Asymmetric Dimethylarginine and NT-proBNP Levels Provide Synergistic Information in Pulmonary Arterial Hypertension.

BACKGROUND: Plasma asymmetric dimethylarginine (ADMA) is elevated in pulmonary arterial hypertension (PAH) and is associated with unfavorable outcomes. OBJECTIVES: The aim of this study was to assess changes in ADMA plasma levels for monitoring disease progression and outcomes during PAH-specific therapy. METHODS: ADMA was measured at baseline and after at least 6 months of follow-up using enzyme-linked immunosorbent assay and high-performance liquid chromatography. Changes in ADMA were analyzed in relation to changes in established PAH markers, including hemodynamic status, N-terminal pro-brain natriuretic peptide (NT-proBNP) and risk assessment scores. Impact on survival was assessed using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: Between 2008 and 2019, ADMA samples were collected prospectively from 215 patients with PAH. Change in ADMA plasma level was a predictor of disease progression and survival. ΔADMA (median -0.03 µmol/L; 95% CI: -0.145 to 0.0135) was correlated with change in mean pulmonary arterial pressure (P < 0.005; rS = 0.287) but was not significantly correlated with ΔNT-proBNP (P = 0.056; rS = 0.135). Patients with decreased ADMA plasma levels at follow-up had better 3-year and 5-year survival rates (88% and 80%, respectively, vs 72% and 53% in those without decreases in ADMA) (P < 0.005; pulmonary hypertension-related mortality or lung transplantation). Patients with decreases in both ADMA and NT-proBNP had better survival rates compared with patients in whom only 1 parameter improved (P < 0.005). ΔADMA was a significant predictor of survival in Cox regression analysis and also when corrected for ΔNT-proBNP (HRs: 1.27 and 1.35, respectively; P < 0.005). CONCLUSIONS: ADMA and NT-proBNP provide synergistic prognostic information for patients with PAH. ADMA could be used as an objective and distinct biomarker for monitoring treatment response in PAH.

Longitudinal analysis of chest Q-SPECT/CT in patients with severe COVID-19.

INTRODUCTION: Patients with COVID-19 have an increased risk for microvascular lung thrombosis. In order to evaluate the type and prevalence of perfusion defects, we performed a longitudinal analysis of combined perfusion single-photon emission and low-dose computed tomography (Q-SPECT/CT scan) in patients with COVID-19 pneumonia. METHODS: Consecutive patients with severe COVID-19 (B.1.1.7 variant SARS-CoV-2) and respiratory insufficiency underwent chest Q-SPECT/CT during hospitalization, and 3 months after discharge. At follow-up (FU), Q-SPECT/CT were analyzed and compared with pulmonary function tests (PFT), blood analysis (CRP, D-dimers, ferritin), modified Medical Research Council (mMRC) dyspnea scale, and high-resolution CT scans (HRCT). Patients with one or more segmental perfusion defects outside the area of inflammation (PDOI) were treated with anticoagulation until FU. RESULTS: At baseline, PDOI were found in 50 of 105 patients (47.6 %). At FU, Q-SPECT/CT scans had improved significantly (p < 0.001) and PDOI were recorded in 14 of 77 (18.2 %) patients. There was a significant correlation between mMRC score and the number of segmental perfusion defects (r = 0.511, p < 0.001), and a weaker correlation with DLCO (r = -0.333, p = 0.002) and KCO (r = -0.373, p = 0.001) at FU. Neither corticosteroid therapy nor HRCT results showed an influence on Q-SPECT/CT changes (p = 0.94, p = 0.74). CRP, D-Dimers and ferritin improved but did not show any association with the FU Q-SPECT/CT results (p = 0.08). CONCLUSION: Segmental mismatched perfusion defects are common in severe COVID-19 and are correlated with the degree of dyspnea. Longitudinal analyses of Q-SPECT/CT scans in severe COVID-19 may help understand possible mechanisms of long COVID and prolonged dyspnea.

Risk stratification and risk-adapted management of acute pulmonary embolism.

Pulmonary embolism is one of the leading causes of cardiovascular death in Europe. Rapid diagnosis and treatment initiation are essential, especially in hemodynamically unstable patients. For normotensive patients, the diagnostic workflow is based on the clinical probability of pulmonary embolism. Due to numerous differential diagnoses and a highly variable clinical presentation, diagnosis of acute pulmonary embolism still remains a clinical challenge. Computed tomography angiography is the common gold standard to confirm pulmonary embolism and bedside echocardiography adds a major impact in clinical decision making. The European Society of Cardiology guidelines serve as a framework for a standardized diagnostic approach and risk prediction. Based on vital signs, clinical scores, biomarkers and imaging results, four risk categories can be defined and treatment is accordingly. To optimize the individual management of critical patients, multidisciplinary pulmonary embolism response teams are increasingly designated in specialized centers. This article provides an overview of the current risk-adapted management of patients with acute pulmonary embolism.

