ENPP1 enzyme replacement therapy improves blood pressure and cardiovascular function in a mouse model of generalized arterial calcification of infancy.

Generalized arterial calcification of infancy (GACI) is a rare, life-threatening disorder caused by loss-of-function mutations in the gene encoding ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), which normally hydrolyzes extracellular ATP into AMP and pyrophosphate (PPi). The disease is characterized by extensive arterial calcification and stenosis of large- and medium-sized vessels, leading to vascular-related complications of hypertension and heart failure. There is currently no effective treatment available, but bisphosphonates - nonhydrolyzable PPi analogs - are being used off-label to reduce arterial calcification, although this has no reported impact on the hypertension and cardiac dysfunction features of GACI. In this study, the efficacy of a recombinant human ENPP1 protein therapeutic (rhENPP1) was tested in Enpp1asj-2J homozygous mice (Asj-2J or Asj-2J hom), a model previously described to show extensive mineralization in the arterial vasculature, similar to GACI patients. In a disease prevention study, Asj-2J mice treated with rhENPP1 for 3 weeks showed >95% reduction in aorta calcification. Terminal hemodynamics and echocardiography imaging of Asj-2J mice also revealed that a 6-week rhENPP1 treatment normalized elevated arterial and left ventricular pressure, which translated into significant improvements in myocardial compliance, contractility, heart workload and global cardiovascular efficiency. This study suggests that ENPP1 enzyme replacement therapy could be a more effective GACI therapeutic than bisphosphonates, treating not just the vascular calcification, but also the hypertension that eventually leads to cardiac failure in GACI patients.

Lipid-rich pleural mesothelioma in a dog.

An 11-year-old, neutered, male Golden Retriever cross dog was euthanized following a history of recurrent pericardial effusions. At necropsy, blood-tinged pericardial and intrathoracic effusions were seen along with numerous firm to hard plaque-like masses that studded the epicardial, pericardial, mediastinal, and costal pleural surfaces. Within the right thorax, the lesions coalesced into a large mass that occupied most of the cavity. Histologically, the masses were composed of solid sheets and papillary aggregates of medium-sized polygonal cells that contained abundant vacuolated to clear cytoplasm. Some of the cytoplasmic vacuoles stained positive with oil red O. The stroma contained metaplastic trabeculae of woven and lamellar bone. Immunohistochemically, the neoplastic cells expressed vimentin, pancytokeratin, and S-100 protein. Transmission electron microscopy corroborated the presence of intracytoplasmic vacuoles and demonstrated prominent intercellular junctional complexes and apically located microvilli. These findings are consistent with a lipid-rich variant of mesothelioma. To the authors' knowledge, this is the first report of a lipid-rich mesothelioma in a dog.