Methods

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Study Participants

We analyzed data from studies of 144 healthy persons 16 to 45 years of age, none of whom had a history of hyperlipidemia, hypertension, or diabetes mellitus or were regularly taking cardiovascular medications. Participants were community volunteers. All participants gave informed consent, and the study was approved by our institutional ethics committees.

The Chinese participants were all studied in Shek Kei Village (population, 3000) in Guangdong province, southern China. Most of the villagers still consume a traditional Chinese diet based on vegetables, rice, fish, and green tea. The annual rate of acute myocardial infarction (fatal and nonfatal) in this region of China is less than one fifth that in westernized countries [6, 11].

On the basis of prospectively defined entry criteria, we included 72 Chinese persons in our study: 36 nonsmoking controls (16 men and 20 women), 21 active smokers (13 men and 8 women), and 15 passive smokers (2 men and 13 women). Controls had never regularly smoked cigarettes and had no regular exposure to environmental cigarette smoke (<1 hour per week). Active smokers had a lifetime dose of 2 pack-years or more; passive smokers had never been active smokers and had been exposed to environmental cigarette smoke for 1 hour or more per day for at least the past 3 years. The intensity of passive exposure to smoke was scored as described elsewhere [10]. Results from the Chinese nonsmokers and the Chinese smokers were compared with the results from white participants (36 lifelong nonsmokers, 21 active smokers, and 15 passive smokers) studied in Sydney, Australia, or London, United Kingdom. White participants were matched with Chinese participants for sex, smoking history, and vessel size [4, 10, 12].

Study Design

A detailed medical history and a self-reported smoking history were elicited from each participant; the smoking history was verified in approximately 75% of the Chinese participants and 20% of the white participants through the measurement of exhaled carbon monoxide levels (Carboxymeter, Bedfont Scientific, Kent, England). In all participants, supine resting blood pressure was measured and venous blood was sampled for enzymatic measurement of total cholesterol level. Endothelial function was assessed by using ultrasonography to measure the brachial artery diameter at rest, during reactive hyperemia (leading to flow-mediated endothelium-dependent dilatation), and after administration of sublingual nitroglycerin (an endothelium-independent dilator), as described and validated elsewhere [4, 10, 13]. Scans were recorded on super-VHS videotape for later off-line analysis; in every case, the diameter of the artery was measured by two independent observers who were blinded to the identity of the participants and to the stage of the experiment. Doppler-derived arterial flow was measured at rest and during hyperemia [9]. All ultrasonographic scans in all study locations were obtained by the same operators using the same type of equipment (an Acuson 128 XP/10 mainframe with 7-MHz linear array transducer [Acuson, Mountain View, California]).

Statistical Analysis

Descriptive data are expressed as the mean ±SD. Exposure to cigarette smoke was compared between ethnic groups by using independent sample t-tests. Analysis of variance was done for the four groups (Chinese nonsmokers, Chinese active or passive smokers, white nonsmokers, and white active or passive smokers) and was followed by the Student-Neuman-Keuls test for multiple comparisons. In the Chinese and then in the white participants, the determinants of endothelium-dependent and nitroglycerin-induced dilatation (expressed as percentage dilatation compared with baseline vessel size) were assessed by forced-entry multiple regression, with smoking group (nonsmoker or active or passive smoker), ethnic group (Chinese or white), age, sex, mean blood pressure, total cholesterol level, degree of hyperemia, and vessel size entered as the independent variables. A smoking-ethnicity interaction variable was not significantly related when added to these multivariable regression models. Statistical significance was defined as a P value less than 0.05.

Industry Role

No source of financial support for this study played any role in gathering, analyzing, or interpreting the data or in deciding whether to submit the manuscript for publication.

Results

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Baseline Characteristics

The average age of both Chinese and white nonsmokers was 30 years. The Chinese active smokers were 31 ± 6 years of age (range, 18 to 42 years of age) and had smoked for 9 ± 6 pack-years (range, 2 to 20 pack-years). The white active smokers were younger (22 ± 3 years of age [range, 16 to 28 years of age]) but had similar direct exposure to cigarette smoke (7 ± 4 pack-years range, 2 to 16 pack-years; P = 0.13). The Chinese passive smokers were 32 ± 6 years of age (range, 23 to 40 years of age), with scores for intensity of exposure to environmental cigarette smoke of 1.8 ± 0.7. The white passive smokers were younger (22 ± 5 years of age [range, 16 to 30 years of age]) but had similar scores for intensity of exposure to smoke (2.1 ± 0.9) (P > 0.2). Vessel size and other baseline characteristics were similar in both ethnic groups among nonsmokers and active or passive smokers (Table 1).

Vascular Studies

In the nonsmokers, both endothelium-dependent dilatation (7.9% in Chinese participants compared with 8.4% in white participants; P > 0.2) and nitroglycerin-induced dilatation (18% in Chinese participants compared with 20% in white participants; P = 0.15) were similar in the two ethnic groups. In the active or passive smokers, endothelium-dependent dilatation was less in the white participants than in the Chinese participants (3.9% compared with 7.3%; P < 0.001) (Figure 1). Nitroglycerin-induced dilatation was similar in the nonsmokers and the active or passive smokers in both ethnic groups.

