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r I JACC Yul. ;2. No. b November 15. 1993:1731-3 1751 1 I I LETTERS TO THE EDITOR Increased Experimental Atherosclerosis in Cholesterol-Fed Rabbits Exposed to Passive Smoke: Taking Issue With Study Design and Methods of Analysis The report of Zhu et al. (1) attempts to show that New Zealand male saabbits, fed a high cholesterol diet followed by,ezposure i.o a„"low" and "high" concentration of environmental tobacco smoke (ETS) for an extended period of time, have altered platelet Nnction and increased aortic and pulmonary artery atherosclerosis. The authors conclude that their findings are consistent with reviews that claimthat epidemiologic studies demonstrate an association between ETS exposure and increased risk of heart disease mortality. The ETS referred to by Zhu et al. is actually represented by eilher fresh sidestream smoke or aged mainstream smoke ard not ETS. The exposure mode of 6 hlday for 5 days/week over 10 weeks. involving unrealistically high doses af smoke, is entirely arbitrary and does not approach real•life situations. Zhu et al. have reported that animals treated in such a manner are exposed to a significantly higher concentration of carbon mon- oxide and respirable particulates than their control group. The concentration of respirable paniculates was reported to be posi- tively correlated withh plasma cotinine levels. The concentrations of both respirable particulates and carbon monoxide were reportedly associated with elevated Sudan IV-stained lipid streaks in both the aorta and pulmonary arteries. Their findings on platelet functian, however, are of doubtful significance. It is an oversimplification for Zhu et al. to equate lipid streaks with atherosclerotic lesions. Moreover, failure to consider some fundamental design and meth- odologic issues makes their report inconclusive. The results of Zhu et al. could be related to a design bias. Although cholesterobfed animals have commonly beeu-used to show that high dietary cholesterol is a significant risk factor for the development of atherosclerosis (2), these animals aro not suitable for showing the possible effects of ETS because it is not known whether specific intesutions exist between dietary cholesterol asuf the presence of E1S. The animals used by T.hu et af. were primed with cholesterol for 2 weeks, but the effects of such priming were not addressed. No explanation was given for the kuge difference in the concentration of cholesterol observed among the three groups before they were expossd to ETS (Table 2, column 1). To experi- mentally investigate the alleged link between ETS and coronary heart disease, it is essential to use animals fsee from any other widely recognized and accepted risk factori of =oYonary heart disease. Failure to control for such confounden would render any laboratory findings extremely difficult, if not impossible, to inter- pret. Zhu et al. could have used animals fed a regular diet as a control for more properly assessing the possible effects of ETS. The number of animals used in the control and the "low" and "high" exposure groups difiers by a factor of 2. Moreover, male animals were used. Because the majority of the epidemiologic studies addressing the possible effects of ETS exposure on coronary heart disease actually refer to women reportedly exposed to ETS generated by smoking husbands (3,1), and because important gender-specific differences have been observed with respect to the age of onset, clinical manifestation and prognosis of heart disease (5), it is questionable whether the findings of Zhu et al. can be readily applied to humans. ' Several assays used by Zhu et al. also wartent comment. For example, methods used to quantify plalelet aggregation are known to be highly sensitive, variable and open to numerous subtleties(6). A better marker for platelet abnormality or dysfunction would have . been to measure the level of plasma platelet-0edved growth factor which, because of its generally recognized role in the development of atherosclerosis (7), could have provided greater insight into whether ETS exposure deserves to be considered as a factor for atherosclerosis. ` In the absence of other supporting evidence, it is not appropriate to interpret the measured lipid streaks as equivalent to the develop- ment of atherosclerosis. Indeed, such streaks have been found in children as young as 3 years from many countries (regardless of community prevalence of adult coronary artery disease) (g.9). Given the multitude of factors reportedly associated with athero- sclerosis, the complex nature and the long incubation period for the disease to be fully developed, I found the claim of Zhu et al. to be quite surprising because the three purported major risk factors-- elevated blood pressure, high serum cholesterol concentration, history of active smoking-collectively am unable to predict >50% of new cues of the disease (to). JOSEPH M. WU, PHD• Department of Liorhnniatrs, New YanF Mra7raf College Yalhalla, NY 16595 References . 1. Lm 6Q. Sua Yd. Seven gE Irenbrrl wM. Glamr SA. hrnder wW. hssire sewkinr inneeser eayernnemY alh<~ io dmkemtalfed Mbiu. l Am Coll CudiW 9021:2tS-1i .... . . . 1 fameno A. xou x. Hsrker L Studies ef aypnchoknemkA+: the eeMu.ra primsx. l. Qapes nm Ia4 to fsnr vtek fanntion. Anenoulemm 19HA:3SLq. z~ S. Oluns SA. hrmtey ww. wrive smokins and heus dirrue: e0idemidqy. qry l Vrio4 ~ aty, and blurhemiury. Cardalion 1991Ji:1-R 4. 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