Severe Pulmonary Vascular Disease Research Articles

Definition, classification and diagnosis of pulmonary hypertension.

Pulmonary hypertension (PH) is a haemodynamic condition characterised by elevation of mean pulmonary arterial pressure (mPAP) >20 mmHg, assessed by right heart catheterisation. Pulmonary arterial wedge pressure (PAWP) and pulmonary vascular resistance (PVR) distinguish pre-capillary PH (PAWP ≤15 mmHg, PVR >2 Wood Units (WU)), isolated post-capillary PH (PAWP >15 mmHg, PVR ≤2 WU) and combined post- and pre-capillary PH (PAWP >15 mmHg, PVR >2 WU). Exercise PH is a haemodynamic condition describing a normal mPAP at rest with an abnormal increase of mPAP during exercise, defined as a mPAP/cardiac output slope >3 mmHg/L/min between rest and exercise. The core structure of the clinical classification of PH has been retained, including the five major groups. However, some changes are presented herewith, such as the re-introduction of "long-term responders to calcium channel blockers" as a subgroup of idiopathic pulmonary arterial hypertension, the addition of subgroups in group 2 PH and the differentiation of group 3 PH subgroups based on pulmonary diseases instead of functional abnormalities. Mitomycin-C and carfilzomib have been added to the list of drugs with "definite association" with PAH. For diagnosis of PH, we propose a stepwise approach with the main aim of discerning those patients who need to be referred to a PH centre and who should undergo invasive haemodynamic assessment. In case of high probability of severe pulmonary vascular disease, especially if there are signs of right heart failure, a fast-track referral to a PH centre is recommended at any point during the clinical workup.

Cardiac function, haemodynamics, and valve competence with exercise in patients with heart failure with preserved ejection fraction and mild to moderate secondary mitral regurgitation.

This study aimed to evaluate the clinical significance of secondary mitral regurgitation (MR) in patients with heart failure with preserved ejection fraction (HFpEF). We conducted a prospective study enrolling consecutively evaluated patients with HFpEF undergoing invasive haemodynamic exercise testing with simultaneous echocardiography. Compared to HFpEF without MR (n = 145, 79.7%), those with mild or moderate MR (n = 37, 20.3%) were older, more likely to be women, had more left ventricular (LV) systolic dysfunction, and more likely to have left atrial (LA) myopathy reflected by greater burden of atrial fibrillation, more LA dilatation, and poorer LA function. Pulmonary artery (PA) wedge pressure was higher at rest in HFpEF with MR (17 ± 5 mmHg vs. 20 ± 5 mmHg, p = 0.005), but there was no difference with exercise. At rest, only 2 (1.1%) patients had moderate MR, and none developed severe MR. Pulmonary vascular resistance was higher, and right ventricular (RV)-PA coupling was more impaired in patients with HFpEF and MR at rest and exercise. LV and LA myocardial dysfunction remained more severe in patients with MR during stress compared to those without MR, characterized by greater LA dilatation during all stages of exertion, lower LA emptying fraction and compliance, steeper and rightward-shifted LA pressure-volume relationships, and reduced LV longitudinal contractile function. Patients with HFpEF and mild or moderate MR have more severe LV systolic dysfunction, LA myopathy, RV-PA uncoupling, and more severe pulmonary vascular disease. Mitral valve incompetence in this setting is a phenotypic marker of more advanced disease but is not a causal factor in development of HFpEF.

Patent ductus arteriosus presenting as dilated cardiomyopathy with heart failure in an adult managed with percutaneous intervention

ABSTRACT Patent ductus arteriosus (PDA) is a common congenital heart disease, presenting with symptoms of increased pulmonary blood flow in infancy and childhood. In adults PDA if it is small detected accidentally because of the continuous murmur or if PDA is large they develop severe pulmonary vascular disease and develop Eisenmenger syndrome. Very few patients with large PDA present with dilated cardiomyopathy without pulmonary hypertension. Herewith, we report a case of large PDA who presented with symptoms of heart failure without pulmonary vascular disease and manage successfully with percutaneous device closure.

