Rodent Models of Group 1 Pulmonary Hypertension

Pulmonary hypertension (PH) is associated with meta-inflammation related to obesity but the role of adipose tissue in PH pathogenesis is unknown. We hypothesized that adipose tissue-derived metabolic regulators are altered in human and experimental PH. We measured circulating levels of fatty acid binding protein 4 (FABP-4), fibroblast growth factor -21 (FGF-21), adiponectin, and the mRNA levels of FABP-4, FGF-21, and peroxisome proliferator-activated receptor γ (PPARγ) in lung tissue of patients with idiopathic PH and healthy controls. We also evaluated lung and adipose tissue expression of these mediators in the three most commonly used experimental rodent models of pulmonary hypertension. Circulating levels of FABP-4, FGF-21, and adiponectin were significantly elevated in PH patients compared to controls and the mRNA levels of these regulators and PPARγ were also significantly increased in human PH lungs and in the lungs of rats with experimental PH compared to controls. These findings were coupled with increased levels of adipose tissue mRNA of genes related to glucose uptake, glycolysis, tricarboxylic acid cycle, and fatty acid oxidation in experimental PH. Our results support that metabolic alterations in human PH are recapitulated in rodent models of the disease and suggest that adipose tissue may contribute to PH pathogenesis.

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Abstract 15193: Pulmonary Hypertension in Pregnancy: WHO Group 1 Outcomes Improved, Time to Focus on WHO Group 2

Circulation ◽

10.1161/circ.142.suppl_3.15193 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

William H Marshall ◽

Stephen Gee ◽

Woobeen Lim ◽

Elisa A Bradley ◽

Lauren Lastinger ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Post Partum ◽

Systolic Pressure ◽

Adverse Outcomes ◽

Cardiac Events ◽

Ventricular Systolic Pressure ◽

Group 5 ◽

Group 2 ◽

In Pregnancy ◽

Group 1

Introduction: Pregnancy is contraindicated in women with pulmonary hypertension (PH), yet many still decide to pursue pregnancy. Hypothesis: We hypothesized improved maternal mortality with PH at our center’s cardio-obstetrics program and sought to identify factors to estimate the risk of major adverse cardiac events (MACE). Methods: Pregnant women with right ventricular systolic pressure (RVSP) ≥35 mmHg or tricuspid regurgitant velocity > 2.8 m/s on transthoracic echocardiogram (TTE) were identified. Women with intermediate to high probability PH by ESC criteria (TTE or catheterization, n = 70) were classified using the 6 th World Society of PH definitions. Results: In 70 women with PH (30 ± 6 years-old, RVSP 52 ± 16 mmHg) there were 12 (17%) with WHO Group 1 PH, 45 (64%) with Group 2 PH, 4 (6%) with Group 3 PH and 9 (13%) with Group 5 PH (Figure A). Baseline characteristics were similar except: Group 1 PH had 83% on prostacyclin (PC) therapy, higher RVSP (78 ± 20 mmHg vs. Groups 2 (46 ± 9), 3 (44 ± 2 mmHg) and 5 PH (48 ± 10mmHg), p<0.01), and compared to Group 2 PH, more Group 1 PH women were diagnosed pre-pregnancy (9 (75%) vs. 12 (27%), p = 0.01) and had cardio-obstetrics care (10 (83%) vs. 16 (36%), p < 0.01) (Figure B - E). There were no peripartum deaths, however 3 (4.3%) women with Group 2 PH had late mortality (7 ± 4 months post-partum). MACE occurred in 24 (34%) women and was more likely in those with: NYHA FC ≥ 2 (95% CI 4.7-57, p < 0.01), pre-eclampsia (95% CI 1.2-13, p = 0.03), RVSP >50 mmHg (95% CI 1.3-10, p = 0.02) and LVEF <50% (95% CI 1.1-8.8, p = 0.04) (Figure F). Preterm birth occurred in 32 (49%) pregnancies, with no neonatal mortality. Conclusion: To conclude, in a large single center cohort we report 100% 1-year survival in Groups 1, 3, and 5 PH, with most Group 1 PH patients on PC therapy and under cardio-obstetrics care. We identify Group 2 PH as an under-recognized group for adverse outcomes in pregnancy, with NYHA FC, pre-eclampsia, RVSP >50 mmHg and LVEF <50% associated with increased MACE.