View larger version (21K): [in this window] [in a new window]   Figure 1. Endothelium-dependent dilatation in Chinese and white nonsmokers and Chinese and white active or passive smokers. Analysis of variance followed by pairwise comparisons showed that endothelium-dependent dilatation was significantly lower (P < 0.001) in the white active or passive smokers than in the white nonsmokers, Chinese active or passive smokers, and Chinese nonsmokers. This dilatation was similar among the latter three groups (P > 0.2). In each box plot, the bottom and top of the box represent the 25th percentile and the 75th percentile, respectively. The line across each box represents the median value, and the vertical lines encompass the entire range of values for each group of participants. Striped boxes represent Chinese participants; white boxes represent white participants.

Forced multiple regression analysis of all participants showed that impaired endothelium-dependent dilatation was associated with white ethnicity (regression coefficient, –1.6%[95% CI, –0.5% to –2.7%];P = 0.009), active or passive smoking (regression coefficient, –2.6%[CI, –1.6% to –3.6%];P < 0.001), and larger vessel size (regression coefficient, –1.6%[95% CI, –0.3% to –2.9%];P = 0.02) but not with age, sex, total cholesterol level, blood pressure, or degree of hyperemia. For the 72 white participants only, a history of active or passive smoking was independently associated with impaired endothelium-dependent dilatation (regression coefficient, 6.5% [CI, 4.6% to 8.3%]; P < 0.001). In contrast, in the Chinese participants, endothelium-dependent dilatation was not independently associated with a history of exposure to smoke (P > 0.2). Neither ethnic group nor smoking history were significantly associated with nitroglycerin-induced dilatation.

Discussion

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In this study, young Chinese adults seemed to be less susceptible than white persons to cigarette smoke-related endothelial dysfunction. There are several possible explanations for this finding. The chemical composition of the cigarettes smoked in China may be different from that of cigarettes smoked elsewhere; however, most Chinese smokers use imported cigarettes or smoke locally made nonfiltered cigarettes that contain high levels of tar (23 to 34 mg per cigarette) and nicotine (0.7 to 1.2 mg per cigarette) [14]. In addition, smoke-related endothelial damage may be less marked in Chinese persons because they generally start smoking later (in the late teen years or early 20s) than white persons [7]. Despite these potential confounding factors, the magnitude of the difference between Chinese and white smokers suggests that some protective factor or factors may have been operating in the Chinese participants.

Genetic or Environmental Factors

Despite the importance of endothelial dysfunction in atherogenesis [8], no studies of endothelial physiology in persons from mainland China have been reported other than by our group. Our finding that endothelial function is similar in young, healthy, nonsmoking Chinese and white adults who do not have known vascular risk factors argues against a simple genetic advantage for Chinese persons. Environmental factors may be important. Although total and low-density lipoprotein (LDL)-cholesterol levels were similar in the Chinese and white participants in this study, the greater consumption of antioxidant-containing teas and foods by the Chinese participants [15] may be associated with a lower susceptibility of LDL cholesterol to oxidation. The oxidation status of LDL cholesterol seems to be important in determining the degree of Cholesterol-related endothelial dysfunction, particularly in cigarette smokers [16]. Other aspects of the diet of persons from southern China, such as high intake of soy protein, plant phytoestrogens, and fish oil, may also contribute to vascular protection [17].

Study Limitations

In this study, the two groups of smokers were matched primarily for their degree of smoke exposure rather than for age to test the hypothesis that Chinese persons have less smoke-related endothelial dysfunction. Data on exposure to smoke were derived from self-report and therefore may be prone to some inaccuracy. Because the group sizes were relatively small, subgroup analyses were not done for active versus passive smokers or for men versus women. We found that the degree of peak reactive hyperemia after cuff occlusion and release was higher in Chinese persons than in white persons. The mechanism behind this difference is unknown. Nonetheless, the hyperemic response was high (>400%) in all groups, and the endothelial responses were not correlated with the degree of hyperemia observed. Otherwise, the vascular study results should be directly comparable in the Chinese and white participants because the studies were done by the same personnel using identical methods and equipment.

Conclusions

Cigarette smoking is one of the major modifiable risk factors for atherosclerosis and thrombosis, which are the most common causes of death in westernized countries. Cigarette smoking is clearly also a health hazard in China, where it is associated with many thousands of deaths annually, primarily because of pulmonary diseases [14]. However, Chinese persons appear to be less susceptible than white persons to cigarette smoke-related endothelial dysfunction. Elucidation of the factors that might contribute to arterial protection in Chinese smokers may be important in minimizing smoke-related arterial damage in otherwise healthy young adults.

From Chinese University of Hong Kong, Hong Kong; Royal Prince Alfred Hospital and The Heart Research Institute, Sydney, Australia; Pan Yu County Hospital, Pan Yu, PR China; and Great Ormond Street Hospital for Children, London, England.

Ms. Robinson: The Blood Flow Lab, Nuclear Medicine Department, Liverpool Hospital, PO Box 103, Liverpool 2170, Australia.

Drs. Adams and Celermajer: Department of Cardiology, Royal Prince Alfred Hospital, Missenden Road, Camperdown 2050, Sydney, Australia.

Dr. Mai: Pan Yu County Hospital, Pan Yu, PR China.

Dr. Lam: Department of Chemical Pathology, Prince of Wales Hospital, Shatin, NT, Hong Kong.

Dr. Sorensen: Department of Cardiology, Skejby Sygehus, Aarhus, Denmark.

Dr. Deanfield: Cardiothoracic Unit, Great Ormond Street Hospital for Children, London WCIN 3JH, England.