Prognosis Of Pulmonary Hypertension Research Articles

Dephosphorylated uncarboxylated Matrix-Gla-Protein as candidate biomarker for immune-mediated vascular remodeling and prognosis in pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a disease characterized by pulmonary vascular remodeling. Since dephosphorylated-uncarboxylated Matrix Gla-Protein (dp-ucMGP) is associated with cardiovascular mortality in systemic sclerosis, a disease associated with PAH, and immune-system involvement in PAH is increasingly recognized, we investigated the relationship between dp-ucMGP, vascular remodeling and soluble immune-checkpoint proteins in PAH. This prospective cohort study included patients with idiopathic (I)PAH, connective tissue disease (CTD)-PAH, chronic thrombo-embolic PH (CTEPH) and CTD patients without PAH. Patients with IPAH and CTD-PAH were stratified by clinical signs of immune-mediated inflammatory disease (IMID). We measured dp-ucMGP plasma levels, soluble immune-checkpoint proteins (sICPs), and vascular smooth muscle cell (iVSMC) calcification. We found elevated dp-ucMGP levels in all PAH subtypes and CTD patients compared to healthy controls. PAH patients showed increased iVSMC calcification, but no direct correlation was found with dp-ucMGP. IMID-PAH patients had higher dp-ucMGP levels than non-IMID PAH patients. dp-ucMGP correlated with several sICPs in both IPAH and CTD patients; multiple sICPs were elevated in IMID PAH patients. High dp-ucMGP levels in IPAH patients were associated with worse survival. Our findings suggest dp-ucMGP as a potential biomarker of immune-mediated vascular remodeling in PAH. Hence, dp-ucMGP, could help identify PAH patients who might benefit from immunosuppressive therapies.

Analysis of Incidence Rate, Risk Factors and Prognosis of Pulmonary Hypertension in Ph-MPNs Patients

To explore and analyze the incidence rate, influencing factors and impact on prognosis of pulmonary hypertension (PH) in patients with Philadelphia chromosome negative myeloproliferative neoplasms (Ph- MPNs). The clinical data of 271 patients with Ph- MPNs were retrospectively analyzed, and different disease subtypes were classified. Patients with different disease types were further divided into PH+ and PH- groups according to whether HP occurred. Statistical methods were used to analyze the incidence rate, risk factors, and impact on prognosis of PH in Ph- MPNs patients. The overall incidence rate of PH among 271 patients was 26.9%, and according to the classification of disease subtypes, it was found that the incidence rate of PH in patients with primary myelofibrosis (PMF) was significantly higher than those of patients with polycythemia vera and essential thrombocythemia (both P <0.05). Multivariate regression analysis showed that advanced age, long disease course, JAK2 positive and increased hematocrit, lactate dehydrogenase, monocyte count, and uric acid level were independent risk factors for PH in Ph- MPNs patients (OR >1, P <0.05), and there were some differences in the independent risk factors between different disease subtypes. Survival analysis results showed that the overall survival (OS) rate of PH+ patients was significantly lower than that of PH- patients in other types except for PMF (all P <0.05). The incidence rate of PH in Ph- MPNs patients is high, and its risk factors are diverse. The OS rate of Ph- MPNs patients with PH is low. Therefore, we should be highly alert to the occurrence of PH in Ph- MPNs patients clinically.

The Role of Echocardiography in the Diagnosis and Prognosis of Pulmonary Hypertension.

The right heart catheterisation constitutes the gold standard for pulmonary hypertension (PH) diagnosis. However, echocardiography remains a reliable, non-invasive, inexpensive, convenient, and easily reproducible modality not only for the preliminary screening of PH but also for PH prognosis. The aim of this review is to describe a cluster of echocardiographic parameters for the detection and prognosis of PH and analyse the challenges of echocardiography implementation in patients with suspected or established PH. The most important echocardiographic index is the calculation of pulmonary arterial systolic pressure (PASP) through the tricuspid regurgitation (TR). It has shown high correlation with invasive measurement of pulmonary pressure, but several drawbacks have questioned its accuracy. Besides this, the right ventricular outflow track acceleration time (RVOT-AT) has been proposed for PH diagnosis. A plethora of echocardiographic indices: right atrial area, pericardial effusion, the tricuspid annular plane systolic excursion (TAPSE), the TAPSE/PASP ratio, tricuspid annular systolic velocity (s'), can reflect the severity and prognosis of PH. Recent advances in echocardiography with 3-dimensional right ventricular (RV) ejection fraction, RV free wall strain and right atrial strain may further assist the prognosis of PH.

