The comorbidity of increased arterial stiffness and microalbuminuria in a survey of middle-aged adults in China

Background Increased arterial stiffness (iAS) and microalbuminuria (MAU), which may occur simultaneously or separately in the general population and share similar risk factors, are markers of macro- and microvascular injuries. Our research investigated the comorbidity of iAS and MAU in the middle-aged population and examined the heterogeneous effects of metabolic risk factors on iAS and MAU. Methods We selected 11,911 individuals aged 45 to 60 years who underwent a health examination at the 3rd Xiangya Hospital between 2010 and 2014. Metabolic syndrome (MetS) was determined according to IDF/NHLBI/AHA-2009 criteria. Multinomial logistic regression was applied to evaluate the influence of MetS, components of MetS and clusters of MetS on the co-occurrence (MAU(+)/iAS(+)) or non-co-occurrence (MAU(+)/iAS(−) and MAU(−)/iAS(+)) of MAU and iAS. Results Reference group was MAU(−)/iAS(−). A positive effect of MetS on the presence of MAU(+)/iAS(−), MAU(−)/iAS(+), or MAU(+)/iAS(+) is listed in ascending order based on odds ratios (ORs = 2.11, 2.41, 4.61, respectively; P < 0.05). Compared with MAU(+)/iAS(−), Elevated blood pressure (BP) (OR = 1.62 vs. 4.83, P < 0.05), triglycerides(TG) (OR = 1.20 vs. 1.37, P < 0.05) were more strongly associated with MAU(−)/iAS(+), whereas fasting blood glucose (FBG) was less associated (OR = 1.37 vs. 1.31, P < 0.05). Decreased high-density lipoprotein cholesterol(HDL-c) (OR = 1.84, P < 0.01) and elevated waist circumference(WC) (OR = 1.28 P < 0.01) were the most strongly associated with MAU(+)/iAS(−). Compared with the individuals without MetS, individuals with the elevated BP, FBG, TG and decreased HDL-c cluster had the greatest likelihood of presenting a MAU(−)/iAS(+) (OR = 5.98, P < 0.01) and MAU(+)/iAS(+) (OR = 13.17, P < 0.01), these likelihood was even greater than the cluster with simultaneous alteration in all five MetS components (OR = 3.89 and 10.77, respectively, P < 0.01), which showed the most strongly association with MAU(+)/iAS(+) (OR = 5.22, P < 0.01). Conclusion Based on the heterogeneous influences of MetS-related risk factors on MAU and iAS, these influences could be selectively targeted to identify different types of vascular injuries.


Background
Increased arterial stiffness (iAS) and microalbuminuria (MAU) are surrogate markers of macro [1] -and microvascular [2] damages, respectively; however, their comorbidity in the general population is unknown.
The formation of MAU is due to the leaking of small amounts of albumin from kidney into the urine [2], this reversible indicator is initiated by endothelial dysfunction and becomes fixed with the progression of renal microvascular abnormality [2]. iAS occurs as a consequence of biological aging [3] and arteriosclerosis [4], and pulse wave velocity is measured as a sign of macroangiopathy that reflects functional changes [5].
As manifestations of vascular damage in different areas [1,2], since iAS and MAU have correlation and share common risk factors mentioned above, we hypothesize that taken together, iAS and MAU may represent a continuum in some populations; that is, individuals with less severe vascular disease express only one of these markers, while individuals with more severe disease express both. Systematic screening of this continuum is lacking in adults despite its potentially high utility in predicting vascular mortality; consequently, research regarding modifiable metabolic risk factors for MAU and iAS could be important for developing effective public health care initiatives.
The aims of our study were to measure the comorbidity of elevated MAU and iAS in the middle-aged population to determine whether MAU and iAS share a common pattern of individual risk factors for metabolic syndrome.

