Background: Compared to acyanotic congenital heart disease (CHD), cyanotic CHD has an increased risk of lifelong mortality and morbidity. These adverse outcomes may be attributed to delayed cardiomyocyte maturation, since the transition from a hypoxic fetal milieu to oxygen rich postnatal environment is disrupted. We established a rodent model to replicate hypoxic myocardial conditions spanning perinatal development, and tested the hypothesis that chronic hypoxia impairs cardiac development. Methods: Pregnant mice were housed in hypoxia beginning at embryonic day 16. Pups stayed in hypoxia until postnatal day (P)8 when cardiac development is nearly complete. Global gene expression was quantified at P8 and at P30, after recovering in normoxia. Phenotypic testing included electrocardiogram, echocardiogram, and ex-vivo electrophysiology study. Results: Hypoxic P8 animals were 47% smaller than controls with preserved heart size. Gene expression was grossly altered by hypoxia at P8 (1427 genes affected), but normalized after recovery (P30). Electrocardiograms revealed bradycardia and slowed conduction velocity in hypoxic animals at P8, with noticeable resolution after recovery (P30). Notable differences that persisted after recovery (P30) included a 65% prolongation in ventricular effective refractory period, sinus node dysfunction, 23% reduction in ejection fraction, and 16% reduction in fractional shortening in animals exposed to hypoxia. Conclusions: We investigated the impact of chronic hypoxia on the developing heart. Perinatal hypoxia was associated with changes in gene expression and cardiac function. Persistent changes to the electrophysiologic substrate and contractile function warrant further investigation and may contribute to adverse outcomes observed in the cyanotic CHD population.

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Multiple sclerosis (MS) is a debilitating disease of the central nervous system that is most commonly seen in early to middle adulthood, although it can be diagnosed during childhood or later in life. While cognitive impairment can become more prevalent and severe as the disease progresses, signs of cognitive involvement can be apparent in the early stages of the disease. In this review, we discuss the prevalence and types of cognitive impairment seen in early MS, including the specific measures used to identify them, as well as the challenges in characterizing their frequency and progression. In addition to examining the progression of early cognitive involvement over time, we explore the clinical factors associated with early cognitive involvement, including demographics, level of physical disability, disease modifying therapy use, vocational status, and psychological and physical symptoms. Given the prevalence and functional impact these impairments can have for persons with MS, considerations for clinicians are provided, such as the role of early cognitive screenings and the importance of comprehensive neuropsychological assessments.