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How is juvenile rheumatic heart disease different: baseline results from a prospective north Indian registry

European Heart Journal ◽

10.1093/ehjci/ehaa946.1898 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

K Mahajan ◽

D.R Prakash Chand Negi

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Pulmonary Hypertension ◽

Heart Disease ◽

Funding Source ◽

Thromboembolic Events ◽

Group 3 ◽

Group 2 ◽

Rheumatic Heart ◽

Group 1

Abstract Introduction Juvenile rheumatic heart disease (RHD) refers to RHD in patients <20 years of age. There are no contemporary data highlighting the differences between juvenile and older RHD patients. Purpose We aim to report the age related differences in the pattern, and consequencies of valvular dysfunction in patients of RHD. Methods The 2475 consecutive patients of RHD diagnosed using clinical and echocardiographic criteria were registered prospectively from 2011 till December 2019. Patients were divided into 3 groups according to their age: Group 1 (Juvenile RHD), Group 2 (21–50 years), and Group 2 (>51 years).The data concerning the socio-demographic and clinical profile were recorded systematically, and the nature and severity of valvular dysfunction was assessed by echocardiography. The data were analyzed using the Epi-InfoTM Software. Results Out of 2475 RHD patients, Juvenile RHD comprised of 211 (8.5%) patients. Group 2 and 3 comprised of 1691 (68.3%) and 573 (23.2%) patients respectively. Overall, 1767 (71.4%) patients were females, however this female predilection was less pronounced in juvenile RHD (55.5% females vs 44.5% males) as compared to older groups. Past history of acute rheumatic fever was more commonly recorded in Juvenile RHD group (37.9% vs 18.8% in group 2 and 10% in group 3, p=0.0001). At the time of registration, the presence of advanced heart failure symptoms (dyspnea class III and IV) (11.4% group 1 vs 13.9% group 2 vs 20.6% group 3, p<0.0001), right heart failure symptoms (0.9% group 1 vs 2.5% group 2 vs 7.3% group 3, p<0.01), thromboembolic events (0% group 1 vs 4.1% group 2 vs 3.3% group 3, p<0.01), atrial fibrillation (2.8% group 1 vs 24.5% group 2 vs 45.9% group 3, p<0.0001), and pulmonary hypertension (27.1% group 1 vs 40.3% group 2 vs 51.9% group 3, p<0.01), were all more commonly recorded in non-juvenile older RHD groups. Multivalvular involvement was also less common in juvenile RHD (34.6% vs 42.4% and 44.5%, p=0.04). Mitral regurgitation was the most common lesion in Juvenile RHD followed by aortic regurgitation (68.7% and 40.2% respectively). Stenotic lesions (both mitral and aortic) were present more commonly in older age groups. Conclusion RHD is predominantly a disease of females, however the predilection is less common in juvenile patients. Juvenile RHD predominantly affects the mitral valve and mainly leads to regurgitant lesions. As the age advances, the complications of RHD, mainly heart failure symptoms, thromboembolic events, pulmonary hypertension, and atrial fibrillation, become more common. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Self sponsored registry

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Abstract 16078: Pulmonary Vasculopathy Assessed By Intravascular Ultrasound in Persistent Pulmonary Hypertension After Mitral Valve Replacement, Comparation to Idiopathic Pulmonary Arterial Hypertension and Healthy Controls

Circulation ◽

10.1161/circ.132.suppl_3.16078 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Juan Carlos J Grignola ◽

Leticia L Fernandez-Lopez ◽

Enric E Domingo-Ribas ◽

Rio R Aguilar ◽

Cristian Humberto C Arredondo ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Elastic Modulus ◽

Mitral Valve ◽

Valve Replacement ◽

Mitral Valve Replacement ◽

Persistent Pulmonary Hypertension ◽

Pulmonary Arterial ◽

Group 3 ◽

Group 2 ◽

Group 1

Purpose: The aim of the study is to assess pulmonary vasculopathy (wall fibrosis, pulmonary arterial pulsatility and elastic modulus ) in patients with persistent pulmonary hypertension (pulmonary systolic pressure by ECHO > 50 mmhg ) at least 1 year after mitral valve replacement with normal function of the valve. The evaluation was carried out by intravascular ultrasound (IVUS) in medium sized pulmonary arteries. We compared three groups: Group 1 ( persistent pulmonary hypertension after mitral valve replacement), Group 2 (pulmonary hypertension belonging to the group 1 of the Dana Point classification) and Group 3 (healthy controls). Methods: We studied 43 patients, 15 in Group 1 , 18 Group 2 and 10 in Group 3. Group 1: 13 females, the mean age of this group was 74+-7 years; Group 2: 14 females, 53+-14 years and Group 3: 6 females, 51+-5 years. All patients were submitted to left and right heart catheterization, and IVUS in medium sized elastic PA ( 2-3 mm diameter ) of the inferior lobes. Studied variables were: mean pulmonary artery pressure (PAP, mm Hg), pulmonary wedge pressure, aortic pressure, cardiac output (CO,l/min), pulmonary vascular resistance (PVR, Wood Units), IVUS pulsatility and elastic modulus (EM,mm Hg). Local pulsatility was estimated by IVUS: (systolic- diastolic lumen area/ diastolic lumen area) X 100. PA stiffness was assessed by the elastic modulus (EM= pulse pressure/ IVUSp). Results: In Group 3 all variables were statistically different from the other 2 groups (p<0.01). Variables are shown in table. Conclusions: Group 1, even with a lower mean PAP than Group 2 (p<0.05) showed a similar anatomical ( wall fibrosis ) and similar functional wall remodeling ( EM ).

