Elevated Plasma Bioactive Adrenomedullin and Mortality in Cardiogenic Shock: Results from the OptimaCC Trial

Aims: Bioactive adrenomedullin (bio-ADM) was recently shown to be a prognostic marker in patients with acute circulatory failure. We investigate the association of bio-ADM with organ injury, functional impairment, and survival in cardiogenic shock (CS). Methods: OptimaCC was a multicenter and randomized trial in 57 patients with CS. In this post-hoc analysis, the primary endpoint was to assess the association between bio-ADM and 30-day all-cause mortality. Secondary endpoints included adverse events and parameters of organ injury or functional impairment. Results: Bio-ADM values were higher in 30-day non-survivors than 30-day survivors at inclusion (median (interquartile range) 67.0 (54.6–142.9) pg/mL vs. 38.7 (23.8–63.6) pg/mL, p = 0.010), at 24 h (p = 0.012), and up to 48 h (p = 0.027). Using a bio-ADM cutoff of 53.8 pg/mL, patients with increased bio-ADM had a HR of 3.90 (95% confidence interval 1.43–10.68, p = 0.008) for 30-day all-cause mortality, and similar results were observed even after adjustment for severity scores. Patients with the occurrence of refractory CS had higher bio-ADM value at inclusion (90.7 (59.9–147.7) pg/mL vs. 40.7 (23.0–64.7) pg/mL p = 0.005). Bio-ADM values at inclusion were correlated with pulmonary vascular resistance index, estimated glomerular filtration rate, and N-terminal pro-B-type natriuretic peptide (r = 0.49, r = –0.47, and r = 0.64, respectively; p < 0.001). Conclusions: In CS patients, the values of bio-ADM are associated with some parameters of organ injury and functional impairment and are prognostic for the occurrence of refractory CS and 30-day mortality.

EXPRESS: Efficacy and Safety of Pulmonary Vasodilators in the Patients with Eisenmenger Syndrome: A Meta-analysis of Randomized Controlled Trials

Background: Few meta-analyses evaluated the efficacy and safety of pulmonary vasodilators in patients with Eisenmenger syndrome (ES). Recently, some studies have reported conflicting results regarding improvements in exercise capacity. This study evaluated the efficacy and safety of pulmonary vasodilators in patients with ES. Methods and Results: Relevant studies were identified by searching major databases. Pooled outcomes were used to assess the efficacy and safety of pulmonary vasodilators. In total, 5 studies with 508 patients were included. Meta-analysis indicated that the pulmonary vasodilators reduced the mortality (odd risk (OR) = 0.35; 95% CI, 0.13 to 0.95; P = 0.04), slashed the mean pulmonary artery pressure (mean difference (MD) = -4.35 mmHg; 95% CI, -7.19 to -1.50; P = 0.003), decreased pulmonary vascular resistance index (MD = -480.08 dyn·s·cm-5·m2; 95% CI, -753.51 to -206.64; P = 0.0006), increased the 6-minute walk distance (MD = 28.38 m; 95% CI, 2.99 to 53.77; P = 0.03), and elevated the systemic oxygen saturation at rest (MD = 1.00%; 95% CI, 0.12 to 1.88; P = 0.03). Pulmonary vasodilators were generally well tolerated. Conclusions: Pulmonary vasodilators decrease mortality and improve hemodynamics and exercise capacity in patients with ES. Overall, pulmonary vasodilators are well tolerated

Chronic Inhibition of Toll‐Like Receptor 9 Ameliorates Pulmonary Hypertension in Rats