Early switch to oral anticoagulation in patients with acute intermediate-risk pulmonary embolism (PEITHO-2): a multinational, multicentre, single-arm, phase 4 trial.

BACKGROUND: Current guidelines recommend a risk-adjusted treatment strategy for the management of acute pulmonary embolism. This is a particular patient category for whom optimal treatment (anticoagulant treatment, reperfusion strategies, and duration of hospitalisation) is currently unknown. We investigated whether treatment of acute intermediate-risk pulmonary embolism with parenteral anticoagulation for a short period of 72 h, followed by a switch to a direct oral anticoagulant (dabigatran), is effective and safe. METHODS: We did a multinational, multicentre, single-arm, phase 4 trial at 42 hospitals in Austria, Belgium, France, Germany, Italy, Netherlands, Romania, Slovenia, and Spain. Adult patients (aged ≥18 years) with symptomatic intermediate-risk pulmonary embolism, with or without deep-vein thrombosis, were enrolled. Patients received parenteral low-molecular-weight or unfractionated heparin for 72 h after diagnosis of pulmonary embolism before switching to oral dabigatran 150 mg twice per day following a standard clinical assessment. The primary outcome was recurrent symptomatic venous thromboembolism or pulmonary embolism-related death within 6 months. The primary and safety outcomes were assessed in the intention-to-treat population. The study was terminated early, as advised by the data safety and monitoring board, following sample size adaptation after the predefined interim analysis on Dec 18, 2018. This trial is registered with the EU Clinical Trials Register (EudraCT 2015-001830-12) and ClinicalTrials.gov (NCT02596555). FINDINGS: Between Jan 1, 2016, and July 31, 2019, 1418 patients with pulmonary embolism were screened, of whom 402 were enrolled and were included in the intention-to-treat analysis (median age was 69·5 years [IQR 60·0-78·0); 192 [48%] were women and 210 [52%] were men). Median follow-up was 217 days (IQR 210-224) and 370 (92%) patients adhered to the protocol. The primary outcome occurred in seven (2% [upper bound of right-sided 95% CI 3]; p<0·0001 for rejecting the null hypothesis) patients, with all events occurring in those with intermediate-high-risk pulmonary embolism (seven [3%; upper bound of right-sided 95% CI 5] of 283). At 6 months, 11 (3% [95% CI 1-5]) of 402 patients had at least one major bleeding event and 16 (4% [2-6]) had at least one clinically relevant non-major bleeding event; the only fatal haemorrhage occurred in one (<1%) patient before the switch to dabigatran. INTERPRETATION: A strategy of early switch from heparin to dabigatran following standard clinical assessment was effective and safe in patients with intermediate-risk pulmonary embolism. Our results can help to refine guideline recommendations for the initial treatment of acute intermediate-risk pulmonary embolism, optimising the use of resources and avoiding extended hospitalisation. FUNDING: German Federal Ministry of Education and Research, University Medical Center Mainz, and Boehringer Ingelheim.

Exploratory echocardiographic strain parameters for the estimation of myocardial infarct size in ST-elevation myocardial infarction.

BACKGROUND: Outcome after ST-elevation myocardial infarction (STEMI) can be most reliably estimated by cardiac magnetic resonance (CMR) imaging. However, CMR is expensive, laborious, and has only limited availability. In comparison, transthoracic echocardiography (TTE) is widely available and cost-efficient. HYPOTHESIS: TTE strain parameters can be used as surrogate markers for CMR-measured parameters after STEMI. METHODS: TTE strain analysis was performed of patients included in a controlled, prospective STEMI trial (NCT01777750) 4 ± 2 days after the event. Longitudinal peak strain (LPS), post-systolic shortening, early systolic lengthening, early systolic lengthening time, and time to peak shortening were measured, and index parameters were computed. Global longitudinal strain (GLS) and ejection fraction (EF) were compiled. Parameters were correlated with CMR-measured variables 4 ± 2 days after STEMI. RESULTS: In 70 STEMI patients, high quality CMR and TTE data were available. Highest correlation with CMR-measured infarct size was observed with GLS (r = 0.577, p < 0.0001), LPS (r = 0.571, p < 0.0001), and EF (r = -0.533, p < 0.0001). Highest correlation with CMR-measured area at risk was observed with GLS (r = 0.666, p < 0.0001), LPS (0.661, p < 0.0001) and early systolic lengthening index (r = 0.540, p < 0.0001). Receiver operating characteristics for the detection of large infarcts (quartile with highest infarct size) showed the highest area under the curve for LPS, GLS, EF, and myocardial dysfunction index. Multiple linear regression displayed the best association between GLS and infarct size. CONCLUSION: Exploratory strain parameters significantly correlate with CMR-measured area at risk and infarct size and are of potential interest as endpoint variables in clinical trials.

