Search

Chronic thromboembolic pulmonary hypertension is a progressive and life-threatening condition that is believed to be related to inadequate dissolution of acute pulmonary thromboemboli, followed by fibrotic organization. Without appropriate treatment, progressive pulmonary hypertension, right ventricular failure, and death may occur. While the disorder was initially described nearly a century ago in autopsy studies, antemortem diagnosis became feasible with the advent of cardiac catheterization and angiography techniques in the 1940s, while surgical thromboendarterectomy was not attempted until the 1960s. However, this procedure initially had high mortality rates until refinements in management and surgical techniques resulted in much improved outcomes starting in the 1980s. Many questions remain about the pathophysiology and epidemiology of this condition, with unclear contributions of genetics and environmental exposures. The optimal approach to diagnosis also continues to evolve, with improvements in preoperative imaging and hemodynamic assessment. Treatment of chronic thromboembolic pulmonary hypertension has not remained static, as surgical techniques continue to improve and newer pharmacological treatments and percutaneous catheter-based interventions may play therapeutic roles in selected patients. This is the introductory article of a series that provides a state-of-the-art review of chronic thromboembolic pulmonary hypertension.

Reperfusion lung injury is a postoperative complication of pulmonary thromboendarterectomy that can significantly affect morbidity and mortality. Studies in other postoperative patient populations have demonstrated a reduction in acute lung injury with the use of a low-tidal volume (Vt) ventilation strategy. Whether this approach benefits patients undergoing thromboendarterectomy is unknown.We sought to determine if low-Vt ventilation reduces reperfusion lung injury in patients with chronic thromboembolic pulmonary hypertension undergoing thromboendarterectomy.Patients undergoing thromboendarterectomy at one center were randomized to receive either low (6 ml/kg predicted body weight) or usual care Vts (10 ml/kg) from the initiation of mechanical ventilation in the operating room through Postoperative Day 3. The primary endpoint was the onset of reperfusion lung injury. Secondary outcomes included severity of hypoxemia, days on mechanical ventilation, and intensive care unit and hospital lengths of stay.A total of 128 patients were enrolled and included in the analysis; 63 were randomized to the low-Vt group and 65 were randomized to the usual care group. There was no statistically significant difference in the incidence of reperfusion lung injury between groups (32%, n=20 in the low-Vt group vs. 23%, n=15 in the usual care group; P=0.367). Although differences were noted in plateau pressures (17.9 cm H2O vs. 20.1 cm H2O, P0.001) and peak inspiratory pressures (20.4 cm H2O vs. 23.0 cm H2O, P0.001) between the low-Vt and usual care groups, respectively, mean airway pressures, PaO2/FiO2, days on mechanical ventilation, and ICU and hospital lengths of stay were all similar between groups.In patients with chronic thromboembolic pulmonary hypertension undergoing pulmonary thromboendarterectomy, intra- and postoperative ventilation using low Vts (6 mg/kg) compared with usual care Vts (10 mg/kg) does not reduce the incidence of reperfusion lung injury or improve clinical outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT00747045).

Over the past 4 decades, chronic thromboembolic pulmonary hypertension has evolved from an autopsy curiosity to a potentially correctable form of pulmonary hypertension. Advances in surgical techniques along with the introduction of pulmonary hypertension disease-modifying therapies provide a therapeutic option for the majority of patients afflicted with the disease. Approximately 5,000 thromboendarterectomy procedures have now been performed worldwide with mortality rates reported by established programs experienced in the management of this disease process falling to a range of 4 to 7%. A mortality rate of 1.3% has been reported in patients at low risk based on their preoperative hemodynamic profile. After a successful pulmonary thromboendarterectomy, substantial improvement and often normalization can be achieved in right ventricular function, gas exchange, exercise capacity, and quality of life. For patients not candidates for thromboendarterectomy, or for those with persistent post-thromboendarterectomy pulmonary hypertension, disease-modifying medical therapies have been demonstrated to stabilize and improve pulmonary hemodynamics, albeit not to the same extent as primary thromboendarterectomy. The current review focuses on the diagnostic approach to chronic thromboembolic pulmonary hypertension and the available surgical and medical therapeutic options. Additional research is necessary to more accurately predict postoperative hemodynamic outcome and to define the optimal therapeutic approach, especially in patients with involvement of the distal vasculature.

Although acute pulmonary embolism is epidemiologically associated with chronic thromboembolic pulmonary hypertension, the factors responsible for resistance to thrombolysis and a shift toward vascular remodeling within the pulmonary arteries of patients with chronic thromboembolic pulmonary hypertension are unknown.Determine whether fibrin from patients is more resistant to plasmin-mediated lysis than fibrin from healthy control subjects.Fibrinogen purified from patients and control subjects was used to prepare fibrin clots, which were subsequently digested with plasmin for various periods of time. The degradation of the alpha-, beta-, and gamma-chains of fibrin and the appearance of peptide fragments over time were assessed by polyacrylamide gel electrophoresis and Western blotting.Densitometry of Coomassie-stained gels revealed significantly slower cleavage of all three polypeptide chains of fibrin from patients compared with control subjects (p0.05). In particular, release of N-terminal fragments from the beta-chain of fibrin, which promote cell signaling, cell migration, and angiogenesis, was retarded in patients compared with control subjects (p0.01).The relative resistance of patient fibrin to plasmin-mediated lysis may be due to alterations in fibrin(ogen) structure affecting accessibility to plasmin cleavage sites. The persistence of structural motifs of fibrin, such as the beta-chain N-terminus, within the pulmonary vasculature could promote the transition from acute thromboemboli into chronic obstructive vascular scars.

Pulmonary thromboendartectomy (PTE) for chronic thromboembolic pulmonary hypertension may be complicated by reperfusion lung injury. This has previously been demonstrated to be neutrophil-mediated. We postulated that blocking selectin-mediated adhesion of neutrophils to the endothelium with Cylexin (CY-1503) would prevent reperfusion lung injury in this patient population. In this double-blind, randomized, placebo-controlled, parallel study, 26 patients received Cylexin the day of surgery and 25 received placebo. Significantly fewer patients in the treated group (31%) compared with the placebo group (60%) developed lung injury (p = 0.036). However, the average number of days of mechanical ventilation, days in the intensive care unit (ICU) and hospital, as well as mortality were not significantly different between the treatment groups. Those with reperfusion lung injury had significantly elevated percent neutrophils, total protein, and soluble P-selectin in bronchoalveolar lavage fluid compared with those without lung injury. We conclude that reperfusion lung injury after PTE is a high-permeability lung injury and its incidence can be reduced by the administration of Cylexin on the day of surgery.

Patients with sickle cell disease have been reported to have an increased risk of thromboembolism and pulmonary hypertension. Some of these patients may benefit from pulmonary thromboendarterectomy (PTE), a procedure that requires profound hypothermia, cardiopulmonary bypass, and periods of circulatory arrest, factors that may potentially increase the risk of sickling. Two patients with sickle cell disease (sickle-thalassemia [Hb S/beta+] and Hb SS) presented to the Pulmonary Vascular Center of UCSD Medical Center with significant shortness of breath and limitation of daily activities. Both of these patients were found to have surgically accessible chronic thromboembolic disease with pulmonary hypertension. PTE was performed in both patients using exchange transfusion, with avoidance of anemia, hypoxia, and acidosis. A successful outcome with resolution of pulmonary hypertension was achieved in both cases. To our knowledge this is the first report of patients with sickle cell disease who successfully underwent PTE for chronic thromboembolic pulmonary hypertension.