Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy. METHODS: The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm5 and ≥800 dyne·s/cm5). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm5 or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed. FINDINGS: From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm5 (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm5 (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group. INTERPRETATION: Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH. FUNDING: Gossamer Bio.

The diverging roles of insulin-like growth factor binding proteins in pulmonary arterial hypertension.

Pulmonary hypertension (PH) is a progressive, severe and to date not curable disease of the pulmonary vasculature. Alterations of the insulin-like growth factor 1 (IGF-1) system are known to play a role in vascular pathologies and IGF-binding proteins (IGFBPs) are important regulators of the bioavailability and function of IGFs. In this study, we show that circulating plasma levels of IGFBP-1, IGFBP-2 and IGFBP-3 are increased in idiopathic pulmonary arterial hypertension (IPAH) patients compared to healthy individuals. These binding proteins inhibit the IGF-1 induced IGF-1 receptor (IGF1R) phosphorylation and exhibit diverging effects on the IGF-1 induced signaling pathways in human pulmonary arterial cells (i.e. healthy as well as IPAH-hPASMCs, and healthy hPAECs). Furthermore, IGFBPs are differentially expressed in an experimental mouse model of PH. In hypoxic mouse lungs, IGFBP-1 mRNA expression is decreased whereas the mRNA for IGFBP-2 is increased. In contrast to IGFBP-1, IGFBP-2 shows vaso-constrictive properties in the murine pulmonary vasculature. Our analyses show that IGFBP-1 and IGFBP-2 exhibit diverging effects on IGF-1 signaling and display a unique IGF1R-independent kinase activation pattern in human pulmonary arterial smooth muscle cells (hPASMCs), which represent a major contributor of PAH pathobiology. Furthermore, we could show that IGFBP-2, in contrast to IGFBP-1, induces epidermal growth factor receptor (EGFR) signaling, Stat-3 activation and expression of Stat-3 target genes. Based on our results, we conclude that the IGFBP family, especially IGFBP-1, IGFBP-2 and IGFBP-3, are deregulated in PAH, that they affect IGF signaling and thereby regulate the cellular phenotype in PH.

Electrocardiographic Changes after Endovascular Mechanical Thrombectomy in a Patient with Pulmonary Embolism-A Case Report and Literature Review.

Background: Pulmonary embolism (PE) is a common disease with an annual incidence of about 1/1000 persons. About every sixth patient dies within the first 30 days after diagnosis. The electrocardiogram (ECG) is one of the first diagnostic tests performed, and is able to confirm the suspicion of PE with typical electrocardiographic signs. Some ECG signs and their regression are also prognostically relevant. Endovascular mechanical thrombectomy is one option for PE treatment, and aims to relieve right heart strain immediately. The first studies on endovascular mechanical thrombectomy using a dedicated device (FlowTriever System, Inari Medical, Irvine, CA, USA) yielded promising results. Methods: In the following, we report the case of a 66-year-old male patient who presented with New York Heart Association III dyspnea in our emergency department. Among typical clinical and laboratory results, he displayed very impressive electrocardiographic and radiological findings at the time of PE diagnosis. Results: After endovascular mechanical thrombectomy, the patient's complaints and pulmonary hemodynamics improved remarkably. In contrast, the ECG worsened paradoxically 18 h after intervention. Nevertheless, control echocardiography 4 days after the intervention no longer showed any signs of right heart strain, and dyspnea had disappeared completely. At a 4-month follow-up visit, the patient presented as completely symptom-free with a high quality of life. His ECG and echocardiography were normal and excluded recurrent right heart strain. Conclusions: Overall, the patient benefitted remarkably from endovascular mechanical thrombectomy, resulting in an almost complete resolution of electrocardiographic PE signs at the 4-month follow-up after exhibiting multiple typical electrocardiographic PE signs at time of diagnosis and initial electrocardiographic worsening 18 h post successful intervention.

Physiological mechanisms behind respiratory variations in right atrial pressure in pulmonary hypertension.