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

BackgroundPulmonary 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. MethodsSixty-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). ResultsCompared 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). ConclusionsShear wave liver elastography yields important information regarding right heart function and may complement risk assessment in patients with (suspected) PH.

The Prognostic Value of One-Year Changes in Biventricular Mechanics for Three-Year Survival in Patients with Precapillary Pulmonary Hypertension: A Cardiovascular Magnetic Resonance Feature Tracking Study.

Background and Objectives: The management of patients with pulmonary hypertension (PH) poses a considerable challenge. While baseline cardiac magnetic resonance imaging (cMRI) indices are recognized for survival prognosis in PH, the prognostic value of one-year changes in biventricular mechanics, especially as assessed using feature tracking (FT) technology, remains underexplored. This study aims to assess the predictive value of one-year change in cMRI-derived biventricular function and mechanics parameters, along with N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and six-minute walking test (6MWT) results for three-year mortality in precapillary PH patients. Materials and Methods: In this retrospective study, 36 patients diagnosed with precapillary pulmonary hypertension (mPAP 55.0 [46.3-70.5] mmHg, pulmonary capillary wedge pressure 10.0 [6.0-11.0] mmHg) were included. Baseline and one-year follow-up cMRI assessments, clinical data, and NT-proBNP levels were analyzed. FT technology was utilized to assess biventricular strain parameters. Patients were categorized into survival and non-survival groups based on three-year outcomes. Statistical analyses, including univariate logistic regression and Cox regression, were performed to identify predictive parameters. Results: The observed three-year survival rate was 83.3%. Baseline right ventricle (RV) ejection fraction (EF) was significantly higher in the survival group compared to non-survivors (41.0 [33.75-47.25]% vs. 28.0 [23.5-36.3]%, p = 0.044), and values of ≤32.5% were linked to a 20-fold increase in mortality risk. RV septum longitudinal strain (LS) and RV global LS exhibited significant improvement over a one-year period in the survival group compared to the non-survival group (-1.2 [-6.4-1.6]% vs. 4.9 [1.5-6.7]%, p = 0.038 and -3.1 [-9.1-2.6]% vs. 4.5 [-2.1-8.5]%, p = 0.048, respectively). Declines in RV septum LS by ≥2.95% and in RV GLS by ≥3.60% were associated with a 25-fold and 8-fold increase in mortality risk, respectively. Conclusions: The decrease in right ventricular septal and global longitudinal strain over a one-year period demonstrates a significant predictive value and an association with an increased three-year mortality risk in patients with precapillary PH.

Inhaled nitric oxide testing in predicting prognosis in pulmonary hypertension due to left-sided heart diseases.

The pathophysiology of pulmonary hypertension (PH) due to left-sided heart disease (Group 2 PH) is distinct from that of other groups of PH, yet there are still no approved therapies that selectively target pulmonary circulation. The increase in pulmonary capillary pressure due to left-sided heart disease is a trigger event for physical and biological alterations of the pulmonary circulation, including the nitric oxide (NO)-soluble guanylate cyclase-cyclic guanosine monophosphate axis. This study investigated inhaled NO vasoreactivity tests for patients with Group 2 PH and hypothesized that these changes may have a prognostic impact. This was a single-centre, retrospective study with a median follow-up of 365days. From January 2011 to December 2015, we studied 69 patients with Group 2 PH [age, 61.5±13.0 (standard deviation) years; male:female, 49:20; left ventricular ejection fraction, 50.1±20.4%; mean pulmonary arterial pressure, ≥25mmHg; and pulmonary arterial wedge pressure (PAWP), >15mmHg]. No adverse events were observed after NO inhalation. Thirty-four patients with Group 2 PH showed increased PAWP (ΔPAWP: 3.26±2.22mmHg), while the remaining 35 patients did not (ΔPAWP: -2.11±2.29mmHg). Multivariate analysis revealed that increased PAWP was the only significant predictor of all-cause death or hospitalization for heart failure (HF) after 1year (hazard ratio 4.35; 95% confidence interval, 1.27-14.83; P=0.019). The acute response of PAWP to NO differed between HF with preserved and reduced ejection fractions. Patients with Group 2 PH were tolerant of the inhaled NO test. NO-induced PAWP is a novel prognostic indicator.

Usefulness of NT-proBNP in dogs with heartworm: could this biomarker be useful to evaluate pulmonary hypertension?

