Insights Into Differences in Pulmonary Hemodynamics in Hispanic Patients With Pulmonary Arterial Hypertension.

Background: Emerging data suggest that Hispanic patients with pulmonary arterial hypertension (PAH) exhibit improved survival rates compared to individuals of other ethnicities with similar baseline hemodynamics. However, the underlying reasons for this survival advantage remain unclear. This study focused on comparing pulmonary hemodynamics in Hispanic and non-Hispanic PAH patients and how these differences may contribute to varied clinical outcomes. Methods: A retrospective analysis of right heart catheterization data was conducted on a treatment-naive PAH patient cohort from a single center. Results: Over a 10-year period, a total of 226 PAH patients were identified, of which 138 (61%) were Hispanic and 88 (39%) were non-Hispanic. Hispanic patients presented with lower pulmonary artery pressures, lower pulmonary vascular resistance, and exhibited significantly higher pulmonary arterial compliance (PAc). Hispanic patients had better 5-year survival rates. Conclusions: This study highlights the importance of exploring phenotypic differences in ethnically diverse PAH cohorts.

Evaluation of Four Validated Risk Scores to Predict Outcomes in Hispanic Patients With Acute Pulmonary Embolism.

Risk stratification plays an essential role in the management of acute pulmonary embolism (PE). Several risk scores have been studied to support risk stratification and management. While ethnic differences in acute PE risk factors exist, current risk scores lack validation for Hispanic patients. Therefore, the present study retrospectively investigated the performance of the pulmonary embolism severity index (PESI), simplified PESI (sPESI), the European Society of Cardiology risk assessment (ESC), and the Bova score, to predict 30-day mortality in Hispanic patients presenting with an acute PE. Among 437 patients admitted with acute PE, 30-day mortality was 10.8%; 30-day mortality in low-risk groups ranged from 0% (sPESI, ESC) to 0.2% (PESI, Bova), and 3.0% (Bova) to 5.7% (PESI) in the highest risk groups, respectively. All four scores produced statistically significant discrimination between different risk strata. However, no single scoring system was able to identify all patients with 30-day mortality. The findings of the present study suggest that PESI, sPESI, ESC, and Bova scores provide important information about 30-day mortality in Hispanic in-patients presenting with acute PE. However, additional clinical information could further improve predictability that is not provided by a single scoring system.

Reduced-Dose Thrombolysis in Acute Pulmonary Embolism A Systematic Review.

Pulmonary embolism (PE) is the third-leading cause of cardiovascular mortality and the second-leading cause of death in cancer patients. The clinical efficacy of thrombolysis for acute PE has been proven, yet the therapeutic window seems narrow, and the optimal dosing for pharmaceutical reperfusion therapy has not been established. Higher doses of systemic thrombolysis inevitably associated with an incremental increase in major bleeding risk. To date, there is no high-quality evidence regarding dosing and infusion rates of thrombolytic agents to treat acute PE. Most clinical trials have focused on thrombolysis compared with anticoagulation alone, but dose-finding studies are lacking. Evidence is now emerging that lower-dose thrombolytic administered through a peripheral vein is efficacious in accelerating thrombolysis in the central pulmonary artery and preventing acute right heart failure, with reduced risk for major bleeding. The present review will systematically summarize the current evidence of low-dose thrombolysis in acute PE.

Prevalence and clinical significance of deep vein thrombosis in Hispanic patients with acute pulmonary embolism.

