Pulmonary Hypertension Due To Left Heart Disease Research Articles

Aldehyde Dehydrogenase 2 (ALDH2) rs671 Polymorphism is a Predictor of Pulmonary Hypertension Due to Left Heart Disease

Pulmonary hypertension due to left heart disease (PH-LHD) is commonly seen in patients with heart failure (HF), but there are limited treatment options. Recent studies have shown an association between aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphisms and pulmonary hypertension (PH). Therefore, this study aimed to investigate the occurrence of ALDH2 rs671 polymorphisms, and the association between ALDH2 and risk of PH-LHD in patients with HF. It also investigated different ALDH2 genotypes and examined their association with cardiac structure and function in HF patients with PH-LHD. A total of 178 HF patients were consecutively enrolled in this study: 102 without PH-LHD and 76 with PH-LHD. Clinical data, parameters of echocardiography, and relevant biochemical indexes were recorded in both groups. Differences in data obtained between groups were compared, and the risk of variant ALDH2 polymorphisms with PH-LHD in HF patients was analysed using univariate and multivariate logistic regression. The prevalence of ALDH2 rs671 GA/AA polymorphisms (variant ALDH2) was 24 of 102 patients (23.53%) in the HF without PH-LHD group, and 32 of 76 patients (42.10%) in the HF with PH-LHD group, with a statistically significant difference. Univariate and multivariate logistical regression showed that variant ALDH2 is an independent risk factor for HF combined with PH-LHD. A higher proportion of patients with variant ALDH2 in the HF with PH-LHD group had a tricuspid regurgitation velocity >2.8 m/s, and they had higher values of peak early diastolic velocity of the mitral orifice/peak velocity of the early diastolic wave of the mitral orifice, maximum frequency shift of pulmonary valve flow, and pulmonary artery stiffness. Variant ALDH2 may be an independent risk factor for HF combined with PH-LHD. Variant ALDH2 may also be involved in pulmonary artery remodelling and is a potential new target for clinical treatment of PH-LHD.

Machine learning to differentiate pulmonary hypertension due to left heart disease from pulmonary arterial hypertension.

Pulmonary hypertension due to left heart disease (PH-LHD) is the most frequent form of PH. As differential diagnosis with pulmonary arterial hypertension (PAH) has therapeutic implications, it is important to accurately and noninvasively differentiate PH-LHD from PAH before referral to PH centres. The aim was to develop and validate a machine learning (ML) model to improve prediction of PH-LHD in a population of PAH and PH-LHD patients. Noninvasive PH-LHD predictors from 172 PAH and 172 PH-LHD patients from the PH centre database at the University Hospitals of Leuven (Leuven, Belgium) were used to develop an ML model. The Jacobs score was used as performance benchmark. The dataset was split into a training and test set (70:30) and the best model was selected after 10-fold cross-validation on the training dataset (n=240). The final model was externally validated using 165 patients (91 PAH, 74 PH-LHD) from Erasme Hospital (Brussels, Belgium). In the internal test dataset (n=104), a random forest-based model correctly diagnosed 70% of PH-LHD patients (sensitivity: n=35/50), with 100% positive predicted value, 78% negative predicted value and 100% specificity. The model outperformed the Jacobs score, which identified 18% (n=9/50) of the patients with PH-LHD without false positives. In external validation, the model had 64% sensitivity at 100% specificity, while the Jacobs score had a sensitivity of 3% for no false positives. ML significantly improves the sensitivity of PH-LHD prediction at 100% specificity. Such a model may substantially reduce the number of patients referred for invasive diagnostics without missing PAH diagnoses.

The emerging role of sacubitril/valsartan in pulmonary hypertension with heart failure.

Pulmonary hypertension due to left heart disease (PH-LHD) represents approximately 65%-80% of all patients with PH. The progression, prognosis, and mortality of individuals with left heart failure (LHF) are significantly influenced by PH and right ventricular (RV) dysfunction. Consequently, cardiologists should devote ample attention to the interplay between HF and PH. Patients with PH and HF may not receive optimal benefits from the therapeutic effects of prostaglandins, endothelin receptor antagonists, or phosphodiesterase inhibitors, which are specific drugs for pulmonary arterial hypertension (PAH). Sacubitril/valsartan, the angiotensin receptor II blocker-neprilysin inhibitor (ARNI), was recommended as the first-line therapy for patients with heart failure with reduced ejection fraction (HFrEF) by the 2021 European Society of Cardiology Guidelines. Although ARNI is effective in treating left ventricular (LV) enlargement and lower ejection fraction, its efficacy in treating individuals with PH and HF remains underexplored. Considering its vasodilatory effect at the pre-capillary level and a natriuretic drainage role at the post-capillary level, ARNI is believed to have a broad range of potential applications in treating PH-LHD. This review discusses the fundamental pathophysiological connections between PH and HF, emphasizing the latest research and potential benefits of ARNI in PH with various types of LHF and RV dysfunction.

