scholarly journals Combination Therapy With Rapamycin and Low Dose Imatinib in Pulmonary Hypertension

2021 ◽  
Vol 12 ◽  
Author(s):  
Yinan Shi ◽  
Chenxin Gu ◽  
Tongtong Zhao ◽  
Yangfan Jia ◽  
Changlei Bao ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Combination Therapy ◽  
Systolic Pressure ◽  
Growth Factor Receptor ◽  
Vascular Wall ◽  
Nuclear Antigen ◽  
Ventricular Systolic Pressure ◽  
Short Term Exposure ◽  
Distal Migration ◽  
Pulmonary Arterial

Rationale: Enhanced proliferation and distal migration of human pulmonary arterial smooth muscle cells (hPASMCs) both contribute to the progressive increases in pulmonary vascular remodeling and resistance in pulmonary arterial hypertension (PAH). Our previous studies revealed that Rictor deletion, to disrupt mTOR Complex 2 (mTORC2), over longer periods result in a paradoxical rise in platelet-derived growth factor receptor (PDGFR) expression in PASMCs. Thus, the purpose of this study was to evaluate the role of combination therapy targeting both mTOR signaling with PDGFR inhibition to attenuate the development and progression of PAH.Methods and Results: Immunoblotting analyses revealed that short-term exposure to rapamycin (6h) significantly reduced phosphorylation of p70S6K (mTORC1-specific) in hPASMCs but had no effect on the phosphorylation of AKT (p-AKT S473, considered mTORC2-specific). In contrast, longer rapamycin exposure (>24 h), resulted in differential AKT (T308) and AKT (S473) phosphorylation with increases in phosphorylation of AKT at T308 and decreased phosphorylation at S473. Phosphorylation of both PDGFRα and PDGFRβ was increased in hPASMCs after treatment with rapamycin for 48 and 72 h. Based on co-immunoprecipitation studies, longer exposure to rapamycin (24–72 h) significantly inhibited the binding of mTOR to Rictor, mechanistically suggesting mTORC2 inhibition by rapamycin. Combined exposure of rapamycin with the PDGFR inhibitor, imatinib significantly reduced the proliferation and migration of hPASMCs compared to either agent alone. Pre-clinical studies validated increased therapeutic efficacy of rapamycin combined with imatinib in attenuating PAH over either drug alone. Specifically, combination therapy further attenuated the development of monocrotaline (MCT)- or Hypoxia/Sugen-induced pulmonary hypertension (PH) in rats as demonstrated by further reductions in the Fulton index, right ventricular systolic pressure (RVSP), pulmonary vascular wall thickness and vessel muscularization, and decreased proliferating cell nuclear antigen (PCNA) staining in PASMCs.Conclusion: Prolonged rapamycin treatment activates PDGFR signaling, in part, via mTORC2 inhibition. Combination therapy with rapamycin and imatinib may be a more effective strategy for the treatment of PAH.

Serotonin transporter is not required for the development of severe pulmonary hypertension in the Sugen hypoxia rat model

2015 ◽  
Vol 309 (10) ◽  
pp. L1164-L1173 ◽  
Author(s):  
Michiel Alexander de Raaf ◽  
Yvet Kroeze ◽  
Anthonieke Middelman ◽  
Frances S. de Man ◽  
Helma de Jong ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Serotonin Transporter ◽  
Rat Model ◽  
Systolic Pressure ◽  
Serum Levels ◽  
Normal Function ◽  
Ventricular Systolic Pressure ◽  
Serotonin System ◽  
Pulmonary Arterial

Increased serotonin serum levels have been proposed to play a key role in pulmonary arterial hypertension (PAH) by regulating vessel tone and vascular smooth muscle cell proliferation. An intact serotonin system, which critically depends on a normal function of the serotonin transporter (SERT), is required for the development of experimental pulmonary hypertension in rodents exposed to hypoxia or monocrotaline. While these animal models resemble human PAH only with respect to vascular media remodeling, we hypothesized that SERT is likewise required for the presence of lumen-obliterating intima remodeling, a hallmark of human PAH reproduced in the Sugen hypoxia (SuHx) rat model of severe angioproliferative pulmonary hypertension. Therefore, SERT wild-type (WT) and knockout (KO) rats were exposed to the SuHx protocol. SERT KO rats, while completely lacking SERT, were hemodynamically indistinguishable from WT rats. After exposure to SuHx, similar degrees of severe angioproliferative pulmonary hypertension and right ventricular hypertrophy developed in WT and KO rats (right ventricular systolic pressure 60 vs. 55 mmHg, intima thickness 38 vs. 30%, respectively). In conclusion, despite its implicated importance in PAH, SERT does not play an essential role in the pathogenesis of severe angioobliterative pulmonary hypertension in rats exposed to SuHx.