Background Recent accumulating evidence suggests that toll‐like receptor 9 (TLR9) is involved in the pathogenesis of cardiovascular diseases. However, its role in pulmonary hypertension remains uncertain. We hypothesized that TLR9 is involved in the development of pulmonary hypertension. Methods and Results A rat model of monocrotaline‐induced pulmonary hypertension was used to investigate the effects of TLR9 on hemodynamic parameters, vascular remodeling, and survival. Monocrotaline‐exposed rats significantly showed increases in plasma levels of mitochondrial DNA markers, which are recognized by TLR9, TLR9 activation in the lung, and interleukin‐6 mRNA level in the lung on day 14 after monocrotaline injection. Meanwhile, monocrotaline‐exposed rats showed elevated right ventricular systolic pressure, total pulmonary vascular resistance index and vascular remodeling, together with macrophage accumulation on day 21. In the preventive protocol, administration (days −3 to 21 after monocrotaline injection) of selective (E6446) or nonselective TLR9 inhibitor (chloroquine) significantly ameliorated the elevations of right ventricular systolic pressure and total pulmonary vascular resistance index as well as vascular remodeling and macrophage accumulation on day 21. These inhibitors also significantly reduced NF‐κB activation and interleukin‐6 mRNA levels to a similar extent. In the short‐term reversal protocol, E646 treatment (days 14–17 after monocrotaline injection) almost normalized NF‐κB activation and interleukin‐6 mRNA level, and reduced macrophage accumulation. In the prolonged reversal protocol, E6446 treatment (days 14–24 after monocrotaline injection) reversed total pulmonary vascular resistance index and vascular remodeling, and improved survival in monocrotaline‐exposed rats. Conclusions TLR9 is involved in the development of pulmonary hypertension concomitant via activation of the NF‐κB‒IL‐6 pathway. Inhibition of TLR9 may be a novel therapeutic strategy for pulmonary hypertension.

Pulmonary hemodaynamic in obesity

Background Higher prevalence of pulmonary hypertension exist in obesity subjects. Little known about pulmonary hemodynamics during exercise in obesity population. Purpose To assess and compare the response of pulmonary vascular resistance during exercise in obese subjects vs healthy controls. Methods Seventeen obesity subjects (gender: 25%men, age: 44±11 years, height: 1.7±0.1 m, weight: 111±17 kilogram, BMI: 38±4 kg/m2) were compared to twenty gender-, age-, height- and race-matched healthy control subjects (age: 46±12 years, height: 1.7±0.1 m, weight: 64±11 kilogram, BMI: 22±2 kg/m2). All subjects underwent an incremental exercise stress echocardiography with measurements of pulmonary artery pressure (PAP), cardiac output (CO), cardiac index (CI) and tricuspid annular plane systolic excursion (TAPSE) at rest and at increasing exercise intensities. Total pulmonary vascular resistance index (PVRi) was calculated as mean PAP/CI and right ventricular-arterial coupling as TAPSE/systolic PAP. Results The results are described in the table 1. Pulmonary hemodynamic was not different at rest between two groups, but lower at maximal exercise in obesity subjects. In obesity subjects, identical exercise level was associated with a higher mean PAP and PVRi, and a lower TAPSE/systolic PAP ratio. Conclusion While pulmonary hemodynamic seems preserved at rest in obesity patients, pulmonary vascular resistance is increased and right ventricular coupling is decreased, particularly at exercise. Funding Acknowledgement Type of funding source: None

Effects of Pulmonary Vascular Resistance Index on Oxygen Saturation in Patients with Atrial Septal Defect

<p>Atrial septal defect (ASD) is a congenital lesion in atrium septum. The lesion may cause pulmonary hypertension due to the high pressure in the right ventricle. This condition leads to cyanosis in ASD patient, but the pathophysiology of cyanosis in ASD patient is still unknown. This study aimed to identify the pathophysiology of cyanosis in ASD patients using the Pulmonary Vascular Resistance index (PVRi). The design of this study was retrospective cohort study. The data used in this study were the results of right heart catheterization procedure taken from forty ASD patient medical records at Dr. Sardjito general hospital. The exclusions criteria were the history of previous vasodilator administration and incomplete medical records. The median age of the patients was 30 (18-55) years old. The mean of the Qp/Qs ratio was 1.210 (0.57-6.33). Optimum oxygen saturation was found in vessel leaving the heart. The PVRi median is 61.98 (-15.58-676.64). The PVRi has a significant correlation with oxygen saturation, except in the right atrium. There is a significant correlation between PVRi and oxygen saturation in various heart chambers. Pathophysiology of cyanosis in ASD patients is central cyanosis.</p>

Bosentan Therapy in a Patient with Failed Fontan Procedure: A Case Report

Background: Increased pulmonary vascular resistance index (PVR) leads to several complications in patients after a Fontan operation. This increase is mainly attributed to the overexpression of endothelin-1 for a long duration after the Fontan procedure. Here, we describe the case of a 3-year-old boy with a failed Fontan operation who was treated with bosentan, an endothelin-1 receptor blocker. Case report: Cardiac catheterization was performed, which showed a main pulmonary artery pressure (MPAP) of 19 mmHg and PVRI of 5.6 woods/m2. Oral bosentan regimen at a dose of 31.25 mg was initiated twice a day. The treatment was continued as pleural effusion and ascites persisted. No adverse events were observed, and the treatment was well tolerated. Pleural effusion disappeared, and ascites decreased markedly after 4 weeks, whereas the MPAP was 15 mmHg and the PVRI was 4.3 woods/m2. After 3 months of bosentan therapy, the MPAP was 12 mmHg and the PVRI was 4.1 woods/m2. Conclusion: We observed that bosentan reduces the PVRI and complications such as pleural effusion and ascites after a failed Fontan procedure.

