therapeutic advances for managing pulmonary hypertension. However, the current literature is limited by a lack of pediatric-specific studies, with much of the data extrapolated from adult populations and animal models, especially rats. This review highlights the need for targeted research to develop effective nutritional interventions aimed at improving outcomes for pediatric patients.

Honokiol and Nicotinamide Adenine Dinucleotide Improve Exercise Endurance in Pulmonary Hypertensive Rats Through Increasing SIRT3 Function in Skeletal Muscle.

Pulmonary hypertension (PH) significantly impairs exercise capacity and the quality of life in patients, which is influenced by dysfunctions in multiple organ systems, including the right ventricle, lungs, and skeletal muscles. Recent research has identified metabolic reprogramming and mitochondrial dysfunction as contributing factors to reduced exercise tolerance in PH patients. In this study, we investigated the therapeutic potential of enhancing mitochondrial function through the activation of the mitochondrial deacetylase SIRT3, using SIRT3 activator Honokiol combined with the SIRT3 co-factor nicotinamide adenine dinucleotide (NAD), in a Sugen/Hypoxia-induced PH rat model. Our results show that Sugen/Hypoxia-induced PH significantly impairs RV, lung, and skeletal muscle function, leading to reduced exercise capacity. Treatment with Honokiol and NAD notably improved exercise endurance, primarily by restoring SIRT3 levels in skeletal muscles, reducing proteolysis and atrophy in the gastrocnemius, and enhancing mitochondrial complex I levels in the soleus. These effects were independent of changes in cardiopulmonary hemodynamics. We concluded that targeting skeletal muscle dysfunction may be a promising approach to improving exercise capacity and overall quality of life in PH patients.

Editorial for “3D Vortex‐Energetics in the Left Pulmonary Artery for Differentiating Pulmonary Arterial Hypertension and Pulmonary Venous Hypertension Groups Using 4D Flow MRI”

Editorial for “<scp>3D</scp> Vortex‐Energetics in the Left Pulmonary Artery for Differentiating Pulmonary Arterial Hypertension and Pulmonary Venous Hypertension Groups Using <scp>4D</scp> Flow <scp>MRI</scp>”

Guarding the Endothelium: SOX17's Crucial Role in Pulmonary Hypertension.

Guarding the Endothelium: SOX17's Crucial Role in Pulmonary Hypertension.

Branched-chain α-ketoacids aerobically activate HIF1α signalling in vascular cells.

Hypoxia-inducible factor 1α (HIF1α) is a master regulator of biological processes in hypoxia. Yet, the mechanisms and biological consequences of aerobic HIF1α activation by intrinsic factors, particularly in normal (primary) cells, remain elusive. Here we show that HIF1α signalling is activated in several human primary vascular cells in normoxia and in vascular smooth muscle cells of normal human lungs. Mechanistically, aerobic HIF1α activation is mediated by paracrine secretion of three branched-chain α-ketoacids (BCKAs), which suppress PHD2 activity via direct inhibition and via LDHA-mediated generation of L-2-hydroxyglutarate. BCKA-mediated HIF1α signalling activation stimulated glycolytic activity and governed a phenotypic switch of pulmonary artery smooth muscle cells, which correlated with BCKA metabolic dysregulation and pathophenotypic changes in pulmonary arterial hypertension patients and male rat models. We thus identify BCKAs as previously unrecognized signalling metabolites that aerobically activate HIF1α and that the BCKA-HIF1α pathway modulates vascular smooth muscle cell function, an effect that may be relevant to pulmonary vascular pathobiology.

Changing patterns in clinical, echocardiographic and haemodynamic characteristics, and management strategies that may be translated to improved survival in pulmonary hypertension

