Elevated Mean Pulmonary Artery Pressure Research Articles

Outcomes of extracardiac Fontan operation: A single institution experience with 398 patients

ObjectiveThe study objective was to evaluate the outcomes of the extracardiac Fontan operation at a single institution. MethodsWe conducted a retrospective study of 398 patients from a single institution who underwent their initial extracardiac Fontan operation between 1997 and 2020. We determined the incidence of and risk factors for failure of the Fontan circulation, which includes death, Fontan takedown, heart transplantation, protein-losing enteropathy, plastic bronchitis, and functional status at the last follow-up. ResultsThe median follow-up time was 10.3 years (interquartile range, 6.4-14.6). The overall survival was 96% and 86% at 10 and 20 years after extracardiac Fontan operation, respectively. There were 6 early deaths (6/398, 1.5%) and 15 late deaths (15/398, 3.8%). Forty-nine patients (12.5%) developed failure of the Fontan circulation. Freedom from the failure of Fontan circulation was 88% at 10 years and 76% at 20 years. Risk factors for failure of the Fontan circulation were right ventricular dominance (hazard ratio, 4.7; P < .001; 95% CI, 2.1-10.5), aortic atresia (hazard ratio, 5.5; P < .001; 95% CI, 2.3-12.8), and elevated mean pulmonary artery pressure (hazard ratio, 2.3; P = .002; 95% CI, 1.2-6.7). ConclusionsRates of failure of the Fontan circulation are low after the contemporary extracardiac Fontan operation. Risk factors for failure of the extracardiac Fontan circulation include right ventricular dominance, aortic atresia, and elevated pulmonary artery pressures.

Ethanol-induced lung and cardiac right ventricular inflammation and remodeling underlie progression to pulmonary arterial hypertension.

Current research on ethanol-induced cardiovascular anomalies has focused on left ventricular (LV) function and blood pressure. To extend this area of research, we sought to determine whether ethanol-induced alterations in the structure and function of the right cardiac ventricle (RV) and pulmonary artery (PA) lead to pulmonary arterial hypertension (PAH). Two groups of male Sprague-Dawley rats received a balanced liquid diet containing 5% ethanol (w/v) or a pair-fed isocaloric liquid diet for 8 weeks. Weekly echocardiography was conducted to evaluate cardiopulmonary function, and lung and RV tissues were collected for exvivo histological and molecular studies. The ethanol-treated rats exhibited: (1) Elevated mean pulmonary arterial pressure and decreased pulmonary artery acceleration time/ejection time; (2) Pulmonary vascular remodeling comprising intrapulmonary artery medial layer thickening; and (3) RV hypertrophy along with increased RV/LV + septum, RV diameter, RV cardiomyocyte cross-sectional area, and LV mass/body weight ratio. These responses were associated with increased lung and RV pro-inflammatory markers, endothelin-1 (ET-1), TNF-α, and IL-6 levels and higher ET-1,ET-1 type A/B receptor ratio, and downregulation of the cytoprotective protein, bone morphogenetic protein receptor 2 (BMPR2), in the lungs. These findings show that moderate ethanol-induced cardiopulmonary changes underlie progression to PAH via an upregulated proinflammatory ET1-TNFα-IL6 pathway and suppression of the anti-inflammatory BMPR2.

OPN silencing reduces hypoxic pulmonary hypertension via PI3K-AKT-induced protective autophagy.

Hypoxic pulmonary hypertension (HPH) is a pulmonary vascular disease primarily characterized by progressive pulmonary vascular remodeling in a hypoxic environment, posing a significant clinical challenge. Leveraging data from the Gene Expression Omnibus (GEO) and human autophagy-specific databases, osteopontin (OPN) emerged as a differentially expressed gene, upregulated in cardiovascular diseases such as pulmonary arterial hypertension (PAH). Despite this association, the precise mechanism by which OPN regulates autophagy in HPH remains unclear, prompting the focus of this study. Through biosignature analysis, we observed significant alterations in the PI3K-AKT signaling pathway in PAH-associated autophagy. Subsequently, we utilized an animal model of OPNfl/fl-TAGLN-Cre mice and PASMCs with OPN shRNA to validate these findings. Our results revealed right ventricular hypertrophy and elevated mean pulmonary arterial pressure (mPAP) in hypoxic pulmonary hypertension model mice. Notably, these effects were attenuated in conditionally deleted OPN-knockout mice or OPN-silenced hypoxic PASMCs. Furthermore, hypoxic PASMCs with OPN shRNA exhibited increased autophagy compared to those in hypoxia alone. Consistent findings from in vivo and in vitro experiments indicated that OPN inhibition during hypoxia reduced PI3K expression while increasing LC3B and Beclin1 expression. Similarly, PASMCs exposed to hypoxia and PI3K inhibitors had higher expression levels of LC3B and Beclin1 and suppressed AKT expression. Based on these findings, our study suggests that OPNfl/fl-TAGLN-Cre effectively alleviates HPH, potentially through OPN-mediated inhibition of autophagy, thereby promoting PASMCs proliferation via the PI3K-AKT signaling pathway. Consequently, OPN emerges as a novel therapeutic target for HPH.

