Sleep apnea and cardiovascular risk.

PURPOSE OF REVIEW: Obstructive sleep apnea (OSA) is associated with several cardiovascular risk predictors that have only recently begun to be studied in detail. The strong association between OSA and hypertension, coronary artery disease, congestive heart failure, and sudden cardiac death underscores its significant impact on cardiovascular health. This brief review considers the links between OSA and cardiovascular risk. RECENT FINDINGS: OSA is an important contributor to endothelial dysfunction and damage, while repetitive hypoxia and hypercarbia contribute to autonomic dysfunction and sympathetic stimulation. In turn, these derangements have deleterious hematologic effects, including hypercoagulability and abnormal platelet aggregability, which are important in the pathogenesis of atherothrombotic disease. SUMMARY: The varied deleterious effects of OSA on cardiovascular health stem from a unique 'perfect storm' of hypoxic oxidative stress, autonomic dysregulation, endothelial damage, and inflammation occurring at the microvascular level. Further research may disentangle these multiple etiologic threads and provide a better understanding of the underlying pathophysiological relationship between OSA and cardiovascular disease.

Cardiovascular Morbidity in Individuals with Impaired FEV1.

PURPOSE OF REVIEW: This review is intended to give an overview of the epidemiology of cardiovascular morbidity and mortality in patients with impaired lung function with an emphasis on patients with COPD. RECENT FINDINGS: Despite shared risk factors, lung disease is an emerging independent risk factor for cardiovascular disease and cardio-vascular disease (CVD) outcomes. Both CVD and chronic lung disease contribute significantly to overall mortality. Especially patients with chronic obstructive pulmonary disease (COPD) are at high risk for CVD-related mortality. In patients with chronic lung disease, a low index of suspicion should be maintained to assess for CVD and vice versa. Early detection of chronic lung disease as a potentially modifiable CVD risk factor could have important impact on patient outcomes.

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.

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.

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.

Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis.

RATIONALE: Systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) portends worse outcome than other forms of PAH. Vasoconstrictive and vascular remodeling actions of endothelin (ET) 1 and angiotensin (Ang) II via endothelin receptor type A (ETAR) and Ang receptor type-1 (AT1R) activation are implicated in PAH pathogenesis. OBJECTIVES: We hypothesized that stimulating autoantibodies (Abs) targeting and activating AT1R and ETAR may contribute to SSc-PAH pathogenesis, and tested their functional and biomarker relevance. METHODS: Anti-AT1R and -ETAR Abs were detected by ELISA in different cohorts of patients and tested in vitro and in an animal model for their pathophysiological effects. MEASUREMENTS AND MAIN RESULTS: The Abs were significantly higher and more prevalent in patients with SSc-PAH (n = 81) and connective tissue disease-associated PAH (n = 110) compared with other forms of PAH/pulmonary hypertension (n = 106). High anti-AT1R and anti-ETAR Abs predicted development of SSc-PAH and SSc-PAH-related mortality in a prospective analysis. Both Abs increased endothelial cytosolic Ca(2+) concentrations in isolated perfused rat lungs, which could be blocked by respective specific receptor antagonists. Ab-mediated stimulation of intralobar pulmonary rat artery ring segments increased vasoconstrictive responses to Ang II and ET-1, and implicated cross-talk between both pathways demonstrated by reciprocal blockade with respective antagonists. Transfer of SSc-IgG containing both autoantibodies into healthy C57BL/6J mice led to more abundant vascular and airway α-smooth muscle actin expression and inflammatory pulmonary vasculopathy. CONCLUSIONS: Anti-AT1R and -ETAR Abs are more frequent in SSc-PAH/connective tissue disease-PAH compared with other forms of pulmonary hypertension, and serve as predictive and prognostic biomarkers in SSc-PAH. Both antibodies may contribute to SSc-PAH via increased vascular endothelial reactivity and induction of pulmonary vasculopathy.

Loss of adenomatous poliposis coli-α3 integrin interaction promotes endothelial apoptosis in mice and humans.