Impaired respiratory variation of right atrial pressure (RAP) in severe pulmonary hypertension (PH) suggests difficulty tolerating increased preload during inspiration. Our study explores whether this impairment links to specific factors: right ventricular (RV) diastolic function, elevated RV afterload, systolic RV function, or RV-pulmonary arterial (PA) coupling. We retrospectively evaluated respiratory RAP variation in all participants enrolled in the EXERTION study. Impaired respiratory variation was defined as end-expiratory RAP - end-inspiratory RAP ≤ 2 mm Hg. RV function and afterload were evaluated using conductance catheterization. Impaired diastolic RV function was defined as end-diastolic elastance (Eed) ≥ median (0.19 mm Hg/mL). Seventy-five patients were included; PH was diagnosed in 57 patients and invasively excluded in 18 patients. Of the 75 patients, 31 (41%) had impaired RAP variation, which was linked with impaired RV systolic function and RV-PA coupling and increased tricuspid regurgitation and Eed as compared to patients with preserved RAP variation. In backward regression, RAP variation associated only with Eed. RAP variation but not simple RAP identified impaired diastolic RV function (area under the receiver operating characteristic curve [95% confidence interval]: 0.712 [0.592, 0.832] and 0.496 [0.358, 0.634], respectively). During exercise, patients with impaired RAP variation experienced greater RV dilatation and reduced diastolic reserve and cardiac output/index compared with patients with preserved RAP variation. Preserved RAP variation was associated with a better prognosis than impaired RAP variation based on the 2022 European Society of Cardiology/European Respiratory Society risk score (chi-square P = 0.025) and survival free from clinical worsening (91% vs 71% at 1 year and 79% vs 50% at 2 years [log-rank P = 0.020]; hazard ratio: 0.397 [95% confidence interval: 0.178, 0.884]). Subgroup analyses in patients with group 1 and group 4 PH demonstrated consistent findings with those observed in the overall study cohort. Respiratory RAP variations reflect RV diastolic function, are independent of RV-PA coupling or tricuspid regurgitation, are associated with exercise-induced haemodynamic changes, and are prognostic in PH.Trial registration. NCT04663217.

Microscopic computed tomography with AI-CNN-powered image analysis: the path to phenotype bleomycin-induced lung injury.

Bleomycin (BLM)-induced lung injury in mice is a valuable model for investigating the molecular mechanisms that drive inflammation and fibrosis and for evaluating potential therapeutic approaches to treat the disease. Given high variability in the BLM model, it is critical to accurately phenotype the animals in the course of an experiment. In the present study, we aimed to demonstrate the utility of microscopic computed tomography (µCT) imaging combined with an artificial intelligence (AI)-convolutional neural network (CNN)-powered lung segmentation for rapid phenotyping of BLM mice. µCT was performed in freely breathing C57BL/6J mice under isoflurane anesthesia on days 7 and 21 after BLM administration. Terminal invasive lung function measurement and histological assessment of the left lung collagen content were conducted as well. µCT image analysis demonstrated gradual and time-dependent development of lung injury as evident by alterations in the lung density, air-to-tissue volume ratio, and lung aeration in mice treated with BLM. The right and left lung were unequally affected. µCT-derived parameters such as lung density, air-to-tissue volume ratio, and nonaerated lung volume correlated well with the invasive lung function measurement and left lung collagen content. Our study demonstrates the utility of AI-CNN-powered µCT image analysis for rapid and accurate phenotyping of BLM mice in the course of disease development and progression.NEW & NOTEWORTHY Microscopic computed tomography (µCT) imaging combined with an artificial intelligence (AI)-convolutional neural network (CNN)-powered lung segmentation is a rapid and powerful tool for noninvasive phenotyping of bleomycin mice over the course of the disease. This, in turn, allows earlier and more reliable identification of therapeutic effects of new drug candidates, ultimately leading to the reduction of unnecessary procedures in animals in pharmacological research.

Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study.