Abstract Background and aims In this retrospective analysis of a single-center series on pulmonary hypertension (PH), we aimed to evaluate clinical, echocardiographic, and hemodynamic characteristics, management strategies, morbidity, and mortality in PH subgroups across three consecutive periods. Methods The study included 1071 patients enrolled in the Evaluation of Pulmonary Hypertension Risk factors Associated with Survival study (EUPHRATES). In reference to enrollment time, patients were assessed in three periods ; before 2016, the era of primarily monotherapy or sequential combinations; between 2016 and 2019, post-approval and reimbursement of macitentan in our country, marking a shift towards more proactive sequential combinations; and after 2019, signifying the initiation of earlier sequential combinations with selexipag in pulmonary arterial hypertension (PAH). The ESC/ERS 2022 risk scoring, COMPERA 2.0 and REVEAL lite 2 models were used for risk predictions. Composite endpoint (CEP) definitions were adopted from the SERAPHIN and GRIPHON trials. Annual incidence curves for mortality and CEP were evaluated, but 2020 analysis was adjusted to account for the possible adverse effects of the COVID-19. Results During the 1st, 2nd and 3rd periods, 481, 352, and 238 patients with PH were diagnosed, respectively. Incident cases comprised 91% of them. Idiopathic PAH (IPAH), PAH-associated with congenital heart diseases (CHD-PAH), PAH-associated with connective tissue diseases (CTD-PAH), group II, III, IV and V PH were documented in 24 %, 28 %, 4.6 %, 4.3 %, 11%, 27 % and 0.7 % of patients, respectively. Age and female dominance remained unchanged. Incidences of Group 1 PH and CHD-PAH decreased while IPAH, drug-associated PAH, and Group II and IV PH increased across three periods (p-values varying from &amp;lt;0.001 to 0.03). Although baseline functional class became worse (p=0.013), six-minute walk distance, N-terminal pro brain natriuretic peptide and risk scores showed no change (p=NS). Baseline echo and hemodynamic measures became better, and triple combinations increased after 2019 (p&amp;lt;0.001 for all). For overall PH, rates of all-cause mortality and CEPs at 1st, 2nd and 3rd periods were 52 % and 59 %, 30 % and 35 %, and 11 % and 13 %, respectively (p&amp;lt; 0.001, for all). Mortality rates for 1st, 2nd and 3rd periods were 36 %, 38 % and 26 % in IPAH, 60 %, 28 % and 13 % in CHD-PAH, 55 %, 22% and 22% in CTD-PAH, 38 %, 38% and 24 % in group IV PH, respectively (p&amp;lt; 0.001, for all). Mortality curves showed sudden increases in 2020, but excluding 2020, a steady improvement in the annual mortality was evident. Conclusions Our findings suggest a trend towards better clinical, echocardiographic, and hemodynamic presentations and improved survival in the PAH subgroups, and Group IV PH across the three periods that might be attributed to more proactive management strategies favouring earlier initiation of combinations.

Periprocedural changes in systolic pulmonary artery pressure in transcatheter aortic valve implantation

Abstract Background Pulmonary hypertension (PH) is common in patients with aortic stenosis and associated with increased mortality following transcatheter aortic valve replacement (TAVR). PH often improves after TAVR and systolic pulmonary artery pressure (sPAP) can change, but to what extent these changes in sPAP following TAVR affect long-term prognosis is unclear. Purpose To investigate the association between periprocedural changes in sPAP and long-term prognosis after TAVR. Methods Patients undergoing TAVR between 2012-2021 from the Swedish Transcatheter Cardiac Intervention Registry (SWENTRY) were included. sPAP was estimated from echocardiography before and after TAVR and categorized as: (1) No PH before and unchanged (≤5 mmHg change) after, (2) No PH before and worsened (&amp;gt;5 mmHg increase) after, (3) PH before and improved (&amp;gt;5 mmHg decrease) after, (4) PH before and unchanged after and (5) PH before and worsened after. An sPAP cutoff at &amp;gt;50 mmHg was applied for PH. Patients were followed for a median of 3.1 years for the primary endpoint heart failure hospitalizations (HFH) and the secondary endpoint all-cause mortality. Cox regression analyses were performed and adjusted for age, sex, body mass index, atrial fibrillation, eGFR class, diabetes, frailty, left ventricular ejection fraction and chronic obstructive pulmonary disease. Results In total, 4926 patients were included (mean age 82 years, 50% female) among whom 2596 (53%) patients had no PH and unchanged, 864 (18%) had no PH and worsened after, 912 (19%) had PH and improved after, 401 (8%) had PH and unchanged after and 153 (3%) had PH and worsened after. The mean sPAP levels preoperatively in each group were 36, 31, 60, 58, 57 mmHg respectively. Mean change in patients with no PH and worsened was +16 mmHg, in patients with PH and improved -20 mmHg and in patients with PH and worsened +14 mmHg. Cumulative incidence rates of HFH at 5 years among the five groups were 18%, 25%, 32%, 41%, and 52%, respectively (p&amp;lt;0.001). In adjusted analyses, there was a stepwise increase in the risk of HFH (Figure 1A) and all-cause mortality (Figure 1B) for no PH and worsened, PH and improved, PH and unchanged and PH and worsened as compared with no PH and unchanged. Conclusion Increase of periprocedural sPAP in patients with and without known PH before TAVR was associated with worse prognosis whereas reduction of sPAP was associated with improved outcomes.

