Albuminuria Is Associated With Early Carotid Atherosclerosis
Albuminuria Is Associated With Early Carotid Atherosclerosis
In the present study, we found that higher UACR within the normal range was associated with elevated CIMT and with higher incidence of carotid plaque but not with carotid stenosis, even after adjusting for traditional cardiovascular disease risk factors and eGFR in Chinese community-based patients with T2DM. To the best of our knowledge, this is the first time the relationship between low-grade albuminuria and carotid atherosclerotic lesions has been systematically studied in Chinese patients with type 2 diabetes. The association of microalbuminuria with cardiovascular disease has been well established in a number of populations, including diabetics, hypertensive patients and general subjects, but not until recently have several studies reported that cardiovascular morbidity and mortality are increased even in patients with much lower UACR levels. For example, the HOPE study demonstrated that UACR above 0.58 mg/mmol, a value well below the cutoff for microalbuminuria, had remarkable correlation with cardiovascular events and that every 0.4 mg/mmol increment in UACR was associated with a 5.9% increase in the risk of occurrence of a major cardiovascular event. The Framingham Heart Study also revealed that subjects with UACR values at or above 3.9 mg/g (equivalent to 0.52 mg/mmol) for men and 7.5 mg/g (equivalent to 0.99 mg/mmol) for women were associated with a 3-fold risk of developing cardiovascular diseases in comparison to patients with UACR below these levels. Likewise, the Strong Heart Study indicated that albuminuria levels below the threshold definition of microalbuminuria can predict cardiovascular diseases in middle-aged and elderly American Indians.
The foregoing findings indicate that further exploration of the association between the normal range of UACR and the occurrence of cardiovascular disease is of great importance for the early detection and intervention of such disease. Although CIMT has been widely adopted as an early marker of cardiovascular disease, it does not well predict the absence, extent, severity or prognosis of coronary artery disease, which carotid plaque and stenosis do. We therefore comprehensively studied the association between UACR within the normal range and carotid atherosclerotic lesions, including CIMT, carotid plaque and stenosis.
Consistent with our results, Huang et al. and Kweon et al. also showed that higher normal ranges of UACR are positively and independently associated with CIMT in patients with diabetes and in the general population, respectively. In the present study, men had higher CIMT than women in each UACR tertile, but a significant difference between men and women existed only in the highest UACR tertile, in which the mean age was 68. Similar findings were also reported by Bo et al., who found a gender difference in CIMT only in a group in which the mean age was greater than 69 years. Another main finding of our study was that patients 65 years of age or older also had higher CIMT than patients below 65 years of age, a result that is in keeping with other studies.
Consistent with the results of the Shanghai Changfeng Study, we found that the odds ratio of carotid plaques increased steadily across UACR tertiles in patients with type 2 diabetes. Lee et al. also demonstrated that compared with low normoalbuminuria subjects (UACR < 15.0 mg/g, equivalent to 1.99 mg/mmol), community-dwelling Koreans with high normoalbuminuria (UACR > 15.0 mg/g, equivalent to 1.99 mg/mmol) had significantly higher risk of carotid plaque.
Importantly, our study demonstrated that there was no significant association between normal UACR and carotid stenosis even after adjustment for other variables. This may be due to the lower prevalence of carotid stenosis compared to carotid plaque and the fact that it represents a later stage in the atherosclerotic process. To our knowledge, this is the first time the relationship between UACR in the high normal range and carotid stenosis has been investigated, although some authors have reported that microalbuminuria correlates with the prevalence and severity of coronary artery stenosis.
Similar to our previous and other studies, we found that older patients (age ≥ 65) had a higher mean CIMT and prevalence of carotid plaque compared with younger patients (age < 65) in each UACR tertile group. Gender difference in carotid atherosclerosis has been confirmed in general population and patients with diabetes, but in the present study, sex-related differences in the mean CIMT and in the prevalence of carotid plaque existed only in the highest UACR tertile group. This can be explained by the fact that age in the highest UACR tertile group was significantly older than in the first and second UACR tertile groups. This finding was consistent with a previous study, which found that sex difference in CIMT was not significant in young population and gradually increased with age. Unlike CIMT and carotid plaque, there were neither sex-related nor age-related significant differences in the prevalence of carotid stenosis in any of the tertile groups, which may be due to low prevalence of carotid stenosis and relatively small samples in the present study.
Lastly, consistent with the results of previous studies, our study demonstrated that three parameters of carotid lesions (CIMT, atherosclerotic plaque, and stenosis) generally correlate well with each other. Bonithon et al. reported that the odds ratio for having at least one plaque associated with a 0.10 mm increase in CIMT was 1.18 in the EVA study. Gnasso et al. showed that CIMT was strongly and significantly associated with the presence of plaques and/or stenosis in the carotid arteries after adjustment for coronary heart disease risk factors. The Aging Vascular Study, the Tromsø Study, the San Daniele Project and a study of health in Pomerania also confirmed that CIMT independently predicts incident carotid plaque formation in a prospective manner.