Cell Death in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a severe pulmonary vascular disease characterized by increased pulmonary vascular resistance because of vascular remodeling and vasoconstriction. Subsequently, PAH leads to right ventricular hypertrophy and heart failure. Cell death mechanisms play a significant role in development and tissue homeostasis, and regulate the balance between cell proliferation and differentiation. Several basic and clinical studies have demonstrated that multiple mechanisms of cell death, including pyroptosis, apoptosis, autophagy, ferroptosis, anoikis, parthanatos, and senescence, are closely linked with the pathogenesis of PAH. This review summarizes different cell death mechanisms involved in the death of pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs), the primary target cells in PAH. This review summarizes the role of these cell death mechanisms, associated signaling pathways, unique effector molecules, and various pro-survival or reprogramming mechanisms. The aim of this review is to summarize the currently known molecular mechanisms underlying PAH. Further investigations of the cell death mechanisms may unravel new avenues for the prevention and treatment of PAH.

Biatrial myopathy in heart failure with preserved ejection fraction.

Left atrial (LA) myopathy is increasingly recognized as an important phenotypic trait in heart failure (HF) with preserved ejection fraction (HFpEF). Right atrial (RA) remodelling and dysfunction also develop in HFpEF, but little data are available regarding the clinical characteristics and pathophysiology among patients with isolated LA, RA, or biatrial myopathy. Patients with HFpEF underwent invasive haemodynamic exercise testing, comprehensive imaging including speckle tracking strain echocardiography, and clinical follow-up at Mayo Clinic between 2006 and 2018. LA myopathy was defined as LA volume index >34 ml/m2 and/or LA reservoir strain ≤24% and RA myopathy by RA volume index >39 ml/m2 in men and >33 ml/m2 in women and/or RA reservoir strain ≤19.8%. Of 476 consecutively evaluated patients with HFpEF defined by invasive exercise testing with evaluable atrial structure/function, 125 (26%) had no atrial myopathy, 147 (31%) had isolated LA myopathy, 184 (39%) had biatrial myopathy, and 20 (4%) had isolated RA myopathy. Patients with HFpEF and biatrial myopathy had more atrial fibrillation, poorer left ventricular systolic and diastolic function, more severe pulmonary vascular disease, tricuspid regurgitation, ventricular interdependence and right ventricular dysfunction, and poorer cardiac output reserve with exercise. There were 94 patients with events over a median follow-up of 2.9 (interquartile range 1.4-4.6) years. Individuals with biatrial myopathy had an 84% higher risk of HF hospitalization or death as compared to those with isolated LA myopathy (hazard ratio 1.84; 95% confidence interval 1.16-2.92, p = 0.01). Biatrial myopathy identifies patients with more advanced HFpEF characterized by more severe pulmonary vascular disease, right HF, poorer cardiac reserve, and a greater risk for adverse outcomes. Further study is required to define optimal strategies to treat and prevent biatrial myopathy in HFpEF.

Abstract 17226: Role of BMPR2 Mutation in the Development of RV Failure in Rat Experimental Pulmonary Hypertension

Introduction: BMPR2 mutations are the major genetic risk factor for pulmonary arterial hypertension (PAH) and are associated with increased disease severity and worse survival. Although worsening disease severity and prognosis in BMPR2 mutation carriers has been explained by more severe pulmonary vascular disease (PVD), recent reports suggest that BMPR2 mutations affect right ventricular (RV) myocardium and its function independently of PAH. However, mechanism of dysfunctional RV in BMPR2 mutations carriers are unknown.[Hypothesis]Rats with Bmpr2 mutation have impaired RV function independently of PVD compared to wild-type (WT) rats. Methods: Bmpr2 mutant rats were generated by CRISPR/Cas9 genome editing. Monocrotaline (MCT)-PH model was generated in mutant rats and WT littermates and changes in RV function over time with disease progression were assessed by echocardiography and catheterization in rats with (n=23) or without tadalafil treatment (n=88) Results: In untreated setting, there were no significant differences in RV systolic pressure (RVSP) and RV function between the two groups on 21 days after MCT, whereas RV-fractional area change (FAC) and cardiac index (CI), assessed at later disease stage (23 to 25 days), were significantly lower in Bmpr2 mutant rats than in WT (RV-FAC: WT 41.0±8.3 vs Bmpr2 mutant 27.5±11.5%, p<.0001; CI: 413.2±114.0 vs 263.0±92.9ml/min/kg, p<.0001) at comparable RVSP (64.5±11.6 vs 66.7±8.0mmHg) but higher total pulmonary resistance index (TPRI: 0.16±0.06 vs 0.27±0.09mmHg/ml/min/kg, p<.0001). In rats with tadalafil treatment, Bmpr2 mutant rats had significantly lower RV-FAC (34.4±8.2 vs 23.6±5.4%, p<.05) and more severe RV myocardial fibrosis compared to WT littermates despite no significant differences in RVSP (75.4±8.7 vs 71.0±8.2mmHg) and TPRI (0.19±0.06 vs 0.22±0.08mmHg/ml/min/kg) on 30 days after MCT. Conclusion: In untreated setting, RV dysfunction in Bmpr2 mutant was associated with increased afterload due to exacerbation of vascular lesions; rats treated with PDE5i and with prolonged survival had reduced RV function at comparable afterload, indicating the importance of managing RV function under treatment of PAH.

