Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents.
OBJECTIVE
Because endothelial dysfunction is an early event in atherogenesis, we aimed to determine whether endothelial function is normal or impaired in the systemic arteries of children with homozygous homocystinuria or in those of heterozygous adults, or both.


BACKGROUND
Homocystinuria is strongly associated with premature vascular disease in homozygotes, and even heterozygotes have been shown to be at increased risk from early atherosclerosis associated with hyperhomocystinemia.


METHODS
We conducted noninvasive studies on the superficial femoral or brachial arteries of 9 children aged 4 to 17 years (mean 11) with homozygous homocystinuria and on the brachial arteries of 14 obligate heterozygous parents age 33 to 49 years (mean 41). Each subject was matched with two control subjects. Using high resolution ultrasound, we measured vessel diameter at rest, during reactive hyperemia (with flow increase causing endothelium-dependent dilation) and after sublingual administration of nitroglycerin (an endothelium-independent vasodilator).


RESULTS
Flow-mediated dilation was observed in the control children (9 +/- 0.6%, range 6% to 14%) but was impaired in the children with homocystinuria (2.8 +/- 0.7%, range 0% to 7%, p < 0.0001). In contrast, nitroglycerin-mediated dilation was similar in both groups (15.7 +/- 1.6% vs. 13.1 +/- 1.2%, p = 0.27), indicating that the impaired flow-mediated dilation is secondary to endothelial dysfunction. In the heterozygous parents, both flow-mediated dilation and nitroglycerin responses (6.3 +/- 0.9%, 17 +/- 1.4%, respectively) were similar to control values (6.8 +/- 0.7%, 20.7 +/- 1.7%, p > 0.10).


CONCLUSIONS
Children with homozygous homocystinuria had impaired endothelial function in the systemic arteries as early as 4 years of age, representing an early event in their premature vascular disease. However, endothelial function was preserved in the heterozygous adults.
Celermajer
D S
DS
Cardiothoracic Unit, Hospital for Sick Children, London, England, United Kingdom.
Sorensen
K
K
Ryalls
M
M
Robinson
J
J
Thomas
O
O
Leonard
J V
JV
Deanfield
J E
JE
D000293:Adolescent; D000328:Adult; D000596:Amino Acids / Q000032:analysis; D001916:Brachial Artery / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology*; D002648:Child; D002675:Child, Preschool; D004730:Endothelium, Vascular / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D005263:Femoral Artery / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology*; D006579:Heterozygote; D006712:Homocystinuria / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000378:metabolism / Q000503:physiopathology*; D006720:Homozygote; D006801:Humans; D008297:Male; D005996:Nitroglycerin; D012044:Regression Analysis; D014463:Ultrasonography; D014664:Vasodilation / Q000187:drug effects
D000596:Amino Acids; D005996:Nitroglycerin