scholarly journals Macitentan reverses early obstructive pulmonary vasculopathy in rats: early intervention in overcoming the survivin-mediated resistance to apoptosis

2015 ◽  
Vol 308 (6) ◽  
pp. L523-L538 ◽  
Author(s):  
Tsutomu Shinohara ◽  
Hirofumi Sawada ◽  
Shoichiro Otsuki ◽  
Noriko Yodoya ◽  
Taichi Kato ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Systolic Pressure ◽  
Growth Factor Receptor ◽  
Survivin Expression ◽  
Pulmonary Vascular Disease ◽  
Ventricular Systolic Pressure ◽  
Targeting Therapy ◽  
Pulmonary Arterial ◽  
Medial Wall Thickness ◽  
Endothelial Growth Factor

It remains unknown whether current disease-targeting therapy can histologically reverse obstructive pulmonary vasculopathy and how the timing of the therapy influences the antiremodeling effects of the compound. We test the hypothesis that a novel endothelin receptor antagonist macitentan reverses the early and/or late stages of occlusive pulmonary vascular disease (PVD) in rats. Rats with pulmonary arterial hypertension (PAH), which were produced by combined exposure to a vascular endothelial growth factor receptor inhibitor Sugen 5416 and hypobaric hypoxia for 3 wk, were assigned to receive macitentan or vehicle during 3–5 wk (early study) or during 5–8 wk (late study) after Sugen injection. Compared with vehicle-treated PAH rats and PAH rats evaluated before treatment initiation, the macitentan-treated rats showed decreases in the proportion of occlusive lesions in the early study, a finding consistent with the reversal of right ventricular systolic pressure and indexes of right ventricular hypertrophy and medial wall thickness. Macitentan ameliorated but did not reverse the proportion of occlusive lesions in the late study. Although macitentan decreased the proportion of Ki67+ lesions in both studies, macitentan increased the proportion of cleaved caspase 3+ lesions and suppressed an antiapoptotic molecule survivin expression in the early study but not in the late study. In conclusion, macitentan reversed early but not late obstructive PVD in rats. This reversal was associated with the suppression of survivin-related resistance to apoptosis and proliferation of cells in PVD.

Cystamine Treatment Fails to Prevent the Development of Pulmonary Hypertension in Chronic Hypoxic Rats

2021 ◽  
pp. 1-15
Author(s):  
Lars K. Markvardsen ◽  
Lene D. Sønderskov ◽  
Christine Wandall-Frostholm ◽  
Estéfano Pinilla ◽  
Judit Prat-Duran ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricle ◽  
Right Ventricular ◽  
Lung Tissue ◽  
Ventricular Hypertrophy ◽  
Systolic Pressure ◽  
Right Ventricular Hypertrophy ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial ◽  
The Right

<b><i>Introduction:</i></b> Pulmonary hypertension is characterized by vasoconstriction and remodeling of pulmonary arteries, leading to right ventricular hypertrophy and failure. We have previously found upregulation of transglutaminase 2 (TG2) in the right ventricle of chronic hypoxic rats. The hypothesis of the present study was that treatment with the transglutaminase inhibitor, cystamine, would inhibit the development of pulmonary arterial remodeling, pulmonary hypertension, and right ventricular hypertrophy. <b><i>Methods:</i></b> Effect of cystamine on transamidase activity was investigated in tissue homogenates. Wistar rats were exposed to chronic hypoxia and treated with vehicle, cystamine (40 mg/kg/day in mini-osmotic pumps), sildenafil (25 mg/kg/day), or the combination for 2 weeks. <b><i>Results:</i></b> Cystamine concentration-dependently inhibited TG2 transamidase activity in liver and lung homogenates. In contrast to cystamine, sildenafil reduced right ventricular systolic pressure and hypertrophy and decreased pulmonary vascular resistance and muscularization in chronic hypoxic rats. Fibrosis in the lung tissue decreased in chronic hypoxic rats treated with cystamine. TG2 expression was similar in the right ventricle and lung tissue of drug and vehicle-treated hypoxic rats. <b><i>Discussion/Conclusions:</i></b> Cystamine inhibited TG2 transamidase activity, but cystamine failed to prevent pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial muscularization in the chronic hypoxic rat.

scholarly journals DDCI-01, a novel long acting phospdiesterase-5 inhibitor, attenuated monocrotaline-induced pulmonary hypertension in rats