Determinants of physical quality of life in patients with chronic thromboembolic pulmonary hypertension after treatment: Insights from invasive exercise stress test

BackgroundImpaired quality of life (QoL) is prevalent among patients with chronic thromboembolic pulmonary hypertension (CTEPH) despite improved survival due to medical advances. We clarified the physical QoL of patients with CTEPH with mildly elevated pulmonary hemodynamics and evaluated its determinants using a database of patients with CTEPH evaluated for hemodynamics during exercise. MethodsThe QoL was measured in 144 patients with CTEPH (age, 66 (58-73) years; men/women, 48/96) with mildly elevated mean pulmonary artery pressure (< 30 mmHg) at rest after treatment with balloon pulmonary angioplasty and/or pulmonary endarterectomy using the Short-Form 36 (SF-36) questionnaire. The enrolled patients were divided into two groups: physical component summary (PCS) scores in the SF-36 over 50 as PCS-good and those under 50 as PCS-poor. ResultsThe median PCS in SF-36 score was 43.4 (IQR 32.4-49.5) points. The PCS-poor group (n = 110) was older and had lower exercise capacity and SaO2 during exercise. PCS scores were correlated with 6-minute walk distance (rs = 0.40, p < 0.001), quadriceps strength (rs = 0.34, p < 0.001), peak VO2 (rs = 0.31, p < 0.001), SaO2 at rest (rs = 0.35, p < 0.001) and peak exercise (rs = 0.33, p < 0.001), home oxygen therapy usage (rs = −0.28, p = 0.001), and pulmonary vascular resistance at peak exercise (rs = −0.26, p = 0.002). ConclusionsThe impairment of physical QoL was common in patients with CTEPH with improved hemodynamics; exercise capacity, hypoxemia, and hemodynamic status during exercise were related to the physical QoL.

Mild elevation of pulmonary vascular resistance predicts mortality regardless of mean pulmonary artery pressure in mild interstitial lung disease

BackgroundPulmonary hypertension (PH) is defined by elevated mean pulmonary arterial pressure (MPAP), and elevated pulmonary vascular resistance (PVR) reflects pulmonary vascular abnormalities. The clinical significance of non-severe PH in patients...

Reversal of Pulmonary Hypertension in a Human-Like Model: Therapeutic Targeting of Endothelial DHFR.

Pulmonary hypertension (PH) is a progressive disorder characterized by remodeling of the pulmonary vasculature and elevated mean pulmonary arterial pressure, resulting in right heart failure. Here, we show that direct targeting of the endothelium to uncouple eNOS (endothelial nitric oxide synthase) with DAHP (2,4-diamino 6-hydroxypyrimidine; an inhibitor of GTP cyclohydrolase 1, the rate-limiting synthetic enzyme for the critical eNOS cofactor tetrahydrobiopterin) induces human-like, time-dependent progression of PH phenotypes in mice. Critical phenotypic features include progressive elevation in mean pulmonary arterial pressure, right ventricular systolic blood pressure, and right ventricle (RV)/left ventricle plus septum (LV+S) weight ratio; extensive vascular remodeling of pulmonary arterioles with increased medial thickness/perivascular collagen deposition and increased expression of PCNA (proliferative cell nuclear antigen) and alpha-actin; markedly increased total and mitochondrial superoxide production, substantially reduced tetrahydrobiopterin and nitric oxide bioavailabilities; and formation of an array of human-like vascular lesions. Intriguingly, novel in-house generated endothelial-specific dihydrofolate reductase (DHFR) transgenic mice (tg-EC-DHFR) were completely protected from the pathophysiological and molecular features of PH upon DAHP treatment or hypoxia exposure. Furthermore, DHFR overexpression with a pCMV-DHFR plasmid transfection in mice after initiation of DAHP treatment completely reversed PH phenotypes. DHFR knockout mice spontaneously developed PH at baseline and had no additional deterioration in response to hypoxia, indicating an intrinsic role of DHFR deficiency in causing PH. RNA-sequencing experiments indicated great similarity in gene regulation profiles between the DAHP model and human patients with PH. Taken together, these results establish a novel human-like murine model of PH that has long been lacking in the field, which can be broadly used for future mechanistic and translational studies. These data also indicate that targeting endothelial DHFR deficiency represents a novel and robust therapeutic strategy for the treatment of PH.