A modified primary culture method of rat pulmonary vein smooth muscle cells

BackgroundAlthough the pressure of pulmonary vein increases before pulmonary artery in pulmonary hypertension due to left heart disease (PH-LHD), only a few studies have assessed pulmonary vein smooth muscle cells (PVSMCs) because of the lack of a simple and feasible isolation method.MethodsIn this study, we introduced a simple method to obtain PVSMCs. Primary pulmonary veins were removed by puncture needle cannula guidance. Then, PVSMCs were cultured by the tissue explant method and purified by the differential adhesion method. The cells were characterized by hematoxylin-eosin (HE) staining, immunohistochemistry, western blotting, and immunofluorescence to observe the morphology and verify the expression of alpha-smooth muscle actin (α-SMA).ResultsThe HE staining results showed that the pulmonary vein media was thinner than the pulmonary artery, the intima and adventitia of the pulmonary vein were removed by this method, and the obtained cells with good activity exhibited morphological characteristics of smooth muscle cells. In addition, higher α-SMA expression was observed in the cells obtained by our isolation method than in the traditional method.ConclusionThis study established a simple and feasible method to isolate and culture PVSMCs that might facilitate the cytological experiments for PH-LHD.

Sotatercept analog improves cardiopulmonary remodeling and pulmonary hypertension in experimental left heart failure.

Pulmonary hypertension due to left heart disease (PH-LHD) is the most frequent manifestation of PH but lacks any approved treatment. Activin receptor type IIA-Fc fusion protein (ActRIIA-Fc) was found previously to be efficacious in experimental and human pulmonary arterial hypertension (PAH). Here we tested the hypothesis that ActRIIA-Fc improves pulmonary vascular remodeling and alleviates PH in models of PH-LHD, specifically in subtypes of heart failure with reduced ejection fraction (PH-HFrEF) and preserved ejection fraction (PH-HFpEF). Treatment with murine ActRIIA-Fc reduced cardiac remodeling and improved cardiac function in two mouse models of left heart disease without PH, confirming that this inhibitor of activin-class ligand signaling can exert cardioprotective effects in heart failure. In a mouse model of PH-HFrEF with prolonged pressure overload caused by transverse aortic constriction, ActRIIA-Fc treatment significantly reduced pulmonary vascular remodeling, pulmonary fibrosis, and pulmonary hypertension while exerting beneficial structural, functional, and histological effects on both the left and right heart. Additionally, in an obese ZSF1-SU5416 rat model of PH-HFpEF with metabolic dysregulation, therapeutic treatment with ActRIIA-Fc normalized SMAD3 overactivation in pulmonary vascular and perivascular cells, reversed pathologic pulmonary vascular and cardiac remodeling, improved pulmonary and cardiac fibrosis, alleviated PH, and produced marked functional improvements in both cardiac ventricles. Studies in vitro revealed that treatment with ActRIIA-Fc prevents an abnormal, glucose-induced, activin-mediated, migratory phenotype in human pulmonary artery smooth muscle cells, providing a mechanism by which ActRIIA-Fc could exert therapeutic effects in experimental PH-HFpEF with metabolic dysregulation. Our results demonstrate that ActRIIA-Fc broadly corrects cardiopulmonary structure and function in experimental PH-LHD, including models of PH-HFrEF and PH-HFpEF, leading to alleviation of PH under diverse pathophysiological conditions. These findings highlight the important pathogenic contributions of activin-class ligands in multiple forms of experimental PH and support ongoing clinical evaluation of human ActRIIA-Fc (sotatercept) in patients with PH-HFpEF.

Long-Term Follow-up of Human Immunodeficiency Virus-Associated Pulmonary Hypertension: Clinical Features and Survival Outcomes of the Pan Africa Pulmonary Hypertension Cohort (PAPUCO).

Data characterizing risk factors and long-term outcome studies on human immunodeficiency virus (HIV)-associated pulmonary hypertension (PH) in Africa are lacking. The Pan African Pulmonary Hypertension Cohort, a multinational registry of 254 consecutive patients diagnosed with PH (97% of African descent) from 9 centers in 4 African countries was implemented. We compared baseline characteristics and 3-year survival of an HIV-infected cohort newly diagnosed with PH (PH/HIV+) to an HIV-uninfected cohort with PH (PH/HIV-). One hundred thirty-four participants with PH completed follow up (47 PH/HIV+ and 87 PH/HIV-; age median, 36 versus 44 years; P = .0004). Cardiovascular risk factors and comorbidities were similar except for previous tuberculosis (62% versus 18%, P < .0001). Six-minute walk distance (6MWD) <300 meters was common in PH/HIV- (P = .0030), but PH/HIV+ had higher heart (P = .0160) and respiratory (P = .0374) rates. Thirty-six percent of PH/HIV+ and 15% of PH/HIV- presented with pulmonary arterial hypertension (PAH) (P = .0084), whereas 36% of PH/HIV+ and 72% of PH/HIV- exhibited PH due to left heart disease (PHLHD) (P = .0009). Pulmonary hypertension due to lung diseases and hypoxia (PHLD) was frequent in PH/HIV+ (36% versus 15%) but did not reach statistical significance. Human immunodeficiency virus-associated PAH tended to have a poorer survival rate compared with PHLHD/PHLD in HIV-infected patients. The PH/HIV + patients were younger and commonly had previous tuberculosis compared to PH/HIV- patients. Despite a better 6MWD at presentation, they had more signs and symptoms of early onset heart failure and a worse survival rate. Early echocardiography assessment should be performed in HIV-infected patients with history of tuberculosis who present with signs and symptoms of heart failure or posttuberculosis lung disease.