2020 ◽  
Vol 10 (4) ◽  
pp. 204589402093984
Author(s):  
Ailing Li ◽  
Zhongkai Zhu ◽  
Yangke He ◽  
Qian Dong ◽  
Dianyong Tang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Right Heart Failure ◽  
Guanosine Monophosphate ◽  
Transverse Diameter ◽  
Ventricular Systolic Pressure ◽  
Significant Difference ◽  
Pulmonary Arterial ◽  
Long Acting

Pulmonary arterial hypertension is a progressive, malignant heart disease, characterized by pulmonary arteriole remodeling and increased pulmonary vascular resistance, which eventually leads to right heart failure. This study sought to evaluate the effects of a novel long-acting phospdiesterase-5 inhibitor, namely DDCI-01, as an early intervention for monocrotaline-induced pulmonary hypertensive rats. To establish this model, 50 mg/kg of monocrotaline was intraperitoneally injected into rats. At Day 7 after monocrotaline injection, two doses of DDCI-01 (3 or 9 mg/kg/day) or tadalafil (at 3 or 9 mg/kg/day) were intragastrically administered. The rats were anesthetized with pentobarbital for hemodynamic and echocardiographic measurements, at Day 21 after monocrotaline injection. Compared to the monocrotaline group, DDCI-01 at 3 and 9 mg/kg/day (P) reduced the mean pulmonary arterial pressure (mPAP), right ventricular systolic pressure, right ventricular transverse diameter, pulmonary arterial medial wall thickness (WT%), and right ventricle hypertrophy. However, no significant difference in the indices mentioned as above was found between DDCI-01 (3 mg/kg/day) and tadalafil (3 mg/kg/day). In addition, DDCI-01 at 9 mg/kg/day resulted in lower mPAP and WT%, as well as higher cyclic guanosine monophosphate levels in the lung and plasma compared with the same dose of tadalafil (9 mg/kg/day) (all P < 0.05). These findings suggested that DDCI-01 improved monocrotaline-induced pulmonary hypertension in rats, and a dose of DDCI-01 of 9 mg/kg/day might be more effective than the same dose of tadalafil in monocrotaline-induced pulmonary hypertension in rats.

scholarly journals JNK2 regulates vascular remodeling in pulmonary hypertension

2018 ◽  
Vol 8 (3) ◽  
pp. 204589401877815
Author(s):  
Mita Das ◽  
W. Michael Zawada ◽  
James West ◽  
Kurt R. Stenmark
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Wall Thickening ◽  
Ventricular Systolic Pressure ◽  
Vascular Abnormalities ◽  
Map Kinase Phosphatase ◽  
Pulmonary Arterial ◽  
Jnk Isoforms

Pulmonary arterial (PA) wall modifications are key pathological features of pulmonary hypertension (PH). Although such abnormalities correlate with heightened phosphorylation of c-Jun N-terminal kinases 1/2 (JNK1/2) in a rat model of PH, the contribution of specific JNK isoforms to the pathophysiology of PH is unknown. Hence, we hypothesized that activation of either one, or both JNK isoforms regulates PA remodeling in PH. We detected increased JNK1/2 phosphorylation in the thickened vessels of PH patients’ lungs compared to that in lungs of healthy individuals. JNK1/2 phosphorylation paralleled a marked reduction in MAP kinase phosphatase 1 (JNK dephosphorylator) expression in patients’ lungs. Association of JNK1/2 activation with vascular modification was confirmed in the calf model of severe hypoxia-induced PH. To ascertain the role of each JNK isoform in pathophysiology of PH, wild-type (WT), JNK1 null (JNK1-/-), and JNK2 null (JNK2-/-) mice were exposed to chronic hypoxia (10% O2 for six weeks) to develop PH. In hypoxic WT lungs, an increase in JNK1/2 phosphorylation was associated with PH-like pathology. Hallmarks of PH pathophysiology, i.e. excessive accumulation of extracellular matrix and vessel muscularization with medial wall thickening, was also detected in hypoxic JNK1-/- lungs, but not in hypoxia-exposed JNK2-/- lungs. However, hypoxia-induced increases in right ventricular systolic pressure (RVSP) and in right ventricular hypertrophy (RVH) were similar in all three genotypes. Our findings suggest that JNK2 participates in PA remodeling (but likely not in vasoconstriction) in murine hypoxic PH and that modulating JNK2 actions might quell vascular abnormalities and limit the course of PH.

