The atherosclerotic propensity of hyperhomocyst(e)inemic patients results from endothelial dysfunction and injury. Patients with homocystinuria usually have a homozygous deficiency of cystathionine β-synthase (CBS) and die at an early age of arterial and venous thrombo-embolism. Their hétérozygote relatives do not seem to be clinically affected. The purpose of our study was firstly to enumerate CECs in homozygotes for CBS deficiency and to examine these cells for evidence of an activated and procoagulant phenotype. Secondly we evaluated CECs in hétérozygotes for CBS deficiency before and after a methionine load to determine whether post loading transient hyperhomocyst(e)inemia leads to an increase in CEC numbers and a change in their phenotype. Results: 1] Homocystinuric patients (n=5) all had elevated fasting homocyst(e)ine levels and increased numbers of CECs (33±13/ ml whole blood) compared to normal controls (3±2 / ml). The homocystinuric CEC phenotype was abnormal. Immunofluorescent staining for tissue factor showed that 94±7% of the patient's CECs stained positive for tissue factor compared to normal CECs where only 10±13% were positive (n=lO). The homocystinuric CECs exhibited abnormal expression of VCAM-1,79±9% versus 13±11 % in normal subjects. The same was true for ICAM-1 expression, 78±7% compared|to 33+2%. 2]Methionine loading was performed on three obligate hétérozygote relatives of he homocystinuric patients. All subjects had normal fasting homocyst(e)ine levels, with abnormally elevated values at 4 and 8 hours after loading. CECs from CBS hétérozygotes were normal in number and VCAM expression at baseline and were not significantly different after 4 or 8 hours following the methionine load. CECs from three nomal controls also showed no changes in number or VCAM expression at the 4 and 8 hour ti ne points. In conclusion, patients with homocystinuria have elevated numbers of CECs t iat have an abnormal procoagulant and proadhesive phenotype which may reflect endothe ial damage mediated by chronic high grade hyperhomocyst(e)inemia. Similar changes wre not observed in obligate carriers of homocystinuria even after transient hyperhomocyst(e)inemia induced by methionine loading.
|Original language||English (US)|
|Issue number||11 PART I|
|State||Published - Dec 1 2000|