Microsoft Word search phase 3 Title Page Amendment

Macrovascular Disease.  Non-invasive techniques are now used to evaluate 
arterial structure and function well before diabetes-related vascular disease 
becomes irreversible 
(25 - 30)
.  Pulse wave velocity (PWV), a measure of arterial 
stiffness (AS), is associated with CVD risk factors 
(31)
 and predicts mortality in 
both T1 and T2 diabetic adults independently of traditional CV risk factors and 
glycemic control 
(32)
.  In adults with T1D 
(27, 33)
 or T2D 
(28)
 another measure of 
arterial stiffness, the augmentation index (Aix), was found to be increased 
compared with controls.  From a limited number of small studies in youth, higher 
PWV in children with either T1D 
(34)
 or T2D 
(35)
 was found compared to controls, 
and increased AIx was observed in children with T1D 
(36)
. 
From a sub-set of SEARCH patients with T1D (N=535) and T2D (N=60) age 10-
23 years, from Colorado and Ohio sites (diabetes duration 65+/-49 months) 
(37, 38)
, 
youth with T2D had increased PWV and AIx than those with T1D (p<0.01 for 
each).  These differences were largely mediated through increased central 
adiposity and higher blood pressure in youth with T2D.  In addition, youth with 
T1D had significantly worse PWV and AIx than 241 historical controls from Ohio 
(38)
.  An ongoing SEARCH ancillary study in Colorado and Ohio (SEARCH 
CVD, R01DK078542, Dabelea PI) is collecting these and other measures in youth 
with T1D and healthy controls and will be able to provide a healthy control group 
to SEARCH.  Our data, together with the limited available literature, suggest that 
premature CVD is already present in youth with both T1D and T2D, even at 
young ages and with relatively short disease duration.  Study of the evolution of 
CV risk profile and subclinical atherosclerosis within a contemporary cohort of 
youth with T1 and T2D will provide insights into natural history of vascular 
disease in diabetes that will substantially inform new directions to what otherwise 
appears to be intractable excess risk.