Utility of Balloon Occlusion Testing in Determining Fontan Suitability Among Patients with Elevated Pulmonary Artery Pressure and Additional Antegrade Pulmonary Blood Flow.

In individuals with a single ventricle undergoing evaluation before Fontan surgery, the presence of excessive pulmonary blood flow can contribute to increased pulmonary artery pressure, notably in those who had a Glenn procedure with antegrade pulmonary flow. 28 patients who had previously undergone Glenn anastomosis with antegrade pulmonary blood flow (APBF) and with elevated mean pulmonary artery (mPAP) pressure > 15mmHg in diagnostic catheter angiography were included in the study. After addressing other anatomical factors that could affect pulmonary artery pressure, APBF was occluded with semi-compliant, Wedge or sizing balloons to measure pulmonary artery pressure accurately. 23 patients (82% of the cohort) advanced to Fontan completion. In this group, median mPAP dropped from 20.5 (IQR 19-22) mmHg to 13 (IQR 12-14) mmHg post-test (p < 0.001). Median PVR post-test was 1.8 (IQR 1.5-2.1) WUm2. SpO2 levels decreased from a median of 88% (IQR 86%-93%) pre-test to 80% (IQR 75%-84%) post-test (p < 0.001). In five patients, elevated mPAP post-test occlusion on diagnostic catheter angiography led to non-completion of Fontan circulation. In this group, median pre- and post-test mPAP were 23mmHg (IQR 21.5-23.5) and 19mmHg (IQR 18.5-20), respectively (p = 0.038). Median post-test PVR was 3.8 (IQR 3.6-4.5) WUm2. SpO2 levels decreased from a median of 79% (IQR 76%-81%) pre-test to 77% (IQR 73.5%-80%) post-test (p = 0.039). Our study presents a specialized approach for patients initially deemed unsuitable for Fontan due to elevated pulmonary artery pressures. We were able to successfully complete the Fontan procedure in the majority of these high-risk cases after temporary balloon occlusion test.

Unilateral Lung Removal in Combination with Monocrotaline or SU5416 in Rodents: A Reliable Model to Mimic the Pathology of the Human Pulmonary Hypertension.

Pulmonary hypertension (PH) is a chronic and progressive disorder characterized by elevated mean pulmonary arterial pressure, pulmonary vascular remodeling, and the development of concentric laminar intimal fibrosis with plexiform lesions. While rodent models have been developed to study PH, they have certain deficiencies and do not entirely replicate the human disease due to the heterogeneity of PH pathology. Therefore, combined models are necessary to study PH. Recent studies have shown that altered pulmonary blood flow is a significant trigger in the development of vascular remodeling and neointimal lesions. One of the most promising rodent models for increased pulmonary flow is the combination of unilateral left pneumonectomy with a "second hit" of monocrotaline (MCT) or SU5416. The removal of one lung in this model forces blood to circulate only in the other lung and induces increased and turbulent pulmonary blood flow. This increased vascular flow leads to progressive remodeling and occlusion of small pulmonary arteries. The second hit by MCT or SU5416 leads to endothelial cell dysfunction, resulting in severe PH and the development of plexiform arteriopathy.

PAH-specific treatment for patients with combined pre- and post-capillary pulmonary hypertension