Treatment of right ventricular dysfunction and heart failure in pulmonary arterial hypertension.

Right heart dysfunction and failure is the principal determinant of adverse outcomes in patients with pulmonary arterial hypertension (PAH). In addition to right ventricular (RV) dysfunction, systemic congestion, increased afterload and impaired myocardial contractility play an important role in the pathophysiology of RV failure. The behavior of the RV in response to the hemodynamic overload is primarily modulated by the ventricular interaction and its coupling to the pulmonary circulation. The presentation can be acute with hemodynamic instability and shock or chronic producing symptoms of systemic venous congestion and low cardiac output. The prognostic factors associated with poor outcomes in hospitalized patients include systemic hypotension, hyponatremia, severe tricuspid insufficiency, inotropic support use and the presence of pericardial effusion. Effective therapeutic management strategies involve identification and effective treatment of the triggering factors, improving cardiopulmonary hemodynamics by optimization of volume to improve diastolic ventricular interactions, improving contractility by use of inotropes, and reducing afterload by use of drugs targeting pulmonary circulation. The medical therapies approved for PAH act primarily on the pulmonary vasculature with secondary effects on the right ventricle. Mechanical circulatory support as a bridge to transplantation has also gained traction in medically refractory cases. The current review was undertaken to summarize recent insights into the evaluation and treatment of RV dysfunction and failure attributable to PAH.

The importance of right ventricular evaluation in risk assessment and therapeutic strategies: Raising the bar in pulmonary arterial hypertension.

Pulmonary arterial hypertension is an obstructive pulmonary vasculopathy that leads to increased pulmonary vascular resistance, right ventricular overload and failure, and death. Patients' clinical status and prognosis depend mostly on the capability of the right ventricle to adapt to the increased afterload, maintain function, and preserve cardiac output. As a result, reducing the hemodynamic burden of the right ventricle should be a key target of current treatments, along with improvement in WHO functional class, 6-minute walk distance, and rates of hospitalization. However, physicians still find it challenging to integrate the evaluation of right ventricular function into widely accepted clinical parameters in order to stratify patients more accurately. This limitation is very relevant, since higher-risk patients are more likely to benefit from a more aggressive therapeutic approach. We analyzed the hemodynamic burden in pulmonary arterial hypertension, the importance of echocardiographic evaluation of the right ventricle, the impact of current treatments on hemodynamic parameters, and the identification of patients who are more likely to benefit from a more aggressive therapeutic approach.

Treprostinil for the treatment of chronic thromboembolic pulmonary hypertension.

Introduction: Parenteral treprostinil for patients with pulmonary arterial hypertension has resulted in improvement of exercise capacity, functional class, hemodynamics, and survival. Recently, a first randomized trial performed in patients with chronic thromboembolic pulmonary hypertension confirmed the efficacy of subcutaneous treprostinil in this subset of pulmonary hypertension. Areas covered: Treprostinil sodium is a prostacyclin analog produced synthetically. Drug characteristics include potent systemic and pulmonary vasodilatory effects. Local side-effects of subcutaneous treprostinil have been an obstacle for its use. However, in contrast to other prostacyclins, treprostinil has favorable features. We performed a literature survey by searching PubMed for clinical trials published in any language, investigating medicinal treatments for CTEPH. We used the search terms 'inoperable', and 'chronic thromboembolic pulmonary hypertension' with 'randomized clinical trial', and have put treprostinil for CTEPH in the contest of published literature. Expert opinion: Drugs approved for PAH have recently shown excellent efficacy in patients with non-operable CTEPH. Rather than head-to-head comparisons of drugs, combination treatments are to be expected in the near future. Furthermore, drugs will have to be tested alongside with pulmonary endarterectomy (PEA), and alongside balloon pulmonary angioplasty, a promising percutaneous mechanical treatment for CTEPH that is not suited for PEA.

Thrombotic and hemorrhagic burden in women: Gender-related issues in the response to antithrombotic therapies.