The prevalence of concomitant deep vein thrombosis (DVT) and its impact on 30-day outcomes in Hispanic patients with acute pulmonary embolism (PE) is unknown. We retrospectively studied a cohort of Hispanic patients admitted for acute PE to determine the relationship of concomitant DVT to clot burden on chest computer tomography (CT), right heart strain, and 30-day mortality. We identified 391 patients admitted with acute PE; 168 (42.9%) had concomitant DVTs on admission; 39 patients (9.9%) died during the 30-day follow-up: 12 patients without concomitant DVT and 27 with concomitant DVT, respectively (p < .001). The presence of a proximal DVT independently predicted 30-day mortality even after adjusting for age, gender and admission PE severity index scores (PESI) (hazard ratio [HR] 2.0; 95% confidence interval [CI]: 1.4-3.0, p = .001). Proximal DVTs remained a significant predictor of 30-day mortality in patients with low and intermediate PESI scores (HR 2.5; 95% CI: 1.1-6.0, p = .035). The prevalence of concomitant DVT in Hispanic patients presenting with acute DVT is relatively lower than other ethnic groups. However, a proximal location of a DVT is of significant prognostic relevance. Hispanic patients with acute PE should routinely undergo compression doppler ultrasonography (CDUS) of the lower extremities.

Low-Dose Alteplase versus Conventional Anticoagulation to treat Submassive Pulmonary Embolism in Hispanic Patients.

The use of low-dose tissue plasminogen activator (tPA) in Hispanic patients with submassive pulmonary embolism (PE) is understudied. The purpose of this study is to explore the use of low-dose tPA in Hispanic patients with submissive PE compared with counterparts that received heparin alone. We retrospectively analyzed a single-center registry of patients with acute PE between 2016 and 2022. Out of 72 patients admitted for acute PE and cor pulmonale, we identified six patients that were treated with conventional anticoagulation (heparin alone) and six patients who received low-dose tPA (and heparin afterward). We analyzed if low-dose tPA was associated with differences in length of stay (LOS) and bleeding complications. Both groups were similar in regard to age, gender, and PE severity (based on Pulmonary Embolism Severity Index scores). Mean total LOS for the low-dose tPA group was 5.3 days, compared with 7.3 days in the heparin group ( p = 0.29). Mean intensive care unit (ICU) LOS for the low-dose tPA group was 1.3 days compared with 3 days in the heparin group ( p = 0.035). There were no clinically relevant bleeding complications documented in either the heparin or the low-dose tPA group. Low-dose tPA for submassive PE in Hispanic patients was associated with a shorter ICU LOS without a significant increase in bleeding risk. Low-dose tPA appears to be a reasonable treatment option in Hispanic patients with submassive PE who are not at high bleeding risk (<5%).

Prognosis in Hispanic patient population with pulmonary arterial hypertension: An application of common risk stratification models.

Pulmonary arterial hypertension (PAH) is a cardiovascular disease with high mortality rate. Current guidelines propose initiation and escalation of PAH-targeted treatment based on a goal-directed approach targeting hemodynamic, functional, and biochemical variables. This approach has been successfully validated in large Caucasian cohorts. However, given the low number of Hispanic patients enrolled in large PAH trials and registries, it is unknown if the same prognostic tools can be applied to this patient population. We analyzed a single-center outpatient cohort that consisted of 135 Hispanic patients diagnosed with PAH. Baseline characteristics were calculated based on COMPERA, COMPERA 2.0 and REVEAL 2.0 risk scores before the initiation of PAH-targeted therapies. The survival rate at 1 year after diagnosis was 88% for the entire cohort. The three established risk scores to predict PAH outcomes yielded similar results with reasonable discrimination of mortality in the different risk strata (all p < 0.001). Hispanic patients with PAH have a high mortality rate. Our analysis suggests that guideline proposed risk assessment at baseline yields important prognostic information in this patient population.

Targeted Therapies in Patients with Pulmonary Arterial Hypertension Due to Congenital Heart Disease.

