Evaluation of Asymmetric Dimethylarginine Levels in Patients With Chronic Thromboembolic Pulmonary Hypertension Undergoing Pulmonary Endarterectomy.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary embolism, and pulmonary endarterectomy (PEA) is the surgical treatment. Asymmetric dimethylarginine (ADMA) levels are increased in pulmonary hypertension. This study aimed to investigate serum ADMA levels in patients with CTEPH, the effect of PEA on ADMA, and its prognostic value in long-term mortality. METHOD: Eighty (80) patients with CTEPH and 32 healthy controls were included. Preoperative serum ADMA levels, determined using an enzyme-linked immunosorbent assay, were compared between patients with CTEPH and controls. Of 80 patients, 64 had PEA. Pre- and 6-month postoperative serum ADMA levels, 6-minute walk distance (6MWD), and haemodynamic parameters were collected from patients undergoing PEA. Patients were followed-up for survival analysis. RESULTS: Mean ± standard deviation serum ADMA levels were significantly higher in patients with CTEPH compared with controls (0.79±0.32 µmol/L vs 0.52±0.12 µmol/L; p=0.0001). Statistically significant differences were observed between preoperative and postoperative serum ADMA levels (0.78±0.30 µmol/L vs 0.62±0.22 µmol/L; p=0.0001), 6MWD (p=0.0001), and pulmonary vascular resistance (p=0.0001) in 60 patients who underwent and survived PEA. The decrease in serum ADMA levels and increase in 6MWD were significantly correlated (r=-0.286, p=0.027). No other correlation was found. Perioperative mortality was 6.3%, and the survival rate with a mean follow-up of 34.57±8.20 months was 93.3%. Patients with serum ADMA levels >0.8 µmol/L had a significantly lower survival rate (logrank: 5.86; p=0.015). CONCLUSIONS: Levels of circulating ADMA might add diagnostic and prognostic information in CTEPH. Pulmonary endarterectomy is associated with an improvement in serum ADMA levels. Preoperative serum ADMA levels may be useful for estimating the outcome of PEA.

Raising the bar to ultradisciplinary collaborations in management of chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension is an underdiagnosed and potentially fatal subgroup of pulmonary hypertension, if left untreated. Clinical signs include exertional dyspnea and non-specific symptoms. Diagnosis requires multimodality imaging and heart catheterization. Pulmonary endarterectomy, an open heart surgery, is the gold standard treatment of choice in selected patients in specialized centers. Targeted medical therapy and balloon pulmonary angioplasty can be effective in high-risk patients with significant comorbidities, distal pulmonary vascular obstructions, or recurrent/persistent pulmonary hypertension after pulmonary endarterectomy. Currently, there is a limited number of data regarding novel coronavirus-2019 infection in patients with chronic thromboembolic pulmonary hypertension and the changing spectrum of the disease during the pandemic. Challenging times during this outbreak due to healthcare crisis and relatively higher case-fatality rates require convergence; that is an ultradisciplinary collaboration, which crosses disciplinary and sectorial boundaries to develop integrated knowledge and new paradigms. Management strategies for the "new normal" such as virtual care, preparedness for further threats, redesigned standards and working conditions, reevaluation of specific recommendations, and online collaborations for optimal decisions for chronic thromboembolic pulmonary hypertension patients may change the poor outcomes.

Evaluation of apoptotic molecular pathways for smooth muscle cells isolated from thoracic aortic aneurysms in response to oxidized sterols.

Oxysterols, oxygenated derivatives of cholesterol, are found abundantly in the plasma and atherosclerotic plaques, a common risk factor for thoracic aortic aneurysms (TAAs). Among the oxysterols, namely 7-ketocholesterol (7-KC) and 25-hydroxycholesterol (25-OHC), lead both to induction of reactive oxygen species (ROS) in cells and to apoptosis in smooth muscle cells (SMCs) probably due to increased oxidative stress. Since loss of SMCs through apoptosis is a major event in TAA formation, it is important to understand the molecular pathways of apoptosis in response to ROS in TAAs. Very little is known about the effect of oxysterols on TAA SMCs. Therefore, we investigated molecular pathways participating in the oxysterol induced cell death of TAAs. Our results showed that TAA SMCs died mainly as a result of apoptosis as suggested by cellular shrinkage, blebbing, DNA condensation/fragmentation in response to oxysterol treatment. There was no significant difference in oxysterol induced cell death between TAA and control SMCs. Addition of antioxidant molecules prevented cell death, hence ROS appears to be involved in the apoptosis of these cells. While oxysterol treatment increased caspase 3 activity, cell death was not rescued in its absence. Efficient silencing of other targets including apoptotic proteins (p53, Bax), and survival proteins (Akt1, Akt2) showed that apoptosis can occur through p53, and Bax independent pathways. Silencing Akt1 or Akt2 did not lead to further cell death. These results indicate that oxysterols can induce several cell death pathways in TAA SMCs.