Thrombotic and bleeding risks, as well as the incidence and presentation of cardiovascular events and related outcomes, appear to differ between genders, partly in relation to variability in age, comorbidities and body size. Women experience frequent fluctuations of pro-thrombotic activity during their lifetime, related to menstrual cycles, the use of oral contraceptives, pregnancy, menopause, and hormone replacement therapy, all with potential impact on the clinical manifestations of atherosclerotic disease. On the other hand, compared with men, women feature an increased risk of bleeding during hospitalization in the setting of acute coronary syndromes or percutaneous coronary interventions. At the same time, benefits of antithrombotic therapy may differ in women compared with men in several clinical settings and according to the type of antithrombotic agent used for primary and secondary cardiovascular prevention, for the prevention of thromboembolism in patients with atrial fibrillation, and for the prevention and treatment of venous thromboembolism. Data from observational and interventional studies do not exclude gender-specific differences in either the thrombotic and hemorrhagic burden, and the effects of antithrombotic drugs on clinical outcomes might also differ between men and women. Pathophysiological mechanisms causing these disparities are not entirely clear. Multiple factors in platelet function and coagulation mechanisms in different vascular beds, partly related to the hormonal status, might contribute to such gender differences.

Intermittent Hypoxia Activates Duration-Dependent Protective and Injurious Mechanisms in Mouse Lung Endothelial Cells.

Intermittent hypoxia is a major factor in clinical conditions like the obstructive sleep apnea syndrome or the cyclic recruitment and derecruitment of atelectasis in acute respiratory distress syndrome and positive pressure mechanical ventilation. In vivo investigations of the direct impact of intermittent hypoxia are frequently hampered by multiple co-morbidities of patients. Therefore, cell culture experiments are important model systems to elucidate molecular mechanisms that are involved in the cellular response to alternating oxygen conditions and could represent future targets for tailored therapies. In this study, we focused on mouse lung endothelial cells as a first frontier to encounter altered oxygen due to disturbances in airway or lung function, that play an important role in the development of secondary diseases like vascular disease and pulmonary hypertension. We analyzed key markers for endothelial function including cell adhesion molecules, molecules involved in regulation of fibrinolysis, hemostasis, redox balance, and regulators of gene expression like miRNAs. Results show that short-time exposure to intermittent hypoxia has little impact on vitality and health of cells. At early timepoints and up to 24 h, many endothelial markers are unchanged in their expression and some indicators of injury are even downregulated. However, in the long-term, multiple signaling pathways are activated, that ultimately result in cellular inflammation, oxidative stress, and apoptosis.

Association of Platelet-to-Lymphocyte Ratio and Neutrophil-to-Lymphocyte Ratio with the Risk of Thromboembolism and Mortality in Patients with Cancer.

Patients with cancer are at risk of developing venous and arterial thromboembolism (VTE and ATE). Elevated platelet-to-lymphocyte (PLR) and neutrophil-to-lymphocyte ratios (NLR) have been suggested as potential biomarkers for cancer-associated chronic inflammation, VTE and mortality. We investigated the association between PLR and NLR with VTE, ATE and mortality in patients with cancer. Within a prospective cohort study, we followed-up patients with newly diagnosed or progressing cancer for objectively confirmed, symptomatic VTE, ATE and death. Fine and Gray competing-risk regression was used to model the risk of VTE and ATE. Overall survival was analysed with Kaplan-Meier estimators. From 2003 to 2013, 1,469 patients with solid cancer (median age: 61 years; 47.3% female) were recruited and followed for 2 years. Overall, 128 (8.7%) patients developed VTE, 41 (2.8%) ATE and 643 (43.8%) patients died. The sub-distribution hazard ratios (SHRs) for VTE per doubling of PLR and NLR were 1.0 (95% confidence interval [CI]: 0.8-1.3, p = 0.899) and 1.2 (1.0-1.4, p = 0.059), respectively. For ATE, the SHR per doubling of PLR and NLR were 1.0 (0.7-1.5, p = 0.940) and 1.2 (0.9-1.6, p = 0.191), respectively. A higher PLR (hazard ratio [HR] per doubling = 1.5, 1.4-1.7, p < 0.001) and a higher NLR (HR per doubling = 1.5, 1.4-1.7, p < 0.001) were associated with an increased risk of mortality after adjusting for age, sex and cancer stage. There was no statistically significant association between NLR and VTE occurrence in patients with cancer. Neither PLR nor NLR were associated with the risk of ATE. Both elevated PLR and NLR were independently associated with a twofold increased risk of mortality.