Study population and measurements
A cross-sectional study was conducted in a general population. The medical records of 11,911 participants from Central South China who underwent a health check at the Health Examination Management Center of the 3rd Xiangya Hospital from January 1, 2010, to October 31, 2014, were reviewed by trained staff. The inclusion criteria were as follows: age between 45 and 60 years and Han ethnicity. The exclusion criteria were heart failure, chronic nephritis, renal insufficiency, and pregnancy. The history of medication, smoking and cardiovascular disease was reviewed.
We only included middle-aged participants because vascular aging is common in older people [22]. This study was conducted according to the principles expressed in the Declaration of Helsinki and was approved by the Ethics Committee of the Third Xiangya Hospital, and the consent form was signed by each participant.
Waist circumference (WC) was measured by wrapping a measuring tape completely around the waist 0.5 cm above the belly button [23]. Systolic and diastolic blood pressure (SBP and DBP) was measured between 8 AM and 10 AM,following the guidelines from the American Health Association [24], all measurement were conducted using an automatic digital BP monitor(Omron 9020), with the participants seated after a 10-min rest period, with feet straight upon the ground and the back and arm supported, and with the antecubital fossa at the level of the heart. The maximum cuff inflation was calculated by adding 30 mmHg to the pulse obliteration pressure, and the cuff was deflated at a constant rate of 2 to 4 mmHg per second. Venous blood was collected in the morning after overnight fasting, serum samples were stored at 4°C and were subject to testing (Hitachi 7170 s autoanalyzer) within 2 days, according to the instruction of analyzer, fasting blood glucose (FBG), triglycerides (TG), and high density lipoprotein cholesterol (HDL), cholesterol, uric acid, serum creatinine (Scr) were measured by enzymatic method using fullautomatic biochemical analyser (Hitachi 7170 s). Estimated glomerular filtration rate [25] All the participants' morning urine specimens were tested. Urinary microalbumin was measured using the ELISA method. MAU < 20 mg/L was defined as normoalbuminuria, while ≥20 mg/L was defined as high MAU [26].
Brachial-ankle artery pulse wave velocity (baPWV) was used to evaluate arterial stiffness. After a 5-min rest in a supine position, baPWV was measured using the Colin-VP1000 (Omron, Japan) by trained nurses between 7 AM and 9 AM, with monitoring cuffs placed around both the upper and lower extremities, the data were recorded simultaneously by the instrument [27]. The time interval between the wave front of brachial waveform and that of ankle waveform was defined as the time interval between brachium and ankle (ΔTba). The path length from the heart to the brachium (Lb) was expressed using the following equation: Lb = 0.2195 × height of the patient (cm) − 2.0734. The path length from the heart to ankle (La) was expressed using the following equation: La = (0.8129 × height of the patient (cm) + 12.328). The baPWV was then calculated as follows: baPWV = (La/Lb)/Tba. baPWV≥1400 cm/s was considered high arterial stiffness [28].