BackgroundIn recent years, the usefulness of echocardiography and serum biomarkers in the diagnosis of pulmonary hypertension (PH) in dogs with heartworm disease has been studied. Previously, N-terminal pro B-type natriuretic peptide (NT-proBNP) has shown high concentrations in dogs with heart disease and/or PH as well as its usefulness as a prognostic indicator, but it has never been evaluated in the diagnosis and prognosis of PH in dogs with heartworm disease. The aim was to evaluate the serum concentrations of NT-proBNP in dogs infected by Dirofilaria immitis to determine its usefulness as a tool to detect precapillary PH.MethodsNT-proBNP was determined in 50 heartworm-infected dogs. Presence/absence of PH was determined echocardiographically, using the Right Pulmonary Artery Distensibility Index (RPAD Index) and the systolic flow of tricuspid regurgitation mainly, together with other echocardiographic measurements following the guidelines of the American College of Veterinary Internal Medicine (ACVIM) for the diagnosis of PH. Other epidemiological parameters (breed, age, sex, status: client-owned or shelter dogs) and clinical parameters (microfilaremia, parasite burden, presence of symptoms, body condition) were collected as well.ResultsModerate-severe PH was present in 40% of the dogs (RPAD Index < 29.5%), NT-proBNP concentrations being significantly higher compared with dogs that did not have PH. A cutoff for NT-proBNP of ≥ 1178.45 pmol/l showed a sensitivity of 64.3% and a specificity of 95.5% for the presence of moderate-severe PH. Older dogs and dogs from shelters showed significantly higher NT-proBNP concentrations. Dogs with symptoms and low body condition presented significantly higher NT-proBNP concentrations as well.ConclusionsThe determination of NT-pro-BNP concentration can be a useful tool in the diagnostic work-up of dogs with heartworm disease and associated PH and can help to identify animals in the more advanced stage of this disorder.Graphical abstract

Could Heart Rate Variability Serve as a Prognostic Factor in Patients with Pulmonary Hypertension? A Single-center Pilot Study.

Heart rate variability (HRV), which is defined as cyclic changes in sinus rate with time, is used as a measure of cardiac autonomic tone. Our aim was to determine the impact of HRV on short-term prognosis in pulmonary hypertension (PH). We enrolled 64 PH patients and 69 healthy subjects (control group). Patients were evaluated by Holter-ECG, echocardiography, and laboratory tests. 24-h Holter-ECG monitoring was used for HRV. The development of adverse events (right heart failure, hospitalization, syncope, and death) during the 6-month follow-up was evaluated in PH group. PH group (39 ± 16 years, 37.5% males) comprised of 16 patients with idiopathic pulmonary arterial hypertension (PAH) (25%), 36 patients with PAH associated with congenital heart disease (56.3%), 3 PAH associated with connective tissue disease (4.7%), 1 with portopulmonary (1.6%), and 8 chronic thromboembolic PH (12.5%). The time-dependent (standard deviation of all NN intervals for a selected time period [SDNN], standard deviation of the 5-min mean R-R intervals tabulated over an entire day [SDANN], SDNN Index, and Triangular Index) and frequency-dependent HRV indices (low frequency, high-frequency power, and total power,) were significantly reduced in those with PH. Functional class was negatively associated with SDNN, SDANN, SDNN Index, and Triangular Index. Adverse events developed in 25% of the patients during the 6-month follow-up period (200 ± 92 days) (7 patients had right-heart failure, 5 syncope, 12 patients were hospitalized, and 9 had died). All the time and frequency-dependent indices significantly associated with adverse events. Mortality correlated with SDNN (rS = -0.354, P = 0.005), SDANN (rS = -0.368, P = 0.004), SDNN Index (rS = -0.257, P = 0.045), Triangular Index (rS = -0.310, P = 0.014), and VLF (rS = -0.265, P = 0.039). HRV is significantly depressed in patients with PH and is associated with the clinical status. HRV indices might predict clinical deterioration, adverse events, and mortality for 6 months. Non-invasive assessment of HRV through Holter-ECG may be a valuable and practical tool in risk stratification of patients with PH for short-term outcomes.