CТ densitometry as an additional method in the diagnosis of pulmonary hypertension: a prospective study

INTRODUCTION: This article presents the results of application of CT densitometry in the computed tomography (CT) of the chest to diagnose various forms of pulmonary hypertension.OBJECTIVES: To determine the diagnostic value of CT densitometry using comparative analysis of lung tissue density in patients with various forms of pulmonary hypertension.MATERIALS AND METHODS: The study included 528 patients diagnosed with pulmonary hypertension by means of right heart catheterization (RHC) of the National Research Cardiac Surgery Center, Republic of Kazakhstan. All patients were divided into 4 groups according to the classification of pulmonary hypertension of the World Health Organization (ESC/ERS Guidelines) from 2015. The first group included 254 patients with pulmonary hypertension pulmonary hypertension due to left heart disease (PHLHD). The second group included 210 patients with pulmonary arterial hypertension (PAH). The third group included 49 patients with chronic thromboembolic pulmonary hypertension (CTEPH). The fourth group — 15 patients with pulmonary hypertension due to respiratory disease (PHDRD). The mean age of the patients was 52.15±16.75 years. Contrast-enhanced chest CT imaging performed with a 64-slice multislice computed tomography system (Somatom Definition AS, Siemens) with post-processing to assess the lung tissue densitometric parameters, analyse the diameters of the pulmonary trunk and its main branches. The CT examination was carried in accordance with an «Embolism» protocol with intravenous administration of a contrast agent according to indications. Statistics: analysis was conducted using the Statistica 10 software. To quantitatively compare the two groups nonparametric Mann-Whitney test and the Kruskal-Wallace test were applied. Mean value and standard deviation in the format of «M±S» were used for quantitative parameters. Correlation analysis was carried out using Spearman’s nonparametric rank correlation.RESULTS: In patients with severe pulmonary hypertension a tendency for fibrotic changes was most clearly observed in cases of pulmonary hypertension due to left heart disease (–809.92±26.52), and emphysematous changes in the pulmonary arterial hypertension group (–843.27±43.88).CONCLUSION: CT lung densitometry should be performed in all patients with suspected pulmonary hypertension as an additional method of examination.

The role of exercise right heart catheterization to guide pulmonary hypertension therapy in older adults.

The spectrum of patients referred for suspected pulmonary arterial hypertension (PAH) includes a population with clinical features suggestive of pulmonary hypertension due to left heart disease (PH‐LHD). Even after right heart catheterization (RHC) performed at rest, it can be a challenge to identify patients who will clearly benefit from PAH drug therapy. Therefore, the objective of this study was to evaluate the role of exercise RHC to influence decisions regarding prescription of PAH drug therapy in this population. A retrospective cohort study was conducted of older adults with risk factors for PH‐LHD and suspected PH referred for exercise RHC. One year follow‐up was conducted to record clinical outcomes, all changes in PAH drug therapy, and changes in patient‐reported quality of life. The final cohort included 61 patients, mean age of 69 ± 10; 44% and 34% had a history of coronary artery disease and atrial fibrillation respectively. Exercise changed the proportional breakdown of hemodynamic diagnoses from 36% No PH, 44% PAH, and 20% PH‐LHD at rest to 15% No PH, 36% PAH, and 49% PH‐LHD. Although a significant proportion of patients were reclassified as PH‐LHD, there was an overall increase in the proportion of patients receiving PAH drug therapy, particularly for those with PAH confirmed by exercise RHC. A total of 11 PAH drug prescriptions were employed before exercise RHC increasing to 24 after (p = 0.002). Patients receiving PAH therapy demonstrated significant improvement in self‐reported quality of life. Exercise RHC appeared to influence selection of PAH drug therapy.

Pulmonary Vascular Reverse Remodeling After Left Ventricular Assist Device Implantation in Patients With Pulmonary Hypertension.

