Abstract

Introduction

The definition and diagnostic criteria for metabolic syndrome (Met-S) in Japan were established in April 2005 (Nippon Naikagakkai, 2005). Japanese criteria are based on the following inclusion criteria: (a) Waist circumference 85cm for men and 90cm for women are essential conditions, plus two or more of the following three criteria: (b) Fasting blood glucose 110mg/dL or taking diabetes medication; (c) Triglyceride 150mg/dL mmol/L or HDL-C<40mg/dL or taking lipid-lowering medication: and (d) Systolic blood pressure 130mmHg or Diastolic blood pressure 85mmHg or taking hypertension drugs (Nippon Naikagakkai, 2005).

It is now well-known that the presence of Met-S is associated with increased coronary artery disease (CAD) events and cardiovascular mortality (Gui et al., 2017; Mottillo et al., 2010; Ninomiya et al., 2007). Met-S is also reported to be a predictor of subclinical atherosclerosis. Also, the purpose of diagnosis and intervention for Met-S is not only early detection of subclinical atherosclerosis but also the prevention of development of type 2 diabetes mellitus. Patients with diabetes mellitus are at increased risk for CAD (Singh et al., 2013; Turner et al., 1998). Therefore, if patients with Met-S develop type 2 diabetes mellitus, their risk for CAD may further increase. Indeed, our previous observation revealed that the metabolic syndrome subjects with type 2 diabetes mellitus, are at a further elevated risk for CAD than the non-metabolic syndrome subjects with type 2 diabetes mellitus (Nakano et al., 2010).

Small, dense LDL cholesterol (sLDL-C) has been demonstrated to be a residual risk factor for the development of CAD in Western countries as well as in Japan (Duran et al., 2020; Koba et al., 2002). LDL size is usually measured by gradient gel electrophoresis using polyacrylamide gel (Krauss & Burke, 1982). This standard assay procedure requires long assay time and high cost. Meanwhile, Hirano et al. developed a simple and rapid assay system for the measurement of concentration of sLDL-C using heparin-magnesium precipitation and direct LDL assay (Hirano et al., 2003).

On the other hand, aging itself is known as one of the important risk factors for CAD. Our previous observation revealed that older diabetic subjects had increased sLDL-C even if their LDL-cholesterol is not elevated (Yoshino et al., 2015). Also, we have reported that the Met-S subjects with type 2 diabetes mellitus, are at a further elevated risk for CAD compared to non-metabolic syndrome subjects with type 2 diabetes mellitus (Nakano et al., 2010).

Using data, we continued to explore whether the CAD risk of the older patients with Met-S who develop type 2 diabetes mellitus increases more than that of older type 2 diabetic subjects without Met-S estimating plasma high sensitivity C-reactive protein (hs-CRP), sLDL-C, and plaque score of the carotid artery (PS).

Methods

Results

Clinical characteristics of middle-aged and older subjects are shown in Table 1. The average age of middle-aged and older subjects were 49.5±10.8years and 71.5±5.9years, respectively. The number of type 2 diabetes mellitus were also 88 and 47 respectively. There were significant differences in age, BMI, HbA1c, TG, and PS between the two groups (Table 1). Simple regression analysis in middle-aged subjects revealed that the determinant of PS were age, gender, BMI, DM, Met-S, and hs-CRP (Table 2a). Multiple regression analysis in middle-aged subjects showed that the determinant of PS were age, BMI, Met-S, and hs-CRP (Table 3a). On the other hand, Simple regression analysis in older subjects revealed that the determinant of PS were DM, hs-CPR, and sLDL-C (Table 2b). Multiple regression analysis in older subjects showed that neither age nor Met-S was included as significant determinant of PS. On the other hand, hs- CRP, and s LDL-C were significant determinants of PS (Table 3b).

Table 1.

Characteristics of Subjects.