Eisenmenger syndrome arising from aortopulmonary window diagnosed in adulthood: An unusual presentation as ischemic stroke

Aortopulmonary window (AP window) is an uncommon congenital heart condition marked by a connection between the ascending aorta and the pulmonary trunk. Numerous individuals diagnosed with AP window typically manifest symptoms in their early childhood, which may include recurring respiratory tract infections due to a left-to-right shunt, signs of congestive heart failure, and, if not treated in early childhood, the condition can progress to severe pulmonary vascular disease and Eisenmenger syndrome. Without treatment, very few patients survive beyond their second decade of life. In this case, we present a patient who exhibited symptoms of an ischemic stroke while having an undiagnosed large AP window and Eisenmenger syndrome.

A Health State Utility Study to Elicit Societal Values Associated with Pulmonary Hypertension.

Pulmonary hypertension (PH) is a rare, severe, and progressive pulmonary vascular disease, which includes five subgroups with similar presentation. Symptoms include dyspnea, and fatigue, and can significantly impact one's health-related quality of life (HRQL). Although treatments are mainly medical, PH group 4, chronic thromboembolic pulmonary hypertension (CTEPH), can be managed with procedures, ie pulmonary endarterectomy (PEA) and balloon pulmonary angioplasty (BPA). Currently, drugs in Europe are only approved for pulmonary arterial hypertension (PAH), and CTEPH therefore the aim of this study was to elicit novel societal health state utilities in the UK for PAH and CTEPH based on disease severity, functional class (FC), clinical events, and treatment procedures specifically for CTEPH. Six health states were defined: World Health Organization (WHO)-FC II, WHO-FC III, and WHO-FC IV [defined by the New York Heart Association (NYHA)]; PH-related hospitalization; and "BPA procedure and recovery" and "PEA surgery and recovery". Health states were based on a targeted literature review and two rounds of interviews with clinical experts (N = 4) and patients (N = 6). Draft health states were validated in cognitive debriefing interviews with clinical experts (N = 3). Health states were valued by the UK general public (n = 200), using a visual analogue scale (VAS) and time trade-off (TTO) assessment with the lead time method. The mean TTO values/utilities were 0.81 (FC II), 0.80 (BPA), 0.78 (PEA), 0.59 (FC III), 0.28 (FC IV), and 0.25 (PH-related hospitalization). Each progression in FC was associated with worse TTO scores. This study reports societal utility values for PAH and CTEPH in the UK. It provides first utility estimates for states such as BPA procedure and recovery, PEA surgery and recovery and PH-related hospitalization for this population. The results show important distinctions between FC, treatment procedures, and hospitalization, and the significant burden of disease on HRQL.

Left Atrial Myopathy in Heart Failure With Preserved Ejection Fraction.

The left atrium (LA) plays an important role in facilitating left ventricular (LV) filling by acting as a reservoir, passive conduit, and active booster pump, as well as a regulator of blood volume through A-type natriuretic peptide secretion in response to stimulation by mechanical stretch of the cavity. LA myopathy has emerged as one of the most important non-LV contributors to disease progression in heart failure with preserved ejection fraction (HFpEF). LA dysfunction is common in HFpEF and is associated with more severe pulmonary vascular disease and right ventricular dysfunction, and increases the risk of incident atrial fibrillation or atrial functional mitral regurgitation, leading to limitations in cardiac output reserve and reduced exercise capacity. LA deformation assessed by 2-dimensional speckle-tracking echocardiography is useful for estimating abnormal hemodynamics or exercise capacity, discriminating HFpEF from non-cardiac dyspnea and is an independent predictor of adverse outcome in HFpEF. Thus, interventions directly targeting LA myopathy may improve outcomes in HFpEF with LA myopathy. This review provides information regarding the physiology of the LA in patients with HFpEF and discusses the importance of evaluation of LA function, management issues, and future directions through ongoing trials of medical interventions.