Prevalence of combined pre- and post-capillary (Cpc) pulmonary hypertension (PH) in patients with PH due to left heart disease (PH-LHD) and the long-term impact of left ventricular assist device (LVAD) implantation in patients with Cpc-PH are not fully elucidated. Eighty-nine patients with PH-LHD who underwent LVAD implantation were retrospectively analyzed. Patients were divided into two groups according to their preoperative pulmonary vascular resistance (PVR) and diastolic pressure gradient (DPG) values (Cpc-PH group, PVR >3 wood units [WU], or DPG ≥7 mmHg; isolated postcapillary [Ipc]-PH group, PVR ≤3 WU, and DPG <7 mmHg). There were 50 patients with Cpc-PH (PVR >3 WU [group A, n = 41]; PVR >3 WU and DPG ≥7 mmHg [group B, n = 8]; DPG ≥7 mmHg [group C, n = 1]), and 39 patients with Ipc-PH. Despite a successful LVAD implantation in all participants, 13 and two patients remained in groups A and B, respectively, early after LVAD implantation, whereas two patients each remained in groups A and B 1 year postoperatively. Values of PVR and DPG in the Cpc-PH group returned to normal levels by 3 years postoperatively. Over 50% of patients with PH-LHD had Cpc-PH, and PVR and DPG normalized in all participants within 3 years after LVAD implantation.

A Model of Reverse Vascular Remodeling in Pulmonary Hypertension Due to Left Heart Disease by Aortic Debanding in Rats.

Pulmonary hypertension due to left heart disease (PH-LHD) is the most common form of PH, yet its pathophysiology is poorly characterized than pulmonary arterial hypertension (PAH). As a result, approved therapeutic interventions for the treatment or prevention of PH-LHD are missing. Medications used to treat PH in PAH patients are not recommended for treatment of PH-LHD, as reduced pulmonary vascular resistance (PVR) and increased pulmonary blood flow in the presence of increased left-sided filling pressures may cause left heart decompensation and pulmonary edema. New strategies need to be developed to reverse PH in LHD patients. In contrast to PAH, PH-LHD develops due to increased mechanical load caused by congestion of blood into the lung circulation during left heart failure. Clinically, mechanical unloading of the left ventricle (LV) by aortic valve replacement in aortic stenosis patients or by implantation of LV assist devices in end-stage heart failure patients normalizes not only pulmonary arterial and right ventricular (RV) pressures but also PVR, thus providing indirect evidence for reverse remodeling in the pulmonary vasculature. Using an established rat model of PH-LHD due to left heart failure triggered by pressure overload with subsequent development of PH, a model is developed to study the molecular and cellular mechanisms of this physiological reverse remodeling process. Specifically, an aortic debanding surgery was performed, which resulted in reverse remodeling of the LV myocardium and its unloading. In parallel, complete normalization of RV systolic pressure and significant but incomplete reversal of RV hypertrophy was detectable. This model may present a valuable tool to study the mechanisms of physiological reverse remodeling in the pulmonary circulation and the RV, aiming to develop therapeutic strategies for treating PH-LHD and other forms of PH.

Risk prediction in pulmonary hypertension due to chronic heart failure: incremental prognostic value of pulmonary hemodynamics

BackgroundThere is no generally accepted comprehensive risk prediction model cooperating risk factors associated with heart failure and pulmonary hemodynamics for patients with pulmonary hypertension due to left heart disease (PH-LHD). We aimed to explore outcome correlates and evaluate incremental prognostic value of pulmonary hemodynamics for risk prediction in PH-LHD.MethodsConsecutive patients with chronic heart failure undergoing right heart catheterization were prospectively enrolled. The primary endpoint was all-cause mortality. Individual variable selection was performed by machine learning methods. Cox proportional hazards models were conducted to identify the association between variables and mortality. Incremental value of hemodynamics was evaluated based on the Seattle heart failure model (SHFM) and Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) scores.ResultsA total of 276 PH-LHD patients were enrolled, with a median follow-up time of 34.7 months. By L1-penalized regression model and random forest approach, diastolic pressure gradient (DPG) and mixed venous oxygen saturation (SvO2) were the hemodynamic predictors most strongly associated with mortality (coefficient: 0.0255 and -0.0176, respectively), with consistent significance after adjusted for SHFM [DPG: HR 1.067, 95% CI 1.024–1.113, P = 0.022; SvO2: HR 0.969, 95% CI 0.953–0.985, P = 0.002] or MAGGIC (DPG: HR 1.069, 95% CI 1.026–1.114, P = 0.011; SvO2: HR 0.970, 95% CI 0.954–0.986, P = 0.004) scores. The inclusion of DPG and SvO2 improved risk prediction compared with using SHFM [net classification improvement (NRI): 0.468 (0.161–0.752); integrated discriminatory index (IDI): 0.092 (0.035–0.171); likelihood ratio test: P < 0.001] or MAGGIC [NRI: 0.298 (0.106–0.615); IDI: 0.084 (0.033–0.151); likelihood ratio: P < 0.001] scores alone.ConclusionIn PH-LHD, pulmonary hemodynamics can provide incremental prognostic value for risk prediction.Clinical trial registration: NCT02164526 at https://clinicaltrials.gov.

Animal models of pulmonary hypertension due to left heart disease.

