Circulating transforming growth factor-beta1 levels in asymptomatic carotid plaques.

Circulating Transforming Growth Factor1 Levels in Asymptomatic Carotid Plaques To the Editor: It was with great interest we read the report by Cipollone et al1 on the role of transforming growth factor1 (TGF1) in the process of plaque stabilization. The authors demonstrate that TGFmRNA levels are increased up to 3-fold in asymptomatic as compared with symptomatic plaques, with a parallel increase in protein expression at immunocytochemistry and Western blot analyses.1 In addition, TGF1 expression was associated with a comparable increase in plaque procollagen and collagen content, thus providing a tangible mechanism of plaque stabilization.1 As Cipollone et al acknowledge in their discussion, one important issue would be to measure systemic levels of TGF1 to verify whether a correlation exist between the localized expression and circulating levels of this cytokine; this correlation would suggest a systemic process in these patients rather than a local phenomenon, and probably might add prognostic information to the management of patients with carotid plaques. We have only recently completed reviewing the data collected in a 10-year prospective study of the incidence of major cardiovascular events in 42 patients with asymptomatic lowgrade carotid stenosis. Patients were consecutively enrolled over a 1-year period from those presenting at the Department of Internal Medicine of the Palermo University Hospital for ultrasound evaluation (high-resolution B-mode ultrasonography using a 7.5-MHz duplex-type probe; Toshiba) of carotid atherosclerotic involvement because of the presence of at least 1 cardiovascular risk factor. Percent carotid lumen stenosis was graded as lowgrade lumen stenosis because of plaque 15% but 50% (intima-media thickness 0.85 and 1.5 mm). Plasma TGF1 levels were determined by enzyme immunoassay (R&D Systems Inc, Minneapolis, Minn). Patients with asymptomatic low-grade carotid stenosis had markedly higher baseline levels of TGF1 (median, 3.7 pg/mL; interquartile range, 0.5 to 10.8 pg/mL) compared with control subjects in whom no lesion could be detected (mean, 0.5 pg/mL; interquartile range, 0.5 to 4.8 pg/mL; P 0.0001) independently of the presence of cardiovascular risk factors, which is in agreement with the finding of Cipollone et al.1 All patient were longitudinally followed-up for a median of 8.8 years. During this period, 14 (33%) patients with asymptomatic low-grade stenosis experienced a hard endpoint (nonfatal myocardial infarction, n 4; stroke, n 2; transient ischemic attack, n 4; intermittent claudication, n 2; percutaneous revascularization procedure, n 2). Surprisingly, these patients had significantly higher baseline values of TGF1 (median, 7.2 pg/mL, interquartile range, 0.8 to 10.8 versus median, 2.4 pg/mL, interquartile range, 0.5 to 10.6 pg/mL; P 0.02) than those who remained event-free during the follow-up. Nine of 19 (47%) patients with TGF1 levels 4.8 pg/mL (upper quartile of values observed in control subjects) experienced a hard endpoint compared with 5 of 23 (22%) patients with TGF1 levels 4.8 (log-rank test 1.9; P 0.06). These results suggest that mechanism(s) other than local expression might be responsible for the increased TGF1 levels in the circulation. In this respect, we must consider that platelets are a major source of TGF1 in the circulation as they release and activate latent growth factor in response to activation.2 This has been clearly demonstrated in the setting of visceral obesity, a condition associated to increased incidence of cardiovascular events, in which we observed that TGF1 levels were independently related to prothrombin fragment F1 23 and correlate to the rate of urinary thromboxane metabolite excretion (Rho 0.37; P 0.05) (G. Davı̀, unpublished observation, 2003). It is therefore conceivable to hypothesize that the increased TGF1 levels found in plasma samples from patients with low-grade carotid stenosis might be caused by a procoagulant state. Specific trials should be designed to directly address the issue of platelet release of TGF1 in this clinical setting.