Higher circulating Trimethylamine N-oxide levels are associated with worse severity and prognosis in pulmonary hypertension: a cohort study

BackgroundTrimethylamine N-oxide (TMAO), the gut microbiota-dependent metabolite, is a potential biomarker in several cardiovascular diseases. However, no study has investigated its value in pulmonary hypertension (PH). Therefore, this study aimed to explore the association between plasma TMAO levels and prognosis in patients with PH.MethodsInpatients with idiopathic/heritable pulmonary arterial hypertension (IPAH/HPAH), PAH associated with congenital heart disease (CHD-PAH), and chronic thromboembolic pulmonary hypertension (CTEPH) at Fuwai Hospital were enrolled after excluding those with relative comorbidities. The endpoint was defined as a composite outcome including death, rehospitalisation due to heart failure, and at least 15% decreased 6-min walk distance from the baseline. Fasting blood samples were collected to measure plasma levels of TMAO and other clinical indicators. The associations between TMAO levels with disease severity and patients’ prognosis were investigated.ResultsIn total, 163 patients with PH were included, with a mean follow-up duration of 1.3 years. After adjusting for confounding factors, elevated TMAO levels were still associated with severe disease conditions. TMAO levels dynamically decreased in stable and improved patients after treatment [ΔTMAO = − 0.2 (− 1.6, 0.7) μmol/L, P = 0.006]. Moreover, high plasma TMAO levels predicted a poor prognosis in the PH cohort (P < 0.001), and the association remained significant after adjusting the confounders, including treatment, risk stratification, and PH subtypes.ConclusionElevated plasma TMAO levels were associated with severe disease conditions and poor prognosis in patients with PH, indicating its potential biomarker role in PH.

Pulmonary hypertension in connective tissue diseases: epidemiology, pathogenesis, and treatment.

Pulmonary hypertension (PH) is a clinical condition characterized by increased pulmonary arterial pressure arising from a heterogeneous range of diseases that has a deteriorating effect on the quality of life and may cause early mortality if left untreated. Connective tissue disorders (CTD)-associated PH is the second most common cause of pulmonary arterial hypertension (PAH), after the idiopathic form, categorized as group I. Systemic scleroderma (SSc) accounts for 75% of CTD-associated PH cases. Although SSc ranks first place for CTD-associated PH, SSc is followed by systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD), having a lesser frequency of PH occurrence, while it occurs as a rare complication in cases with rheumatoid arthritis (RA) and inflammatory myositis. PH may also occur during non-SSc CTDs and even other rheumatic diseases, including Behcet's disease and adult-onset Still's disease, albeit to a lesser extent. The prognosis of CTD-associated PH is worse than the other forms of PH. Although, as in idiopathic pulmonary arterial hypertension (IPAH), the mechanism of CTD-related PH is associated with an increase in vasoconstrictors like endothelin-1 and a decrease in vasodilators like prostacyclin and nitric oxide production, inflammation, and autoimmune mechanisms also play a role in the development and progression of PH. This may lead to the involvement of more than one mechanism in CTD-associated PH. Knowing which mechanism is dominant is very important in determining the treatment option. This review will primarily focus on the epidemiology, risk factors, and prognosis of PH that develops during rheumatic diseases; the pathogenesis and treatment will be briefly mentioned in light of the newly published guidelines. Key Points • Pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) in Western countries is the second most common type of PAH after idiopathic PAH (IPAH). • CTD-PH can be seen most often in systemic scleroderma (SSc), less in systemic lupus erythematosus (SLE), mixed CTD (MCTD), and rarely in other CTDs. • While current guidelines recommend annual transthoracic echocardiography as a screening test for asymptomatic SSc patients, screening for PH is not advised in the absence of symptoms suggestive of PH in other CTDs. • CTD-PH treatment can be divided into specific vasodilator PH treatments and immunosuppressive therapy. Current treatment guidelines recommend the same treatment algorithm for patients with CTD-associated PH as for patients with IPAH. Several case series have shown the beneficial effect of immunosuppressive agents in patients with SLE-PH and MCTD-PH.

Abstract 14089: CT Analysis of Small Pulmonary Vessels and Its Association With Pulmonary Function Tests and Prognosis in Pulmonary Hypertension