Abstract Introduction Pulmonary hypertension (PH) due to left heart disease (PH-LHD) is the most frequent form of PH, constituting approximately 70% of PH patients. Depending on the extent of pressure increase in the pre-capillary bed, PH-LHD is divided into isolated post-capillary PH, where pulmonary vascular resistance (PVR) is ≤2 WU, and combined pre- and post-capillary PH (Cpc-PH), where PVR exceeds 2 WU. Compared to Ipc-PH, Cpc-PH portents substantial morbidity and poor prognosis. Current PH guidelines recommend optimal treatment of underlying pathology, with drugs approved for pulmonary arterial hypertension (PAH) being not recommended; however, therapeutic regimens specifically targeting increases in pre-capillary pressure are urgently required. Methods For this analysis, we included all patients diagnosed with Cpc-PH invluding using right heart catheterization, who presented at the PH outpatient clinic of the Medical University of Vienna, Austria, between 02/2022 and 02/2023. Cpc-PH was defined hemodynamically as an elevated mean pulmonary arterial pressure (mPAP) of &amp;gt;20 mmHg and a PVR &amp;gt;2 WU. Results A total of 30 (6.5%) patients were diagnosed with Cpc-PH. Of these, 21 (70%) were female; median age was 75 [70, 76] years. Cardiovascular risk factors were arterial hypertension in 27 (90%), diabetes mellitus in 7 (23%), hyperlipidemia in 22 (73%), atrial fibrillation in 24 (80%), chronic kidney disease in 21 (70%), and coronary artery disease in 13 (43%) patients. At diagnosis, median mPAP was 42 [36, 53] mmHg, with a PVR of 5.5 [3.4, 5.3] WU. Laboratory evidence of heart failure was illustrated by elevated NT-proBNP levels (2076 [1461, 3959] pg/mL). Transthoracic echocardiography showed mildly, moderately and severely reduced right ventricular (RV) function in 7 (23%), 9 (30%) and 3 (10%) patients. At diagnosis, 6 (20%), 20 (67%) and 4 (13%) patients were in WHO functional class II, III and IV, respectively. PAH-specific therapy was initiated in 11 (37%) patients: 7 (23%) were put on treprostinil, 4 (13%) on macitentan, 3 (10%) on riociguat, and 3 (10%) on sildenafil. In 3 (10%) patients, combination therapy was started; one (3%) patient received triple therapy. In patients in whom PAH-specific therapy was initiated, PVR at baseline was higher (6.9 [5.4, 9.9] vs. 4.9 [3.1, 5.9] WU, p=0.019). Patients on PAH-specific therapy had a higher rate of improvement in WHO-FC at follow-up (82% vs. 31%, p=0.019). Conclusions In patients suffering from Cpc-PH, PAH-specific therapy leads to improvement of symptoms. Further studies are required to extend this finding to a larger patient group to assess whether PAH-specific drugs may also improve hemodynamics, right ventricular function and mortality.

Exercise-Induced Electrocardiography Changes in Pulmonary Arterial Hypertension

Cardiopulmonary exercise testing (CPET) is an important tool in assessing the functional status of patients with pulmonary arterial hypertension (PAH). During CPET, continuous electrocardiography (ECG) is used as a marker of exercise-induced ischemia or arrhythmia. We hypothesize that ECG changes with exercise may be an early indicator of clinical worsening in PAH and could predict adverse outcomes. Clinical, hemodynamic, and CPET data of 155 children and young adult patients with PAH who underwent CPET between 2012 and 2019 in our pulmonary hypertension (PH) center were included in this retrospective analysis. ECGs were analyzed for ST depressions and T-wave inversions, along with coincident hemodynamic data. These data were correlated with adverse outcomes divided into 2 categories: severe worsening (death or receiving lung transplant) and mild to moderate worsening (PAH medication escalation, hospitalization, shunt creation, or listing for lung transplant). The median age was 19years (range 7 to 40years), 69% were female, and the average follow-up time was 5years (range 1 to 8years). A total of 63 patients (41%) had at least 1 adverse outcome. A total of 39 patients (25%) demonstrated significant ST-T-wave changes with exercise. Patients with ST-T-wave changes were 20% more likely to die or need lung transplant than those without. The multiple linear regression found that ST-T-wave changes were a predictor of elevated mean pulmonary arterial pressure (mPAP) found on catheterization (R=0.489, p=0.003), although not of pulmonary vascular resistance index (R=-0.112, p=0.484). An mPAP of 55mm Hg was the most sensitive and specific point in identifying when ST-T-wave changes with exercise begin to appear. In conclusion, ST-T-wave changes on exercise ECG are significantly associated with adverse outcomes in PH in a medium-term follow-up study, and the presence of ST-T-wave changes correlates with higher mPAP. These ECG changes with exercise may be used as early indicators of clinical worsening in PH and predictors of adverse outcomes.

Predictors of outcomes in mild pulmonary hypertension according to 2022 ESC/ERS Guidelines: the EVIDENCE-PAH UK study.