3D Vortex-Energetics in the Left Pulmonary Artery for Differentiating Pulmonary Arterial Hypertension and Pulmonary Venous Hypertension Groups Using 4D Flow MRI.

Pulmonary hypertension (PH) is a life-threatening. Differentiation pulmonary arterial hypertension (PAH) from pulmonary venous hypertension (PVH) is important due to distinct treatment protocols. Invasive right heart catheterization (RHC) remains the reference standard but noninvasive alternatives are needed. To evaluate 4D Flow MRI-derived 3D vortex energetics in the left pulmonary artery (LPA) for distinguishing PAH from PVH. Prospective case-control. Fourteen PAH patients (11 female) and 18 PVH patients (9 female) diagnosed from RHC, 23 healthy controls (9 female). 1.5 T; gradient recalled echo 4D flow and balanced steady-state free precession (bSSFP) cardiac cine sequences. LPA 3D vortex cores were identified using the lambda2 method. Peak vortex-contained kinetic energy (vortex-KE) and viscous energy loss (vortex-EL) were computed from 4D flow MRI. Left and right ventricular (LV, RV) stroke volume (LVSV, RVSV) and ejection fraction (LVEF, RVEF) were computed from bSSFP. In PH patients, mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure (PCWR) and pulmonary vascular resistance (PVR) were determined from RHC. Mann-Whitney U test for group comparisons, Spearman's rho for correlations, logistic regression for identifying predictors of PAH vs. PVH and develop models, area under the receiver operating characteristic curve (AUC) for model performance. Significance was set at P < 0.05. PAH patients showed significantly lower vortex-KE (37.14 [14.68-78.52] vs. 76.48 [51.07-120.51]) and vortex-EL (9.93 [5.69-25.70] vs. 24.22 [12.20-32.01]) than PVH patients. The combined vortex-KE and LVEF model achieved an AUC of 0.89 for differentiating PAH from PVH. Vortex-EL showed significant negative correlations with mPAP (rho = -0.43), PCWP (rho = 0.37), PVR (rho = -0.64). In the PAH group, PVR was significantly negatively correlated with LPA vortex-KE (rho = -0.73) and vortex-EL (rho = -0.71), and vortex-KE significantly correlated with RVEF (rho = 0.69), RVSV, (rho = 0.70). In the PVH group, vortex-KE (rho = 0.52), vortex-EL significantly correlated with RVSV (rho = 0.58). These preliminary findings suggest that 4D flow MRI-derived LPA vortex energetics have potential to noninvasively differentiate PAH from PVH and correlate with invasive hemodynamic parameters. 1 TECHNICAL EFFICACY: Stage 3.

A systematic review and meta-analysis of health-related quality of life (HRQoL) outcomes in randomised controlled trials for pulmonary arterial hypertension (PAH)