Pulmonary hypertension due to left heart disease (PH‐LHD) is regarded as the most prevalent form of pulmonary hypertension (PH). Indeed, PH is an independent risk factor and predicts adverse prognosis for patients with left heart disease (LHD). Clinically, there are no drugs or treatments that directly address PH‐LHD, and treatment of LHD alone will not also ameliorate PH. To target the underlying physiopathological alterations of PH‐LHD and to develop novel therapeutic approaches for this population, animal models that simulate the pathophysiology of PH‐LHD are required. There are several available models for PH‐LHD that have been successfully employed in rodents or large animals by artificially provoking an elevated pressure load on the left heart, which by transduction elicits an escalated pressure in pulmonary artery. In addition, metabolic derangement combined with aortic banding or vascular endothelial growth factor receptor antagonist is also currently applied to reproduce the phenotype of PH‐LHD. As of today, none of the animal models exactly recapitulates the condition of patients with PH‐LHD. Nevertheless, the selection of an appropriate animal model is essential in basic and translational studies of PH‐LHD. Therefore, this review will summarize the characteristics of each PH‐LHD animal model and discuss the advantages and limitations of the different models.

Evaluation of Lung Glucose Uptake with Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/CT in Patients with Pulmonary Arterial Hypertension and Pulmonary Hypertension Due to Left Heart Disease.

Aim: Previous studies have demonstrated increased glucose uptake by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in lung parenchyma in animal models or small pulmonary arterial hypertension (PAH) cohorts. However, it is not well known whether increased FDG uptake in the lung is a unique phenomenon in PAH or whether elevated pulmonary artery pressure (PAP) induces FDG uptake. Methods and results: Nineteen patients with PAH, 8 patients with pulmonary hypertension due to left heart disease (PH-LHD), and 14 age matched control subjects were included. All PH patients underwent right heart catheterization and FDG-PET. The mean standard uptake value (SUV g/mL) of FDG in each lung was obtained and average values of both lungs were calculated as mean lung FDG SUV. The correlation between hemodynamics and mean lung FDG SUV was also analyzed in PH patients. Mean PAP (mPAP) was not significantly different between PAH and PH-LHD (45±11 vs 43±5 mmHg, p=0.51). PAH patients demonstrated significantly increased mean lung FDG SUV compared with PH-LHD and controls (PAH: 0.76±0.26 vs PH-LHD: 0.51±0.12 vs controls: 0.53±0.16, p=0.0025). The mean lung FDG SUV did not correlate with mPAP either in PAH or PH-LHD. Conclusion: PAH is associated with increased lung FDG uptake indicating increased glucose utilization in the lung. This may represent metabolic shift to glycolysis and/or active inflammation in the remodeled pulmonary vasculature, and is observed to a greater extent in PAH than in patients with PH secondary to LHD and control subjects without PH.

Emerging therapies: The potential roles SGLT2 inhibitors, GLP1 agonists, and ARNI therapy for ARNI pulmonary hypertension.

Pulmonary hypertension (PH) is a highly morbid condition. PH due to left heart disease (PH‐LHD) has no specific therapies and pulmonary arterial hypertension (PAH) has substantial residual risk despite several approved therapies. Multiple lines of experimental evidence link metabolic dysfunction to the pathogenesis and outcomes in PH‐LHD and PAH, and novel metabolic agents hold promise to improve outcomes in these populations. The antidiabetic sodium–glucose cotransporter 2 (SGLT2) inhibitors and glucagon‐like peptide‐1 (GLP1) agonists targeting metabolic dysfunction and improve outcomes in patients with LHD but have not been tested specifically in patients with PH. The angiotensin receptor/neprilysin inhibitors (ARNIs) produce significant improvements in cardiac hemodynamics and may improve metabolic dysfunction that could benefit the pulmonary circulation and right ventricle function. On the basis of promising preclinical work with these medications and clinical rationale, we explore the potential of SGLT2 inhibitors, GLP1 agonists, and ARNIs as therapies for both PH‐LHD and PAH.

Evaluation of Pulmonary Hypertension Using 4D Flow MRI.

Cardiac magnetic resonance imaging (MRI) is becoming an alternative to right heart catheterization (RHC) for evaluating pulmonary hypertension (PH). A need exists to further evaluate cardiac MRI's ability to characterize PH. To evaluate the potential for four-dimensional (4D) flow MRI-derived pulmonary artery velocities to characterize PH. Prospective case-control. Fifty-four PH patients (56% female); 25 controls (36% female). 1.5 T; gradient recalled echo 4D flow and balanced steady-state free precession cardiac cine. RHC was used to derive patients' pulmonary vascular resistance (PVR). 4D flow measured blood velocities at the main, left, and right pulmonary arteries (MPA, LPA, and RPA); cine measured ejection fraction, end diastolic, and end systolic volumes (EF, EDV, and ESV). EDV and ESV were normalized (indexed) to body surface area (ESVI and EDVI). Parameters were evaluated between, and within, PH subgroups: pulmonary arterial hypertension (PAH); PH due to left heart disease (PH-LHD)/chronic lung disease (PH-CLD)/or chronic thrombo-emboli (CTE-PH). Analysis of variance and Kruskal-Wallis tests compared parameters between subgroups. Pearson's r assessed velocity, PVR, and volume correlations. Significance definition: P < 0.05. PAH peak and mean velocities were significantly lower than in controls at the LPA (36 ± 12 cm/second and 20 ± 4 cm/second vs. 59 ± 15 cm/second and 32 ± 9 cm/second). At the RPA, mean velocities were significantly lower in PAH vs. controls (27 ± 6 cm/second vs. 40 ± 9 cm/second). Peak velocities significantly correlated with right ventricular EF at the MPA (r=0.286), RPA (r=0.400), and LPA (r=0.401). Peak velocity significantly correlated with right ventricular ESVI at the RPA (r=-0.355) and LPA (r=-0.316). Significant correlations between peak velocities and PVR were moderate at the LPA in PAH (r=-0.641) and in PH-LHD (r=-0.606) patients, and at the MPA in PH-CLD (r=-0.728). CTE-PH showed non-significant correlations between peak velocity and PVR at all locations. Preliminary findings suggest 4D flow can identify PAH and track PVR changes. 1 TECHNICAL EFFICACY: Stage 5.