Interventional studies in pulmonary arterial hypertension completed to date have shown to be effective in symptomatic patients with significantly elevated mean pulmonary artery pressure (mPAP) (≥25 mmHg) and pulmonary vascular resistance (PVR) > 3 Wood Unit (WU). However, in health the mPAP does not exceed 20 mmHg and PVR is 2 WU or lower, at rest. The ESC/ERS guidelines have recently been updated to reflect this. There is limited published data on the nature of these newly defined populations (mPAP 21-24 mmHg and PVR >2-≤3 WU) and the role of comorbidity in determining their natural history. With the change in guidelines, there is a need to understand this population and the impact of the ESC/ERS guidelines in greater detail. A retrospective nationwide evaluation of the role of pulmonary haemodynamics and comorbidity in predicting survival among patients referred to the UK pulmonary hypertension (PH) centres between 2009 and 2017. In total, 2929 patients were included in the study. Patients were stratified by mPAP (<21 mmHg, 21-24 mmHg, and ≥25 mmHg) and PVR (≤2 WU, > 2-≤3 WU, and >3 WU), with 968 (33.0%) in the mPAP <21 mmHg group, 689 (23.5%) in the mPAP 21-24 mmHg group, and 1272 (43.4%) in the mPAP ≥25 mmHg group. Survival was negatively correlated with mPAP and PVR in the population as a whole. Survival in patients with mildly elevated mPAP (21-24 mmHg) or PVR (>2-≤3WU) was lower than among those with normal pressures (mPAP <21 mmHg) and normal PVR (PVR ≤ 2WU) independent of comorbid lung and heart disease [hazard ratio (HR) 1.36, 95% confidence interval (CI) 1.14-1.61, P = .0004 for mPAP vs. HR 1.28, 95% CI 1.10-1.49, P = .0012 for PVR]. Among patients with mildly elevated mPAP, a mildly elevated PVR remained an independent predictor of survival when adjusted for comorbid lung and heart disease (HR 1.33, 95% CI 1.01-1.75, P = .042 vs. HR 1.4, 95% CI 1.06-1.86, P = .019). 68.2% of patients with a mPAP 21-24 mmHg had evidence of underlying heart or lung disease. Patients with mildly abnormal haemodynamics were not more symptomatic than patients with normal haemodynamics. Excluding patients with heart and lung disease, connective tissue disease was associated with a poorer survival among those with PH. In this subpopulation evaluating those with a mPAP of 21-24 mmHg, survival curves only diverged after 5 years. This study supports the change in diagnostic category of the ESC/ERS guidelines in a PH population. The newly included patients have an increased mortality independent of significant lung or heart disease. The majority of patients in this new category have underlying heart or lung disease rather than an isolated pulmonary vasculopathy. Mortality is higher if comorbidity is present. Rigorous phenotyping will be pivotal to determine which patients are at risk of progressive vasculopathic disease and in whom surveillance and recruitment to studies may be of benefit. This study provides an insight into the population defined by the new guidelines.

Elevated Pulmonary Arterial Compliance Is Associated with Survival in Pulmonary Hypertension: Results from a Novel Network Medicine Analysis.

Rationale: Predictors of adverse outcome in pulmonary hypertension (PH) are well established; however, data that inform survival are lacking. Objectives: We aim to identify clinical markers and therapeutic targets that inform the survival in PH. Methods: We included data from patients with elevated mean pulmonary artery pressure (mPAP) diagnosed by right heart catheterization in the U.S. Veterans Affairs system (October 1, 2006-September 30, 2018). Network medicine framework was used to subgroup patients when considering an N of 79 variables per patient. The results informed outcome analyses in the discovery cohort and a sex-balanced validation right heart catheterization cohort from Vanderbilt University (September 24, 1998-December 20, 2013). Measurements and Main Results: From an N of 4,737 complete case patients with mPAP of 19-24 mm Hg, there were 21 distinct subgroups (network modules) (all-cause mortality range = 15.9-61.2% per module). Pulmonary arterial compliance (PAC) drove patient assignment to modules characterized by increased survival. When modeled continuously in patients with mPAP ⩾19 mm Hg (N = 37,744; age, 67.2 yr [range = 61.7-73.8 yr]; 96.7% male; median follow-up time, 1,236 d [range = 570-1,971 d]), the adjusted all-cause mortality hazard ratio was <1.0 beginning at PAC ⩾3.0 ml/mm Hg and decreased progressively to ∼7 ml/mm Hg. A protective association between PAC ⩾3.0 ml/mm Hg and mortality was also observed in the validation cohort (N = 1,514; age, 60.2 yr [range = 49.2-69.1 yr]; 48.0% male; median follow-up time, 2,485 d [range = 671-3,580 d]). The association was strongest in patients with precapillary PH at the time of catheterization, in whom 41% (95% confidence interval, 0.55-0.62; P < 0.001) and 49% (95% confidence interval, 0.38-0.69; P < 0.001) improvements in survival were observed for PAC ⩾3.0 versus <3.0 ml/mm Hg in the discovery and validation cohorts, respectively. Conclusions: These data identify elevated PAC as an important parameter associated with survival in PH. Prospective studies are warranted that consider PAC ⩾3.0 ml/mm Hg as a therapeutic target to achieve through proven interventions.