Abstract Introduction ESC guidelines recognise the under use of disease-specific health-related quality of life (HRQoL) instruments. These include CAMPHOR, PAH-SYMPACT, Emphasis-10 and Living with Pulmonary Hypertension (LPH). Patients highly value HRQoL as a treatment outcome in PAH. This is the first meta-analysis to evaluate HRQoL instruments and outcomes in RCTs in pulmonary arterial hypertension (PAH). Purpose To evaluate which PAH-RCT interventions improve HRQoL outcomes and compare the suitability of HRQoL instruments used. Method We searched MEDLINE (Jan 1970 to Dec 2023) and Cochrane Library from Jan 1990 to Dec 2023 (EMBASE, CT.gov, ICTRP, CINAHL) for RCTs in PAH. Abstracts and unpublished studies were excluded and PRISMA reporting structure followed. Trials meeting final selection criteria included HRQoL instruments sufficiently powered to detect a minimal clinically important difference (MCID). Effective sample sizes were calculated in GPower3.1 from a two independent means model for 80% power, 5% significance, one-tailed test. Meta-analysis was performed in SPSSv28.1. Full search criteria are registered on PROSPERO (ID: CRD42024484021). Results After removal of duplicates, 896 records were screened, 43 studies included a HRQoL endpoint. 8 studies were included in the meta-analysis after exclusion for insufficient data (n=10) or power (n=25). 3 of these did not meet the MCID (&amp;gt;33m) for six-minute walk distance (6MWD) and evaluated separately to discriminate accuracy of HRQoL instrument. Instruments available for comparison were Short Form-36(SF-36), EuroQol (EQ-5D-5L) and Living with Pulmonary Hypertension (LPH). Studies not reaching MCID for 6MWD also showed no change in HRQoL (figure 1). Ambrisentan and exercise training demonstrate a significant improvement (p&amp;lt;0.05) in SF-36 physical(P) component (figure 2). This component was anchored to determine 6MWD MCID; other HRQoL values responded variably. Utility weighting to account for geographical variation was not reported with EQ-5D-5L and SF-36 in multicentre studies however AIR 2002 (Iloprost) was significant for both EQ-5D-5L instruments. The total component score of the disease-specific LPH was more sensitive to functional improvements and overall change in HRQoL compared to EQ-5D-5L (p&amp;lt;0.05). Conclusion Fewer than 10% of all RCTs in PAH have adequately considered a HRQoL outcome measure. 8 RCTs were powered to assess HRQoL. Iloprost, ambrisentan, riociguat and exercise training interventions demonstrate significant improvement in HRQoL. LPH was the only PAH-instrument powered to detect change. LPH was more sensitive to HRQoL than generic instruments and is multidimensional. Geographical indexing should be considered for generic instruments such as EQ-5D-5L and SF-36 in multicentre trials. As a highly valued outcome for patients, future studies should prioritise HRQoL as an endpoint.Figure 1Figure 2

Assessment of sub clinical right ventricular ischemia using oxygen sensitive cardiac magnetic resonance imaging in patients with systemic sclerosis: mechanistic insights from advanced cardiac imaging

Abstract Background Cardiac involvement in Systemic Sclerosis (SSc) is common, with manifestations ranging from subclinical to life-threatening 1. Cardiopulmonary complications, including, right ventricular (RV) dysfunction is the leading cause of SSc-related mortality2. Pulmonary arterial hypertension (PAH) occurs in 8-12% of SSc patients and remains a leading cause of death, with a 3-year survival rate around 50%2. The progressive decline in RV function in PAH is often attributed to RV ischemia3. Oxygen Sensitive Cardiac Magnetic Resonance imaging (OS-CMR) has been previously used by our group to assess RV myocardial oxygenation in patients with PAH3, including SSc-associated PAH 3. The objective of this study was to use OS-CMR to assess RV myocardial oxygenation in SSc patients prior to the onset of PAH. Methodology In this prospective, multicentre study, three study groups were established. Group 1 comprised SSc patients without PAH or known cardiac disease. Group 2 included stable PAH patients confirmed by right heart catheterization, matched for age and sex, but without SSc. Group 3 comprised healthy normal volunteers (NV), matched for age and sex. All patients underwent a 3T CMR which included: cine images, rest cine OS-CMR, stress cine OS-CMR, native T1 mapping, stress perfusion, and late gadolinium enhancement (LGE). The primary outcome was change in inferior RV myocardial signal intensity (SI) in diastole, measured by the change in OS-CMR between rest and stress within each group. Two experienced independent reviewers performed the CMR analysis with an inter-assessor correlation coefficient of 0.8, 95% Cl [0.3, 0.9]. Results A total of 44 patients were enrolled. Of these, n=26 group 1 (SSc), n=8 group 2 (PAH), n=10 group 3 (NV). Study results are listed in Table 1. Mean age within the SSc, PAH, and NV groups were 59±10, 67±12 and 57 ±7 years respectively (p=0.482). The RV OS-CMR SI was significantly lower in the SSc group when compared to the NV group (p=0.017). In contrast, there was no significant difference between the PAH and SSc groups (p=0.426), indicating a similar degree of RV ischemia in the established PAH patients and the SSc patients. All SSc patients exhibited inferior and anterior RV insertion fibrosis, with no perfusion defects noted. Five (19%) of SSc patients presented with LGE hyperenhancement in the LV. Eighteen (69%) of SSc patients obtained at least 1 abnormal T1 mapping segment in the LV. Conclusion SSc patients without overt PAH had a similar degree of RV ischemia when compared to patients with overt PAH from other causes. Our findings imply that in SSc, RV adverse effects occur prior to the onset of PAH, and that this effect is mediated by RV ischemia secondary to changes in the microvasculature. Our findings may have screening and/or therapeutic implications.