BACKGROUND: Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar. METHODS: The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II-IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm5 and a walk distance of 150-450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292. FINDINGS: Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 71·5% of baseline in the macitentan group and to 87·6% in the placebo group (geometric means ratio 0·81, 95% CI 0·70-0·95, p=0·0098). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%]). INTERPRETATION: In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated. FUNDING: Actelion Pharmaceuticals Ltd.

Right ventricular pressure-strain relationship-derived myocardial work reflects contractility: Validation with invasive pressure-volume analysis.

Three-dimensional (3D) echocardiography-derived right ventricular (RV) ejection fraction (EF) and global longitudinal strain (GLS) are valuable RV functional markers; nevertheless, they are substantially load-dependent. Global myocardial work index (GMWI) is a novel parameter calculated by the area of the RV pressure-strain loop. By adjusting myocardial deformation to instantaneous pressure, it may reflect contractility. To test this hypothesis, we enrolled 60 patients who underwent RV pressure-conductance catheterization to determine load-independent markers of RV contractility and ventriculo-arterial coupling. Detailed 3D echocardiography was also performed, and we calculated RV EF, RV GLS, and using the RV pressure trace curve, RV GWMI. While neither RV EF nor GLS correlated with Ees, GMWI strongly correlated with Ees. In contrast, RV EF and GLS showed a relationship with Ees/Ea. By dividing the population based on their Reveal Lite 2 risk classification, different characteristics were seen among the subgroups. RV GMWI may emerge as a useful clinical tool for risk stratification and follow-up in patients with RV dysfunction.

A Novel Rat Model of Mild Pulmonary Hypertension Associated with Pulmonary Venous Congestion Induced by Left Pulmonary Vein Banding.

Pulmonary hypertension (PH) associated with left heart disease (PH-LHD) is the most common form of PH. In PH-LHD, changes in the pulmonary vasculature are assumed to be mainly caused by pulmonary venous congestion. However, the underlying mechanisms of this form of PH are poorly understood. We aimed to establish a model of PH associated with pulmonary venous congestion. Wistar-Kyoto rats underwent partial occlusion of the left pulmonary vein to induce pulmonary venous congestion or sham surgery and were assessed at various time points post-surgery (3, 6, 9, 12 weeks). In vivo cardiopulmonary phenotyping was performed by using echocardiography along with heart catheterization. Histomorphometry methods were used to assess pulmonary vascular remodeling (e.g., wall thickness, degree of muscularization). Left pulmonary vein banding (PVB) resulted in mildly elevated right ventricular systolic pressure and moderate right ventricular hypertrophy. In PVB rats, small- and medium-sized pulmonary vessels in the left lung were characterized by increased wall thickness and muscularization. Taken together, our data demonstrate that left PVB-induced pulmonary venous congestion is associated with pulmonary vascular remodeling and mild PH.

A Simple and Safe Method for Checking the Position of Central Venous Catheters-A New and Reliable Threshold for Right Atrial Swirl Sign in Microbubbles Tests.

Background: Central venous catheters (CVCs) are indispensable tools in intensive care and emergency medicine. CVC malpositions still occur frequently and can cause various complications leading to increased patient mortality. A microbubbles test (MBT) can be used to confirm correct CVC positioning. However, there is serious doubt regarding whether the currently applied threshold of a 2 s push-to-bubbles time (PTB time) for rapid atrial swirl sign (RASS) in an MBT is reliable and accurate. The aim of the present study was to prove the quality of a new threshold: 1 s. Methods: Consecutive patients who were admitted to the intensive care unit (ICU) in a German neurological specialist hospital from 1 March 2021 to 20 July 2022 were enrolled. After ultrasound-guided CVC insertion, an MBT was performed, PTB time was measured, and RASS was interpreted. Additionally, a chest X-ray (CXR) was requested to check CVC position. Results: A total of 102 CVCs (98% jugular and 2% subclavian) were inserted in 102 patients (38% female and 62% male; median age: 66 years). Negative RASS (PTB time > 1 s) was observed in 2 out of 102 patients, resulting in an echocardiographic malposition rate of 2.0%. CXR confirmed the echocardiographic results. After correcting CVC position in the initially malpositioned CVCs, the PTB time was <1 s (positive RASS). The MBT protocol took about 0.5 min on average, while the CXR results were all available within 30 min. Sensitivity, specificity, and positive and negative predictive value were each 100% for the detection of CVC malpositions via an MBT using a threshold of 1 s compared to CXR. Conclusions: A new threshold of a 1 s PTB time for RASS in an MBT could detect CVC malpositions with excellent quality compared to CXR. Since the MBT was fast and safe and could be performed at the bedside, we propose that an MBT with the new and reliable threshold of 1 s should be routinely used in patient care.