Introduction: The in vivo relationship between small pulmonary vessels (SPV) and pulmonary hypertension (PH) and its association with pulmonary function and prognosis in PH is not fully understood. Hypothesis: The morphological change in SPV volumes (SPVV) can be quantitatively estimated from CT pulmonary angiography (CTPA) in different subtypes of PH and is associated with pulmonary function metrics and prognosis in PH. Methods: : In this retrospective single center study performed from January 2008 to February 2018, quantitative CTPA analysis of total SPVV (TSPVV) (0.4-2mm vessel diameter) was performed using VIDA Diagnostics software (LungPrintTM, VIDA Diagnostics, Inc., Coralville, IA, USA). Results: 1823 patients (mean (SD) age 69 (13) years, 65% females) were analysed. 1593 patients with PH (mPAP = 43 (13) mmHg) were compared to 230 patient controls (mPAP=20 (3) mmHg). Mean small vessel volumes at a diameter below 2 mm were lower in PAH and PH associated with left heart disease compared to controls (-4.3 (-8 to -0.1) ml for 1.6 mm vessels, p=.03 and -6.8 (-11 to -2) ml, p&lt;.001, respectively). In patients with PH, the most significant positive correlation was noted with FVC%predicted (r=0.30-0.40, all p&lt;.001). Median survival for TSPVV≤1.2mm greater than 50 ml was longer than TSPVV≤1.2mm less than or equal 50 ml (85 versus 71 months, 95% C.I 73-97, p=.02, respectively). Median survival for TSPVV&gt;1.2mm greater than 135 ml was longer than TSPVV&gt;1.2mm less than or equal 135 ml (88 versus 72 months, 95% C.I 73-98, p=.02, respectively). TSPVV≤1.2mm greater than 50 ml (HR 0.851, p=.02) and TSPVV&gt;1.2mm greater than 135 ml (HR 0.839, p=.02) were significant predictors of mortality on univariate analysis. TSPVV≤1.2mm greater than 50 ml (HR 0.785, p=.04) was independent predictor of mortality on multivariate analysis in addition to age, Male gender, mRAP, PVR and SvO2. Conclusions: The morphological change in small vessels can be successfully quantified from CTPA in different subtypes of PH and is associated with pulmonary function metrics and prognosis in PH.

The hemodynamic and prognostic impact of systolic pressure change during right ventricular ejection in patients with HFREF

Abstract Background and purpose The gold-standard method to evaluate right ventricular (RV) function in pulmonary hypertension (PH) relies on invasive pressure-volume loop (PV-loop) measurement of RV-pulmonary artery (PA) coupling defined as the ratio of end-systolic RV elastance to pulmonary arterial elastance (Ees/Ea). The normal RV PV-loop has a triangular shape with a peaking early systolic pressure (early-SP). With progression of PH the PV-loop changes from trapezoid to a rectangular and ultimately to a trapezoid shape. Along with these geometric changes, the ratio between early-SP and end-systolic pressure (ESP) decreases from &amp;gt;1 to &amp;lt;1 with a late systolic peaking of RV pressure. How all these changes relate to RV afterload, RV-PA coupling, non-invasive RV function, and prognosis in PH due to left heart disease is incomplete understood. Methods We analyzed and categorized the conductance catheter-derived single-beat RV PV-loops in 133 patients with HFREF (110 patients: a post-hoc analysis of the Magdeburg CRT Responder Trial, 23 from a local PV-L-derived CRT-optimization trial) according their shape (triangular, rectangular, trapezoid), and determined the early-SP/ESP ratio. Results Using multivariate linear regression analysis (adjusted for afterload parameter PVR, PA-compliance, PCWP, PAmean), only PCWP (beta=−0.17) and PA-compliance (beta=0.61) remained significant determinants of the early-SP/ESP ratio and PV-loop shape. In turn, early-SP/ESP ratio seems to be an important determinant of RV-PA coupling efficiency (Ees/Ea) of the RV to afterload (r=0.8, p&amp;lt;0.001). The association between early-SP/ESP ratio and Ees/Ea ratio was closer than Ees/Ea ratio to the other afterload parameters Ea (r=−0.7), PVR (r=−0.41), and PA-compliance (r=0.62). Furthermore, the early-SP/ESP ratio was significantly associated with parameters of non-invasive RV function such as TAPSE (r=0.67), FAC (r=0.76), RVEF (r=0.7), and the non-invasive RV-PA coupling parameter TAPSE/PASP (r=0.8) (all p&amp;lt;0.001). In cox regression analysis, the early-SP/ESP ratio was a strong indicator for long-term survival (median FU 4.2 years) (OR 0.025, CI 95% 0.007–0.09). Simple categorization of the RV PV-loop shapes into “triangular” (early-SP/ESP ratio &amp;gt;1.1, mean survival 7.7 years), “rectangular” (0.9–1.1, 6.4 years) and “trapezoid” (&amp;lt;0.9, 3.2 years) clearly differentiated long-term survival of HFREF patients (log rank, Chi square 50.1, p&amp;lt;0.001). Conclusion The early-SP/ESP ratio determines the shape of RV-PV-loops and is closely associated with predominately pulsatile PA load, RV-PA coupling capacity, RV function, and long-term prognosis of patients with HFREF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boston Scientific