Impairment of Angiogenesis-Driven Clot Resolution Is a Key Event in the Progression to Chronic Thromboembolic Pulmonary Hypertension: Validation in a Novel Rabbit Model.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition and rare complication of acute pulmonary embolism. Mechanisms underlying impaired clot resolution and in sustained fibrothrombotic obstruction of the pulmonary arterial bed remain poorly understood. Since defective angiogenesis correlated to defective clot resolution based on observations in surgical material from patients with CTEPH, we aimed to validate its crucial pathogenic role by intrathrombus inhibition of angiogenesis in a novel CTEPH rabbit model. We aimed to compare whether intrathrombus administration of an antifibrinolytic agent, tranexamic acid, or an inhibitor of angiogenesis, SU5416, would contribute to CTEPH progression. Both products were administered on a weekly basis by autologous clot embolization in rabbits. Right ventricular pressure was monitored by telemetry, right ventricular function by transthoracic echocardiography, and a complete pulmonary hemodynamic evaluation was obtained through right heart catheterization. Markers of inflammation, endothelial dysfunction, heart failure, and fibrinolysis were measured in plasma. Pulmonary vessel remodeling was analyzed by immunohistochemistry. Impairing intrathrombus angiogenesis by repeatedly embolizing autologous blood clots containing SU5416 resulted in elevated mean pulmonary arterial pressure (38 mm Hg), increased indexed pulmonary vascular resistance, and enhanced right ventricular hypertrophy (80%, 1.9-fold, 36%, respectively, compared with rabbits embolized with clots containing an antifibrinolytic agent). This was caused by both obstruction of large pulmonary arteries with fibrothrombotic material and muscularization of pulmonary microvessels, and accompanied by inflammatory cell infiltration and increased circulating endothelin-1. The key role of angiogenesis-driven clot resolution was validated in a reliable small-animal model reproducing the major pathophysiological hallmarks of CTEPH.

Pulmonary hypertension in patients with multiple myeloma: A comprehensive review.

Multiple myeloma (MM) is a common hematological malignancy resulting from clonal proliferation of plasma cells and is defined by criteria set forth by the international myeloma working group. Pulmonary hypertension (PH) is defined by an elevated mean pulmonary artery pressure >20 mmHg measured during right heart catheterization. Echocardiography-diagnosed PH is relatively common in patients with MM and has been associated with increased mortality, morbidity, and poor stem cell transplant outcomes. PH in patients with MM (PH-MM) is usually multifactorial in origin. MM disease-specific factors, host comorbidities, and treatment-related adverse effects are the key factors for the development of PH-MM. Pragmatically, patients with PH-MM can be grouped into either (i) PH in patients with a new diagnosis of MM or (ii) PH that develops or worsens along the way of MM treatment. In the latter group, drug-induced PH, venous thromboembolism, pulmonary veno occlusive disease, and cardiotoxicity should be considered as possible causes. PH-MM should be evaluated and managed in a multidisciplinary setting. Select individuals with PH-MM could be considered for pulmonary vasodilators at PH-specialized centers.

Prognostic Value of Respiratory Variation in Right Atrial Pressure in Patients With Precapillary Pulmonary Hypertension

Precapillary pulmonary hypertension (PH) is characterized by elevated mean pulmonary artery pressure from increased pulmonary vascular resistance (PVR). Lack of respiratory variation in right atrial pressure (RAP) can be viewed as a surrogate for severe PH and inability of the right ventricle (RV) to tolerate preload augmentation during inspiration. Is the lack of respiratory variation in RAP predictive of RV dysfunction and worse clinical outcomes in precapillary PH? We retrospectively reviewed RAP tracings of patients with precapillary PH who underwent right heart catheterization. Patients with respiratory variation in RAP (end expiratory - end inspiratory) ≤2 mmHg were considered to have effectively no meaningful variation in RAP. Lack of respiratory variation in RAP was associated with lower cardiac index by indirect Fick (2.34±0.09 vs. 2.76±0.1 L/min/m2, p=0.001), lower pulmonary artery saturation (60±1.02% vs 64±1.15%, p=0.007), higher PVR (8.9±0.44 vs 6.1±0.49 Wood units, p<0.0001), RV dysfunction on echocardiography (87.3% vs 38.8%, p<0.0001), higher proBNP (2163±2997 vs 633±402 ng/ml, p<0.0001), and more hospitalizations within 1 year for RV failure (65.4% vs 29.6%, p<0.0001). There was also a trend toward higher mortality at 1 year in patients with no respiratory variation in RAP (25.4% vs 11.1%, p=0.06). Lack of respiratory variation in RAP is associated with poor clinical outcomes, adverse hemodynamic parameters, and RV dysfunction in patients with precapillary PH. Larger studies are needed to further evaluate its utility in prognosis and potential risk stratification in patients with precapillary PH.