Comparison of Contemporary Risk Scores in All Groups of Pulmonary Hypertension: A Pulmonary Vascular Research Institute GoDeep Meta-Registry Analysis.

BACKGROUND: Pulmonary hypertension (PH) is a heterogeneous disease with a poor prognosis. Accurate risk stratification is essential for guiding treatment decisions in pulmonary arterial hypertension (PAH). Although various risk models have been developed for PAH, their comparative prognostic potential requires further exploration. Additionally, the applicability of risk scores in PH groups beyond group 1 remains to be investigated. RESEARCH QUESTION: Are risk scores originally developed for PAH predictive in PH groups 1 through 4? STUDY DESIGN AND METHODS: We conducted a comprehensive analysis of outcomes among patients with incident PH enrolled in the multicenter worldwide Pulmonary Vascular Research Institute GoDeep meta-registry. Analyses were performed across PH groups 1 through 4 and further subgroups to evaluate the predictive value of PAH risk scores, including REVEAL Lite 2, REVEAL 2.0, ESC/ERS 2022, COMPERA 3-strata, and COMPERA 4-strata. RESULTS: Eight thousand five hundred sixty-five patients were included in the study, of whom 3,537 patients were assigned to group 1 PH, whereas 1,807 patients, 1,635 patients, and 1,586 patients were assigned to group 2 PH, group 3 PH, and group 4 PH, respectively. Pulmonary hemodynamics were impaired with median mean pulmonary arterial pressure of 42 mm Hg (33-52 mm Hg) and pulmonary vascular resistance of 7 WU (4-11 WU). All risk scores were prognostic in the entire PH population and in each of the PH groups 1 through 4. The REVEAL scores, when used as continuous prediction models, demonstrated the highest statistical prognostic power and granularity; the COMPERA 4-strata risk score provided subdifferentiation of the intermediate-risk group. Similar results were obtained when separately analyzing various subgroups (PH subgroups 1.1, 1.4.1, and 1.4.4; PH subgroups 3.1 and 3.2; group 2 with isolated postcapillary PH vs combined precapillary and postcapillary PH; patients of all groups with concomitant cardiac comorbidities; and severe [> 5 WU] vs nonsevere PH). INTERPRETATION: This comprehensive study with real-world data from 15 PH centers showed that PAH-designed risk scores possess predictive power in a large PH cohort, whether considered as common to the group or calculated separately for each PH group (1-4) and various subgroups.

Liver stiffness is associated with right heart dysfunction, cardiohepatic syndrome, and prognosis in pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) can lead to congestive hepatopathy, known as cardiohepatic syndrome (CHS). Hepatic congestion is associated with increased liver stiffness, which can be quantified using shear wave elastography. We aimed to investigate whether hepatic shear wave elastography detects patients at risk in the early stages of PH. METHODS: Sixty-three prospectively enrolled patients undergoing right heart catheterization (52 diagnosed with PH and 11 with invasive exclusion of PH) and 52 healthy volunteers underwent assessments including echocardiography and hepatic shear wave elastography. CHS was defined as increased levels of ≥2 of the following: gamma-glutamyl transferase, alkaline phosphatase, and bilirubin. Liver stiffness was defined as normal (≤5.0 kPa) or high (>5.0 kPa). RESULTS: Compared with normal liver stiffness, high liver stiffness was associated with impaired right ventricular (RV) and right atrial (RA) function (median [interquartile range] RV ejection fraction: 54 [49; 57]% vs 45 [34; 51]%, p < 0.001; RA reservoir strain: 49 [41; 54]% vs 33 [22; 41]%, p < 0.001), more severe tricuspid insufficiency (p < 0.001), and higher prevalence of hepatovenous backflow (2% vs 29%, p < 0.001) and CHS (2% vs 10%, p = 0.038). In the patient subgroup with precapillary PH (n = 48), CHS and high liver stiffness were associated with increased European Society of Cardiology/European Respiratory Society 2022 risk scores (p = 0.003). CONCLUSIONS: Shear wave liver elastography yields important information regarding right heart function and may complement risk assessment in patients with (suspected) PH.

