Development Of Pulmonary Hypertension In Patients Research Articles

Impact of Pulmonary Hypertension on Mortality after Surgery for Aortic Stenosis.

Background and Objectives: The prognosis of patients with aortic stenosis (AS) adding pulmonary hypertension (PHT) is worse than in those with normal pulmonary artery pressure (PAP), and there are few results reported for the association between PHT and adverse outcomes of AS. We aimed to determine the predictive factors for the development of PHT in patients with surgical AS and to identify those factors that may predict the surgical prognosis. We aimed to identify the independent predictors for PHT regression at 2 years after surgery. Additionally, we tried to evaluate the involvement of PHT as an additional perioperative risk factor in patients with AS undergoing surgical aortic valve replacement (AVR). Materials and Methods: We carried out a two-year prospective study on 340 patients with AS undergoing surgical AVR. Results: The independent predictors for the occurrence of PHT in patients with surgical AS were: age > 75 years (RR = 6, p = 0.001), a restrictive left ventricle diastolic filling pattern (LVDFP) (RR = 9, p = 0.001) and associated moderate mitral regurgitation (MR) (RR = 9, p = 0.0001). The presence of severe PHT increased by 7.6 times the early postoperative risk of death, regardless of the presence of other parameters. The independent predictors for early postoperative mortality were: severe PHT, restrictive left ventricle diastolic pattern, age > 75 years, interventricular septum (IVS) thickness >18 mm and the presence of comorbidities. Conclusions: The presence of a severe PHT in patients with AS undergoing surgical AVR is associated with an early postoperative increased mortality rate. The mean PAP is a more reliable parameter for prognosis appreciation than the LV systolic function.

A RARE CASE OF PORTOPULMONARY HYPERTENSION AS A COMPLICATION OF CRYPTOGENIC CIRRHOSIS

SESSION TITLE: Medical Student/Resident Pulmonary Vascular Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Portopulmonary hypertension (PoPH) is a rare and serious complication of liver cirrhosis. The prevalence of PoPH is about 0.25–4% among patients with cirrhosis. Untreated PoPH can have a poor prognosis. We report a rare case of PoPH. CASE PRESENTATION: A 35 year old female with a history of cryptogenic liver cirrhosis with portal hypertension and transjugular intrahepatic portosystemic shunt (TIPS) presented to the emergency room with complaints of dyspnea, orthopnea, and dizziness which started 2 days after her 5th caesarean section. Her exercise tolerance was reduced to one block. The patient had an elevated ProBNP of 1100. Computed tomographic pulmonary angiography was negative for pulmonary embolism. Transthoracic echocardiogram showed right ventricular systolic pressure elevated at >60mm Hg, consistent with severe pulmonary hypertension (PAH) with severely dilated right atrium. The patient was transferred to a tertiary care hospital for confirmation of the diagnosis of PoPH. The patient underwent Right Heart Catheterization which confirmed severe PAH with elevated mean pulmonary artery pressure (mPAP) of 60mmhg, normal pulmonary capillary wedge pressure of 12mmhg, elevated pulmonary vascular resistance of 17 wood units. The hepatic vein wedge pressure was 23mmHg and hepatic vein pressure was 20mmHg.The hepatic venous pressure gradient (HVPG) was 3mmhg which was normal and was consistent with the fact that the patient already underwent TIPS due to underlying portal hypertension. The patient met the diagnostic criteria for PoPH. The patient was started on treprostinil infusion for pulmonary vasodilatation. The patient improved symptomatically and was eventually discharged. In her follow up pulmonary clinic appointment her exercise tolerance improved to 10 blocks with complete resolution of orthopnea. DISCUSSION: The development of PAH in patients with cirrhosis can be explained by shunting of vasoactive mediators from splanchnic to pulmonary circulation through portosystemic shunts causing vasoconstriction of the pulmonary vasculature. The acute volume loading with mobilization of plasma volume in the immediate postpartum period may have tipped the patient into acute on chronic right ventricular failure and thereby revealed her symptomatic PAH. The prompt recognition of PoPH and initiation of appropriate medical treatment ensured the recovery of the patient. CONCLUSIONS: The diagnosis of PoPH is crucial before liver transplantation as there is a high risk of death following liver transplantation if the mPAP is more than 35 mmHg. Medical treatment is essential to lower the mPAP to less than 35mmhg before proceeding for liver transplantation. Liver transplantation can be planned after successful medical treatment of PoPH with pulmonary arterial vasomodulators like prostanoids, phosphodiesterase inhibitors, and endothelin antagonists. Reference #1: Benjaminov FS, Prentice M, Sniderman KW, et al. Portopulmonary hypertension in decompensated cirrhosis with refractory ascites. Gut 2003; 52: 1355-1362. Reference #2: Saleemi S. Portopulmonary hypertension.Ann Thorac Med. 2010 Jan-Mar; 5(1): 5–9. Reference #3: Porres-Aguilar M, Zuckerman MJ, Figueroa-Casas JB, et al.Portopulmonaryhypertension: state of the art. Ann Hepatol 2008; 7:321-330 DISCLOSURES: No relevant relationships by Antony Arumairaj, source=Web Response No relevant relationships by Diana Cativo, source=Web Response No relevant relationships by Imnett Habtes, source=Web Response