Imaging of the right ventricle in predicting the development of chronic thromboembolic pulmonary hypertension (CTEPH)

There is increasing evidence in the literature emphasizing the importance of right ventricular (RV) imaging in the prognosis of pulmonary hypertension. We aimed to investigate the predictive role of RV dysfunction parameters assessed by echocardiography (ECHO) and thorax computed tomography (CT) in developing CTEPH. We included prospectively patients diagnosed with pulmonary embolism (PE). All patients underwent ECHO and CT within 24 hours after admission. We repeated CT and ECHO after six months and one year to assess the incidence of CTEPH and the predictive role of RV dysfunction factors in the development of CTEPH. We included twenty-two patients (seven male) with a mean age of 53.9±17.9 years; CTEPH developed in two patients during the follow-up. Baseline PO2 levels were significantly lower in patients with CTEPH (61.5±11.4 vs 77.8±25.2, p&lt;0.05). The baseline RV diameter, RV EF, and systolic PAP levels evaluated by ECHO differed significantly in two patients who developed CTEPH. Two patients that developed CTEPH had the lowest RVS (-10.3% and -11.7%). This study claims that hypoxemia, decreased RV EF, RVS, increased systolic PAP values in ECHO, and increased RV/LV ratio evaluated in thorax CT indicate the severity of RV dysfunction in acute PE and may predict CTEPH development.

Stabilization of RyR2 maintains right ventricular function, reduces the development of ventricular arrhythmias, and improves prognosis in pulmonary hypertension.

Right ventricular (RV) dysfunction and its associated arrhythmias are recognized as important determinants of the prognosis of pulmonary arterial hypertension (PAH). Here, we aimed to investigate whether direct pharmacological intervention in the RV muscle with dantrolene (DAN), a stabilizer of the cardiac ryanodine receptor (RyR2), has a protective effect against RV dysfunction and arrhythmia in a monocrotaline (MCT)-induced PAH rat model. Male 8-week-old Sprague-Dawley rats were injected with MCT for the induction of PAH. Induction of ventricular tachycardia (VT) by catecholamines was also evaluated in association with RyR2-mediated Ca2+ release properties in isolated cardiomyocytes. A pulmonary artery-banding model has also been established to assess the independent effects of chronic pressure overload on RV morphology and function. In the MCT-induced PAH rat model, RV hypertrophy, dilation, and functional decline were observed, with a survival rate of 0% 2 months after MCT induction. In contrast, chronic DAN treatment improved all these RV parameters and increased survival by 80%. Chronic DAN treatment also prevented the dissociation of calmodulin from RyR2, thereby inhibiting Ca2+ sparks and spontaneous Ca2+ transients in MCT-induced hypertrophied RV cardiomyocytes. Epinephrine induced VT in more than 50% of rats with MCT-induced PAH, but complete suppression of VT was achieved by chronic DAN treatment. Stabilization of RyR2 by DAN has potential as a new therapeutic agent against the development of RV dysfunction and fatal arrhythmia associated with PAH.

Abstract 11271: Three-Dimensional Deep-Tissue Imaging of the Right Ventricle Reveals Decreased Capillary-Cardiomyocyte Contact Surface in Decompensated Right Heart Failure

Introduction: Right ventricular (RV) function determines the prognosis of pulmonary hypertension. Capillary rarefaction using 2D imaging has been proposed as the hallmark of RV failure, although this paradigm is controversially discussed. By applying 3D deep-tissue imaging, we characterized the adaptive and maladaptive response of the capillaries in the pressure-overloaded RV in hypertrophy and failure. Methods and Results: Mice subjected to pulmonary artery banding (PAB) were harvested after 3 weeks (w) (compensated RV hypertrophy) and 7w post-surgery (decompensated RV failure). Hearts were sectioned into 250 μm and capillaries were stained with isolectin B4. Samples were imaged with confocal microscopy and reconstructed into 3D using Imaris imaging software (Fig. A, n=4). In the RV free wall, mean capillary length decreased, and branching, tortuosity, mean and total capillary diameter increased 3w post-PAB. Mean and total diameter, and total length decreased at 7w resulting in a reduced capillary volume normalized to heart volume at 7w vs 3w, but not significantly reduced vs baseline suggesting that this is not the mechanism of RV failure (Fig. B). However, most strikingly we uncovered by sparsely labeling cardiomyocytes that the capillary-cardiomyocyte contact surface was maintained at w3, yet significantly decreased in areas of interstitial fibrosis in the decompensated RV at 7w compared to baseline and 3w (Fig. C, D). Conclusions: 3D deep-tissue imaging uncovered the remarkable adaptive response of the RV microvasculature in the pressure-overloaded RV to maintain an adequate capillary-cardiomyocyte contact by increasing capillary branching, length and diameter. These mechanisms failed in the decompensating RV when interstitial fibrosis impaired the capillary-cardiomyocyte interaction. Our method offers the unprecedented opportunity to study microvascular adaption in the pressure overloaded RV and is readily transferable to human tissue.