Differences in pulmonary arterial flow hemodynamics between children and adults with pulmonary arterial hypertension as assessed by 4D-flow CMR studies

Despite different developmental and pathological processes affecting lung vascular remodeling in both patient populations, differences in 4D MRI findings between children and adults with PAH have not been studied. The purpose of this study was to compare flow hemodynamic state, including flow-mediated shear forces, between pediatric and adult patients with PAH matched by severity of pulmonary vascular resistance index (PVRi). Adults ( n = 10) and children ( n = 10) with PAH matched by pulmonary vascular resistance index (PVRi) and healthy adult ( n = 10) and pediatric ( n = 10) subjects underwent comprehensive 4D-flow MRI to assess peak systolic wall shear stress (WSSmax) measured in the main (MPA), right (RPA), and left pulmonary arteries (LPA), viscous energy loss (EL) along the MPA-RPA and MPA-LPA tract, and qualitative analysis of secondary flow hemodynamics. WSSmax was decreased in all pulmonary vessels in children with PAH when compared with the same age group (all P < 0.05). Similarly, WSSmax was decreased in all pulmonary vessels in adult PAH patients when compared with healthy adult subjects (all P < 0.01). Average EL was increased in adult patients with PAH when compared with the same age group along both MPA-RPA ( P = 0.020) and MPA-LPA ( P = 0.025) tracts. There were no differences in EL indices between adults and pediatric patients. Children and adult patients with PAH have decreased shear hemodynamic forces. However, pathological flow hemodynamic formations appear to be more consistent in adult patients, whereas flow hemodynamic abnormalities appear to be more variable in children with PAH for comparable severity of PVRi. NEW & NOTEWORTHY Both children and adult patients with PAH have decreased shear hemodynamic forces inside the pulmonary arteries associated with the degree of vessel dilation and stiffness. These differences also exist between healthy normotensive children and adults. However, pathological flow hemodynamic formations appear to more uniform in adult patients, whereas in children with PAH flow, hemodynamic abnormalities appear to be more variable. Pathological flow formations appear not to have a major effect on viscous energy loss associated with the flow conduction through proximal pulmonary arteries.

Adverse Events of Prostacyclin Mimetics in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis

Prostacyclin mimetics (PMs) are effective for the treatment of pulmonary arterial hypertension (PAH). However, their clinical use may be limited by their adverse events. This study aims to quantify the different PM adverse events (AEs) with regard to their selectivity towards the prostacyclin (IP) receptor and their administrative routes. The study included randomised, placebo-controlled trials comparing iloprost, beraprost, treprostinil, and selexipag to placebo (published 2002–2016). We report the group efficacy differences between treatment and placebo by weighted and standardised mean difference. The probability of adverse events was determined by the odds ratio (OR). Of the 14 randomised clinical trials involving 3518 PAH patients, outcome and adverse event data were meta-analysed by drug type and route of administration. Prostacyclin mimetics comparison demonstrated a more significant discontinuation of the IP-selective agonist, selexipag, due to an adverse event (OR = 2.2; 95% CI: 1.5, 3.3). Compared to placebo, site pain associated with subcutaneously administered treprostinil was the most significant likely adverse event (OR = 17.5; 95% CI: 11.1, 27.1). Parenteral PMs were associated with fewer adverse effects overall. The overall efficacy of PMs to improve 6-minute walk distance by 16.3 meters was significant (95% CI: 13.0, 19.7). Decreases in pulmonary vascular resistance index (SMD = −5.5; 95% CI: −10.1, −0.9; I2 = 98%) and mean pulmonary arterial pressure (SMD = −1.0; 95% CI: −2.6, −0.7; I2 = 99%) in treatment groups were found to be significant. Adverse event profiles varied in response to administration route and PM type but were not negated by use of a selective IP agonist. Prostacyclin mimetics exposure to non-target IP receptors may underpin some AEs reported.