Recorrido histórico de la niñez en Colombia.

Visceral fat, waist subcutaneous fat and hip subcutaneous fat were very similar at baseline (Table 1). After 52 weeks of treatment, the visceral and subcutaneous adipose tissue did not Table 3. Circulating progenitor cells counts

Variable

Placebo-lifestyle Rosiglitazone-lifestyle P-value

At baseline No. of patients 22 23 CD34+KDR+ (number/μL) 0.028 [0.013 to 0.043] 0.013 [0 to 0.032] 0.07 CD34+ (number/μL) 1.181 [0.786 to 2.160] 1.311 [0.476 to 1.845] 0.65 At 52 weeks No. of patients 22 23 CD34+KDR+ (number/μL) 0.016 [0 to 0.057] 0.016 [0 to 0.043] 0.81 CD34+ (number/μL) 1.475 [0.737 to 2.103] 1.580 [1.052 to 2.707] 0.28

Diff erence from baseline at 52 weeks

CD34+KDR+ (number/μL) -0.002 [-0.025 to 0.017] 0.001 [-0.024 to 0.020] 0.62 CD34+ (number/μL) 0.142 [-0.470 to 0.426] 0.654 [0.033 to 1.083]* 0.03

Rosiglitazone plus lifestyle therapy increases CD34+ cells in men with visceral obesity and elevated C-reactive protein 113

signifi cantly diff er between groups (Table 2). However, the median [IQR] change of waist subcutaneous adipose tissue had decreased signifi cantly more in the placebo-lifestyle group by -112[-231.9 to -57.5]cm² compared to -55.2 [-99.4 to 15.2]cm² in the rosiglitazone-lifestyle group (P=0.006). Visceral adipose tissue decreased with -147.5 [-256.4 to -50.8]cm² in the placebo-lifestyle group and with -86.4 [-173.4 to -27.0]cm² in the rosiglitazone-lifestyle group (P=0.06).

DISCUSSION

The results of our study demonstrate that the addition of rosiglitazone therapy to intensive lifestyle treatment signifi cantly changed circulating progenitor cell profi les in non-diabetic patients with visceral obesity and elevated C-reactive protein levels. The primary outcome, the change in the number of CD34+ cells after 52 weeks of treatment was signifi cantly increased in rosiglitazone-lifestyle treated patients. The other outcome parameter, the change in CD34+/ KDR+ cell counts, did not signifi cantly diff er between the groups.

Endothelial progenitor cells are known to correlate with cardiovascular risk factors1, 2 _{and have} been proposed as surrogate biological markers of vascular function and cardiovascular dis- ease.7 _{In this regard, CD34+ cells are most closely related to cardiovascular risk.}8 _{We observed} signifi cant increases in CD34+, but not in CD34+/KDR+ cells in response to rosiglitazone therapy in visceral obese male patients with elevated C-reactive protein levels. The available data on the in vivo eff ects of rosiglitazone on circulating endothelial progenitor cell counts are very limited. In a small, uncontrolled clinical study, 12 weeks of rosiglitazone treatment did not change CD34+ cell counts in recent onset DM2 patients.27 _{In an experimental mouse model,} rosiglitazone treatment was shown to promote the diff erentiation of bone marrow derived progenitor cells toward the endothelial linage after the induction of endothelial damage.28 _In contrast to the results of our study, treatment with pioglitazone has been shown to increase both CD34+/KDR+, and CD34+ cell counts in patients with coronary artery disease and normal glucose tolerance and in patients with DM2.29, 30 _{Pioglitazone treatment was also shown to} improve migratory response, adhesion capacity and colony formation capacity of endothelial progenitor cells.29, 30 _{These data and the results of our study show that PPARγ agonists could} increase CD34+ peripheral blood cell counts. The eff ects on CD34+KDR+ cells vary depending on the specifi c PPARγ agonist used.

Several aspects of our study should be addressed when interpreting the results: the study population, the concomitant eff ects of lifestyle intervention, and, the duration of the follow-up period. First, our study population consisted of non-diabetic male patients with visceral obesity and elevated CRP levels without manifest cardiovascular disease. Endothelial progenitor cell

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response after rosiglitazone treatment has not previously been studied in these patients. In this regard, the current results are additive to previous studies showing eff ects in non-diabetic patients without manifest cardiovascular disease. Secondly, the eff ect of rosiglitazone was assessed in addition to lifestyle therapy in our study. Lifestyle therapy is the fi rst treatment step in subjects with visceral obesity. The eff ects of lifestyle therapy are clearly seen in the placebo- lifestyle arm of our study. Lifestyle intervention resulted in reductions in body weight, waist circumference, blood pressure and some metabolic variables. Lifestyle interventions are known to signifi cantly improve progenitor cell profi les.18-20 _{We now found that addition of rosigli-} tazone to eff ective lifestyle therapy further increased CD34+ cell counts. Finally, the presented observations of our study concern a follow-up period of 52 weeks while earlier reports of both rosiglitazone and pioglitazone concern much shorter follow-up periods. Thus, our study is clearly additive as it provides the eff ect of long term follow-up to the earlier reports of studies with shorter follow-up periods.

This study has limitations. First, the infl uence of rosiglitazone independent of lifestyle treat- ment could not be assessed in our study. Furthermore, all patients in our study were males. The current observations remain to be confi rmed in female populations. Current smoking and the presence of premature familial CVD were exclusion criteria in our study due to their known impact on circulating progenitor cells. As a result, the observations of this study can not be extrapolated to subjects with those characteristics. Finally, we only determined CD34+ and CD34+/KDR+ cell counts and did not characterize the functional properties of these cells which may provide valuable additional information in future studies.

In summary, we observed signifi cant increases in CD34+ cell counts in response to rosiglitazone therapy in addition to successful intensive lifestyle treatment in non-diabetic men with visceral obesity and elevated C-reactive protein levels.

Acknowledgments:

This investigator initiated study was partially supported by an unconditional grant from Glaxo- SmithKline.

Rosiglitazone plus lifestyle therapy increases CD34+ cells in men with visceral obesity and elevated C-reactive protein 115

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