Evaluation of troponin I serum levels in patients with arrhythmias with and without coronary artery disease.

BACKGROUND: Elevated levels of cardiac enzymes in the blood are an indicator of ongoing cardiac ischemia. Persistent tachycardia may lead to myocardial ischemia due to oxygen supply-demand mismatch. OBJECTIVES: We sought to evaluate the probability of underlying coronary artery disease (CAD) in patients with symptomatic supraventricular (SVT) or ventricular tachyarrhythmias (VT) based on cardiac enzyme level fluctuation. MATERIALS AND METHODS: Troponin I (TNI) levels were measured twice and coronary angiography was also performed in patients without a history of cardiovascular disease and symptomatic SVT or VT. RESULTS: Of the 114 (group A: CAD (n = 40), group B: no CAD (n = 74)) patients eligible for the study, 34 patients in group A and 64 patients in group B had SVT, while 6 patients in group A and 10 patients in group B had VT. All patients with underlying CAD developed a significantly elevated TNI level compared to baseline, irrespective of arrhythmia type (2.02 ± 7.98 ng/ml vs. 5.64 ± 13.38, p = 0.031). In patients without CAD, TNI level was not significantly elevated compared to the baseline level, irrespective of arrhythmia type (0.34 ± 1.38 ng/ml vs. 0.48 ± 1.48 ng/ml, p = 0.158). Most patients with normal TNI levels (46 of 47 patients; 98 %) had SVT. CAD was present in 13 of 47 patients (27 %) with tachycardia, despite normal TNI levels. CONCLUSIONS: Elevated TNI levels are not helpful to discriminate between SVT and VT. An increase in TNI level in repeated blood sampling can help identify patients with higher probability of underlying CAD. Patients with VT demonstrated higher increases in TNI levels, compared to patients with SVT.

Fibroblast growth factor 10 reverses cigarette smoke- and elastase-induced emphysema and pulmonary hypertension in mice.

BACKGROUND: COPD is an incurable disease and a leading cause of death worldwide. In mice, fibroblast growth factor (FGF)10 is essential for lung morphogenesis, and in humans, polymorphisms in the human FGF10 gene correlate with an increased susceptibility to develop COPD. METHODS: We analysed FGF10 signalling in human lung sections and isolated cells from healthy donor, smoker and COPD lungs. The development of emphysema and PH was investigated in Fgf10+/- and Fgfr2b+/- (FGF receptor 2b) mice upon chronic exposure to cigarette smoke. In addition, we overexpressed FGF10 in mice following elastase- or cigarette smoke-induced emphysema and pulmonary hypertension (PH). RESULTS: We found impaired FGF10 expression in human lung alveolar walls and in primary interstitial COPD lung fibroblasts. In contrast, FGF10 expression was increased in large pulmonary vessels in COPD lungs. Consequently, we identified impaired FGF10 signalling in alveolar walls as an integral part of the pathomechanism that leads to emphysema and PH development: mice with impaired FGF10 signalling (Fgf10+/- and Fgfr2b+/- ) spontaneously developed lung emphysema, PH and other typical pathomechanistic features that generally arise in response to cigarette smoke exposure. CONCLUSION: In a therapeutic approach, FGF10 overexpression successfully restored lung alveolar and vascular structure in mice with established cigarette smoke- and elastase-induced emphysema and PH. FGF10 treatment triggered an initial increase in the number of alveolar type 2 cells that gradually returned to the basal level when the FGF10-mediated repair process progressed. Therefore, the application of recombinant FGF10 or stimulation of the downstream signalling cascade might represent a novel therapeutic strategy in the future.

