Kawut, Steven M.

The tyrosine kinase inhibitor sorafenib improves hepatopulmonary syndrome (HPS) in an experimental model. However, the efficacy and adverse effect profile in patients with HPS are unknown. We aimed to determine the effect of sorafenib on the alveolar‐arterial oxygen gradient (AaPO2) at 3 months in patients with HPS. We performed a randomized, double‐blind, placebo‐controlled parallel trial of sorafenib in patients with HPS at 7 centers. A total of 28 patients with HPS were randomized to sorafenib 400 mg by mouth daily or a matching placebo in a 1:1 ratio. We found no statistically significant difference in the median change in AaPO2 from baseline to 12 weeks between the patients allocated to sorafenib (4.5 mm Hg; IQR, –3.8 to 7.0 mm Hg) and those allocated to placebo (–2.4 mm Hg; IQR, –4.8 to 8.2 mm Hg; P = 0.70). There was also no difference between the groups in terms of degree of intrapulmonary shunting by contrast echocardiography. Sorafenib significantly reduced circulating levels of angiogenic markers, including vascular endothelial growth factor receptors (P < 0.01) and TIE2‐expressing M2 monocytes (P = 0.03), but it reduced the mental component scores of the Short Form 36 (P = 0.04), indicating a worse quality of life. In conclusion, sorafenib did not change the AaPO2 or other disease markers at 3 months in patients with HPS. Alternative antiangiogenic therapies or treatments targeting other pathways should be investigated.

Screening for hepatopulmonary syndrome (HPS) using pulse oximetry is recommended in liver transplant (LT) candidates because mortality is increased, independently of the severity of the oxygenation defect. LT exception points may be afforded to those with HPS and severe hypoxemia. We assessed the screening characteristics of pulse oximetry for HPS. The Pulmonary Vascular Complications of Liver Disease 2 study is a multicenter, prospective cohort study of adults undergoing their first LT evaluation. Patients underwent protocolized assessment of oxygen saturation by pulse oximetry (SpO2), arterial blood gas, spirometry, and contrast‐enhanced echocardiography (CE). HPS was defined as an alveolar‐arterial gradient ≥15 mm Hg (≥20 mm Hg if age >64 years), intrapulmonary vascular dilatation on CE, and absence of lung disease. The study sample included 363 patients. Of these, 75 (20.7%; 95% confidence interval [CI], 16.6%‐25.2%) met the criteria for HPS. The area under the receiver operating characteristic curve (or c‐statistic) for SpO2 in discriminating HPS was 0.59 (95% CI, 0.51‐0.66). An SpO2 <96%, recommended by practice guidelines as a threshold to require further testing, had low sensitivity (28%; 95% CI, 18%‐28%). The c‐statistic of SpO2 in discriminating HPS with a partial pressure of oxygen (PaO2) <60 mm Hg (eligible for LT exception points) was 0.76 (95% CI, 0.46‐1.00). An SpO2 cutoff of <96% had higher sensitivity for detecting HPS with PaO2 <60 mm Hg (71%; 95% CI, 38%‐100%) but was still inadequate. Conclusion: Pulse oximetry is not sufficiently sensitive to screen for HPS in LT candidates. Arterial blood gas and CE are required in LT candidates for diagnosis of HPS.

Abstract The Division of Lung Diseases of the NHLBI and the Cardiovascular Medical Education and Research Fund held a workshop to discuss how to leverage the anticipated scientific output from the recently launched “Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics” (PVDOMICS) program to develop newer approaches to pulmonary vascular disease. PVDOMICS is a collaborative, protocol-driven network to analyze all patient populations with pulmonary hypertension to define novel pulmonary vascular disease (PVD) phenotypes. Stakeholders, including basic, translational, and clinical investigators; clinicians; patient advocacy organizations; regulatory agencies; and pharmaceutical industry experts, joined to discuss the application of precision medicine to PVD clinical trials. Recommendations were generated for discussion of research priorities in line with NHLBI Strategic Vision Goals that include: (1) A national effort, involving all the stakeholders, should seek to coordinate biosamples and biodata from all funded programs to a web-based repository so that information can be shared and correlated with other research projects. Example programs sponsored by NHLBI include PVDOMICS, Pulmonary Hypertension Breakthrough Initiative, the National Biological Sample and Data Repository for PAH, and the National Precision Medicine Initiative. (2) A task force to develop a master clinical trials protocol for PVD to apply precision medicine principles to future clinical trials. Specific features include: (a) adoption of smaller clinical trials that incorporate biomarker-guided enrichment strategies, using adaptive and innovative statistical designs; and (b) development of newer endpoints that reflect well-defined and clinically meaningful changes. (3) Development of updated and systematic variables in imaging, hemodynamic, cellular, genomic, and metabolic tests that will help precisely identify individual and shared features of PVD and serve as the basis of novel phenotypes for therapeutic interventions.