Pulmonary hypertension associated with lung disease

Pulmonary hypertension (PH) is amultifactorial pulmonary vascular disease. PH associated with pre-existing lung disease is common and classified as group3 in the clinical classification. Patients with chronic obstructive or interstitial lung disease are most likely to develop PH, with up to 20% of patients showing signs of PH. Distinguishing between the symptoms of the underlying lung disease and concomitant PH can be difficult. Clinical assessment, lung function tests, laboratory tests, and echocardiography can be helpful. The hemodynamic definition of PH has recently been changed. PH associated with lung disease is apre-capillary form by definition. A special sub-stratification in group3 is the differentiation of hemodynamic severity. Severe PH in group3 is defined as apulmonary vascular resistance (PVR) greater than 5Wood units (WU). This pulmonary vascular phenotype is characterized by rather mild to moderate impairment of lung function or lung parenchymal destruction but with severe pulmonary vascular disease or right heart strain. Currently, there are no specific PH medications approved for group3. However, the use of specific PH medications for the pulmonary vascular phenotype is being discussed in studies or on acase-by-case basis, while in patients with aPVR below 5WU treatment focuses on the underlying disease.

Long-term course of pulmonary arterial hypertension in adults with congenital heart disease under targeted therapy: a retrospective analysis of a single tertiary center.

Pulmonary arterial hypertension (PAH), a common complication in adults with congenital heart disease (CHD), leads to significant morbidity and mortality. Targeted PAH medication is available, but PAH-CHD patient data are limited. Several questions regarding indication, treatment escalation, and combination therapy remain unanswered. The aim of this study was therefore to evaluate PAH-specific treatment in adults with PAH-CHD to better understand PAH-specific therapy management. In this cross-sectional study we retrospectively examined clinical, demographic, and cardiac-catheterization data and medical management for PAH-CHD, and analyzed clinical course and midterm outcome. Over up to 14 years (median, 6.2 years), 103 PAH-CHD patients (66% female) receiving targeted PAH-therapy for pre-tricuspid-shunt (15.5%), post-tricuspid-shunt (32.0%), and complex CHD (52.4%) were followed. Based on modified clinical European Society of Cardiology (ESC) classification, patients were assigned to the following subgroups: Eisenmenger syndrome (ES) (45.6%), severe pulmonary vascular disease (PVD) in complex CHD (20.4%), post-repair patients (19.4%), prevalent systemic-to-pulmonary shunt (3.9%), coincidental/small defects (0%), and Fontan circulation (10.7%). Changes in targeted PAH therapy were observed 249 times, with up to 6 (median, 2) therapy changes over a median period of 1.3 years. Over the study course, the medical treatment strategy changed towards combination therapy (baseline, 13.6%; study-end, 41%), resulting mostly in stabilized functional class or even improvement in cases of prevalent systemic-to-pulmonary shunt, ES, and patients with repaired CHD. Functional class deterioration, however, was seen in patients with severe PVD due to complex CHD, and Fontan patients. Of the 103 patients in the study, 25 died (24.3%). Patients with repaired CHD and patients with systemic-to-pulmonary shunt or ES showed the best survival rates. Mortality was remarkably higher in patients with severe PVD in complex CHD and Fontan patients. Many patients with PAH-CHD benefited from targeted PAH therapy over a median period of 6.2 years. Treatment decisions after targeted PAH-medication initiation were based mainly on clinical assessment. To counteract disease progression, an escalation towards combination therapy was observed during the study course. We consider survival rates under targeted PAH medication to be favorable, particularly in the ES subgroup. Nevertheless, further research is needed to optimize the use of PAH medication, especially in patients with complex CHD.

Pachymic Acid Ameliorates Pulmonary Hypertension by Regulating Nrf2-Keap1-ARE Pathway.