Echocardiographic evaluation of right ventricular diastolic function in pulmonary hypertension.

Background: Right ventricular (RV) diastolic dysfunction may be prognostic in pulmonary hypertension (PH). However, its assessment is complex and relies on conductance catheterisation. We aimed to evaluate echocardiography-based parameters as surrogates of RV diastolic function, provide validation against the gold standard, end-diastolic elastance (Eed), and define the prognostic impact of echocardiography-derived RV diastolic dysfunction. Methods: Patients with suspected PH who underwent right heart catheterisation including conductance catheterisation were prospectively recruited. In this study population, an echocardiography-based RV diastolic function surrogate was derived. Survival analyses were performed in patients with precapillary PH in the Giessen PH Registry, with external validation in patients with pulmonary arterial hypertension at Sapienza University (Rome). Results: In the derivation cohort (n=61), the early/late diastolic tricuspid inflow velocity ratio (E/A) and early tricuspid inflow velocity/early diastolic tricuspid annular velocity ratio (E/e') did not correlate with Eed (p>0.05). Receiver operating characteristic analysis revealed a large area under the curve (AUC) for the peak lateral tricuspid annulus systolic velocity/right atrial area index ratio (S'/RAAi) to detect elevated Eed (AUC 0.913, 95% confidence interval (CI) 0.839-0.986) and elevated end-diastolic pressure (AUC 0.848, 95% CI 0.699-0.998) with an optimal threshold of 0.81 m2·s-1·cm-1. Subgroup analyses demonstrated a large AUC in patients with preserved RV systolic function (AUC 0.963, 95% CI 0.882-1.000). Survival analyses confirmed the prognostic relevance of S'/RAAi in the Giessen PH Registry (n=225) and the external validation cohort (n=106). Conclusions: Our study demonstrates the usefulness of echocardiography-derived S'/RAAi for noninvasive assessment of RV diastolic function and prognosis in PH.

AI-enabled epidermal electronic system to automatically monitor a prognostic parameter for hypertension with a smartphone.

We present a wearable, flexible, wireless and smartphone-enabled epidermal electronic system (EES) for the continuous monitoring of a prognostic parameter for hypertension. The thin and lightweight EES can be tightly attached to the chest of a patient and synchronously monitor first lead electrocardiograms (ECG) and seismocardiograms (SCG). To demonstrate the concept, we developed the EES using state-of-the-art cleanroom technologies. Two types of sensors were integrated: A pair of metal electrodes to contact the skin and to record ECG and a vibration sensor based on a thin piezoelectric polymer to record SCG from the same location of the chest, simultaneously. The complete EES was powered by the near field communication functionality of the smartphone. We developed a machine-learning algorithm and trained it on public ECG data and recorded SCG signals to extract characteristic features of the recordings. Binary classifiers were used to automatically annotate peaks. After training, the algorithm was transferred to the smartphone to continuously analyze the timing between particular ECG and SCG peaks and to extract the Weissler's index as a prognostic parameter for hypertension. Tests with data of healthy control persons and clinical experiments with patients diagnosed with cardio-pulmonary hypertension showed a promising prognostic performance. The presented EES technology could be utilized for pre-screening of cardio-pulmonary hypertension, which is a strong burden in our today's healthcare system.

Hepatorenal dysfunction in patients with chronic thromboembolic pulmonary hypertension.