RATIONALE: Pulmonary hypertension (PH) is characterized by progressive elevation in pulmonary pressure and loss of small pulmonary arteries. As bone morphogenetic proteins promote pulmonary angiogenesis by recruiting the Wnt/ß-catenin pathway, we proposed that ß-catenin activation could reduce loss and induce regeneration of small pulmonary arteries (PAs) and attenuate PH. OBJECTIVE: This study aims to establish the role of ß-catenin in protecting the pulmonary endothelium and stimulating compensatory angiogenesis after injury. METHODS AND RESULTS: To assess the impact of ß-catenin activation on chronic hypoxia-induced PH, we used the adenomatous polyposis coli (Apc(Min/+)) mouse, where reduced APC causes constitutive ß-catenin elevation. Surprisingly, hypoxic Apc(Min/+) mice displayed greater PH and small PA loss compared with control C57Bl6J littermates. PA endothelial cells isolated from Apc(Min/+) demonstrated reduced survival and angiogenic responses along with a profound reduction in adhesion to laminin. The mechanism involved failure of APC to interact with the cytoplasmic domain of the α3 integrin, to stabilize focal adhesions and activate integrin-linked kinase-1 and phospho Akt. We found that PA endothelial cells from lungs of patients with idiopathic PH have reduced APC expression, decreased adhesion to laminin, and impaired vascular tube formation. These defects were corrected in the cultured cells by transfection of APC. CONCLUSIONS: We show that APC is integral to PA endothelial cells adhesion and survival and is reduced in PA endothelial cells from PH patient lungs. The data suggest that decreased APC may be a cause of increased risk or severity of PH in genetically susceptible individuals.

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.

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.

Outcomes of noncardiac, nonobstetric surgery in patients with PAH: an international prospective survey.

We conducted an international, prospective, 3-year questionnaire-based survey among 11 pulmonary hypertension centres to assemble data from patients with pulmonary arterial hypertension (PAH) undergoing noncardiac and nonobstetric surgery. Data were collected between July 2007 and June 2010 from 114 patients with PAH (70% female, mean age 57 years) who underwent major surgery. At the time of surgery, 43% were in functional class III/IV. 82% of the interventions were performed under general anaesthesia and 18% under spinal anaesthesia. Major complications occurred in seven (6.1%) of the patients, of whom four died, resulting in an overall perioperative mortality rate of 3.5%. The mortality rate was 15% (two out of 13) in emergency procedures, compared with 2% (two out of 101) in nonemergency procedures (p=0.01). Risk factors for major complications were an elevated right atrial pressure (OR 1.1, 95% CI 1.0-1.3; p=0.01), a 6-min walking distance <399 m at the last preoperative assessment (OR 2.2, 95% CI 1.1-3.7; p=0.04), the perioperative use of vasopressors (OR 1.5, 95% CI 1.2-2.7; p=0.03) and the need for emergency surgery (OR 2.4, 95% CI 1.4-3.6; p=0.01). Major surgery in patients with PAH continues to be a high-risk procedure, particularly when emergency interventions are needed.

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.

Updates in the Pharmacotherapy of Pulmonary Hypertension in Patients with Heart Failure with Preserved Ejection Fraction.

Pulmonary hypertension (PH) associated with left heart disease (LHD) is a complex cardiopulmonary condition where a variable degree of pulmonary congestion, arterial vasoconstriction and vascular remodeling can lead to PH and right heart strain. Right heart dysfunction has a significant prognostic impact on these patients. Therefore, preserving right ventricular (RV) function is an important treatment goal. However, the treatment of PH in patients with left heart disease has produced conflicting evidence. The transition from pure LHD to LHD with PH is a continuum and clinically challenging. The heart failure with preserved ejection fraction (HFpEF) patient population is heterogeneous when it comes to PH and RV function. Appropriate clinical and hemodynamic phenotyping of patients with HFpEF and concomitant PH is paramount to making the appropriate treatment decision. This manuscript will summarize the current evidence for the use of pulmonary arterial vasodilators in patients with HFpEF.

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.

The Association Between Non-Clinically Apparent Liver Fibrosis and Pulmonary Arterial Hypertension in Hispanic Patients.