Association of Vascular endothelial factor D with pulmonary hypertension in heart failure: the PREHOSP-CHF Study

Abstract Background Pulmonary hypertension (PH) complicated with heart failure (HF) is associated with increased morbidity and mortality. Vascular endothelial growth factor D (VEGF-D), one of key regulators of lymphangiogenesis, was reported to be higher in HF patients with pulmonary congestion on chest X-ray. Furthermore, we previously reported that HF patients with high VEGF-D had higher incidence of major adverse cardiovascular events (MACE), defined as cardiovascular death or heart failure hospitalization. Purpose To investigate the association of VEGF-D with pulmonary hypertension in patients with HF. Methods The PREHOSP-CHF study is a multicenter prospective cohort study to determine the predictive value of angiogenesis-related biomarkers in HF. A total of 1,024 patients (mean age 75.5±12.6 years; 58.7% male) admitted to acute decompensated HF were included in the analyses. Serum levels of VEGF-D, as well as N-terminal pro B-type natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin-I (hs-cTnI), high sensitivity C reactive protein (hs-CRP), were measured at the time of discharge. PH was assessed by tricuspid regurgitation velocity (TRV) in echocardiography. Patients were followed-up over two years. Results Data on PH was obtained in 932 patients. Of these, 44 (4.7%) and 223 (23.9%) patients showed PH (TRV&amp;gt;3.4 m/s) and borderline PH (TRV&amp;gt;2.8 m/s), respectively. Patients with PH/borderline PH were significantly older and had lower body mass index. Prevalence of prior HF hospitalization, HF with preserved ejection fraction, atrial fibrillation, anemia, and chronic kidney disease were higher in patients with PH/borderline PH. Levels of NT-proBNP and VEGF-D, but not hs-cTnI or hs-CRP, were higher in patients with PH/borderline PH (Figure). Levels of NT-proBNP and VEGF-D had weak but significant correlation with TRV (NT-proBNP, R2=0.04, P&amp;lt;0.001; VEGF-D, R2=0.05, P&amp;lt;0.001). After adjustment for these factors, VEGF-D levels were significantly correlated with TRV (β, 3.29; SEM, 0.85, P&amp;lt;0.001). During the follow-up, 12 in PH, 34 in borderline PH, and 53 in no PH patients developed MACE. Unadjusted Hazard ratios [95% confidence intervals] for MACE compared to no PH were 2.44 [1.58-3.60] in PH, and 1.62 [1.26-2.05] in borderline PH. When we divided each PH group into two groups based on the median of VEGF-D levels of each group (no PH, 387 pg/ml; borderline PH, 479 pg/ml; PH, 549 pg/ml), patients with high VEGF-D showed significantly higher incidence of MACE in no PH (unadjusted hazard ratio, 1,70; 95% confidence intervals, 1.29-2.26), and tended to show high incidence of MACE in borderline PH group (unadjusted hazard ratio, 1,39; 95% confidence intervals, 0.93-2.09) and PH group (unadjusted hazard ratio, 1,83; 95% confidence intervals, 0.84-4.18). Conclusions VEGF-D levels were independently associated with PH in patients with HF, and might serve as a predictive biomarker for PH, as well as prognostic biomarker for MACE among patients with HF.

