The major findings of the present study are: 1) the prevalence of subclinical carotid atherosclerosis in CVRFs-free individuals is 23.2%, which rises steeply with advanced age; 2) the prevalence of subclinical carotid atherosclerosis in men is higher than in women; 3) the HDL-C and HbA1c levels are potentially related to high rate of subclinical carotid atherosclerosis. These findings indicate that additional poorly defined factors are likely to contribute to the process of atherogenesis in individuals without conventional CVRFs. Moreover, a significant number of individuals without conventional CVRFs have subclinical carotid atherosclerosis, which indicates that the assessment of subclinical atherosclerosis in this population might provide substantial yield. In addition, the association between HDL-C and the presence of subclinical carotid atherosclerosis is not expected, further suggesting that using pharmacologic inhibitor to increase HDL-C levels might not reduce the rate of cardiovascular events in individuals without conventional CVRFs, and a fundamental assessment of the clinical importance of HDL-C should be warranted.
Atherosclerotic cardiovascular diseases remain to be the major cause of premature death globally.16 Conventional risk factors for atherosclerosis including smoking, dyslipidemia, hypertension and diabetes are used within the risk factor-based approach to identify high-risk groups, such as Framingham risk scores and pooled cohort equation risk scores.17 However, only nearly 40% of cardiovascular events occur in those high-risk group, and approximately 40–60% adverse outcomes occur in the low-risk individuals, accounting for 1/3 of the population. 18 Therefore, the validity of conventional risk factors assessment in identifying risk factors in the next 10 years remains controversial. In our study cohort, up to 23.2% of individuals had carotid atherosclerosis, including 1.31% of participants who have moderate-to-severe carotid stenosis, indicating the clinical importance of carotid atherosclerosis screening.
Screening for asymptomatic carotid stenosis was based on the concept that it was possible to prevent stroke by stenting or operating moderate to severe carotid stenosis.9 However, recent studies reported that carotid operation such as carotid endarterectomy or carotid stent might cause more stroke than it can prevent, which indicated the recommendation against screening for asymptomatic carotid stenosis in view of surgery is now outmoded.19, 20 In addition, previous study reported that the presence of plaque, no matter the size, was a marker of increased risk of cardiovascular events.9 Therefore, subclinical atherosclerosis in regard of selecting optimal medical therapy to reduce cardiovascular risks should be recommended. Previous study suggested that carotid ultrasound is a more readily available and reliable imaging modality for detecting early atherosclerosis when compared to CAC scan.2 Therefore, in the present study, we used ultrasound to evaluate the subclinical atherosclerosis in CVRFs-free population.
LDL-C and HDL-C are crucially involved in the development of atherosclerosis. In contrast to LDL-C promotes the vascular atherosclerotic process, HDL-C was thought to act as a protective agent by preventing endothelial dysfunction.21 Previous studies reported that low concentration of HDL-C was inversely associated with the risk of adverse cardiovascular outcomes in general population.22, 23 However, there are growing evidences suggesting that HDL-C might lose its protective properties in certain conditions.22 Elevated HDL-C levels failed to decrease cardiovascular events and high levels of HDL-C was not correlated with reduced CIMT.24, 25 Our findings indicated that the inverse relationship between HDL-C and atherosclerosis may not apply to the individuals without CVRFs, further suggested that using pharmacologic inhibitor of the cholesterol-ester transfer protein to increase HDL-C levels might not reduce the rate of cardiovascular events in individuals without conventional CVRFs. In addition, PESA study indicated that in CVRF-free middle-aged individuals, LDL-C was independently correlated with the presence of atherosclerosis, even in currently considered normal levels.7 However, in our population, we did not find the correlation, possibly because of the different population selection and definition of atherosclerosis.
Previous study reported that HbA1c was linked to increased CAC and cIMT in 2340 nondiabetic participants.26 In addition, other study reported that HbA1c concentration was independently associated with cIMT progression and adverse cardiovascular outcomes in nondiabetic prospective series.27 In the present study, we found HbA1c level was independently associated with the presence of subclinical carotid atherosclerosis, which consistent with previous studies. 26, 27 This finding might be partially explained by the association between prediabetes and increased cardiovascular risk.
Smoking is an important modifiable risk factor for atherosclerosis, and current smoking and cumulative exposure are significantly related to cardiovascular risks.28 Therefore, smoking cessation is crucially important in reducing cardiovascular risks. In the present study, we did not find any significant association between subclinical atherosclerosis and ever smoking, coincident with previous studies,28 which indicated smoking-related damage to the artery is irreversible, and smoking cessation should be emphasized.
The strengths of the study include its population-based design in Chinese population and a comprehensive estimation of subclinical carotid atherosclerosis by ultrasound. However, this present study also had several limitations. Firstly, we can only provide implications for the association between risk factors and subclinical carotid atherosclerosis, but the causality of this association still needs more longitudinal studies to validate. Secondly, we use carotid ultrasound as a surrogate of subclinical carotid atherosclerosis, which may have led to underestimation of atherosclerosis prevalence. However, atherosclerosis is a systemic disorder, and previous study suggested that screening atherosclerosis by carotid ultrasound is likely to provide the highest yield to detect atherosclerosis.2 Thirdly, our population originated from the rural areas of northeast China, whether our results are suitable to the population in different geographic and economic conditions also needs further studies to confirm. Lastly, women comprised 80.5% of the population, and selection bias was inevitable as women usually had better access to prevention strategies, and were more likely to obey the health education.29