Pregnancy in Patients with Pulmonary Arterial Hypertension in Light of New ESC Guidelines on Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is defined as an elevated mean pulmonary artery pressure (mPAP) of >20 mmHg together with a pulmonary arterial wedge pressure (PAWP) of ≤15 mmHg and pulmonary vascular resistance (PVR) of>2 Wood units (WU). Although the total mortality of pregnant women with PAH has decreased significantly in recent years and is reported to be around 12% in some databases, total mortality is still at an unacceptably high percentage. Moreover, some subgroups, such as patients with Eisenmenger's syndrome, have a particularly high mortality rate of up to 36%. Pregnancy in patients with PAH is contraindicated; its appearance is an indication for a planned termination. Education of patients with PAH, including counseling on effective contraception, is essential. During pregnancy, blood volume, heart rate, and cardiac output increase, while PVR and systemic vascular resistance decrease. The hemostatic balance is shifted towards hypercoagulability. Among PAH-specific drugs, the use of inhaled or intravenous prostacyclins, phosphodiesterase inhibitors, and calcium channel blockers (in patients with preserved vasoreactivity) is acceptable. Endothelin receptor antagonists and riociguat are contraindicated. Childbirth can take place through either vaginal delivery or caesarean section; similarly, neuraxial and general anesthesia have proven indications. In a situation where all pharmacological options have been used in pregnant or postpartum patients in a serious condition, veno-arterial ECMO is a useful therapeutic option. For PAH patients who want to become mothers, an option that does not endanger their lives is adoption.

Hemosiderin-laden macrophages in bronchoalveolar lavage samples of children with bronchopulmonary dysplasia.

To evaluate the prevalence of hemosiderin-laden macrophages in children with bronchopulmonary dysplasia (BPD) and assess for an association between hemosiderin-laden macrophages and pulmonary arterial hypertension. Retrospective case-control study of infants and children with and without BPD who underwent bronchoscopy with bronchoalveolar lavage (BAL) the at Children's Hospital of Philadelphia between 2012 and2021. BAL from 205 children with BPD and 106 controls without BPD matched for tracheostomy, infection, and age were reviewed for hemosiderin-laden macrophages. Seventy-one individuals (34.6%) with BPD had a BAL with 10% or more hemosiderin-laden macrophages compared with 3 (2.8%) controls (P<.0001; OR, 18.19; 95% CI, 5.57-59.41). Patients with pulmonary hypertension by echocardiogram (P=.04; OR, 3.69; 95% CI, 1.05-12.96) or an elevated mean pulmonary artery pressure during cardiac catheterization, rs (14)=0.56, P=.04, were more likely to have elevated hemosiderin-laden macrophages on BAL samples less than 60days from bronchoscopy. After adjusting for birth weight, gestational age, BPD grade, and age at the time of bronchoscopy using logistic regression, pulmonary hypertension was associated with a higher odds of hemosiderin-laden macrophages of 10% or more (P=.02; OR, 6.37; 95% CI, 1.28-31.87). No association was observed between hemosiderin-laden macrophages and sex, race, gestational age, birth weight, tracheostomy, or infectious studies. This retrospective study revealed increased hemosiderin-laden macrophages in BAL samples from patients with BPD and a significant association with pulmonary arterial hypertension. It is unclear whether elevated hemosiderin-laden macrophages within BPD contributes to the pathogenesis of lung and pulmonary vascular disease or is simply a biomarker of pulmonary arterial hypertension.

Abstract 11660: Case Report: Stymied by the Stemi, an Un-Emblematic Pulmonary Embolism

Introduction: Diagnosing a pulmonary embolism (PE) can be challenging, especially when it presents as another “can’t miss” diagnosis like acute coronary syndrome. Although electrocardiogram (EKG) abnormalities can be seen in many PE presentations, rarely are ST elevations noted. We describe a case report of PE presenting as STEMI. Case presentation: A 71-year-old woman with hypertension, hyperlipidemia, type 2 diabetes mellitus, and morbid obesity presented to the emergency department with chest pain radiating to the jaw along with shortness of breath. On initial presentation her heart rate was 110 bpm, respiratory rate 40, 84% SpO2 on room air, and blood pressure 150/84 mmHg. EKG showed ST elevation in anterior leads V1-V2 and reciprocal changes of ST depression in lateral leads I, aVL, V5-V6. Serial troponins were elevated and she underwent left heart catheterization which showed non-obstructive coronary artery disease and hyperdynamic left ventricular function. Right heart catheterization (RHC) showed an elevated mean pulmonary artery pressure of 49 mmHg, and pulmonary artery pulsatility index was 2.2, suggestive of right ventricular dysfunction which prompted an urgent CT pulmonary angiogram and transthoracic echocardiogram. The CT revealed extensive pulmonary embolism and echocardiogram demonstrated dilated right ventricle with hypokinesis and akinetic right ventricular free wall. A left lower extremity ultrasound revealed deep vein thrombosis. Discussion: This patient depicts an uncommon presentation of acute PE masquerading as acute coronary syndrome. Her case was diagnostically challenging as her EKG findings were not consistent with those typically seen in acute PE. Review of the literature reveals only a handful of case reports of a PE appearing to be a STEMI. Although rare, clinicians should entertain the idea of PE when presented with ST elevation and no culprit lesion and a careful RHC may be useful in establishing diagnosis.