Altered Hypoxic-Adenosine Axis and Metabolism in Group III Pulmonary Hypertension.

Group III pulmonary hypertension (PH) is a highly prevalent and deadly lung disorder with limited treatment options other than transplantation. Group III PH affects patients with ongoing chronic lung injury, such as idiopathic pulmonary fibrosis (IPF). Between 30 and 40% of patients with IPF are diagnosed with PH. The diagnosis of PH has devastating consequences to these patients, leading to increased morbidity and mortality, yet the molecular mechanisms involved in the development of PH in patients with chronic lung disease remain elusive. Our hypothesis was that the hypoxic-adenosinergic system is enhanced in patients with group III PH compared with patients with IPF with no PH. Explanted lung tissue was analyzed for markers of the hypoxic-adenosine axis, including expression levels of hypoxia-inducible factor (HIF)-1A, adenosine A2B receptor, CD73, and equilibrative nucleotide transporter-1. In addition, we assessed whether altered mitochondrial metabolism was present in these samples. Increased expression of HIF-1A was observed in tissues from patients with group III PH. These changes were consistent with increased evidence of adenosine accumulation in group III PH. A novel observation of our study was of evidence suggesting altered mitochondrial metabolism in lung tissue from group III PH leading to increased succinate levels that are able to further stabilize HIF-1A. Our data demonstrate that the hypoxic-adenosine axis is up-regulated in group III PH and that subsequent succinate accumulation may play a part in the development of group III PH.

Increased Red Blood Cell Stiffness Increases Pulmonary Vascular Resistance and Pulmonary Arterial Pressure.

Patients with sickle cell anemia (SCD) and pulmonary hypertension (PH) have a significantly increased risk of sudden death compared to patients with SCD alone. Sickled red blood cells (RBCs) are stiffer, more dense, more frequently undergo hemolysis, and have a sixfold shorter lifespan compared to normal RBCs. Here, we sought to investigate the impact of increased RBC stiffness, independent of other SCD-related biological and mechanical RBC abnormalities, on the hemodynamic changes that ultimately cause PH and increase mortality in SCD. To do so, pulmonary vascular impedance (PVZ) measures were recorded in control C57BL6 mice before and after ∼50 μl of blood (Hct = 45%) was extracted and replaced with an equal volume of blood containing either untreated RBCs or RBCs chemically stiffened with glutaraldehyde (Hct = 45%). Chemically stiffened RBCs increased mean pulmonary artery pressure (mPAP) (13.5 ± 0.6 mmHg at baseline to 23.2 ± 0.7 mmHg after the third injection), pulmonary vascular resistance (PVR) (1.23 ± 0.11 mmHg*min/ml at baseline to 2.24 ± 0.14 mmHg*min/ml after the third injection), and wave reflections (0.31 ± 0.02 at baseline to 0.43 ± 0.03 after the third injection). Chemically stiffened RBCs also decreased cardiac output, but did not change hematocrit, blood viscosity, pulmonary arterial compliance, or heart rate. The main finding of this study is that increased RBC stiffness alone affects pulmonary pulsatile hemodynamics, which suggests that RBC stiffness plays an important role in the development of PH in patients with SCD.

A single nucleotide polymorphism in the dimethylarginine dimethylaminohydrolase gene is associated with lower risk of pulmonary hypertension in bronchopulmonary dysplasia.

Pulmonary hypertension (PH) develops in 25-40% of bronchopulmonary dysplasia (BPD) patients, substantially increasing mortality. We have previously found that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) production, is elevated in patients with BPD-associated PH. ADMA is metabolised by N(ᴳ) ,N(ᴳ) -dimethylarginine dimethylaminohydrolase (DDAH). Presently, we test the hypothesis that there are single nucleotide polymorphisms (SNPs) in DDAH1 and/or DDAH2 associated with the development of PH in BPD patients. BPD patients were enrolled (n = 98) at Nationwide Children's Hospital. Clinical characteristics and 36 SNPs in DDAH1 and DDAH2 were compared between BPD-associated PH patients (cases) and BPD-alone patients (controls). In BPD patients, 25 (26%) had echocardiographic evidence of PH (cases). In this cohort, DDAH1 wild-type rs480414 was 92% sensitive and 53% specific for PH in BPD, and the DDAH1 SNP rs480414 decreased the risk of PH in an additive model of inheritance (OR = 0.39; 95% CI [0.18-0.88], p = 0.01). The rs480414 SNP in DDAH1 may be protective against the development of PH in patients with BPD. Furthermore, the DDAH1 rs480414 may be a useful biomarker in developing predictive models for PH in patients with BPD.

