Plasminogen activator inhibitor type 1 in adults with Down syndrome and protection against macrovascular disease

Although most subjects with Down syndrome now live well into adulthood, the incidence of systemic hypertension and atherosclerotic vascular disease ap pears to be low.(1-5) In fact, in 1977 Murdoch et al(3) suggested that Down syndrome may represent "an atheroma-free model.'" The reason for the appar ent lack of macroangiopathy is unknown. Obesity is common, premature aging is evident in other organ systems, and lipid levels are unfavorable compare d with those in unaffected siblings.(6-8) Conversely, mentally retarded sub jects without Down syndrome are not spared from either systemic hypertensio n or atherosclerosis.(3-5) Some have suggested that a genetic "triple-dose effect" is responsible for the apparent protection because the genes for cy stathionine beta synthase and superoxide dismutase are located on chromosom e 21.(4,9) Plasminogen activator inhibitor type-1 (PAI-1), the primary physiologic inh ibitor of plasminogen activation, has been associated with myocardial infar ction in epidemiologic Studies and appears to be a marker or determinant fo r recurrent myocardial infarction.(10,11) We have recently implicated incre ased PAI-1 in vessel walls as a potential determinant of accelerated athero sclerosis and particularly the development of lipid-laden plaques vulnerabl e to rupture.(12) The relative protection against atherosclerosis in Down s yndrome may imply that the expression of greater than or equal to 1 determi nant, including PAI-1, is less prominent than in age, gender, and body habi t-matched unaffected subjects. If such a potential determinant were to be i dentified, the likelihood that the factor would indeed be a causally connec ted contributor to atherogenesis would be increased.