Pulmonary hypertension (PH) is a severe pulmonary vascular disease that eventually leads to right ventricular failure and death. The purpose of this study was to investigate the mechanism by which pachymic acid (PA) pretreatment affects PH and pulmonary vascular remodeling in rats. PH was induced via hypoxia exposure and administration of PA (5 mg/kg per day) in male Sprague-Dawley rats. Hemodynamic parameters were measured using a right ventricular floating catheter and pulmonary vascular morphometry was measured by hematoxylin-eosin (HE), α-SMA and Masson staining. MTT assays and EdU staining were used to detect cell proliferation, and apoptosis was analyzed by TUNEL staining. Western blotting and immunohistochemistry were used to detect the expression of proteins related to the Nrf2-Keap1-ARE pathway. PA significantly alleviated hypoxic PH and reversed right ventricular hypertrophy and pulmonary vascular remodeling. In addition, PA effectively inhibited proliferation and promoted apoptosis in hypoxia-induced pulmonary artery smooth muscle cells (PASMCs). Moreover, PA pretreatment inhibited the expression of peroxy-related factor (MDA) and promoted the expression of antioxidant-related factors (GSH-PX and SOD). Furthermore, hypoxia inhibited the Nrf2-Keap1-ARE signaling pathway, while PA effectively activated this pathway. Most importantly, addition of the Nrf2 inhibitor ML385 reversed the inhibitory effects of PA on ROS generation, proliferation, and apoptosis tolerance in hypoxia-induced PASMCs. Our study suggests that PA may reverse PH by regulating the Nrf2-Keap1-ARE signaling pathway.

Cyanosis in a Previously Well Child.

Cyanosis in a Previously Well Child.

Atrial fibrillation impairs dynamic right ventricular-pulmonary artery coupling and increases lung congestion during exercise in heart failure and preserved ejection fraction

Abstract Background Atrial fibrillation (AF) is common in patients with heart failure and preserved ejection fraction (HFpEF) and associated with left atrial (LA) myopathy, reduced exercise capacity and poor outcomes. However, the mechanisms underlying exercise intolerance in HFpEF with AF are not well-characterized. Purpose To test hypotheses that patients with HFpEF and AF (HFpEF-AF) would display greater acute impairments in right heart-pulmonary vascular coupling during exercise, leading to greater elevations in left and right heart filling pressures and increased lung congestion as compared to patients with HFpEF and no AF (HFpEF-no-AF) and control subjects free of heart failure and AF. As corollary hypotheses, we also posited that these changes would lead to greater ventricular interdependence during exercise in HFpEF-AF, and that pulmonary hypertension in HFpEF-AF was not simply ascribable to the LA dysfunction that accompanies AF, which would provide greater impetus to pursue restoration of sinus rhythm. Methods Subjects with HFpEF-AF (n=35), HFpEF-no-AF (n=85), and controls free of heart failure or AF (n=28) underwent cardiopulmonary exercise testing with invasive hemodynamic assessment and simultaneous echocardiography and lung ultrasound in a prospective study. Results As compared with controls and HFpEF-no-AF, subjects with HFpEF-AF displayed poorer left ventricular (LV) longitudinal strain, lower LA reservoir strain with greater LA volume at rest. With exercise, subjects with HFpEF-AF displayed more severe exercise-induced pulmonary hypertension, higher right atrial pressure (RAP) and more pronounced right ventricular-pulmonary vascular uncoupling. Peak oxygen consumption was lowest in patients with HFpEF-AF, coupled with greater limitations in cardiac output reserve and more severe increases in lung congestion and pulmonary vascular resistance (Figure 1). Dynamic ventricular interaction was greatest in HFpEF-AF, evidenced by greater increases in LV eccentricity index and RAP/PCWP (Figure 2) and less increase in LV transmural pressure compared with HFpEF-no-AF. In a sensitivity analysis, patients with HFpEF-AF displayed more severe pulmonary hypertension and pulmonary vascular disease compared to HFpEF-no-AF even after matching for the severity of LA remodeling and dysfunction. Conclusions Patients with AF and HFpEF display more severe abnormalities in pulmonary vascular reserve with exercise leading to greater lung congestion and enhanced exertional ventricular interdependence compared to patients with HFpEF-no-AF. While many of these differences appear attributable to LA dysfunction, the presence of AF is associated with more severe pulmonary vascular disease independent of LA myopathy, suggesting potential benefit from restoration of sinus rhythm even in the setting of LA myopathy. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): R01 HL128526

Secundum Type Atrial Septal Defect in Patients with Trisomy 21-Therapeutic Strategies, Outcome, and Survival: A Nationwide Study of the German National Registry for Congenital Heart Defects.