Levels of uric acid may predict the future development of pulmonary hypertension in systemic lupus erythematosus: a seven-year follow-up study.

The objective of this paper is to assess whether pulmonary hypertension (PH) may be detected at one point in time or longitudinally predicted by serum uric acid (sUA) levels in systemic lupus erythematosus (SLE). We conducted a post-hoc analysis of a long-term followed cohort of Mexican SLE patients. Echocardiography-based definitions of PH by the ESC/ERS/ISHLT and its associations with clinical and laboratory data on enrollment were studied. Especially, the impact that sUA levels at baseline may have on the future development of PH in patients with normal pulmonary artery systolic pressure (PASP) was explored. Out of the 156 SLE patients originally enrolled in the cohort, 44 met the inclusion criteria for the present study and were grouped as having (n =10) or not having (n = 34) PH. At baseline, sUA levels of 5.83 ± 1.79 and 5.82 ± 1.97 mg/dl (p = ns) were found in patients with and without PH, respectively. No association between PASP and other markers was found. In patients with normal PASP, the presence of sUA ≥ 7 mg/dl at baseline predicted future development of PH (relative risk 8.5, 1.0009 to 72; p = 0.04). In SLE, sUA levels at one point in time are useless to detect PH. However, steady hyperuricemia may predict the future development of PH in patients with normal PASP at baseline.

Bronchopulmonary Dysplasia‐associated Pulmonary Hypertension and Mutations in the DDAH1 Gene

Pulmonary hypertension (PH) is the most common comorbidity in bronchopulmonary dysplasia (BPD). Nitric oxide (NO) is produced by endothelial NO synthase (eNOS) in pulmonary endothelial cells and is a potent vasodilator. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of eNOS. Our group has recently published that ADMA levels are elevated in patients with BPD‐associated PH. ADMA is degraded by the enzyme Nᴳ,Nᴳ‐ dimethylarginine dimethylaminohydrolase (DDAH). We tested the hypothesis that there are single nucleotide polymorphisms (SNPs) in DDAH1 associated with PH in BPD. Neonates diagnosed with BPD were enrolled at Nationwide Children's Hospital. DNA was assayed for 34 SNPs in DDAH1. Calculated minor allele frequency (MAF) for cases and controls were compared using chi‐square. Assuming recessive inheritance, logistic regression was used to estimate the odds ratio. Among 157 patients with BPD, 53 (34%) also had echocardiographic evidence of PH. Gestational age, birth weight, gender, and ethnicity were not different between groups. DDAH1 rs11161637 SNP had a significantly (p=0.04) lower MAF in cases than in controls (0.25 vs. 0.34). DDAH1 rs11161637 was associated with a decreased risk (OR=0.27) of PH in this BPD cohort, although this did not reach statistical significance (p‐value=0.06). These results indicate that rs11161637 SNP of DDAH1 may be protective against the development of PH in patients with BPD. We speculate that the DDAH1 SNP may be a useful biomarker in developing predictive models for PH in patients with BPD.

Pulmonary hypertension in left heart disease

Pulmonary hypertension (PH) is a frequent complication of left heart disease arising from a wide range of cardiac disorders. In the clinical classification, PH associated with left heart disease is classified as Group 2, which includes left heart systolic dysfunction, left heart diastolic dysfunction and left heart valvular disease. In the past, rheumatic mitral valve disease was the most common cause of PH in left heart disease; however, today it is more likely to be associated with hypertensive and/or ischaemic heart disease. As the incidence of these conditions is increasing, the number of patients presenting with PH is also increasing and, today, left heart disease represents the most frequent cause of PH. The development of PH in patients with left heart disease is associated with poor prognosis. However, despite the increasingly large number of patients affected and the impact of PH on outcome, there are currently no specific treatment options for these patients. This review gives an overview of the pathophysiology and epidemiology of PH associated with left heart disease, and discusses the challenges associated with its management and treatment.