Biomarkers of Pulmonary Hypertension Are Altered in Children with Down Syndrome and Pulmonary Hypertension

To evaluate the performance of pulmonary hypertension (PH) biomarkers in children with Down syndrome, an independent risk factor for PH, in whom biomarker performance may differ compared with other populations. Serum endostatin, interleukin (IL)-1 receptor 1 (ST2), galectin-3, N-terminal pro hormone B-natriuretic peptide (NT-proBNP), IL-6, and hepatoma-derived growth factor (HDGF) were measured in subjects with Down syndrome and PH (n=29), subjects with Down syndrome and resolved PH (n=13), subjects with Down syndrome without PH (n=49), and subjects without Down syndrome with World Symposium on Pulmonary Hypertension group I pulmonary arterial hypertension (no Down syndrome PH group; n=173). Each biomarker was assessed to discriminate PH in Down syndrome. A classification tree was created to distinguish PH from resolved PH and no PH in children with Down syndrome. Endostatin, galectin-3, HDGF, and ST2 were elevated in subjects with Down syndrome regardless of PH status. Not all markers differed between subjects with Down syndrome and PH and subjects with Down syndrome and resolved PH. NT-proBNP and IL-6 levels were similar in the Down syndrome with PH group and the no Down syndrome PH group. A classification tree identified NT-proBNP and galectin-3 as the best markers for sequentially distinguishing PH, resolved PH, and no PH in subjects with Down syndrome. Proteomic markers are used to improve the diagnosis and prognosis of PH but, as demonstrated here, can be altered in genetically unique populations such as individuals with Down syndrome. This further suggests that clinical biomarkers should be evaluated in unique groups with the development of population-specific nomograms.

Cardiac catheterization in pediatric pulmonary hypertension: a systematic and practical approach.

Significant progress in the understanding of the etiology, epidemiology, pathobiology and prognosis of pulmonary hypertension (PH) has been made over the last years. Especially in the pediatric patient population the etiology of PH is very heterogeneous. Nevertheless, the most recent change of the definition of PH to a mean pulmonary artery pressure (mPAP) >20 mmHg has been accepted by pediatricians for uniformity and concordance with adult physicians. Based on the diverse underlying medical conditions leading to PH, a comprehensive and systematic approach for diagnosis and treatment is mandatory. Cardiac catheterization remains the gold standard for invasive assessment and acute vasoreactivity testing (AVT) additionally providing detailed information about nature of PH. In most patients repeat cardiac catheterization may be helpful for evaluation of response to targeted PH treatment, risk stratification and indication for lung transplantation. However, the information and results taken from cardiac catheterization should be interpreted by experienced investigators only who are familiar with confounding factors that may influence the results. Here we provide an overview of current recommendations for invasive hemodynamic evaluation in pediatric PH. We point out different patient scenarios and provide a structured approach for AVT and response interpretation.

Carbohydrate Antigen 125 Is a Biomarker of the Severity and Prognosis of Pulmonary Hypertension.

Background: Emerging evidence has showed that serum carbohydrate antigen 125 (CA 125) levels are associated with the severity and prognosis of heart failure. However, its role in pulmonary hypertension remains unclear. This study aimed to investigate the clinical, echocardiographic, hemodynamic, and prognostic associations of CA 125 in pulmonary hypertension.Methods and Results: We conducted a retrospective cohort study of all idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension patients receiving CA 125 measurement in Fuwai Hospital (January 1, 2014–December 31, 2018). The primary end-point was cumulative 1-year clinical worsening-free survival rate. Linear regression was performed to assess the association between CA 125 and clinical, echocardiographic, and hemodynamic parameters. Cox proportional hazards models were used to assess the association between CA 125 and clinical worsening events. Receiver operating characteristic (ROC) curve analysis was performed to determine the predictive performance of CA 125. A total of 231 patients were included. After adjustment, CA 125 still positively correlated with World Health Organization functional class, NT-proBNP, right ventricular end-diastolic diameter, pericardial effusion, mean right atrial pressure and pulmonary arterial wedge pressure; negatively correlated with 6-min walk distance, left ventricular end-diastolic diameter, mixed venous oxygen saturation, and cardiac index. After adjustment, CA 125 > 35 U/ml was associated with over 2 folds increased risk of 1-year clinical worsening. Further, ROC analysis showed that CA 125 provided additional predictive value in addition to the established pulmonary hypertension biomarker NT-proBNP.Conclusion: CA 125 was associated with functional status, echocardiography, hemodynamics and prognosis of pulmonary hypertension.