PULMONARY TO SYSTEMIC PULSATILE AND RESISTIVE VASCULAR RESPONSES TO EXERCISE IN PATIENTS WITH PULMONARY HYPERTENSION SECONDARY TO LEFT HEART DISEASE (HFPEF)

<h3>BACKGROUND</h3> Systemic and pulmonary arterial stiffening with age are said to be linked, and contribute towards the development of pulmonary hypertension (PH) with age. Systemic arterial stiffening may contribute to the development of PH due to left heart disease (PH-LHD). However, the relationships between the systemic and pulmonary circuit have not been as well described in populations with pulmonary hypertension. Exercise during right heart catheterization (RHC) is used to discriminate between PH-LHD and pulmonary arterial hypertension (PAH). In this study we aimed to describe the relationships between pulmonary and systemic compliance (a measure of vascular stiffening, also referred to as pulsatile loading) and vascular resistance (a measure of resistive loading) at rest and during exercise RHC, in patients with normal hemodynamics, PH-LHD and PAH. We hypothesized that systemic and pulmonary arterial stiffening would be linked in PH-LHD but not PAH. <h3>METHODS AND RESULTS</h3> A retrospective hemodynamic analysis was conducted using data from 80 individuals (50% female, 59±15 years) with dyspnea and/or suspected pulmonary hypertension who underwent RHC and a bout of semi-upright submaximal cycling. Exercise hemodynamic classifications were as follows: Normal – change in mean pulmonary artery pressure (mPAP) over cardiac output (CO)(ΔmPAP/ΔCO ≥3.2 woods units (WU)), Exercise PAH - ΔmPAP/ΔCO >3.2WU and exercise pulmonary arterial wedge pressure (PAWP) < 20mmHg, and Exercise PH-LHD - ΔmPAP/ΔCO >3.2WU and PAWP >20mmHg with exercise. Proportional relationships between pulsatile load in the pulmonary vs. systemic circuit are displayed in Table 1. There was a significantly greater increase in the pulmonary pulse pressure (PPP) to systemic pulse pressure (SPP) (73±40% to 93±51% vs. 51±29% to 63±36%, p < 0.001) and pulmonary vascular resistance (PVR) to systemic vascular resistance (SVR) (26±16% to 39±27% vs. 14±11% to 25±18%, p < 0.01) from rest to exercise in the PAH group when compared to PH-LHD. Otherwise, there were no differences in the total pulmonary resistance (TPulmR) to total peripheral resistance (TPR) ratio. There was a significant correlation between pulmonary (PulmCp) and systemic compliance (SysCp), both at rest (r2=0.33, p < 0.01) and during exercise (r2=0.16, p=0.05), in the PH-LHD group (Figure 1). <h3>CONCLUSION</h3> The proportional vascular loads between the pulmonary and systemic circulations differ as expected between PAH and PH-LHD. However, the net proportional resistive load (TPulmR/TPR) was very similar. There was a significant relationship between systemic and pulmonary stiffening (pulsatile load) at rest and exercise only in the PH-LHD group, which provides support for the hypothesis that systemic arterial stiffening is a mechanism that promotes the development of PH-LHD.

RIGHT VENTRICULAR - PULMONARY VASCULAR COUPLING DURING EXERCISE IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION OR PULMONARY HYPERTENSION DUE TO LEFT HEART DISEASE

