Author + information
- Jennifer Romanowicz,
- Ludmila Korotcova,
- Shruti D. Ramachandra,
- Paul D. Morton,
- Amrita Cheema,
- Vittorio Gallo,
- Richard A. Jonas and
- Nobuyuki Ishibashi
Reduced oxygen delivery in complex congenital heart disease (CHD) can cause delayed brain maturation and white matter (WM) injury during fetal life. Currently no treatment exists. Tetrahydrobiopterin (BH4) is a cofactor for neuronal nitric oxide synthase. BH4 availability is reduced upon nitric oxide synthase activation—as occurs in hypoxic conditions—and leads to toxin production. We hypothesize that BH4 levels are depleted in the hypoxic brain and BH4 replacement mitigates hypoxic WM injury.
In transgenic mice, hypoxia was introduced at a postnatal period of WM development equivalent to the human third trimester. BH4 was administered orally during hypoxia. BH4 levels were directly quantified. Apoptosis and oligodendrocyte (OL) developmental stage were determined immunohistologically. Western blot detected myelin basic protein.
Brain BH4 levels depleted with hypoxia. Total OLs increased with hypoxia, consistent with hypoxia-induced proliferation, however CC1+ mature OLs were less prevalent in hypoxia and there was accumulation of CNP+CC1- immature OLs (Fig.). BH4 improved mature OL number such that it did not differ from normoxia, and immature OL accumulation was not observed (Fig.). Similarly, reduced myelination in hypoxia was mitigated by BH4. Apoptosis increased in hypoxia, but decreased with BH4 to normoxic levels.
Suboptimal BH4 levels influence hypoxic WM injury via impaired OL maturation. Replacing BH4 mitigates these toxic effects.
Poster Hall, Hall A/B
Saturday, March 10, 2018, 3:45 p.m.-4:30 p.m.
Session Title: Established and Future Therapies For Congenital Heart Desease
Abstract Category: 11. Congenital Heart Disease: Therapy
Presentation Number: 1164-365
- 2018 American College of Cardiology Foundation