Diagnostic advances and opportunities in chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by the presence of thromboembolic material in the pulmonary circulation, and patients have a poor prognosis without treatment. Patients present with nonspecific symptoms, such as breathlessness and syncope, which means that other more common conditions are sometimes suspected before CTEPH, leading to delayed diagnosis and treatment. This is problematic because CTEPH is potentially curable with surgical pulmonary endarterectomy (PEA); indeed, CTEPH should always be considered in any patient with unexplained pulmonary hypertension (PH).Several key evaluations are necessary and complementary to confirm a diagnosis of CTEPH and assess operability. Echocardiography is initially used to confirm a general diagnosis of PH. Ventilation/perfusion scanning is then essential in the first stage of CTEPH diagnosis, with a wedge-shaped perfusion deficit indicative of CTEPH. This should be followed by right heart catheterisation (RHC) which is mandatory in confirming the diagnosis and providing haemodynamic parameters that are key predictors of the risk associated with PEA and subsequent prognosis. RHC is ideally coupled with conventional pulmonary angiography, the gold-standard technique for confirming the location and extent of disease, and thus whether the obstruction is surgically accessible. Computed tomographic pulmonary angiography is also now routinely used as a complementary technique to aid diagnosis and operability assessment.Recent improvements in the resolution of other noninvasive techniques, such as cardiac magnetic resonance imaging, allow for detailed reconstructions of the vascular tree and imaging of vessel defects, and interest in their use is increasing

Chronic thromboembolic pulmonary disease

: Chronic thromboembolic pulmonary hypertension is a complication of pulmonary embolism and a treatable cause of pulmonary hypertension. The pathology is a unique combination of mechanical obstruction due to failure of clot resolution, and a variable degree of microvascular disease, that both contribute to pulmonary vascular resistance. Accordingly, multiple treatments have been developed to target the disease components. However, accurate diagnosis is often delayed. Evaluation includes high-quality imaging modalities, necessary for disease confirmation and for appropriate treatment planning. All patients with chronic thromboembolic pulmonary disease, and especially those with pulmonary hypertension, should be referred to expert centres for multidisciplinary team decision on treatment. The first decision remains assessment of operability, and the best improvement in symptoms and survival is achieved by the mechanical therapies, pulmonary endarterectomy and balloon pulmonary angioplasty. With the advances in multimodal therapies, excellent outcomes can be achieved with 3-year survival of >90%

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

Riociguat in patients with chronic thromboembolic pulmonary hypertension: results from an early access study

BACKGROUND Following positive results from the Phase III CHEST-1 study in patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), the Phase IIIb CTEPH early access study (EAS) was designed to assess the safety and tolerability of riociguat in real-world clinical practice, as well as to provide patients with early access to riociguat before launch. Riociguat is approved for the treatment of inoperable and persistent/recurrent CTEPH. METHODS We performed an open-label, uncontrolled, single-arm, early access study in which 300 adult patients with inoperable or persistent/recurrent CTEPH received riociguat adjusted from 1 mg three times daily (tid) to a maximum of 2.5 mg tid. Patients switching from unsatisfactory prior pulmonary arterial hypertension (PAH)-targeted therapy (n = 84) underwent a washout period of at least 3 days before initiating riociguat. The primary aim was to assess the safety and tolerability of riociguat, with World Health Organization functional class and 6-min walking distance (6MWD) as exploratory efficacy endpoints. RESULTS In total, 262 patients (87%) completed study treatment and entered the safety follow-up (median treatment duration 47 weeks). Adverse events were reported in 273 patients (91%). The most frequently reported serious adverse events were syncope (6%), right ventricular failure (3%), and pneumonia (2%). There were five deaths, none of which was considered related to study medication. The safety and tolerability of riociguat was similar in patients switched from other PAH-targeted therapies and those who were treatment naïve. In patients with data available, mean ± standard deviation 6MWD had increased by 33 ± 42 m at Week 12 with no clinically relevant differences between the switched and treatment-naïve subgroups. CONCLUSIONS Riociguat was well tolerated in patients with CTEPH who were treatment naïve, and in those who were switched from other PAH-targeted therapies. No new safety signals were observed. TRIAL REGISTRATION ClinicalTrials.org NCT01784562 . Registered February 4, 2013

Canine double-lung transplantation with cadaveric donors

AbstractIf lungs could be retrieved from cadavers after circulatory arrest, the critical shortage of donors for lung transplantation might be alleviated. To assess gas exchange after transplantation of lungs from cadaveric donors, we performed double-lung transplantation through sequential thoracotomies in 12 dogs. Donors were sacrificed by intravenous pentobarbital injection and then ventilated with 100% oxygen. Lungs were harvested 2 hours (n = 6) or 4 hours (n = 6) after death and flushed with 2 L modified Euro-Collins solution. Recipients underwent sequential right and left lung transplantation; they were then monitored while under anesthesia for 8 hours, with adjustments of the fraction of inspired oxygen. Nine of 12 recipients survived the 8-hour study period. Four of six dogs with cadaveric lungs retrieved 2 hours after death survived; deaths were from pulmonary embolism at 6 hours and pulmonary edema at 2 hours. Five of six dogs with cadaveric lungs retrieved 4 hours after death survived; one died of hypoxia during implantation of the left lung, while dependent on the right lung graft. Postoperative hemodynamic and gas exchange parameters were similar in both groups. Alveolar-arterial oxygen gradient rose significantly compared with baseline 1 hour after transplantation in both groups (462 ± 60 vs 38 ± 31 mm Hg for 2-hour group, p < 0.0001, and 484 ± 63 vs 38 ± 14 mm Hg for 4-hour group, p < 0.0002). By 8 hours after operation, the gradients had significantly decreased in both groups (105 ± 37 mm Hg for 2-hour group and 146 ± 53 mm Hg for 4-hour group) and were similar to baseline values. Extravascular lung water also rose significantly 1 hour after transplantation (15.7 ± 2.8 vs 7.9 ± 0.5 ml/kg for 2-hour group, p < 0.02, and 16.9 ± 1.2 vs 6.6 ± 0.4 ml/kg for 4-hour group, p < 0.0001) and decreased gradually during the 8-hour study period. Donor lungs retrieved at 2 and 4 hours postmortem afford similar recipient outcomes. Improvement in alveolar-arterial oxygen gradient and reduction in extravascular lung water during the study period imply that the ischemia-reperfusion injury induced by this model is reversible. If this approach could be safely introduced to clinical practice, substantially more transplant procedures could be performed. (J THORAC CARDIOVASC SURG 1996;112:577-83