<h3>BACKGROUND</h3> Pulmonary hypertension (PH) is a state of high afterload to the right ventricle (RV), which is described as afterload sensitive. The purpose of this study was to examine the effect of exercise on the relationship between RV systolic performance [measured as end-systolic elastance (Ees)], and RV afterload [measured as pulmonary arterial (PA) elastance (Ea)] between 2 groups of patients with pulmonary arterial hypertension (PAH) or PH due to left heart disease (PH-LHD). <h3>METHODS AND RESULTS</h3> Patients with suspected PH underwent right heart catheterization with cycle-ergometry and classified by their exercise hemodynamic responses: 1) Normal 2) PAH and 3) PH-LHD. RV, right atrium (RA), and PA pressures were recorded continuously and analyzed offline. As our lab previously reported, RV Ees and PA Ea were calculated using the single-beat method, and Ees:Ea ratio expresses RV-PA coupling. Ees:Ea is defined as uncoupled if < 0.8. Results were analyzed at semi-upright rest and exercise. Data is presented as Mean ± SD or Median [25th – 75th Percentiles]. We included 40 patients (35%Female; 58±15 years); exercise hemodynamic classification comprised 18 Normal, 11 PAH, and 11 PH-LHD. At rest Ea and Ees were significantly elevated in PAH (0.45[0.38-0.98], p=0.002 and 0.85[0.65-1.20], p=0.003) and PH-LHD (0.51[0.32-0.67], p=0.001 and 0.74[0.39-1.20], p=0.017) vs. Normal (0.22[0.17-0.27] and 0.41[0.29-0.54]). Ea increased significantly with exercise in PAH (0.60[0.51-1.36], p=0.003) and PH-LHD (0.59[0.37-0.91], p=0.002) compared to Normal (0.29[0.21-0.36]). Exercise was associated with a significant decline in Ees:Ea ratio in PH-LHD (∆-0.23±0.72, p=0.022). Ees:Ea ratio was uncoupled at rest/exercise in 6% of the Normal group, 55% of the PAH group and 36% of the PH-LHD group. Figure 1 illustrates the trend to Ees:Ea uncoupling if Ea increased by more than 0.2mmHg/mL. Compared to patients with preserved Ees:Ea coupling, patients with PH and Ees:Ea uncoupling with exercise demonstrated significantly higher increases in RA pressures (∆9±5mmHg vs ∆4±3mmHg, p=0.012) and more impaired stroke volume indexed to body surface area (∆3±9mL/m2 vs ∆12±8mL/m2 p=0.032). <h3>CONCLUSION</h3> During exercise, RV afterload increases in patients with PAH and PH-LHD. In both PH groups, the proportion of patients with Ees:Ea uncoupling was high, and the decline in Ees:Ea ratio reached statistical significance in PH-LHD. Uncoupling of the Ees:Ea ratio occurred with larger increases in Ea and was associated with evidence of impaired RV systolic and diastolic function with exercise. Limiting the increase in Ea with exercise and/or preservation of Ees:Ea coupling may optimize RV function in PH patients.

SIGNIFICANCE OF THE PASSIVE LEG RAISING TEST IN THE DIAGNOSIS OF PULMONARY HYPERTENSION DUE TO LEFT HEART DISEASES IN SYSTEMIC SCLEROSIS

TOPIC: Pulmonary Vascular Disease TYPE: Original Investigations PURPOSE: The association between systemic sclerosis and pulmonary hypertension (PH) is well established. Patients with systemic sclerosis (SSc) are usually older than 50 years, therefore, along with pulmonary arterial hypertension (PAH), they often have PH due to left heart disease (PH-LHD). Some patients with left ventricular diastolic dysfunction may have normal resting pulmonary artery wedge pressure (PAWP) and this bears the potential of misclassifying post-as pre-capillary PH if the PAWP should be lowered to a value below 15 mm Hg. It is very important, that pulmonary vasodilator drugs approved for PAH may have deleterious effects or be ineffective if administered to patients with LHD. In this context, in cases of borderline PAWP (13–15 mm Hg) a "volume challenge" (500 ml of saline within 5–10 min) has been proposed to reverse the "occult LHD", but the therapeutic consequences of such testing remain unclear. In acute circulatory failure, passive leg raising (PLR) is a test that predicts whether the cardiac output will increase with volume expansion. By transferring a volume of around 300 mL of venous blood from the lower body toward the right heart, PLR mimics a fluid challenge.The aim of this study to investigate the possibility of PLR test in the differentiation between PAH and PH due to left heart disease in patients with "normal" PAWP. METHODS: PLR test is applied during 77 catheterizations in 69 patients with SSc and PH, among them 14 patients with established PH-LHD and 55 patients with precapillary PH (45 with PAH, 10 with PH, associated with SSc interstitial lung diseases). The hemodynamic parameters were measured before the test, and on 5 and 10 minutes during the test. It was found that the maximum increase in PAWP occurred 10 minutes from the start of the test. The diagnosis of PH-LHD was established in the presence of lesions of the left heart (CHD or subclinical cardiomyopathy), identified using echocardiography, coronary angiography, and heart MRI. RESULTS: PAWP level was 12 (7; 14) mm Hg at PH-LHD and 8.5 (6; 12) mm Hg, p = 0.06) at patients with PAH. Logistic regression analysis showed that the main differences between the groups were in the age of the patients (OR 1,06 95% CI 1,00-1,12, p 0,036), the PAWP level before the test (OR 1,15 95% CI 1,00 – 1,31, p=0,04), and the increase in PAWP during the test (OR 1,28 95% CI 1,10-1,47, p=0,001). The ROC analysis of PAWP increasing in these two groups showed the area under the curve was 0.837 (0.737; 0,937), p < 0,0001. The cut-off of the PAWP raise was 4 mm Hg with a sensitivity of 82% and a specificity of 73%. CONCLUSIONS: It is advisable to study the PLR ??test for differential diagnosis of PAH and PH-LHD, as a safer and more affordable method. CLINICAL IMPLICATIONS: none DISCLOSURES: No relevant relationships by Ildar Kurmukov, source=Web Response No relevant relationships by Eugene Nasonov, source=Web Response No relevant relationships by Ekaterina Nikolaeva, source=Web Response No relevant relationships by Alexander Volkov, source=Web Response