Nerve growth factor receptor is involved in maintaining homeostasis of pulmonary arterial hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Goten ◽  
S Usui ◽  
O Inoue ◽  
H Okada ◽  
S Takashima ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Chronic Hypoxia ◽  
Systolic Pressure ◽  
Growth Factor Receptor ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial ◽  
The Right

Abstract Introduction Pulmonary arterial hypertension (PAH), characterized by vascular remodeling, is still disease with poor prognosis although many pulmonary vasodilators have been developed, and new mechanism of treatment for PAH is desired. Nerve growth factor receptor (Ngfr) is known to relate to inflammatory reaction and repair process in the damaged tissue. We have reported that Ngfr is associated to vascular remodeling in patients with acute coronary syndrome. However, it is unclear how Ngfr is involved in the pathogenesis of PAH. Purpose In this study, we investigated whether Ngfr relate to pathophysiology in PAH. Methods We estimated the frequency of Ngfr positive cells (% Ngfr+) in peripheral blood mononuclear cells obtained from PAH and non-PAH patients using flowcytometric analysis. In PAH patients, the hemodynamic parameters such as mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and cardiac index (CI) were obtained by right heart catheterization, and evaluated for correlation with the % Ngfr+. Next, adult 8-week-old C57BL/6 (WT) mice and Ngfr knock out (KO) mice were exposed to chronic hypoxia (10% O2) or normoxia for 6 weeks. Then, mice were anesthetized and performed echocardiography and right heart catheterization. Then, mice were exsanguinated and blood sample was collected to evaluate the % Ngfr+ by flow cytometry. Right ventricular weight was measured and lung tissue was also collected for histological assessment and molecular pathway profiling. Results PAH (n=24) patients and non-PAH patients (n=17) were enrolled. The % Ngfr+ was significantly higher in PAH patients than that in non-PAH patients (0.056% versus 0.019%, p&lt;0.0001). In PAH patients, the % Ngfr+ was correlated with severity of hemodynamic parameters such as mPAP (R=0.64 p&lt;0.001), PVR (R=0.62 p&lt;0.005), and CI (R=−0.48 p&lt;0.05). In WT mice, chronic hypoxia significantly increased the right ventricular systolic pressure and induced vascular medial thickness and fibrosis around the pulmonary artery. Flow cytometry analysis revealed that the % Ngfr+ was significantly increased in the hypoxia compared to that in the normoxia. Under hypoxic conditions, the right ventricular systolic pressure was significantly increased in Ngfr KO mice compared to that in WT mice. In histological analysis, hypoxia-induced peripheral vascular fibrosis and medial thickness was more severe in Ngfr KO than that in WT mice. Conclusion Circulating Ngfr-positive cells are associated with severity of PAH in patients. In the hypoxia-induced PH model, gene deletion of Ngfr shows the progression of the pathogenesis of PAH. These results suggest that circulating Ngfr-positive cells have an important role in the pathogenesis of PAH and may be a novel target for PAH therapy. Funding Acknowledgement Type of funding source: None

Abstract 216: Causal Role of Oxidized Lipids in Pulmonary Hypertension Development

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Gregoire Ruffenach ◽  
Soban Umar ◽  
Mylene Vaillancourt ◽  
Victor Grijalva ◽  
Ellen I O’Connor ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Methyl Ester ◽  
Systolic Pressure ◽  
Oxidized Lipids ◽  
Heart Catheterization ◽  
Chow Diet ◽  
Stable Form ◽  
Wild Type ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a deadly disease characterized by increased pulmonary arterial pressure and pulmonary vascular occlusion. Recently, we and others demonstrated a robust increase in oxidized lipids, including 15-hydroxyeicosatetraenoic acids (15-HETE), in the lungs and plasma of PAH patients and animal models of pulmonary hypertension (PH). We hypothesized that diets rich in 15-HETE are sufficient to cause PH in wild type mice. We also examined whether 15-HETE or its metabolites are required to cause PH by comparing the effect of 15-HETE with 15-HETE methyl ester, which is a stable form of 15HETE that is not easily metabolized. C57BL/6 male mice were fed for 3 weeks with 15-HETE diet (5μg/day), 15-HETE methyl ester (15-HETE-ME, 5μg/day), or regular chow diet (n=8-21 mice/group). PH development was followed via weekly serial echocardiography. Right ventricular systolic pressure (RVSP) was measured via direct heart catheterization. RV hypertrophy index (RV/[IVS+LV]) was measured. Lung morphology and lipid accumulation were assessed using H&E and Oil red O staining. Echocardiography revealed the first sign of PH in mice on 15HETE diet as early as one week and a significant decrease in the pulmonary arterial acceleration time after 2 weeks of treatment (16.6±1.9 vs. 21.2±1.4 msec, p<0.05). Mice on 15HETE diet also had significantly higher RVSP (31.3±1.1 vs. 38.4±2.3 mmHg, p<0.05). Increase in RVSP was concomitant with significantly higher RV hypertrophy index (0.26 ± 0.02 vs. 0.33 ±0.02, p<0.05). Pulmonary arteriolar thickness was also significantly increased in mice on 15-HETE diet compared to regular diet (35.1±0.8 vs 53.4±1, p<0.05). Our new model of PH is not a model of atherosclerosis as there was no detectable plaque in aorta of the mice on 15-HETE diet. Finally, mice on 15-HETE-ME diet also developed PH as RVSP was significantly higher compared to control (31.3±1.1 vs. 39±3 mmHg, p<0.05). The severity of PH was similar in 15HETE-ME and 15HETE, confirming 15HETE itself and not its metabolites is sufficient to cause PH in wild type mice. We have developed a new and physiologically relevant animal model to study PH as a consequence of oxidized lipids overload as it occurs in humans with PAH.

