RESUMO
We report a 14-year-old boy finally diagnosed with sitosterolemia, presenting with severe aortic valve stenosis. Genetic analysis revealed homozygous null mutation c.1336 C > T (p.R446X) in ABCG5 gene. His cardiac ultrasound presented aortic valve stenosis and moderate aortic regurgitation. His whole aorta computed tomography angiogram scan revealed aortic stenosis superior to the aortic valve, followed by ascending aorta dilation, whereas his coronary and peripheral arteries appeared normal. His maximum total cholesterol and low-density lipoprotein-cholesterol levels dropped dramatically after diet control, and ezetimibe was prescribed for treatment. The current case indicated that sitosterolemia may be a heterogeneous disease in clinical phenotype.
Assuntos
Aorta/diagnóstico por imagem , Estenose da Valva Aórtica/diagnóstico , Hipercolesterolemia/diagnóstico , Enteropatias/diagnóstico , Erros Inatos do Metabolismo Lipídico/diagnóstico , Fitosteróis/efeitos adversos , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Aorta/patologia , Estenose da Valva Aórtica/dietoterapia , Estenose da Valva Aórtica/genética , Angiografia por Tomografia Computadorizada , Dietoterapia , Humanos , Hipercolesterolemia/dietoterapia , Hipercolesterolemia/genética , Enteropatias/dietoterapia , Enteropatias/genética , Erros Inatos do Metabolismo Lipídico/dietoterapia , Erros Inatos do Metabolismo Lipídico/genética , Lipoproteínas/genética , Masculino , Fenótipo , Fitosteróis/genéticaRESUMO
AIM: Altered vitamin D signaling is associated with cardiac dysfunction, but the pathogenic mechanism is not clearly understood. We examine the mechanism and the role of vitamin D signaling in the development of cardiac dysfunction. METHODS AND RESULTS: We analyzed 1α-hydroxylase (1α-OHase) knockout (1α-OHase-/-) mice, which lack 1α-OH enzymes that convert the inactive form to hormonally active form of vitamin D. 1α-OHase-/- mice showed modest cardiac hypertrophy at baseline. Induction of pressure overload by transverse aortic constriction (TAC) demonstrated exaggerated cardiac dysfunction in 1α-OHase-/- mice compared to their WT littermates with a significant increase in fibrosis and expression of inflammatory cytokines. Analysis of calcium (Ca2+) transient demonstrated profound Ca2+ handling abnormalities in 1α-OHase-/- mouse cardiomyocytes (CMs), and treatment with paricalcitol (PC), an activated vitamin D3 analog, significantly attenuated defective Ca2+ handling in 1α-OHase-/- CMs. We further delineated the effect of vitamin D deficiency condition to TAC by first correcting the vitamin D deficiency in 1α-OHase-/- mice, followed then by either a daily maintenance dose of vitamin D or vehicle (to achieve vitamin D deficiency) at the time of sham or TAC. In mice treated with vitamin D, there was a significant attenuation of TAC-induced cardiac hypertrophy, interstitial fibrosis, inflammatory markers, Ca2+ handling abnormalities and cardiac function compared to the vehicle treated animals. CONCLUSIONS: Our results provide insight into the mechanism of cardiac dysfunction, which is associated with severely defective Ca2+ handling and defective vitamin D signaling in 1α-OHase-/- mice.