Extended Precordial T Wave Inversions Are Associated with Right Ventricular Enlargement and Poor Prognosis in Pulmonary Hypertension.

In pulmonary hypertension (PH), T wave inversions (TWI) are typically observed in precordial leads V1–V3 but can also extend further to the left-sided leads. To date, the cause and prognostic significance of this extension have not yet been assessed. Therefore, we aimed to assess the relationship between heart morphology and precordial TWI range, and the role of TWI in monitoring treatment efficacy and predicting survival. We retrospectively analyzed patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) treated in a reference pulmonary hypertension center. Patients were enrolled if they had a cardiac magnetic resonance (cMR) and 12-lead surface ECG performed at the time of assessment. They were followed from October 2008 until March 2021. We enrolled 77 patients with PAH and 56 patients with inoperable CTEPH. They were followed for a mean of 51 ± 33.5 months, and during this time 47 patients died (35.3%). Precordial TWI in V1–V6 were present in 42 (31.6%) patients, while no precordial TWI were observed only in 9 (6.8%) patients. The precordial TWI range correlated with markers of PH severity, including right ventricle to left ventricle volume (R = 0.76, p < 0.0001). The presence of TWI in consecutive leads from V1 to at least V5 predicted severe RV dilatation ( ≥ 2.3) with a sensitivity of 88.9% and specificity of 84.1% (AUC of 0.90, 95% CI = 0.83–0.94, p < 0.0001). Presence of TWI from V1 to at least V5 was also a predictor of mortality in Kaplan–Meier estimation (p = 0.02). Presence of TWI from V1 to at least V5 had a specificity of 64.3%, sensitivity of 58.1%, negative predictive value of 75%, and positive predictive value of 45.5% as a mortality predictor. In patients showing a reduction in TWI range of at least one lead after treatment compared with patients without this reduction, we observed a significant improvement in RV-EDV and . We concluded that the extension of TWI to left-sided precordial leads reflects significant pathological alterations in heart geometry represented by an increase in RV/LV volume and predicts poor survival in patients with PAH and CTEPH. Additionally, we found that analysis of precordial TWI range can be used to monitor the effectiveness of hemodynamic response to treatment of pulmonary hypertension.

Usefulness of strain imaging to determine prognosis in pulmonary hypertension

Abstract Introduction Pulmonary hypertension (PH) is defined as mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest, measured by right heart catheterization (RHC). Purpose To describe classical and myocardial deformation echocardiographic parameters in patients with established PH and to identify prognostic variables Methods We prospectively enrolled 76 patients with mPAP ≥25 mmHg undergoing RHC between 2017 and 2018. All subjects underwent transthoracic echocardiography (TTE) according to the latest ASE/EACVI guidelines the same day of the RHC. Strain analysis was carried out by speckle-tracking echocardiography (QLAB 10.7, Philips). Clinical events during the follow-up were: acute heart failure hospitalization, cardiac transplant and all-cause mortality. Results Mean age was 59±12, 43.4% were women and 49 patients (64.5%) belonged to group 2 of PH. The median follow-up was 288 (ICR 92–534) days. Total number of events was 42 (55.3%, 9 deaths). Variables associated to events are shown in Table 1. All classic LV and RV systolic function and strain parameters were associated with a worse prognosis, being free-wall RV longitudinal strain (RVLS) the only one that remained as a prognostic factor in mutivariate analysis. Other variables associated with a worse prognosis were PCP&amp;gt;15 mmHg and NT-proBNP&amp;gt;1800, the latter being independent predictor of events. The attached figure shows event-free survival curves for the global population divided according to whether or not they belong to group II PH. Conclusions Our data highlight the prognostic value of free-wall RVLS and NT-proBNP in patients with established PH. NT-ProBNP was only useful in group II PH while free-wall RVLS identified patients with a higher risk of events in both groups, mainly in patients with heart disease Free event survival Curves Funding Acknowledgement Type of funding source: None