Usefulness of thrombosis and inflammation biomarkers in chronic thromboembolic pulmonary hypertension-sampling plasma and surgical specimens.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) results from persistent pulmonary vascular obstructions, presumably due to inflammatory thrombosis. Because estimates of thrombus volume at diagnosis have no predictive value, we investigated the role of the thrombosis marker, D-dimer, and the inflammation marker, C-reactive protein (CRP), for predicting outcomes in CTEPH. METHODS: A total 289 consecutive patients with CTEPH were followed for 57 (median 45 to 69) months. One hundred fifty-seven of these patients underwent surgical pulmonary endarterectomy (PEA). D-dimer and CRP were collected at the time of CTEPH diagnosis and their impact on outcome was analyzed using Cox and logistic regression models. Their association with thrombus composition was analyzed utilizing HistoQuest. RESULTS: D-dimer and CRP levels were separately and independently predictive of death or need for lung transplantation (p = 0.012 and p = 0.025, respectively). For example, 5-year survival was 90% (confidence limits 84% to 96%) in patients with D-dimer levels <0.5 µg/ml and CRP <1 mg/dl at diagnosis, as compared with 50% (36% to 64%) for patients with D-dimer ≥0.5 µg/ml and CRP ≥1 mg/dl (p < 0.001). D-dimer and CRP both decreased significantly after PEA (p < 0.01). The amount of fresh red thrombus in thrombendarterectomy specimens correlated positively with D-dimer levels at diagnosis (r = 0.37, p = 0.003). CONCLUSIONS: D-dimer and CRP at the time of diagnosis are independent and significant predictors of outcome in CTEPH, available at the time of diagnosis. This observation suggests an important role for fibrin turnover and inflammation in the pathogenesis of CTEPH and the associated complications.

Subcutaneous treprostinil in congenital heart disease-related pulmonary arterial hypertension.

OBJECTIVE: To assess the efficacy and safety of subcutaneous treprostinil in adult patients with congenital heart disease (CHD)-associated pulmonary arterial hypertension (PAH) after 12 months of treatment. METHODS: Consecutive adult patients with CHD-PAH received subcutaneous treprostinil to maximum tolerated doses in an observational study. RESULTS: Advanced CHD-PAH patients with WHO class III or IV disease (n=32, age 40±10 years, 20 females) received treprostinil for suboptimal response to bosentan (n=12), WHO functional class IV disease (FC, n=7) or prior to bosentan approval (n=13). In the multivariate mixed model, mean increase in 6 min walk distance (6-MWD) from baseline to 12 months was 114 m (76; 152) (P<0.001). WHO FC improved significantly (P=0.001) and B-type brain natriuretic peptide decreased from 1259 (375; 2368) pg/mL to 380 (144; 1468) pg/mL (P=0.02). In those 14 patients who had haemodynamic data before and after initiation of treprostinil, pulmonary vascular resistance decreased significantly (from 18.4±11.1 to 12.6±7.9 Wood units, P=0.003). The most common adverse events were infusion-site erythema and pain. One patient stopped treatment because of intolerable infusion-site pain after 8 months of treatment. No other major treatment-related complications were observed. Five patients died during early follow-up, having experienced a decrease in their 6-MWD prior. CONCLUSIONS: Subcutaneous treprostinil therapy is generally safe and effective for at least 12 months and may be used in CHD-related PAH class III and IV.

Morphine interaction with prasugrel: a double-blind, cross-over trial in healthy volunteers.

BACKGROUND: Morphine decreases the concentrations and effects of clopidogrel, which could lead to treatment failure in myocardial infarction. OBJECTIVES: To clarify whether more potent P2Y12-inhibitors may provide an effective alternative, we examined drug-drug interactions between morphine and prasugrel. METHODS: Twelve healthy volunteers received 60 mg prasugrel with placebo or 5 mg morphine intravenously in a randomized, double-blind, placebo-controlled, cross-over trial. Pharmacokinetics were determined by liquid chromatography tandem mass spectrometry, and prasugrel effects were measured by platelet function tests. RESULTS: Morphine neither diminished total drug exposure (AUC), which was the primary endpoint, nor significantly delayed drug absorption of prasugrel. However, morphine reduced maximal plasma concentrations (C max) of prasugrel active metabolite by 31 % (p = 0.019). Morphine slightly, but not significantly, delayed the onset of maximal inhibition of platelet plug formation under high shear rates (30 vs. 20 min). Whole blood aggregation was not influenced. CONCLUSIONS: Although morphine significantly decreases the maximal plasma concentrations of prasugrel active metabolite, it does not diminish its effects on platelets to a clinically relevant degree in healthy volunteers. However, it should be considered that the observed decrease in C max of prasugrel active metabolite caused by morphine co-administration may gain relevance in STEMI patients. CLINICAL TRIAL REGISTRATION: NCT01369186, EUDRA-CT#: 2010-023761-22.