There is a remaining controversial issue concerning the independent correlation between albuminuria and atherosclerosis. Ninomiya et al. and Sung et al. noted that elevated CIMT was associated with increased albuminuria after excluding other compound variables, whereas Ishimura et al. and Ito et al. reported that significant association between these two parameters was lost after adjustment for traditional risk factors such as blood pressure and waist-hip ratio. Our results showed that the statistical significance between UACR tertiles and carotid plaque was lost after application of the binary logistic regression analysis in Model I. However, after adding additional risk factors (Model II and Model III), UACR tertile was positively associated with carotid plaque, suggesting that these additional variables may act as compounding factors. When we excluded them, the association between UACR and carotid plaque was obvious. In studies involving patients with diabetes, the duration of diabetes may be the primary cause of discrepancies in the results. For example, Shin et al. reported that microalbuminuria was not related to CIMT in newly diagnosed patients with type 2 diabetes. The median duration of diabetes in our patients and in the study of Huang et al. was 5–7 years, while the patients in Shin's study had a shorter duration of diabetes of approximately 1 year. Because duration of diabetes is closely related to CIMT in patients with type 2 diabetes, studies of patients with different durations of diabetes appear to yield different results. Furthermore, the basic characteristics of the patients in the studies (their ethnic diversity, for example) as well as the use of different methods to measure carotid atherosclerotic lesions could also lead to discrepancies.
The mechanism or mechanisms by which albuminuria increases atherosclerosis are not well-elucidated, but endothelial dysfunction and low-grade chronic inflammation may be responsible for common underlying mechanisms. In addition, synergistic effects of albuminuria in combination with cardiovascular risk factors such as hypertension and dyslipidemia may also partly explain why albuminuria even at levels below the microalbuminuria threshold remains a strongly independent indictor for atherosclerosis. Further studies will be needed to clarify the exact relationship between these factors.
Our study adds powerful clinical evidence supporting the hypothesis that risk of cardiovascular diseases may begin to increase at relatively low UACR levels. However, our study has several limitations that should be noted. First, the number of patients studied was relatively small. Thus, prospective studies of a larger sample should be conducted to verify the relationship between low-grade albuminuria and the presence of carotid atherosclerotic lesions. Second, due to the relatively small sample size, we did not analyze the subjects according to sex-specific UACR tertiles; instead, we studied sex-related differences in each UACR tertile subgroup after adjustment for age. Third, we did not consider the patients' medications.
Discussion
In the present study, we found that higher UACR within the normal range was associated with elevated CIMT and with higher incidence of carotid plaque but not with carotid stenosis, even after adjusting for traditional cardiovascular disease risk factors and eGFR in Chinese community-based patients with T2DM. To the best of our knowledge, this is the first time the relationship between low-grade albuminuria and carotid atherosclerotic lesions has been systematically studied in Chinese patients with type 2 diabetes. The association of microalbuminuria with cardiovascular disease has been well established in a number of populations, including diabetics, hypertensive patients and general subjects, but not until recently have several studies reported that cardiovascular morbidity and mortality are increased even in patients with much lower UACR levels. For example, the HOPE study demonstrated that UACR above 0.58 mg/mmol, a value well below the cutoff for microalbuminuria, had remarkable correlation with cardiovascular events and that every 0.4 mg/mmol increment in UACR was associated with a 5.9% increase in the risk of occurrence of a major cardiovascular event. The Framingham Heart Study also revealed that subjects with UACR values at or above 3.9 mg/g (equivalent to 0.52 mg/mmol) for men and 7.5 mg/g (equivalent to 0.99 mg/mmol) for women were associated with a 3-fold risk of developing cardiovascular diseases in comparison to patients with UACR below these levels. Likewise, the Strong Heart Study indicated that albuminuria levels below the threshold definition of microalbuminuria can predict cardiovascular diseases in middle-aged and elderly American Indians.
The foregoing findings indicate that further exploration of the association between the normal range of UACR and the occurrence of cardiovascular disease is of great importance for the early detection and intervention of such disease. Although CIMT has been widely adopted as an early marker of cardiovascular disease, it does not well predict the absence, extent, severity or prognosis of coronary artery disease, which carotid plaque and stenosis do. We therefore comprehensively studied the association between UACR within the normal range and carotid atherosclerotic lesions, including CIMT, carotid plaque and stenosis.
Consistent with our results, Huang et al. and Kweon et al. also showed that higher normal ranges of UACR are positively and independently associated with CIMT in patients with diabetes and in the general population, respectively. In the present study, men had higher CIMT than women in each UACR tertile, but a significant difference between men and women existed only in the highest UACR tertile, in which the mean age was 68. Similar findings were also reported by Bo et al., who found a gender difference in CIMT only in a group in which the mean age was greater than 69 years. Another main finding of our study was that patients 65 years of age or older also had higher CIMT than patients below 65 years of age, a result that is in keeping with other studies.