Discussion
This current study has shown the heterogeneous association between cross-combination of MAU/iAS and MetS itself, the number of positive MetS components, individual MetS components, the clusters of MetS components.
There are close relation between iAS or MAU to the prediction and development of cardiovascular diseases [29,30]. The influence of MetS on arterial stiffness or MAU has clearly been demonstrated [31][32][33]. The novelty of our study is that we combined the study of iAS and MAU, which both reflect vascular organ damage, and found that MetS-related risk factors heterogeneously contributed to phenotypes of vascular damage to different body parts. To reduce the influence of age, which is an essential factor in vascular aging, we chose  to examine a middle-aged population [34]. We used MLRM instead of the standard logistic regression model (SLRM), which requires that MAU and arterial stiffness be considered separately as dependent variables; however, a limitation of the SLRM its the lower efficacy. For instance, when the predictors of MAU were analyzed, the reference category (i.e., no increase in MAU) consisted of individuals who may suffer from iAS; this may have resulted in a confounding bias in the estimation of risk factors' effects on MAU because high MAU and iAS might share similar risk factors. The same principle applied to the analysis of risk factors of arterial stiffness. Furthermore, the MLRM is more sophisticated, allowing the simultaneous estimation of the risk factors' effects on both the presence of and the association between MAU and iAS without bias arising from the nonindependence of the outcomes [35]. Consistant with our hypothesis that iAS and MAU may represent a continuum in some populations with more severe vascular while individuals with less severe vascular disease express only MAU or iAS, high microalbuminuria and arterial stiffness coexistd in a substantial percentage of individuals who exposed to relatively higher degree of MetS, which suggested increased propensity towards worse vascular condition [36].
Previous studies have reported that an increasing number of MetS components has an increasingly negative effect on iAS [37] or MAU [38]. According to MLRM, the overall risk of having MAU alone was lower than that of having iAS alone with regard to the effect of metabolic disturbances, regardless of the number of MetS components or the presence of MetS. When analyzing individual components, we found that elevated BP was the main distinguishing factor, contributing to a much higher risk of arterial stiffness alone. The ORs for the risk of elevated BP associated with baPWV in a Chinese population were between 5.4 (OR for males) and 12.6 (OR for females) [39]. The risks of having high baPWV with or without MAU in our results were within or below this range and more accurately revealed the different associations between blood pressure and arterial stiffness in the presence of confounding factors. Our research revealed that abdominal obesity was not associated with baPWV alone. Studies have reported a negative association between obesity and vascular stiffness in young people [40,41], but a positive association was reported in older adults and the elderly [42]. The physiological mechanisms linking body fat with arterial stiffness are not fully understood; however, we speculated that with increases in age, body fat becomes increasingly more positively associated with PWV [43], and middle age is a turning point. Mechanism of MetS-related arterial stiffness and microalbuminuria elevation involves oxidative, nitrosative stress [44,45], and inflammation [46], for example, via these products, hyperglycemia increases endothelial [47] and glomerular filtration barrier permeability [48], and accelerates arterial stiffness [49],    inversely, antioxidant effects of HDL-c contributes to the vascular protection [50]. Previous studies examined the clusters of altered MetS components associated with the burden of large arteries [12,51], while the current study reported the simultaneous impact of specific MetS clusters on the heterogeneity of phenotypes of macro-and microvascular abnormalities. The clusters identified as the three most significant determinants of stiff arteries alone and comorbid stiff arteries and microalbuminuria were similar but differed from the determinants of microalbuminuria alone. Moreover, containing B and G was necessary for the clusters to positively impact iAS and MAU, respectively. In light of this disparity, it was possible for us to predict macro-or microvascular complications according to the different predictive powers of specific MetS clusters and to provide specific follow up for patients who are susceptible to these predicted vascular diseases.
The first limitation of our study was that we report analysis from cross-sectional data only. Therefore, we cannot conclude about the role of MetS-related risk factors as potential predictiors of future events (nor was this a goal of the present study). Secondly, baPWV has been criticized to span a more heterogeneous arterial tree than carotidfemoral pulse wave velocity (cfPWV), thus subsumes greater heterogeneity, cfPWV has been more accurate and reliable [52,53], however, as the target arteries may be somewhat difficult to be perceived by probes, the utilization of this cfPWV is lower than baPWV [53]. Since there was a strong positive association between cfPWV and baPWV [54], we assume that the result is also reliable.
This observational study suggested that MetS itself, the number of positive MetS components, individual MetS components, and the clusters of MetS components showed different patterns of associations with MAU or iAS. According to this study, we present the specifically protective pathway of vascular complication, for example, microvascular impairment rather than macrovascular stiffness should be more closely monitored in people with combination of elevated WC, TG, blood pressure. In summary, these heterogeneous influences of MetS-related risk factors suggest possible preventive intervention: identifying, assessing, and following up more selectively individuals with specific metabolic disturbance may facilitate effective prevention of types of vascular injuries.

Conclusion
Heterogeneous association exist between MetS and cross-combination of MAU/iAS, based on these heterogeneous influences of MetS-related risk factors on MAU and iAS, identifying different types of vascular injuries could be selectively targeted.

Availability of data and materials
The raw data is available from the corresponding author upon reasonable request.
Authors' contributions HC made substantial contributions to conception and design. RM was involved in drafting the manuscript and revising it critically for important intellectual content, LW was involved in drafting the manuscript and revision. PN analysised and interpretated the data. YZ contributed in acquisition of data. All authors read and approved the final manuscript. W: increased waist circumference, T: increased triglycerides, B: increased blood pressure, G: increased fasting blood glucose, H: decreased HDL-c. *P < 0.05, **P < 0.01