Simvastatin and dehydroepiandrosterone sulfate effects against hypoxic pulmonary hypertension are not additive

Pulmonary hypertension is a group of disorders characterized by elevated mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance. To test our hypothesis that combining two drugs useful in experimental pulmonary hypertension, statins and dehydroepiandrosterone sulfate (DHEA S), is more effective than either agent alone, we induced pulmonary hypertension in adult male rats by exposing them to hypoxia (10%O2) for 3 weeks. We treated them with simvastatin (60 mg/l) and DHEA S (100 mg/l) in drinking water, either alone or in combination. Both simvastatin and DHEA S reduced mPAP (froma mean±s.d. of 34.4±4.4 to 27.6±5.9 and 26.7±4.8 mmHg, respectively), yet their combination was not more effective (26.7±7.9 mmHg). Differences in the degree of oxidative stress (indicated by malondialdehydeplasma concentration),the rate of superoxide production (electron paramagnetic resonance), or blood nitric oxide levels (chemiluminescence) did not explain the lack of additivity of the effect of DHEA S and simvastatin on pulmonary hypertension. We propose that the main mechanism of both drugs on pulmonary hypertension could be their inhibitory effect on 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, which could explain their lack of additivity.

Evidence of Advanced Pulmonary Vascular Remodeling in Obstructive Hypertrophic Cardiomyopathy With Pulmonary Hypertension

Elevated mean pulmonary artery pressure (mPAP) is common in patients with hypertrophic cardiomyopathy (HCM) and heart failure symptoms. However, dynamic left ventricular (LV) outflow tract obstruction may confound interpretation of pulmonary hypertension (PH) pathophysiologic features in HCM when relying on resting invasive hemodynamic data alone. Do structural changes to the lung vasculature clarify PH pathophysiologic features in patients with HCM with progressive heart failure? Clinical data and ultrarare lung autopsy specimens were acquired retrospectively from the National Institutes of Health (1975-1992). Patients were included based on the availability of lung tissue and recorded mPAP. Discarded tissue from rejected lung donors served as control specimens. Histomorphology was performed on pulmonary arterioles and veins. Comparisons were calculated using the Student t test and Mann-Whitney U test; Pearson correlation was used to assess association between morphometric measurements and HCM cardiac and hemodynamic measurements. The HCM cohort (n= 7; mean ± SD age, 43 ± 18 years; 71%men) showed maximum mean ± SD LV wall thickness of 25 ± 2.8mm, mean ± SD outflow tract gradient of 90 ± 30mmHg, median mPAP of 25mmHg (interquartile range [IQR], 6mmHg), median pulmonary artery wedge pressure (PAWP) of 16mmHg (IQR, 4mmHg), and median pulmonary vascular resistance of 1.8 Wood units (WU; IQR, 2.4 WU). Compared with control samples (n= 5), patients with HCM showed greater indexed pulmonary arterial hypertrophy (20.7 ± 7.2%vs49.7 ± 12%; P< .001) and arterial wall fibrosis (11.5 ± 3.4mm vs21.0 ± 4.7mm; P< .0001), which correlated with mPAP (r= 0.84; P= .018), PAWP (r= 0.74; P= .05), and LV outflow tract gradient (r= 0.78; P= .035). Compared with control samples, pulmonary vein thickness was increased by 2.9-fold (P= .008) in the HCM group, which correlated with mPAP (r= 0.81; P= .03) and LV outflow tract gradient (r= 0.83; P= .02). To the best of our knowledge, these data demonstrate for the first time that in patients with obstructive HCM, heart failure is associated with pathogenic pulmonary vascular remodeling even when mPAP is elevated only mildly. These observations clarify PH pathophysiologic features in HCM, with future implications for clinical strategies that mitigate outflow tract obstruction.