Pulmonary arterial hypertension (PAH) is a devastating cardiovascular disease leading to right heart failure and death if untreated. Medical therapies for PAH have evolved substantially over the last decades and are associated with improvements in functional class, quality of life, and survival. PAH-targeted therapies now consist of multiple inhaled, oral, subcutaneous, and intravenous therapies targeting the phosphodiesterase, guanylate cyclase, endothelin and prostacyclin pathways. Patients with congenital heart disease (CHD) are at high risk of developing PAH and growing evidence exists that PAH-targeted therapy can be beneficial in PAH-CHD. However, the PAH-CHD patient population is challenging to treat due to the heterogeneity and complexity of their cardiac lesions and associated comorbidities. Furthermore, most high-quality randomized placebo-controlled trials investigating the effects of PAH-targeted therapies only included a minority of PAH-CHD patients. Few randomized, controlled trials have investigated the effects of PAH-targeted therapy in pre-specified PAH-CHD populations. Consequently, the results of these clinical trials cannot be extrapolated broadly to the PAH-CHD population. This review summarizes the data from high-quality clinical PAH treatment trials with a specific focus on the PAH-CHD population.

Contemporary Treatment of Pulmonary Embolism: Medical Treatment and Management.

Pulmonary embolus (PE) is defined as obstruction of the pulmonary artery or one of its branches by material (e.g., thrombus, tumor, air, or fat) but most commonly due to thrombus originating from the lower extremity deep veins. We reviewed the current literature describing the optimal medical treatment and management of PE. Databases (PubMed, the Cochrane Library, Embase, EBSCO, Web of Science, and CINAHL) were searched for relevant studies and guidelines for management of patients with PE. The initial approach to patients with suspected PE should focus upon stabilizing the patient while further workup for risk stratification is in progress. In most cases, anticoagulation should ideally be started even prior to confirming PE, if risk-benefit regarding suspicion of PE and bleeding risk is favorable. Once the diagnosis is confirmed, risk stratification will guide further therapies consisting of anticoagulation, thrombolysis, or catheter-directed interventions. Data for initial, long-term, and indefinite anticoagulation, and factors that determine whether or not a patient can be treated in the outpatient setting, are reviewed and discussed.

Liver abnormalities in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a cardiopulmonary disease with high mortality. In recent years, it has been recognized that PAH is a multi-organ system disease, involving the systemic circulation, kidneys, skeletal muscles, and the central nervous system, among others. Right heart failure produces congestive hepatopathy, a disease state that has direct consequences on liver biochemistry, histology, and systemic glucose and lipid metabolism. This article aims to summarize the consequences of congestive hepatopathy with an emphasis on liver biochemistry, histology, and PAH-targeted therapy. Furthermore, PAH-specific changes in glucose and lipid metabolism will be discussed.

Beyond the Lungs: Systemic Manifestations of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a disease characterized by progressive loss and remodeling of the pulmonary arteries, resulting in right heart failure and death. Until recently, PAH was seen as a disease restricted to the pulmonary circulation. However, there is growing evidence that patients with PAH also exhibit systemic vascular dysfunction, as evidenced by impaired brachial artery flow-mediated dilation, abnormal cerebral blood flow, skeletal myopathy, and intrinsic kidney disease. Although some of these anomalies are partially due to right ventricular insufficiency, recent data support a mechanistic link to the genetic and molecular events behind PAH pathogenesis. This review serves as an introduction to the major systemic findings in PAH and the evidence that supports a common mechanistic link with PAH pathophysiology. In addition, it discusses recent studies describing morphological changes in systemic vessels and the possible role of bronchopulmonary anastomoses in the development of plexogenic arteriopathy. On the basis of available evidence, we propose a paradigm in which metabolic abnormalities, genetic injury, and systemic vascular dysfunction contribute to systemic manifestations in PAH. This concept not only opens exciting research possibilities but also encourages clinicians to consider extrapulmonary manifestations in their management of patients with PAH.

The 6th World Symposium on Pulmonary Hypertension: what's old is new.

In February 2018, the 6th World Symposium on Pulmonary Hypertension (WSPH) brought together experts from various disciplines to review the most relevant clinical and scientific advances in the field of PH over the last 5 years. Based on careful review and discussions by members of the different task forces, major revisions were made on the hemodynamic definition for various forms of PH and new genes were added to the list of genetic markers associated with pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease. In addition, the use of risk stratification tools was encouraged as a strategy to reduce one-year mortality risk in PAH patients through early implementation of PAH therapies. While members of the medical community are still debating some of the proposed changes, the new WSPH guidelines advocate early diagnosis and initiation of combination therapy to reduce mortality and improve quality of life in patients with PH.

PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis.

Using proteomic approaches, we uncovered a DNA damage response (DDR) function for peroxisome proliferator activated receptor γ (PPARγ) through its interaction with the DNA damage sensor MRE11-RAD50-NBS1 (MRN) and the E3 ubiquitin ligase UBR5. We show that PPARγ promotes ATM signaling and is essential for UBR5 activity targeting ATM interactor (ATMIN). PPARγ depletion increases ATMIN protein independent of transcription and suppresses DDR-induced ATM signaling. Blocking ATMIN in this context restores ATM activation and DNA repair. We illustrate the physiological relevance of PPARγ DDR functions by using pulmonary arterial hypertension (PAH) as a model that has impaired PPARγ signaling related to endothelial cell (EC) dysfunction and unresolved DNA damage. In pulmonary arterial ECs (PAECs) from PAH patients, we observed disrupted PPARγ-UBR5 interaction, heightened ATMIN expression, and DNA lesions. Blocking ATMIN in PAH PAEC restores ATM activation. Thus, impaired PPARγ DDR functions may explain the genomic instability and loss of endothelial homeostasis in PAH.

Low-grade albuminuria in pulmonary arterial hypertension.

Low-grade albuminuria, determined by the urinary albumin to creatinine ratio, has been linked to systemic vascular dysfunction and is associated with cardiovascular mortality. Pulmonary arterial hypertension is related to mutations in the bone morphogenetic protein receptor type 2, pulmonary vascular dysfunction and is increasingly recognized as a systemic disease. In a total of 283 patients (two independent cohorts) diagnosed with pulmonary arterial hypertension, 18 unaffected BMPR2 mutation carriers and 68 healthy controls, spot urinary albumin to creatinine ratio and its relationship to demographic, functional, hemodynamic and outcome data were analyzed. Pulmonary arterial hypertension patients and unaffected BMPR2 mutation carriers had significantly elevated urinary albumin to creatinine ratios compared with healthy controls ( P < 0.01; P = 0.04). In pulmonary arterial hypertension patients, the urinary albumin to creatinine ratio was associated with older age, lower six-minute walking distance, elevated levels of C-reactive protein and hemoglobin A1c, but there was no correlation between the urinary albumin to creatinine ratio and hemodynamic variables. Pulmonary arterial hypertension patients with a urinary albumin to creatinine ratio above 10 µg/mg had significantly higher rates of poor outcome ( P < 0.001). This study shows that low-grade albuminuria is prevalent in pulmonary arterial hypertension patients and is associated with poor outcome. This study shows that albuminuria in pulmonary arterial hypertension is associated with systemic inflammation and insulin resistance.

RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension.

RATIONALE: Pulmonary arterial hypertension is characterized by endothelial dysregulation, but global changes in gene expression have not been related to perturbations in function. OBJECTIVES: RNA sequencing was used to discriminate changes in transcriptomes of endothelial cells cultured from lungs of patients with idiopathic pulmonary arterial hypertension versus control subjects and to assess the functional significance of major differentially expressed transcripts. METHODS: The endothelial transcriptomes from the lungs of seven control subjects and six patients with idiopathic pulmonary arterial hypertension were analyzed. Differentially expressed genes were related to bone morphogenetic protein type 2 receptor (BMPR2) signaling. Those down-regulated were assessed for function in cultured cells and in a transgenic mouse. MEASUREMENTS AND MAIN RESULTS: Fold differences in 10 genes were significant (P < 0.05), four increased and six decreased in patients versus control subjects. No patient was mutant for BMPR2. However, knockdown of BMPR2 by siRNA in control pulmonary arterial endothelial cells recapitulated 6 of 10 patient-related gene changes, including decreased collagen IV (COL4A1, COL4A2) and ephrinA1 (EFNA1). Reduction of BMPR2-regulated transcripts was related to decreased ß-catenin. Reducing COL4A1, COL4A2, and EFNA1 by siRNA inhibited pulmonary endothelial adhesion, migration, and tube formation. In mice null for the EFNA1 receptor, EphA2, versus control animals, vascular endothelial growth factor receptor blockade and hypoxia caused more severe pulmonary hypertension, judged by elevated right ventricular systolic pressure, right ventricular hypertrophy, and loss of small arteries. CONCLUSIONS: The novel relationship between BMPR2 dysfunction and reduced expression of endothelial COL4 and EFNA1 may underlie vulnerability to injury in pulmonary arterial hypertension.

BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension.

Mitochondrial dysfunction, inflammation, and mutant bone morphogenetic protein receptor 2 (BMPR2) are associated with pulmonary arterial hypertension (PAH), an incurable disease characterized by pulmonary arterial (PA) endothelial cell (EC) apoptosis, decreased microvessels, and occlusive vascular remodeling. We hypothesized that reduced BMPR2 induces PAEC mitochondrial dysfunction, promoting a pro-inflammatory or pro-apoptotic state. Mice with EC deletion of BMPR2 develop hypoxia-induced pulmonary hypertension that, in contrast to non-transgenic littermates, does not reverse upon reoxygenation and is associated with reduced PA microvessels and lung EC p53, PGC1α and TFAM, regulators of mitochondrial biogenesis, and mitochondrial DNA. Decreasing PAEC BMPR2 by siRNA during reoxygenation represses p53, PGC1α, NRF2, TFAM, mitochondrial membrane potential, and ATP and induces mitochondrial DNA deletion and apoptosis. Reducing PAEC BMPR2 in normoxia increases p53, PGC1α, TFAM, mitochondrial membrane potential, ATP production, and glycolysis, and induces mitochondrial fission and a pro-inflammatory state. These features are recapitulated in PAECs from PAH patients with mutant BMPR2.

Elafin Reverses Pulmonary Hypertension via Caveolin-1-Dependent Bone Morphogenetic Protein Signaling.

RATIONALE: Pulmonary arterial hypertension is characterized by endothelial dysfunction, impaired bone morphogenetic protein receptor 2 (BMPR2) signaling, and increased elastase activity. Synthetic elastase inhibitors reverse experimental pulmonary hypertension but cause hepatotoxicity in clinical studies. The endogenous elastase inhibitor elafin attenuates hypoxic pulmonary hypertension in mice, but its potential to improve endothelial function and BMPR2 signaling, and to reverse severe experimental pulmonary hypertension or vascular pathology in the human disease was unknown. OBJECTIVES: To assess elafin-mediated regression of pulmonary vascular pathology in rats and in lung explants from patients with pulmonary hypertension. To determine if elafin amplifies BMPR2 signaling in pulmonary artery endothelial cells and to elucidate the underlying mechanism. METHODS: Rats with pulmonary hypertension induced by vascular endothelial growth factor receptor blockade and hypoxia (Sugen/hypoxia) as well as lung organ cultures from patients with pulmonary hypertension were used to assess elafin-mediated reversibility of pulmonary vascular disease. Pulmonary arterial endothelial cells from patients and control subjects were used to determine the efficacy and mechanism of elafin-mediated BMPR2 signaling. MEASUREMENTS AND MAIN RESULTS: In Sugen/hypoxia rats, elafin reduced elastase activity and reversed pulmonary hypertension, judged by regression of right ventricular systolic pressure and hypertrophy and pulmonary artery occlusive changes. Elafin improved endothelial function by increasing apelin, a BMPR2 target. Elafin induced apoptosis in human pulmonary arterial smooth muscle cells and decreased neointimal lesions in lung organ culture. In normal and patient pulmonary artery endothelial cells, elafin promoted angiogenesis by increasing pSMAD-dependent and -independent BMPR2 signaling. This was linked mechanistically to augmented interaction of BMPR2 with caveolin-1 via elafin-mediated stabilization of endothelial surface caveolin-1. CONCLUSIONS: Elafin reverses obliterative changes in pulmonary arteries via elastase inhibition and caveolin-1-dependent amplification of BMPR2 signaling.

Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension.

Idiopathic pulmonary arterial hypertension (PAH [IPAH]) is an insidious and potentially fatal disease linked to a mutation or reduced expression of bone morphogenetic protein receptor 2 (BMPR2). Because intravascular inflammatory cells are recruited in IPAH pathogenesis, we hypothesized that reduced BMPR2 enhances production of the potent chemokine granulocyte macrophage colony-stimulating factor (GM-CSF) in response to an inflammatory perturbation. When human pulmonary artery (PA) endothelial cells deficient in BMPR2 were stimulated with tumor necrosis factor (TNF), a twofold increase in GM-CSF was observed and related to enhanced messenger RNA (mRNA) translation. The mechanism was associated with disruption of stress granule formation. Specifically, loss of BMPR2 induced prolonged phospho-p38 mitogen-activated protein kinase (MAPK) in response to TNF, and this increased GADD34-PP1 phosphatase activity, dephosphorylating eukaryotic translation initiation factor (eIF2α), and derepressing GM-CSF mRNA translation. Lungs from IPAH patients versus unused donor controls revealed heightened PA expression of GM-CSF co-distributing with increased TNF and expanded populations of hematopoietic and endothelial GM-CSF receptor α (GM-CSFRα)-positive cells. Moreover, a 3-wk infusion of GM-CSF in mice increased hypoxia-induced PAH, in association with increased perivascular macrophages and muscularized distal arteries, whereas blockade of GM-CSF repressed these features. Thus, reduced BMPR2 can subvert a stress granule response, heighten GM-CSF mRNA translation, increase inflammatory cell recruitment, and exacerbate PAH.

Circulating levels of copeptin predict outcome in patients with pulmonary arterial hypertension.

OBJECTIVE: To determine the levels of circulating copeptin in patients with pulmonary arterial hypertension (PAH), and to evaluate its relation with disease severity, outcome and response to treatment. BACKGROUND: Vasopressin is a key regulator of body fluid homeostasis. The co-secreted protein copeptin serves as surrogate for plasma vasopressin levels and increases in acute and chronic left ventricular dysfunction. Copeptin has not been studied in PAH. METHODS: Serum copeptin levels were evaluated in a retrospective cohort of 92 treatment-naïve patients with PAH, 39 patients with normal right ventricular hemodynamics (diseased controls) and 14 apparently healthy individuals (healthy controls). In a second prospective cohort of 15 patients with PAH, serial changes of copeptin levels after initiation of PAH treatment were measured. Copeptin levels were compared with clinical, biochemical and hemodynamic parameters as well as response to treatment and clinical outcome. RESULTS: Circulating copeptin levels were elevated in PAH patients compared to diseased controls (20.1 pmol/l vs. 5.1 pmol/l; p = 0.001). Baseline levels of copeptin correlated with NYHA functional class (r = 0.46; p = 0.01), 6 minute walking distance (r = -0.26; p = 0.04), NT-proBNP (r = 0.49, p = 0.01), creatinine (r = 0.39, p = 0.01) and estimated glomerular filtration rate (r = -0.32, p = 0.01). Copeptin levels did not correlate with hemodynamics but decreased after initiation of PAH therapy (p = 0.001). Elevated copeptin levels were associated with shorter survival (p < 0.001) and independent predictors of mortality in a multiple Cox regression analysis (HR1.4; 95% confidence interval 1.1-2.0; p = 0.02). CONCLUSIONS: Patients with PAH had elevated copeptin levels. High circulating levels of copeptin were independent predictors of poor outcome, which makes copeptin a potentially useful biomarker in PAH.