Background: Pulmonary arterial hypertension (PAH) is a deadly cardiopulmonary disease with multi-organ involvement including impaired liver function. Liver dysfunction in PAH is poorly understood but significantly associated with morbidity and mortality. Hispanics have a significantly higher prevalence of non-alcoholic fatty liver disease (NAFLD) and evidence of more advanced disease in comparison to other ethnic groups. The clinical impact of NAFLD in Hispanic PAH patients is unknown. We aimed to investigate the impact of a validated scoring system, non-alcoholic fatty liver disease fibrosis score (NFS), to predict the degree of liver fibrosis in a Hispanic PAH population and its relationship to hemodynamics, functional class, and outcomes. Methods: A retrospective review of all treatment-naive Hispanic patients with group I World Health Organization (WHO) pulmonary hypertension (PH) at a single academic center between February 2016 and March 2021 was performed. Patients with history of substance or alcohol abuse, non-group I WHO PH, pre-existent liver disease, chronic kidney disease, atrial fibrillation, thyroid disease, and warfarin use were excluded from the study. The diagnosis of group I WHO PH was determined by cardiac catheterization after the exclusion of other etiologies. NFS was calculated for each patient and correlated with functional capacity, hemodynamics, N-terminal-pro-B-type natriuretic peptide (NT-proBNP), and survival. Results: A total of 96 Hispanic patients were included in our study. The median age of patients in our cohort was 49 years (interquartile range: 15) and 69% of our cohort were females. Higher NFSs indicating advanced hepatic fibrosis (F3-F4) were found to correlate with elevated right-sided cardiac filling pressures (r = 0.27, P = 0.03), elevated levels of NT-proBNP (r = 0.32, P = 0.01), lower 6-minute walk distance (6MWD) (r = -0.49, P = 0.001), lower functional capacity (World Health Organization functional class, WHO-FC, r = -0.35, P = 0.051), a higher prevalence of diabetes (21.1% versus 51.9%, P = 0.001), a higher prevalence of risk factors for metabolic syndrome (81.5% versus 65.0%, P = 0.035), and worse 5-year survival rates. Conclusion: In Hispanic patients with PAH, NFSs correlate with the degree of right-sided pressure overload. In addition, advanced NFSs were independently associated with lower 5-year survival rates and added prognostic information to other established risk parameters in PAH. This study suggests that screening for liver disease in this vulnerable patient population can aid in earlier detection leading to discussion of lifestyle modifications and possible escalation of PAH-targeted therapies, thus leading to potential improvement in survival rates.

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.

Plexiform lesions in pulmonary arterial hypertension composition, architecture, and microenvironment.

Pulmonary arterial hypertension (PAH) is a debilitating disease with a high mortality rate. A hallmark of PAH is plexiform lesions (PLs), complex vascular formations originating from remodeled pulmonary arteries. The development and significance of these lesions have been debated and are not yet fully understood. Some features of PLs resemble neoplastic disorders, and there is a striking resemblance to glomeruloid-like lesions (GLLs) in glioblastomas. To further elucidate PLs, we used in situ methods, such as (fluorescent) IHC staining, three-dimensional reconstruction, and laser microdissection, followed by mRNA expression analysis. We generated compartment-specific expression patterns in the lungs of 25 patients (11 with PAH associated with systemic shunts, 6 with idiopathic PAH, and 8 controls) and GLLs from 5 glioblastomas. PLs consisted of vascular channels lined by a continuously proliferating endothelium and backed by a uniform myogenic interstitium. They also showed up-regulation of remodeling-associated genes, such as HIF1a, TGF-ß1, VEGF-α, VEGFR-1/-2, Ang-1, Tie-2, and THBS1, but also of cKIT and sprouting-associated markers, such as NOTCH and matrix metalloproteinases. The cellular composition and signaling seen in GLLs in neural neoplasms differed significantly from those in PLs. In conclusion, PLs show a distinct cellular composition and microenvironment, which contribute to the plexiform phenotype and set them apart from other processes of vascular remodeling in patients with PAH. Neoplastic models of angiogenesis seem to be of limited use in further study of plexiform vasculopathy.

Current Updates in the Pharmacotherapy of Heart Failure with a Preserved Ejection Fraction.

BACKGROUND: Heart failure is the leading cause of morbidity and mortality worldwide. With improved longevity, the incidence and prevalence of heart failure continue to rise with an estimated prevalence of around 26 million worldwide. Heart failure with preserved ejection fraction (HFpEF) constitutes around 50% of the total heart failure cases and is the most common cause of heart failure in the elderly population. The cost of heart failure care continues to rise with care for heart failure hospitalization taking the major bulk. The cost was around 30 billion in the US in 2012 and is projected to reach 70 billion by 2030. OBJECTIVE: This study aims to provide updated pharmacotherapy of heart failure with a preserved ejection fraction (HFpEF). METHODS: We performed a comprehensive literature review to examine the available pharmacotherapeutics in the management of heart failure with a preserved ejection fraction using online databases (PubMed and Embase). RESULTS: We reviewed multiple studies examining pharmacotherapeutics in the management of HFpEF and reducing heart failure hospitalizations in this cohort. Until recently, our management mainly focused on aggressively managing diabetes, hypertension, atrial fibrillation, and coronary artery disease anticipating improving the outcome. Beta-blockers, Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, sildenafil, digoxin, vericiguat, praliciguat, and Ivabradine did not improve heart failure hospitalization in this cohort. CONCLUSION: EMPEROR-PRESERVED (Empagliflozin) and PRESERVED-HF (Dapagliflozin) results in the management of HFpEF look promising irrespective of diabetes status. Sacubitrilvalsartan and Empagliflozon are the only medications approved for its management as per the PARAGON-HF and EMPEROR-PRESERVED studies, respectively.

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.