A role for primary cilia in aortic valve development and disease.

BACKGROUND: Bicuspid aortic valve (BAV) disease is the most common congenital heart defect, affecting 0.5-1.2% of the population and causing significant morbidity and mortality. Only a few genes have been identified in pedigrees, and no single gene model explains BAV inheritance, thus supporting a complex genetic network of interacting genes. However, patients with rare syndromic diseases that stem from alterations in the structure and function of primary cilia ("ciliopathies") exhibit BAV as a frequent cardiovascular finding, suggesting primary cilia may factor broadly in disease etiology. RESULTS: Our data are the first to demonstrate that primary cilia are expressed on aortic valve mesenchymal cells during embryonic development and are lost as these cells differentiate into collagen-secreting fibroblastic-like cells. The function of primary cilia was tested by genetically ablating the critical ciliogenic gene Ift88. Loss of Ift88 resulted in abrogation of primary cilia and increased fibrogenic extracellular matrix (ECM) production. Consequentially, stratification of ECM boundaries normally present in the aortic valve were lost and a highly penetrant BAV phenotype was evident at birth. CONCLUSIONS: Our data support cilia as a novel cellular mechanism for restraining ECM production during aortic valve development and broadly implicate these structures in the etiology of BAV disease in humans. Developmental Dynamics 246:625-634, 2017. © 2017 Wiley Periodicals, Inc.

Magnetic field interactions between current consumer electronics and cardiac implantable electronic devices.

BACKGROUND: Electronic products, including the iPhone 12, Apple Watch Series 6, and 2nd Generation AirPods, contain magnets to facilitate wireless charging. Permanent magnets may affect CIED magnet mode features by causing pacemakers to pace asynchronously and defibrillators to suspend arrhythmia detection. This study determined if CIEDs are affected by static magnetic fields from commonly used portable electronics (PE) at any distance and intends to reinforce FDA recommendations concerning consumer PE which contain permanent magnets. METHODS: The maximum magnet field measurement was evaluated by a Gauss meter. The interaction between PE and CIEDs from Boston Scientific and Medtronic were tested ex vivo using a body torso model. The CIED was placed in physiologic saline, and the PE was placed at the surface and at increasing distances of 0.5, 1.0, and 1.5 cm. Interactions were recorded by assessment of magnet mode status. RESULTS: The iPhone 12 had almost three times the static magnetic field measured at the surface as the iPhone XR, but magnetic field strength decreased dramatically with increasing distance. At the surface of the model, PE triggered magnet mode in all CIEDs. The maximum interaction distance for all combinations of CIEDs and Apple products was 1.5 cm. CONCLUSIONS: The iPhone 12 produces a stronger static magnetic field than previous iPhone models. Magnets in PE tested will not interact with CIEDs when they are 15 cm from the implanted device. Since no interaction was observed beyond 1.5 cm, it is unlikely that magnet mode activation will occur during most daily activities.

Primary cilia defects causing mitral valve prolapse.

Mitral valve prolapse (MVP) affects 1 in 40 people and is the most common indication for mitral valve surgery. MVP can cause arrhythmias, heart failure, and sudden cardiac death, and to date, the causes of this disease are poorly understood. We now demonstrate that defects in primary cilia genes and their regulated pathways can cause MVP in familial and sporadic nonsyndromic MVP cases. Our expression studies and genetic ablation experiments confirmed a role for primary cilia in regulating ECM deposition during cardiac development. Loss of primary cilia during development resulted in progressive myxomatous degeneration and profound mitral valve pathology in the adult setting. Analysis of a large family with inherited, autosomal dominant nonsyndromic MVP identified a deleterious missense mutation in a cilia gene, DZIP1 A mouse model harboring this variant confirmed the pathogenicity of this mutation and revealed impaired ciliogenesis during development, which progressed to adult myxomatous valve disease and functional MVP. Relevance of primary cilia in common forms of MVP was tested using pathway enrichment in a large population of patients with MVP and controls from previously generated genome-wide association studies (GWAS), which confirmed the involvement of primary cilia genes in MVP. Together, our studies establish a developmental basis for MVP through altered cilia-dependent regulation of ECM and suggest that defects in primary cilia genes can be causative to disease phenotype in some patients with MVP.