Severity of pulmonary hypertension and pregnancy outcomes: newer insights from the M-PAC registry

Abstract Background Pregnancy outcomes in women with pulmonary hypertension remain suboptimal. Pregnant women with pulmonary hypertension (PH) are placed in the modified WHO category IV, regardless of the severity or etiology of PH. Earlier studies have indicated that pregnancy outcomes may differ based on the etiology, with more favourable outcomes observed with PH related to left to right shunts. However, it is possible that the pregnancy outcomes may vary based on the severity of PH also. Purpose To analyse pregnancy outcomes in women with PH and investigate differences based on disease severity. Methods M-PAC Registry, is a single center prospective study of pregnancies in women with heart diseases, conducted between July 2016 and December 2019 in a low-and middle-income country from South Asia, whose methodology and outcomes have been published(1). The current study analysed pregnancies with PH enrolled in the M-PAC registry. The tricuspid regurgitation velocity obtained during transthoracic echocardiography, was used to estimate right ventricular systolic pressure (RVSP). Based on the estimated RVSP, PH was classified into three groups; mild (36-45 mm of Hg), moderate (46-64 mm of Hg) and severe (≥ 65 mm of Hg). The differences in the maternal and foetal outcomes among the groups were analysed. Results Of the 1029 pregnancies complicated by heart disease enrolled in the M-PAC registry, 352(34.2%)had PH. Among these 352 pregnancies, 186(52.8%) had mild, 73 (20.7%) had moderate and 93 (26.5%) had severe PH. Adverse maternal cardiac events occurred in 77 pregnancies (21.8%), with heart failure in 53(15.1%) and mortality in 10(2.8%). The composite adverse foetal event rate was 38.6%, foetal loss at 9.7%, low birth weight at 28.9%, and preterm labour at 7.1%. The mean (±standard deviation) RVSP was higher in pregnancies with adverse maternal outcome (58.81±16.9 vs 51.16±15.9; P &amp;lt; 0.001) or adverse foetal outcome (58.10±17.3 vs 49.52±14.9; P &amp;lt; 0.001)compared to those without. When comparing the three groups, pregnancies with mild PH exhibited significantly lower rates of adverse maternal and fetal events compared to those with severe and moderate PH (Fig-1 and Table-1). Mild PH was associated with outcomes similar to those without PH in the M-PAC registry. Conclusion The severity of PH significantly correlated with the adverse pregnancy outcomes. Women with mild PH tend to experience pregnancy outcomes comparable to those without PH, suggesting that pregnancy should not be deemed contraindicated in this subgroup. Therefore, re-evaluation of the placement of PH within the modified World Health Organization (mWHO) classification is warranted, considering the severity of PH.Figure 1:Pregnancy Outcomes &amp; PH SeverityTable-1 PH Severity &amp; Pregnacny Outcomes

The impact of the 2022 definition of pulmonary hypertension on long-term clinical outcomes in patients with heart failure with preserved ejection fraction

Abstract @ Backgrounds: In recent years, the definitions of pulmonary hypertension (PH) have been revised for early diagnosis and risk stratification of patients with PH. Using the 2015 definitions, the development of a precapillary component of PH in addition to a postcapillary PH was associated with right heart dysfunction and poor prognosis in patients with heart failure (HF) with preserved ejection fraction (HFpEF). However, the prognostic impact of revised definitions of PH in patients with HFpEF has not been fully evaluated. Purpose We investigated the impact of the 2018 and 2022 ESC/ERS definitions of PH on long-term clinical outcomes using data from a prospective, multicenter, observational study of patients with HFpEF (PURSUIT-HFpEF). Methods A total of 250 patients hospitalised with acute HF who underwent right heart catheterisation after initial HF treatment were divided into PH categories according to the 2018 and 2022 definitions: isolated postcapillary PH (Ipc-PH), precapillary PH, combined postcapillary and precapillary PH (Cpc-PH), and unclassified PH. The incidence of the composite endpoint of all-cause death and HF rehospitalisation after discharge was compared across the PH categories. Results The overall prevalence of PH defined as a mPAP &amp;gt; 20 mmHg was 54%. Applying the 2022 definition, 42 patients (17%) were reclassified as either precapillary PH or Cpc-PH, resulting in a significant increase in the propotion of patients classified as having PH with a precapillary component (precapillary PH and Cpc-PH) compared with the 2018 definition (26% vs. 11%, p&amp;lt;0.0001). At a median follow-up of 822 days after discharge, PH with a precapillary component was associated with poor clinical outcomes according to the 2018 definition (Figure 1A), but according to the 2022 definition, clinical outcomes did not differ across the PH categories (Figure 1B). PVR ≥3 Wood units (WU) was a significant prognostic indicator, but there was no significant difference between the PVR 2-3 WU and PVR ≤2 WU categories (Figure 2). Conclusions The 2022 definition showed no association between PH classification and clinical outcomes. In patients with HFpEF, PVR ≥3 WU was identified as the key factor increasing the risk of all-cause death and HF hospitalisation.Figure 1Figure 2