Consistent with the results of the Shanghai Changfeng Study, we found that the odds ratio of carotid plaques increased steadily across UACR tertiles in patients with type 2 diabetes. Lee et al. also demonstrated that compared with low normoalbuminuria subjects (UACR < 15.0 mg/g, equivalent to 1.99 mg/mmol), community-dwelling Koreans with high normoalbuminuria (UACR > 15.0 mg/g, equivalent to 1.99 mg/mmol) had significantly higher risk of carotid plaque.
Importantly, our study demonstrated that there was no significant association between normal UACR and carotid stenosis even after adjustment for other variables. This may be due to the lower prevalence of carotid stenosis compared to carotid plaque and the fact that it represents a later stage in the atherosclerotic process. To our knowledge, this is the first time the relationship between UACR in the high normal range and carotid stenosis has been investigated, although some authors have reported that microalbuminuria correlates with the prevalence and severity of coronary artery stenosis.
Similar to our previous and other studies, we found that older patients (age ≥ 65) had a higher mean CIMT and prevalence of carotid plaque compared with younger patients (age < 65) in each UACR tertile group. Gender difference in carotid atherosclerosis has been confirmed in general population and patients with diabetes, but in the present study, sex-related differences in the mean CIMT and in the prevalence of carotid plaque existed only in the highest UACR tertile group. This can be explained by the fact that age in the highest UACR tertile group was significantly older than in the first and second UACR tertile groups. This finding was consistent with a previous study, which found that sex difference in CIMT was not significant in young population and gradually increased with age. Unlike CIMT and carotid plaque, there were neither sex-related nor age-related significant differences in the prevalence of carotid stenosis in any of the tertile groups, which may be due to low prevalence of carotid stenosis and relatively small samples in the present study.
Lastly, consistent with the results of previous studies, our study demonstrated that three parameters of carotid lesions (CIMT, atherosclerotic plaque, and stenosis) generally correlate well with each other. Bonithon et al. reported that the odds ratio for having at least one plaque associated with a 0.10 mm increase in CIMT was 1.18 in the EVA study. Gnasso et al. showed that CIMT was strongly and significantly associated with the presence of plaques and/or stenosis in the carotid arteries after adjustment for coronary heart disease risk factors. The Aging Vascular Study, the Tromsø Study, the San Daniele Project and a study of health in Pomerania also confirmed that CIMT independently predicts incident carotid plaque formation in a prospective manner.
There is a remaining controversial issue concerning the independent correlation between albuminuria and atherosclerosis. Ninomiya et al. and Sung et al. noted that elevated CIMT was associated with increased albuminuria after excluding other compound variables, whereas Ishimura et al. and Ito et al. reported that significant association between these two parameters was lost after adjustment for traditional risk factors such as blood pressure and waist-hip ratio. Our results showed that the statistical significance between UACR tertiles and carotid plaque was lost after application of the binary logistic regression analysis in Model I. However, after adding additional risk factors (Model II and Model III), UACR tertile was positively associated with carotid plaque, suggesting that these additional variables may act as compounding factors. When we excluded them, the association between UACR and carotid plaque was obvious. In studies involving patients with diabetes, the duration of diabetes may be the primary cause of discrepancies in the results. For example, Shin et al. reported that microalbuminuria was not related to CIMT in newly diagnosed patients with type 2 diabetes. The median duration of diabetes in our patients and in the study of Huang et al. was 5–7 years, while the patients in Shin's study had a shorter duration of diabetes of approximately 1 year. Because duration of diabetes is closely related to CIMT in patients with type 2 diabetes, studies of patients with different durations of diabetes appear to yield different results. Furthermore, the basic characteristics of the patients in the studies (their ethnic diversity, for example) as well as the use of different methods to measure carotid atherosclerotic lesions could also lead to discrepancies.
The mechanism or mechanisms by which albuminuria increases atherosclerosis are not well-elucidated, but endothelial dysfunction and low-grade chronic inflammation may be responsible for common underlying mechanisms. In addition, synergistic effects of albuminuria in combination with cardiovascular risk factors such as hypertension and dyslipidemia may also partly explain why albuminuria even at levels below the microalbuminuria threshold remains a strongly independent indictor for atherosclerosis. Further studies will be needed to clarify the exact relationship between these factors.
Limitations
Our study adds powerful clinical evidence supporting the hypothesis that risk of cardiovascular diseases may begin to increase at relatively low UACR levels. However, our study has several limitations that should be noted. First, the number of patients studied was relatively small. Thus, prospective studies of a larger sample should be conducted to verify the relationship between low-grade albuminuria and the presence of carotid atherosclerotic lesions. Second, due to the relatively small sample size, we did not analyze the subjects according to sex-specific UACR tertiles; instead, we studied sex-related differences in each UACR tertile subgroup after adjustment for age. Third, we did not consider the patients' medications.
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