S101 Heterozygous loss of BMPR-II predisposes to inflammatory cytokine secretion and pulmonary vascular smooth muscle proliferation

IntroductionElevated levels of inflammatory cytokines are associated with idiopathic and heritable pulmonary hypertension (PAH) and predict mortality, but their role in the pathobiology of PAH and the underlying mechanisms remain...

Association of interleukin 23 receptor polymorphisms with anti-topoisomerase-I positivity and pulmonary hypertension in systemic sclerosis.

IL23R has been identified as a susceptibility gene for development of multiple autoimmune diseases. We investigated the possible association of IL23R with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis. We tested 9 single-nucleotide polymorphisms (SNP) in IL23R for association with SSc in a cohort of 1402 SSc cases and 1038 controls. IL23R SNP tested were previously identified as SNP showing associations with inflammatory bowel disease. Case-control comparisons revealed no statistically significant differences between patients and healthy controls with any of the IL23R polymorphisms. Analyses of subsets of SSc patients showed that rs11209026 (Arg381Gln variant) was associated with anti-topoisomerase I antibody (ATA)-positive SSc (p = 0.001)) and rs11465804 SNP was associated with diffuse and ATA-positive SSc (p = 0.0001, p = 0.0026, respectively). These associations remained significant after accounting for multiple comparisons using the false discovery rate method. Wild-type genotype at both rs11209026 and rs11465804 showed significant protection against the presence of pulmonary hypertension (PHT). (p = 3x10(-5), p = 1x10(-5), respectively). Polymorphisms in IL23R are associated with susceptibility to ATA-positive SSc and protective against development of PHT in patients with SSc.

Echocardiographic and Clinical Characteristics of Pulmonary Hypertension Complicating Pulmonary Langerhans Cell Histiocytosis

To determine the echocardiographic characteristics and impact on survival of pulmonary hypertension (PH) and correlations between echocardiographic and clinical variables in patients with pulmonary Langerhans cell histiocytosis (PLCH). Of 123 adults seen at our institution between January 1976 and December 2002 with histologically proven PLCH, 17 underwent echocardiographic evaluation. Correlations were performed between echocardiographic measures of PH and clinical variables. Cumulative survival probabilities for patients with PH were estimated using the Kaplan-Meier method and were compared to a historical cohort of patients with PLCH using time-dependent proportional hazard regression. Of the 17 patients, PH (estimated pulmonary artery systolic pressure [PASP] at rest, > 35 mm Hg) was present in 15. Thirteen patients (6 men; median PASP, 67 mm Hg; range, 41.2-90.6 mm Hg) had no other known causes of PH. All patients were smokers. Nine patients had a PASP of more than 50 mm Hg. An inverse correlation was found between the forced vital capacity and PASP (r = -0.61; P = .03); no correlation was found between PASP and other pulmonary function parameters. Seven patients with a PASP greater than 65 mm Hg had an enlarged right ventricle with impaired systolic function. The development of PH in patients with PLCH was associated with increased mortality (hazard ratio, 22.8; 95% confidence interval, 7.6 to > 68.9; P < .001). Severe PH occurs in PLCH, correlates with the forced vital capacity, and has a significant impact on survival. Clinicians should consider echocardiographic screening for PH in all dyspneic patients with PLCH.

Pathophysiology of pulmonary hypertension due to lung disease.

Pulmonary hypertension (PH) often complicates the course of patients with advanced lung disease, and it is associated with a worse prognosis. Per the recent classification of pulmonary hypertensive disorders, PH due to lung disease is considered as a separate category within a group of disorders that was previously referred to as "secondary" PH. Among the lung diseases associated with PH, the incidence and clinical course of PH is best known for patients with COPD. Per studies in patients with COPD and other lung disorders, it is evident that the pathophysiology and treatment of these disorders is generally distinct from that of pulmonary arterial hypertensive disorders. Changes in the pulmonary vasculature that accompany elevations in pulmonary vascular pressure are generally referred to as pulmonary vascular remodeling. Chronic hypoxia is well known to cause pulmonary vascular remodeling and PH, and it is the major mechanism implicated for the development of PH in patients with lung disease. Other mediators have also been implicated in the pathogenesis of PH in animal models and patients with PH, including patients with pulmonary diseases. General features of pulmonary vascular remodeling are discussed with particular emphasis on those changes that have been described in patients with lung diseases. Recent discoveries in these areas are also reviewed, and findings in pulmonary arterial hypertensive diseases are contrasted with those found in patients with PH due to lung diseases. Some of these discoveries have already led to new treatment strategies for patients with the most severe forms of PH. PH due to lung diseases shares some common pathophysiologic features with pulmonary arterial hypertension. Therefore, it is likely that these discoveries and new treatments will also be extended to benefit patients with PH due to lung disease.