Improving morbidity and mortality in patients with pulmonary hypertension: insights from a nation-wide registry

Abstract Background and aims In this retrospective analysis of a nation-wide registry on pulmonary arterial hypertension (PAH), group IV and V, we evaluated management strategies, morbidity and mortality across three consecutive time periods. Methods This study included 903 patients enrolled from 24 cardiology centers participating in the RegiStry on clInical outcoMe and sUrvival in pulmonaRy hypertension Groups (SIMURG II). Patients were divided into three enrollment periods: before 2016, the era of monotherapy or sequential combination therapies; between 2016 and 2019, post-approval and re-imbursement of macitentan in our country, marking a shift towards more proactive sequential combinations; and after 2019, signifying the initiation of earlier sequential combinations with selexipag in PAH. ESC/ERS 2022, COMPERA 2.0 and REVEAL lite 2 models were used for risk predictions. Composite endpoint (CEP) definitions were adopted from the SERAPHIN and GRIPHON trials. Results Age (mean +SD) was 51.27 + 21.37 years, and 72 % were female. Incident cases were noted in 65.9 % of patients. Idiopathic PAH (IPAH), PAH-associated with congenital heart diseases (CHD-PAH), PAH-associated with connective tissue diseases (CTD-PAH), porto-PAH, Group IV and V pulmonary hypertension (PH) were documented in 33 %, 33.5 %, 12 %, 1.6 %, 20 % and 1.7 % of patients, respectively. Background mono and dual targeted combinations, and sequential triple combinations were noted in 17 %, 57 % and 26 % of patients, respectively. Baseline low-, intermediate-, and high-risk were noted in 1.2 %, 14.1 %, and 84.7 %, respectively. Median follow-up time (day) was 867 (412-1667). Overall rates of mortality and CEP were 26 % and 39%, respectively. There were increases in the % of PAH and group IV PH, and decreases in the % of CHD-PAH across the three periods. Prevalent versus incident cases were associated signifinatly lower mortality and CEP ( p=0.028 and p=0.024, respectively). Outcomes for mortality and CEP were predicted by three risk models (p&amp;lt;0.0001 for all). Mortality and CEP rates were 31 % and 44 % in IPAH, 20 % and 39 % in CHD-PAH, 31 % and 43 % in CTD-PAH, and 25 % and 30 % in group IV patients, respectively. In overall PH population, rates of mortality and CEP documented at 1st, 2nd and 3rd periods were 64 % and 67 %, 29 % and 31 %, and 3.5 % and 5.1 %, respectively (p&amp;lt; 0.001, for all). Mortality rates for 1st, 2nd and 3rd periods were 49 %, 39 % and 11 % in IPAH, 62 %, 33 % and 5.3 % in CHD-PAH, 47 %, 45 % and 7.7 in CTD-PAH, and 37 %, 52 % and 11 % in group IV, respectively (p&amp;lt; 0.001, for all). However, mortality curves showed sudden increases in 2020 that might be attributed to COVID-19. Conclusions Our nation-wide data revealed improving survival in the overall PH population, PAH and Group IV PH that might be associated with risk-based earlier targeted combination strategies. However, this trend seems to be counterbalanced with COVID-19 pandemic.