Recurrence of chromosome 10 Thiel-Behnke corneal dystrophy (CDB2) after excimer laser phototherapeutic keratectomy or penetrating keratoplasty.

PURPOSE: To evaluate the recurrence of Thiel-Behnke dystrophy (linked to the 10 q23-q24 locus) after phototherapeutic keratectomy or penetrating keratoplasty. METHODS: This is a retrospective study of 4 patients (8 eyes) who underwent phototherapeutic keratectomy and 1 patient (2 eyes) who underwent penetrating keratoplasty. Best corrected visual acuity was assessed, and biomicroscopic examinations for evidence of recurrent dystrophy were documented and photographed. The location, lesion distribution, and lesion pattern of any recurrence was noted. RESULTS: Follow-up ranged from 8 months to 25 years (mean +/- SD 9.7 +/- 7.97 years). All 10 eyes showed biomicroscopic evidence of central recurrence. Six eyes showed an intermediate zone of honeycomb opacities as well as a peripheral zone of focal and geographic lesions. Despite the high incidence of recurrence, functional central visual acuity was maintained. All eyes maintained functional best corrected visual acuity (ranging from 20/25 to 20/80) despite the postoperative recurrence. CONCLUSION: Recurrence of Thiel-Behnke corneal dystrophy is extremely high after either phototherapeutic keratectomy or penetrating keratoplasty. Despite the high incidence of recurrence, the central cornea is the last to be affected. The peripheral-to-central progression of the lesions points to an epithelial origin for the pathogenesis of the dystrophy. Phototherapeutic keratectomy in the treatment of Thiel-Behnke corneal dystrophy offers a safe and effective treatment modality, providing patients up to 8 years of improved vision ranging from 8 months to 8 years (mean +/- SD 3.7 +/- 2.7 years) and delaying or circumventing the need for more invasive intraocular surgical intervention.

Effect of short-duration silicone intubation in congenital nasolacrimal duct obstruction.

PURPOSE: To determine the incidence of premature dislocation of silicone tubes used in the treatment of congenital nasolacrimal duct obstruction and investigate the effect of early dislocation on treatment outcome. METHODS: This retrospective review of 227 cases of silicone intubation in the treatment of 151 patients with congenital nasolacrimal duct obstruction. Specific attention was given to premature tube displacement, persistent epiphora, and the need for reoperation. The effect of the duration of silicone intubation and patient age on surgical outcome was assessed. Significance was determined using a Mantel-Haenszel chi-square test. RESULTS: Tube displacement and removal prior to postoperative day 31 occurred in 93 of 227 (41%) of eyes. Four of 24 eyes (17%) in children younger than 12 months who had premature dislocation of silicone tubes compared with 7 of 40 eyes (18%) that maintained silicone tubes for 31 days or greater had persistent epiphora (p = 0.932); in eyes of children from age 12 months to 23 months, 5 of 46 (11%) had persistent epiphora compared with 6 of 78 (8%) (p = 0.549); and in children age 24 months or older, 9 of 23 (39%) eyes had tearing compared with 3 of 16 (19%) (p = 0.181). Reoperation rates were 1 of 24 (4%) compared with 0 of 40 (0%) (p = 0.23) of eyes in children younger than 12 months; no difference between groups (0%) in children from age 12 months to 23 months; and 5 of 23 (22%) versus 0 of 16 (0%) (p = 0.049) of eyes in children age 24 months or older for early tube removal versus standard tube removal, respectively. CONCLUSION: Premature tube displacement and tube removal prior to day 31 does not increase the risk of persistent epiphora or reoperation in children younger than 24 months. Children older than 24 months who have early tube removal have poorer outcomes with a significantly higher reoperation rate.