scholarly journals FRI0152 PULMONARY HYPERTENSION IN NEWLY DIAGNOSED SPANISH PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS: DATA FROM THE RELES COHORT

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 660.2-660
Author(s):  
J. Álvarez Troncoso ◽  
Á. Robles Marhuenda ◽  
F. Mitjavila Villero ◽  
F. J. García Hernández ◽  
A. Marín Ballvé ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Pulmonary Hypertension ◽  
Lupus Erythematosus ◽  
Multivariable Analysis ◽  
Systolic Pressure ◽  
High Morbidity ◽  
Inception Cohort ◽  
Systemic Lupus ◽  
Factors Associated ◽  
Pulmonary Arterial

Background:Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multiorgan involvement. Pulmonary hypertension (PH) is an uncommon manifestation with high morbidity and mortality whose characteristics, prevalence and evolution in SLE are not completely defined.Objectives:Using data of patients from the inception cohort Registro Español de Lupus Eritematoso Sistémico (RELES), we aimed to to identify the factors associated with pulmonary hypertension (PH) in systemic lupus erythematosus (SLE).Methods:Prospective observational study on a multicenter Spanish inception cohort. Patients with SLE, diagnosed by the American College of Rheumatology (ACR) criteria, since January 2009, who had at least one transthoracic echocardiogram (TTE) performed were selected. Demographic data, diagnostic criteria, follow-ups, treatments and SLEDAI were analyzed.Results:Of 289 patients diagnosed with SLE with TTE performed, 15 (5.2%) patients were identified to have PH. Mean age was 56,9±7,7 years, of which 93,3% (14) were women and 80% (12) Caucasian. The ACR score at diagnosis was 4.66. Mean SLEDAI was 15. Only 5 patients had dyspnea at the time of diagnosis. Mean pulmonary arterial systolic pressure was 49.2±5.6 mmHg. Among the PH, 4 patients had pericarditis (26.6%), 3 (20%) valvulopathies (1 antiphospholipid syndrome), 1 patient pulmonary embolism and 1 shrinking lung. Multivariable analysis indicated that pericarditis (odds ratio (OR)=2.53), and valvulopathies (OR 8.96) were independently associated with the development of PH in SLE. Having PH was associated with older age at diagnosis (p<0.001), more dyspnea (p<0.001), higher ESR (p=0.007), more serositis (p<0.001), higher SLEDAI (p=0.011), higher SLICC (p <0.001), higher number of admissions (p=0.006) and higher mortality (p=0.003).Conclusion:PH in SLE is a serious comorbidity with high mortality. In the RELES cohort it was associated with increased disease activity, pericarditis and valvulopathies. Performing TTE in patients with SLE may favor early diagnosis and treatment.References:[1]Kim JS, Kim D, Joo YB, et al. Factors associated with development and mortality of pulmonary hypertension in systemic lupus erythematosus patients.Lupus. 2018;27(11):1769–1777.[2]Bazan IS, Mensah KA, Rudkovskaia AA, et al. Pulmonary arterial hypertension in the setting of scleroderma is different than in the setting of lupus: A review.Respir Med. 2018;134:42–46.Disclosure of Interests:Jorge Álvarez Troncoso: None declared, Ángel Robles Marhuenda: None declared, Francesca Mitjavila Villero: None declared, Francisco José García Hernández: None declared, Adela Marín Ballvé: None declared, Antoni Castro Consultant of: Actelion pharmaceuticals, GSK, MSD., Gonzalo Salvador Cervelló: None declared, Eva Fonseca: None declared, Isabel Perales Fraile: None declared, Guillermo Ruiz-Irastorza: None declared

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

Circulation ◽  
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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