Pulmonary arterial hypertension (PAH) is characterized by progressive increases in pulmonary vascular resistance, leading to right heart failure and death. Guidelines recommend customization of treatment, necessitating the development of effective strategies for transitioning patients among treatments. In this study, we characterized our experience with patient transitions from parenteral prostacyclin to inhaled iloprost. We retrospectively assessed records from 11 centers of 37 consecutive patients with PAH aged ≥ 18 years who were treated with intravenous (IV) or subcutaneous (SC) prostacyclin analogues and transitioned to inhaled iloprost. The transition period began on the first day of inhaled iloprost with the intent of discontinuing parenteral prostacyclin and ended on the first day on inhaled iloprost free of parenteral prostacyclin. Persistence was defined as the absence of (1) parenteral prostacyclin while remaining on inhaled iloprost during post‐transition Days 1–90 and (2) no reinitiation of parenteral prostacyclin during post‐transition Days 90–365. All patients were clinically stable before transitioning to inhaled iloprost. The mean age was 46.5 years, 70.3% were female, 51.4% had idiopathic PAH, and 43.0% were in New York Heart Association Functional Class III. Among patients with an overlapping transition, the mean transition period was 10.5 days. A transition dosing algorithm was used in 10 patients (27.0%). At one year, 78.4% of the patients remained persistent on inhaled iloprost and 81.1% were free of clinical worsening. In selected patients on background oral PAH therapy, transitioning from parenteral prostacyclin to inhaled iloprost appears safe and feasible and is associated with long‐term success. Further study is needed to define the optimal patient selection criteria and transition algorithm.

Abstract The Division of Lung Diseases of the National Heart, Lung, and Blood Institute, with the Office of Rare Diseases Research, held a workshop to identify priority areas and strategic goals to enhance and accelerate research that will result in improved understanding of the lung vasculature, translational research needs, and ultimately the care of patients with pulmonary vascular diseases. Multidisciplinary experts with diverse experience in laboratory, translational, and clinical studies identified seven priority areas and discussed limitations in our current knowledge, technologies, and approaches. The focus for future research efforts include the following: (1) better characterizing vascular genotype–phenotype relationships and incorporating systems biology approaches when appropriate; (2) advancing our understanding of pulmonary vascular metabolic regulatory signaling in health and disease; (3) expanding our knowledge of the biologic relationships between the lung circulation and circulating elements, systemic vascular function, and right heart function and disease; (4) improving translational research for identifying disease-modifying therapies for the pulmonary hypertensive diseases; (5) establishing an appropriate and effective platform for advancing translational findings into clinical studies testing; and (6) developing the specific technologies and tools that will be enabling for these goals, such as question-guided imaging techniques and lung vascular investigator training programs. Recommendations from this workshop will be used within the Lung Vascular Biology and Disease Extramural Research Program for planning and strategic implementation purposes.

Abstract Rationale Portopulmonary hypertension (PPHTN) occurs in 6% of liver transplant candidates. The pathogenesis of this complication of portal hypertension is poorly understood. Objectives To identify genetic risk factors for PPHTN in patients with advanced liver disease. Methods We performed a multicenter case-control study of patients with portal hypertension. Cases had a mean pulmonary artery pressure &gt;25 mm Hg, pulmonary vascular resistance &gt;240 dynes·s−1·cm−5, and pulmonary capillary wedge pressure ≤15 mm Hg. Controls had a right ventricular systolic pressure &lt; 40 mm Hg (if estimated) and normal right-sided cardiac morphology by transthoracic echocardiography. We genotyped 1,079 common single nucleotide polymorphisms (SNPs) in 93 candidate genes in each patient. Measurements and Main Results The study sample included 31 cases and 104 controls. Twenty-nine SNPs in 15 candidate genes were associated with the risk of PPHTN (P &lt; 0.05). Multiple SNPs in the genes coding for estrogen receptor 1, aromatase, phosphodiesterase 5, angiopoietin 1, and calcium binding protein A4 were associated with the risk of PPHTN. The biological relevance of one of the aromatase SNPs was supported by an association with plasma estradiol levels. Conclusions Genetic variation in estrogen signaling and cell growth regulators is associated with the risk of PPHTN. These biologic pathways may elucidate the mechanism for the development of PPHTN in certain patients with severe liver disease.