Impact of the new definition of pulmonary hypertension according to world symposium of pulmonary hypertension 2018 on diagnosis of post-capillary pulmonary hypertension

Background:The World Symposium on Pulmonary Hypertension (WSPH) in 2018 recommended new definitions of pulmonary hypertension (PH). We investigated the impact of the updated definition on prevalence of PH due to left heart disease (PH-LHD).Methods:The data of right heart catheterizations in patients with suspected PH-LHD between January 2008 and July 2015 was retrospectively analyzed applying different definitions. The number of patients diagnosed by the updated WSPH hemodynamic criteria of a mean pulmonary artery pressure (mPAP) > 20 mmHg was compared to the number of patients using mPAP ≥ 25 mmHg. The differentiation between patients with isolated post-capillary (Ipc) and combined post-capillary and pre-capillary (Cpc) PH was analyzed comparing the ESC/ERS guidelines, the recommendation of Cologne Consensus Conference (CCC) and WSPH.Results:Of the 726 patients with a suspected PH, 58 patients met the diagnostic criteria of the ESC/ERS guidelines for PH-LHD with 32.8% Ipc-cases, 34.4% Cpc-PH-cases and 32.8% unclassifiable cases. Overall, 58 patients were diagnosed by the CCC criteria, with 34.5% classified as Cpc-PH and 65.5% as Icp-PH. Using the criteria of WSPH, the number of PH-LHD rose by one patient. According to the new definition, 64.4% of the patients were classified as Cpc-PH and had a significantly higher right to left atrial area (RA/LA) ratio than Ipc-PH patients.Conclusion:Applying the new recommendation, the number of diagnosed patients with PH-LHD increases marginally. There is, however, a relevant shift in the number of Cpc-PH cases. An elevated RA/LA ratio might help to identify patients for invasive diagnostic work-up.

Pulmonary Vascular Reverse Remodeling in Combined Post and Pre Capillary Pulmonary Hypertension Occurs Over Time after Left Ventricular Assist Device Implantation

Purpose Left ventricular assist device (LVAD) has been reported to improve pulmonary hypertension (PH) due to left heart disease (PH-LHD). However, prevalence of combined post- and pre-capillary PH (Cpc-PH) in patients with PH-LHD and the impact of LVAD implantation on Cpc-PH has not been fully elucidated. This study aimed to investigate hemodynamic changes following LVAD implantation in patients with PH-LHD to assess pulmonary vascular reverse remodeling. Methods Eighty-nine patients with advanced heart failure complicated by PH-LHD undergoing LVAD implantation who received serial right heart catheterizations at least 3 time points (before, early after, and 1-year after implantation) were retrospectively reviewed. Patients were divided into 2 groups as Cpc-PH group (n=50): pulmonary vascular resistance (PVR) > 3 Wood unit (WU) or diastolic pulmonary pressure gradient (DPG) ≥ 7 mmHg, and isolated post-capillary PH (Ipc-PH) group (n=39). Results Values of brain natriuretic peptide and transaminase in Cpc-PH group were higher than those in Ipc-PH group. Cpc-PH patients were consisted of 41 with PVR > 3 WU, 8 with PVR > 3 WU and DPG ≥ 7 mmHg, and 1 with DPG ≥ 7 mmHg preoperatively. Median values of PVR in both groups significantly decreased early after LVAD implantation [from 4.1 to 2.7 WU (p 3 WU (n=14) or DPG ≥ 7 mmHg (n=1) at that point. Among these 15 patients, 4 patients still remained on their PVR > 3 WU (n=3) or DPG ≥ 7 mmHg (n=1) even 1-year after LVAD implantation. PVR and DPG in these 4 patients turned to normal values at 3-year after implantation. Conclusion Over half of patients with PH-LHD were complicated by Cpc-PH in our study cohort. LVAD implantation readily improved hemodynamics regardless of complication of Cpc-PH, whereas 15 patients were still found to be PVR > 3 WU or DPG ≥ 7 mmHg which should be considered as persistent Cpc-PH. We speculate that most of Cpc-PH in patients with PH-LHD might be caused by alteration of vascular tone which will be promptly relieved by substantial left ventricular unload, however a certain number of patients with Cpc-PH might develop structural remodeling of pulmonary vasculature which requires months or years to achieve pulmonary vascular reverse remodeling.