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The incremental shuttle walk test predicts mortality in non-group 1 pulmonary hypertension: results from the ASPIRE Registry

Pulmonary Circulation ◽

10.1177/2045894019848649 ◽

2019 ◽

Vol 9 (2) ◽

pp. 204589401984864 ◽

Cited By ~ 1

Author(s):

Catherine G. Billings ◽

Robert Lewis ◽

Judith A. Hurdman ◽

Robin Condliffe ◽

Charlie A. Elliot ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Ceiling Effect ◽

Walk Test ◽

Limited Information ◽

Pulmonary Hemodynamics ◽

Disease Etiology ◽

Invasive Test ◽

Group 2 ◽

Test Distance ◽

Group 1

Pulmonary hypertension (PH) is classified into five groups based on disease etiology but there is only limited information on the prognostic value of exercise testing in non-group 1 PH. In group 1 PH, the incremental shuttle walking test (ISWT) distance has been shown to correlate with pulmonary hemodynamics and predict survival without a ceiling effect. This study assessed the ISWT in non-group 1 PH. Data were retrieved from the ASPIRE Registry (Assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre) for consecutive patients diagnosed with PH. Patients were required to have been systematically assessed as group 2–5 PH and to have a baseline ISWT within three months of cardiac catheterization. Patients were stratified according to incremental shuttle walk test distance (ISWD) and ISWT distance percent predicted (ISWD%pred). A total of 479 patients with non-group 1 PH were identified. ISWD and ISWD%pred correlated significantly with symptoms and hemodynamic severity. ISWD and ISWD%pred predicted survival with no ceiling effect. The test was prognostic in groups 2, 3, and 4. ISWD and ISWD%pred and change in ISWD and ISWD%pred at one year were all significant predictors of outcome. In patients with non-group 1 PH the ISWT is a simple non-invasive test that is easy to perform, is predictive of survival at baseline and follow-up, reflects change, and can be used in the assessment of PH of any etiology.

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Hemodynamically Derived Pulmonary Artery Pulsatility Index Predicts Adverse Clinical Outcomes in Group 1 Pulmonary Hypertension. (Analysis of the NIH Pulmonary Hypertension Registry)

Journal of Cardiac Failure ◽

10.1016/j.cardfail.2016.06.022 ◽

2016 ◽

Vol 22 (8) ◽

pp. S3-S4

Author(s):

Timothy S. Welch ◽

Kenneth C. Bilchick ◽

Jamie L.W. Kennedy ◽

David X. Zhuo ◽

LaVone A. Smith ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Artery ◽

Clinical Outcomes ◽

Pulsatility Index ◽

Group 1

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Distinguishing Group 1 Pulmonary Hypertension From Group 2 With Use of Ultrasonography

CHEST Journal ◽

10.1016/j.chest.2017.08.1028 ◽

2017 ◽

Vol 152 (4) ◽

pp. A991

Author(s):

Alexander Fe ◽

Paul Kristan Valestra ◽

Anish Desai ◽

Naveen Tyagi ◽

Maekel Elyasi ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Group 2 ◽

Group 1

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Circulating Plasma Metabolomic Profiles Differentiate Rodent Models of Pulmonary Hypertension and Idiopathic Pulmonary Arterial Hypertension Patients

American Journal of Hypertension ◽

10.1093/ajh/hpz121 ◽

2019 ◽

Vol 32 (11) ◽

pp. 1109-1117

Author(s):

Jun-Han Zhao ◽

Yang-Yang He ◽

Shan-Shan Guo ◽

Yi Yan ◽

Zhe Wang ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Progressive Disease ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Rodent Models ◽

