Collagen COL22A1 maintains vascular stability and mutations in COL22A1 are potentially associated with intracranial aneurysms

Collagen XXII (COL22A1) is a quantitatively minor collagen, which belongs to the family of fibril-associated collagens with interrupted triple helices. Its biological function has been poorly understood. Here, we used a genome-editing approach to generate a loss-of-function mutant in zebrafish col22a1. Homozygous mutant adults exhibit increased incidence of intracranial hemorrhages, which become more prominent with age and after cardiovascular stress. Homozygous col22a1 mutant embryos show higher sensitivity to cardiovascular stress and increased vascular permeability, resulting in a greater percentage of embryos with intracranial hemorrhages. Mutant embryos also exhibit dilations and irregular structure of cranial vessels. To test whether COL22A1 is associated with vascular disease in humans, we analyzed data from a previous study that performed whole-exome sequencing of 45 individuals from seven families with intracranial aneurysms. The rs142175725 single-nucleotide polymorphism was identified, which segregated with the phenotype in all four affected individuals in one of the families, and affects a highly conserved E736 residue in COL22A1 protein, resulting in E736D substitution. Overexpression of human wild-type COL22A1, but not the E736D variant, partially rescued the col22a1 loss-of-function mutant phenotype in zebrafish embryos. Our data further suggest that the E736D mutation interferes with COL22A1 protein secretion, potentially leading to endoplasmic reticulum stress. Altogether, these results argue that COL22A1 is required to maintain vascular integrity. These data further suggest that mutations in COL22A1 could be one of the risk factors for intracranial aneurysms in humans

The impact of the COVID-19 pandemic on individuals with Fontan circulation: Focus on gaps in care

Background: Gaps in subspecialty cardiology care could potentially delay identification and care for multi-organ complications common in patients with Fontan circulation. This study analyzed the frequency of gaps in care for individuals with Fontan circulation during the COVID-19 pandemic and associated demographic and clinical factors. Methods: This retrospective study evaluated individuals with Fontan circulation followed at our center since 2010. A gap in care was defined as an absence of any formal cardiology provider-patient contact (clinic visit or telehealth) for >15 months. Results: Over a third of 308 patients with Fontan circulation experienced at least one gap in care between 2010 and 2022, and 77 experienced a gap in care during the COVID-19 pandemic. Of this latter group, 27 (35%) had never experienced a prior gap in cardiology care until the pandemic. Those who experienced gaps in care during the pandemic were on average older (18.0 [IQR 9.6–25.6] vs. 14.2 [7.2–21.2] years, p = 0.01), more likely to be of Black/African American race (23.4% vs 7.4%, p = 0.001), and less likely to have a diagnosis of protein-losing enteropathy or plastic bronchitis (0% vs. 8.6%, p = 0.005). Those without a gap in care during the pandemic were more likely to have utilized telehealth visits (13% vs 3%, p = 0.02). Conclusion: Gaps in care are common and appear to have been exacerbated by the COVID-19 pandemic in those with a Fontan circulation. Such gaps are particularly common among African American and adult patients, and may potentially be mitigated by expanding telehealth access