Background: Cardiac interactions with organs such as the liver or kidneys have been described in different cardiovascular diseases. However, the clinical relevance of hepatorenal dysfunction in chronic thromboembolic pulmonary hypertension (CTEPH) remains unclear. We determined the association of hepatorenal dysfunction (measured using the Model for End-stage Liver Disease Sodium [MELDNa] score) with right heart function and survival in patients with CTEPH. Methods: We analyzed all patients with CTEPH in the Giessen Pulmonary Hypertension Registry who had available MELDNa scores and were not taking vitamin K antagonists. The MELDNa score was calculated as MELD score - serum Na - (0.025 * MELD score * (140 - serum Na)) + 140; the MELD score was calculated as 10*(0.957*ln(creatinine)+0.378*ln(bilirubin)+1.12*ln(International Normalized Ratio))+6.43. Results: Seventy-two patients were included (74% female; median [Q1, Q3] MELDNa: 9 [6, 11]). MELDNa correlated well with right atrial and ventricular function and pulmonary hemodynamics. Forward regression analysis revealed that hepatorenal dysfunction mainly depends on right atrial strain and tricuspid regurgitation, but not right ventricular systolic dysfunction. Hepatorenal dysfunction predicted mortality at baseline and follow-up (adjusted hazard ratios [95% confidence intervals] per unit increase of MELDNa: 1.6 [1.1, 2.4] and 1.8 [1.1, 2.9], respectively). Changes in hepatorenal function also predicted mortality. Conclusion: Hepatorenal dysfunction in CTEPH is primarily associated with venous congestion rather than cardiac forward failure. As a surrogate parameter for hepatorenal dysfunction, MELDNa is a simple method to identify at-risk patients at baseline and follow-up.

Changes in Doppler-Derived Kidney Venous Flow and Adverse Cardiorenal Outcomes in Patients With Heart Failure.

Background The impact of changes in Doppler-derived kidney venous flow in heart failure (HF) is not well studied. We aimed to investigate the association of Doppler-derived kidney venous stasis index (KVSI) and intrakidney venous-flow (IKVF) patterns with adverse cardiorenal outcomes in patients with HF. Methods and Results In this observational cohort study, consecutive inpatients with HF referred to a nephrologist because of a history of diuretic resistance and abnormal kidney function (n=216) underwent spectral kidney assessments after admission (Doppler 1) and 25 to 35 days later (Doppler 2) to identify IKVF patterns (continuous/pulsatile/biphasic/monophasic) and KVSI levels. Cox proportional hazard regression models were used to evaluate the associations between KVSI/IKVF patterns at Doppler 1 as well as changes from Doppler 1 to Doppler 2 and risk of cardiorenal events up to 18 months after admission. Worsening HF or death occurred in 126 patients. Both baseline KVSI (hazard ratio [HR], 1.49 [95% CI, 1.37-1.61] per 0.1-unit increase) and baseline IKVF pattern (HR, 2.47 [95% CI, 2.01-3.04] per 1 pattern severity increase) were significantly associated with worsening HF/death. Increases in both KVSI and IKVF pattern severity from Doppler 1 to 2 were also associated with an increased risk of worsening HF/death (HR, 3.00 [95% CI, 2.08-4.32] per 0.1-unit increase change; and HR, 6.73 [95% CI, 3.27-13.86] per 1 pattern increase in severity change, respectively). Similar results were observed for kidney outcomes. Conclusions Baseline kidney venous flow predicted adverse cardiorenal events, and inclusion of serial kidney venous flow in cardiorenal risk stratification could facilitate clinical decision-making for patients with HF. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03039959.