(1) Secundum type atrial septal defect (ASD II) is usually considered a relatively benign cardiac lesion amenable to elective closure at preschool age. Patients with trisomy 21 (T21), however, are known to have a higher susceptibility for pulmonary vascular disease (PVD). Therefore, T21 children may present with clinical symptoms earlier than those without associated anomalies. In addition, early PVD may even preclude closure in selected T21 patients. (2) We performed a retrospective analysis of the German National Register for Congenital Heart Defects including T21 patients with associated isolated ASD II. We report incidence, demographics, therapeutic strategy, outcome, and survival of this cohort. (3) Of 46,628 patients included in the registry, 1549 (3.3%) had T21. Of these, 156 (49.4% female) had an isolated ASD II. Fifty-four patients (34.6%) underwent closure at 6.4 ± 9.9 years of age. Over a cumulative follow-up (FU) of 1148 patient-years, (median 7.4 years), only one patient developed Eisenmenger syndrome and five patients died. Survival of T21 patients without PVD was not statistically different to age- and gender-matched controls from the normal population (p = 0.62), whereas children with uncorrected T21/ASD II (including patients with severe PVD, in whom ASD-closure was considered contraindicated) showed a significantly higher mortality. (4) The outcome of T21-patients with ASD II and without PVD is excellent. However, PVD, either precluding ASD-closure or development of progressive PVD after ASD-closure, is associated with significant mortality in this cohort. Thus T21 patients with ASD II who fulfill general criteria for closure and without PVD should be offered defect closure analogous to patients without T21.

Iron Deficiency Is Associated With More Severe Pulmonary Vascular Disease in Pulmonary Hypertension Caused by Chronic Lung Disease

Group 3 pulmonary hypertension (PH) is the second most common type of PH, but it has the highest mortality rate of all PH diseases.1 Current treatment options for group 3 PH are quite limited; although inhaled treprostinil improves exercise capacity,2 patients still carry a heavy morbidity and mortality burden. Therefore, further insights into group 3 PH pathophysiologic findings are needed hopefully to identify potential therapeutic targets to combat the high symptom burden and poor outcomes for these patients.

Experimental design of the Effects of Dehydroepiandrosterone in Pulmonary Hypertension (EDIPHY) trial.

Pulmonary arterial hypertension (PAH) remains life-limiting despite numerous approved vasodilator therapies. Right ventricular (RV) function determines outcome in PAH but no treatments directly target RV adaptation. PAH is more common in women, yet women have better RV function and survival as compared to men with PAH. Lower levels of the adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate ester are associated with more severe pulmonary vascular disease, worse RV function, and mortality independent of other sex hormones in men and women with PAH. DHEA has direct effects on nitric oxide (NO) and endothelin-1 (ET-1) synthesis and signaling, direct antihypertrophic effects on cardiomyocytes, and mitigates oxidative stress. Effects of Dehydroepiandrosterone in Pulmonary Hypertension (EDIPHY) is an on-going randomized double-blind placebo-controlled crossover trial of DHEA in men (n = 13) and pre- and post-menopausal women (n = 13) with Group 1 PAH funded by the National Heart, Lung and Blood Institute. We will determine whether orally administered DHEA 50 mg daily for 18 weeks affects RV longitudinal strain measured by cardiac magnetic resonance imaging, markers of RV remodeling and oxidative stress, NO and ET-1 signaling, sex hormone levels, other PAH intermediate end points, side effects, and safety. The crossover design will elucidate sex-based phenotypes in PAH and whether active treatment with DHEA impacts NO and ET-1 biosynthesis. EDIPHY is the first clinical trial of an endogenous sex hormone in PAH. Herein we present the study’s rationale and experimental design.

Patent foramen ovale and atrial septal defect.