Preclinical Models ◽

Metabolic Dysregulation ◽

Pulmonary Arterial ◽

Significant Pathway

Abstract BACKGROUND Pulmonary arterial hypertension (PAH) is a severe progressive disease with systemic metabolic dysregulation. Monocrotaline (MCT)-induced and hypoxia-induced pulmonary hypertension (PH) rodent models are the most widely used preclinical models, however, whether or not these preclinical models recapitulate metabolomic profiles of PAH patients remain unclear. METHODS In this study, a targeted metabolomics panel of 126 small molecule metabolites was conducted. We applied it to the plasma of the 2 preclinical rodent models of PH and 30 idiopathic pulmonary arterial hypertension (IPAH) patients as well as 30 healthy controls to comparatively assess the metabolomic profiles of PAH patients and rodent models. RESULTS Significantly different metabolomics profiling and pathways were shown among the 2 classical rodent models and IPAH patients. Pathway analysis demonstrated that methionine metabolism and urea cycle metabolism were the most significant pathway involved in the pathogenesis of hypoxia-induced PH model and MCT-induced model, respectively, and both of them were also observed in the dysregulated pathways in IPAH patients. CONCLUSIONS These 2 models may develop PAH through different metabolomic pathways and each of the 2 classical PH model resembles IPAH patients in certain aspects.

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1409Use of phenomapping to determine response of treatment by sacubitril/valsartan in patients with heart failure with reduced ejection fraction

European Heart Journal ◽

10.1093/eurheartj/ehz748.0057 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

M Godet ◽

O Raitiere ◽

H Chopra ◽

P Guignant ◽

C Fauvel ◽

...

Keyword(s):

Heart Failure ◽

Pulmonary Hypertension ◽

Ejection Fraction ◽

Left Ventricular ◽

Heat Map ◽

Reduced Ejection Fraction ◽

Patients With Heart Failure ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Background Treatment by sacubitril/valsartan decreases mortality, improves KCCQ score and ejection fraction in patients with heart failure with reduced ejection fraction (HF REF), but there is currently no data to predict response to treatment. Purpose The purpose of our work was to assess whether unbiased clustering analysis, using dense phenotypic data, could identify phenotypically distinct HF-REF subtypes with good or no response after 6 months of sacubitril/valsartan administration. Methods A total of 78 patients in NYHA functional class 2–3 and treated by ACE inhibitor or AAR2, were prospectively assigned to equimolar sacubitril/valsartan replacement. We collected demographic, clinical, biological and imaging continuous variables. Phenotypic domains were imputed with 5 eigenvectors for missing value, then filtered if the Pearson correlation coefficient was >0.6 and standardized to mean±SD of 0±1. Thereafter, we used agglomerative hierarchical clustering for grouping phenotypic variables and patients, then generate a heat map (figure 1). Subsequently, participants were categorized using Penalized Model-Based Clustering. P<0,05 was considered significant. Results Mean age was 60.4±13.4 yo and 79.0% patients were males. Mean ejection fraction was 29.3±7.0%. Overall, 16 phenotypic domains were isolated (figure 1) and 3 phenogroups were identified (Table 1). Phenogroup 1 was remarkable by isolated left ventricular involvement (LVTDD 64.3±5.9mm vs 73.9±8.7 in group 2 and 63.8±5.7 in group3, p<0.001) with moderate diastolic dysfunction (DD), no mitral regurgitation (MR) and no pulmonary hypertension (PH). Phenogroups 2 and 3 corresponded to patients with severe PH (TRMV: 2.93±0.47m/s in group 2 and 3.15±0.61m/s in groupe 3 vs 2.16±0.32m/s in group 1), related to severe DD (phenogroup 2) or MR (phenogroup 3). In both phenogroups, the left atrium was significantly enlarged and the right ventricle was remodeled, compared with phenogroup 1. Despite more severe remodeling and more compromised hemodynamic in phenogroups 2 and 3, the echocardiographic response to sacubitril/valsartan was comparable in all groups with similar improvement of EF and reduction of cardiac chambers dimensions (response of treatment, defined by improvement of FE +15% and/or decreased of indexed left ventricule diastolic volume −15% = group 2: 22 (76%); group 3: 18 (60%); group 1: 9 (50%); p=0.17; OR group 2 vs 1: OR=3.14; IC95% [0.9–11.03]; p=0.074; OR group 3 vs 1: OR=1.5; IC95% [0.46–4.87]; p=0.5)). The clinical response was even better in phenogroups 2 and 3 (Group 2: 19 (66%); group 3: 21 (78%) vs group 1: 9 (50%); p=0.05). Heat map Conclusion HF-REF patients with severe diastolic dysfunction, significant mitral regurgitation and elevated pulmonary hypertension by echocardiographic had similar reverse remodeling but better clinical improvement than patients with isolated left ventricular systolic dysfunction.

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