Analysis of Electrocardiographic Criteria of Right Ventricular Hypertrophy in Patients with Chronic Thromboembolic Pulmonary Hypertension before and after Balloon Pulmonary Angioplasty.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) may lead to typical electrocardiographic changes that can be reversed by balloon pulmonary angioplasty (BPA). The aim of this study was to investigate the significance of rarely used electrocardiogram (ECG) parameters, possible electrocardiographic differences between residual and significantly improved CTEPH and the role of electrocardiographic parameters in low mPAP (mean pulmonary arterial pressure) ranges since the mPAP threshold for the definition of pulmonary hypertension has recently been adjusted (≥25 mmHg to >20 mmHg). MATERIAL AND METHODS: Between March 2014 and October 2020, 140 patients with CTEPH and 10 with CTEPD (chronic thromboembolic pulmonary disease) without pulmonary hypertension (PH) were retrospectively enrolled (12-lead ECG and right heart catheterization before and 6 months after BPA). The ECG parameters of right heart strain validated by studies and clinical experience were evaluated. Special attention was paid to six specific ECG parameters. After BPA, the cohort was divided into subgroups to investigate possible electrocardiographic differences with regard to the haemodynamic result. RESULTS: The present study confirmed that the typical electrocardiographic signs of CTEPH can be found on an ECG, can regress after BPA and partially correlate well with haemodynamic parameters. "R V1, V2 + S I, aVL - S V1" was a parameter of particular note. BPA reduced its frequency (47% vs. 29%) statistically significantly after Bonferroni correction (p < 0.001). Moreover, it showed a good correlation with mPAP and PVR (r-values: 0.372-0.519, p-values: < 0.001). Exceeding its cut-off value before therapy was associated with more severe CTEPH before therapy (higher mPAP, PVR, NT-pro-BNP and troponin and lower TAPSE) and an increased risk of death. Exceeding its cut-off value before and after therapy was associated with more severe CTEPH after therapy (higher RAP, mPAP, PVR, NT-pro-BNP and NYHA class) and an increased risk of death. Men tend to be affected more frequently. After subgrouping, it was observed that a higher median mPAP was associated with a higher right atrial pressure (RAP), a higher pulmonary vascular resistance (PVR) and a lower cardiac output (CO) before and after BPA. In addition, under these conditions, more and more severe electrocardiographic pathologies were detected before and after BPA. Some patients with low mPAP also continued to show mild ECG changes after BPA. In some cases, very few to no pathological ECG changes were detected, and the ECG could present as mostly normal in some patients (5% before BPA and 13% after BPA). CONCLUSION: "R V1, V2 + S I, aVL - S V1" seems to be able to support the diagnosis of CTEPH, indicate therapeutic improvement and estimate haemodynamics. It also seems capable of predicting a (persistent) severe disease with probably increased need for therapy and increased mortality. Mild PH has been observed to have either no or few mild ECG changes. This might complicate the (early) detection of PH.

Clinical and functional relevance of right ventricular contraction patterns in pulmonary hypertension.

BACKGROUND: The right ventricle has a complex contraction pattern of uncertain clinical relevance. We aimed to assess the relationship between right ventricular (RV) contraction pattern and RV-pulmonary arterial (PA) coupling defined by the gold-standard pressure-volume loop-derived ratio of end-systolic/arterial elastance (Ees/Ea). METHODS: Prospectively enrolled patients with suspected or confirmed pulmonary hypertension underwent three-dimensional echocardiography, standard right heart catheterization, and RV conductance catheterization. RV-PA uncoupling was categorized as severe (Ees/Ea < 0.8), moderate (Ees/Ea 0.8-1.29), and none/mild (Ees/Ea ≥ 1.3). Clinical severity was determined from hemodynamics using a truncated version of the 2022 European Society of Cardiology/European Respiratory Society risk stratification scheme. RESULTS: Fifty-three patients were included, 23 with no/mild, 24 with moderate, and 6 with severe uncoupling. Longitudinal shortening was decreased in patients with moderate vs no/mild uncoupling (p <0.001) and intermediate vs low hemodynamic risk (p < 0.001), discriminating low risk from intermediate/high risk with an optimal threshold of 18% (sensitivity 80%, specificity 87%). Anteroposterior shortening was impaired in patients with severe vs moderate uncoupling (p = 0.033), low vs intermediate risk (p = 0.018), and high vs intermediate risk (p = 0.010), discriminating high risk from intermediate/low risk with an optimal threshold of 15% (sensitivity 100%, specificity 83%). Left ventricular (LV) end-diastolic volume was decreased in patients with severe uncoupling (p = 0.035 vs no/mild uncoupling). CONCLUSIONS: Early RV-PA uncoupling is associated with reduced longitudinal function, whereas advanced RV-PA uncoupling is associated with reduced anteroposterior movement and LV preload, all in a risk-related fashion. CLINICALTRIALS: GOV: NCT04663217.