Atrial septal defects (ASD) are among the most common congenital heart diseases encountered in adulthood. Patent foramen ovale (PFO) is present in up to 25% of the population. ASD could present as isolated lesion or in association with more complex congenital heart disease form as tetralogy of Fallot, or Ebstein's anomaly of tricuspid valve. There is a wide range of clinical presentation ranging from asymptomatic subjects surviving to adulthood undiagnosed to subjects presenting with right heart failure and severe pulmonary vascular disease (Eisenmenger syndrome). This manuscript is an in depth review of the complex atrial septation, the variable clinical presentation of ASD and PFO, and its clinical and therapeutic implications.

Abstract 14287: Iron Deficiency is Associated With More Severe Pulmonary Vascular Disease in Pulmonary Hypertension Due to Chronic Lung Disease

Background: Iron deficiency promotes pulmonary vascular remodeling in pre-clinical models, and is associated with worse outcomes in pulmonary arterial hypertension. However, the consequences of iron deficiency in patients with pulmonary hypertension due to chronic lung disease (Group 3 PH) are unexplored. Methods: We studied 122 consecutive Group 3 PH patients from the University of Minnesota Pulmonary Hypertension Repository. Serum soluble transferrin receptor (sTR) levels quantified iron deficiency. We evaluated the relationship between iron deficiency and pulmonary vascular disease, right ventricular (RV) function, exercise capacity, and survival. Results: The iron deficient group (<4.8mg/L sTR) had significantly higher mean pulmonary arterial pressure (40±9 mmHg, n=59 vs. 44±13 mmHg, n=61; p =.02) and lower pulmonary arterial compliance (2.2±1.2 mL/mmHg, n=52 vs. 1.7±0.8 mL/mmHg, n=55; p =.01), but there was no difference in pulmonary vascular resistance. Moreover, there were trends for higher right atrial pressure (7±4 mmHg, n=58 vs. 9±6 mmHg, n=61; p =0.08) in iron deficient patients. However, iron deficiency did not significantly alter RV function by echocardiography, 6-minute walk distance, or survival. Conclusions: Iron deficiency in Group 3 PH is associated with worse pulmonary vascular disease. This suggests iron deficiency could contribute to pulmonary vascular disease in Group 3 PH, and future studies are needed to determine if iron replacement could be a therapy for this deadly type of PH.

Regulatory effects of Prohibitin 1 on proliferation and apoptosis of pulmonary arterial smooth muscle cells in monocrotaline-induced PAH rats

BackgroundPulmonary arterial hypertension (PAH) is a severe pulmonary vascular disease characterized by unbalanced proliferation and apoptosis of pulmonary arterial smooth muscle cells (PASMCs). Prohibitin 1 (PHB1) is known for its significant anti-proliferative activity. However, the role of PHB1 in PASMCs and PAH have not been elucidated. MethodsMonocrotaline (MCT 60 mg/kg) was used to build a PAH model in SD rats. Right ventricular systolic pressure (RVSP) and right ventricle (RV) hypertrophy were measured. Morphology of pulmonary vessels was observed by Hematoxylin-Eosin (HE) staining. Expression of PHB1 in pulmonary arteries and PASMCs was determinated by immunoblot and immunofluorescence. Cell proliferation was detected by CCK8 and EDU when PASMCs were stimulated by PDGF-BB (20 ng/mL). Furthermore, siRNA for PHB1 and Akt inhibitor were conducted to investigate the mechanism behind the role of PHB1 and AKT signaling pathway in PASMCs proliferation and apoptosis. ResultsThe protein expression of PHB1 in PAH rats lung tissue was significantly up-regulated accompanied by elevated RVSP and enhanced RV hypertrophy. Immunohistochemistry showed that PHB1 was mainly localized in the pulmonary vascular smooth muscle layer. PDGF-BB significantly up-regulated the expression of PHB1 in rat primary PASMCs in a time- and dose-dependent manner. After PHB1 knock down, PASMCs proliferation was significantly suppressed while apoptosis was significantly recovered. Meanwhile the level of proliferating cell nuclear antigen (PCNA) and P-Akt were significantly down-regulated. Perifosine (Akt inhibitor) also significantly inhibit proliferation of PASMCs. ConclusionPHB1 contributes to pulmonary vascular remodeling by accelerating proliferation of PASMCs which involves AKT phosphorylation.