	Middle-aged n=122	Older n=65
Age (year)	49.5±10.8*	71.5±5.9*
Gender (M/F)	85/37	37/28
BMI	27.6±5.9*	23.4±3.4*
DM (n)	88 (72.1%)	47 (72.3%)
HT (n)	56 (45.9%)	35 (53.8%)
DL (n)	82 (67.2%)	51 (78.5%)
Met-S (n)	63 (51.6%)	32 (49.2%)
HbA1c (%)	7.1±2.0**(n=106)	6.4±1.1**(n=62)
LDL-C (mg/dl)	137.6±35.4	130.8±38.9
TG (mg/dl)	175.5±151.8***	133.1±73.2***
HDL-C (mg/dl)	49.8±13.1	52.3±14.2
sLDL-C (mg/dl)	47.9±22.4	47.6±24.8
hs CRP(mg/dl)	0.14±0.11	0.17±0.10
PS	4.47±5.1*	8.25±5.6*

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BMI: Body mass index, DM: Diabetes Mellitus, HT: Hypertension, DL: Dyslipidemia.

Met-S: Metabolic syndrome, LDL-C: fasting low-density lipoprotein cholesterol, TG: fasting triglyceride, HDL-C: fasting high-density lipoprotein cholesterol, sLDL-C: small, dense cholesterol, hs CRP: high sensitivity C-reactive protein, PS: plaque score.

Data are expressed as mean±SD *,**,***:significantly different between the groups.

^*p<.001. ** p<.01. ***p<.05.

Discussion

Visceral fat accumulation has been recognized as an important risk factor for CAD (Kim et al., 2004; Matsuzawa et al., 1999) since Fujioka et al. reported the contribution of intra−abdominal fat accumulation (visceral obesity) to the glucose and lipid metabolism in human obesity (Fujioka et al., 1987). Met-S is a clinical entity characterized by visceral obesity, hypertension, hypertriglyceridemia, low HDL-cholesterol, and glucose intolerance, although there are some incompatibilities of diagnostic criteria among countries. In Japan, the definition of and diagnostic criteria for Met-S were established in April, 2005, in which an association of increased waist circumference was emphasized as the most important component reflecting increased intra−abdominal fat accumulation (Nippon Naikagakkai, 2005). The presence of Met-S is associated with increased CAD events, cardiovascular mortality(Gui et al., 2017; Mottillo et al., 2010; Ninomiya et al., 2007). Met-S is also reported to be predictive of subclinical atherosclerosis (Hulthe et al., 2000). Since a component of Met-S involves glucose intolerance, it is obvious that the patients with Met-S without any clinical intervention may finally develop type 2 diabetes mellitus. Thus, the purpose of diagnosis and intervention for Met-S is not only early detection of subclinical atherosclerosis but also the prevention of developing type 2 diabetes mellitus. It is well-known that patients with diabetes mellitus are at increased risk for CAD (Singh et al., 2013; Turner et al., 1998). Therefore, if patients with metabolic syndrome develop type 2 diabetes mellitus, their risk for CAD will further increase. Indeed, our previous observation revealed that the patients with type 2 diabetes mellitus and metabolic syndrome had higher s LDL-C and hs-CRP than patients with type 2 diabetes without metabolic syndrome (Nakano et al., 2010). Furthermore, presence of Met-S is often associated with increased sLDL-C (Sugino et al., 2011).

Recent research into the inflammatory nature of atherosclerosis suggests that inflammatory-response proteins may serve as potential predictors of clinical events. In particular, one of the inflammatory-response proteins, hs-CRP, has been the focus of much attention. Epidemiological data have shown an independent association between hs-CRP elevation and coronary risk (Iso et al., 2009; Li et al., 2017). Recently, several investigators found that human atherosclerotic lesions, coronary artery smooth muscle cells, aortic endothelial cells, and adipocytes express CRP (Calabró et al., 2003; Calabro et al., 2005; Yasojima et al., 2001). Therefore, persistent production of small amounts of CRP by atherosclerotic lesions and coronary artery smooth muscle cells may lead to slight but chronic CRP elevation. Thus, the hs-CRP assay is now useful and popular for predicting CAD risk (Piepoli et al., 2016)

Aging itself is known as the most important risk factor for CAD. Therefore, it has been a matter of debate whether the CAD risk of elderly patients with Met-S more than non-Met-S elderly subjects. According to Vinluan CM et al, the modified WHO definition of Met-S was associated with increased risk for cerebrovascular events in over 65years old subjects (Vinluan et al., 2012). On the other hand, according to Sakurai et al, Met-s of Japanese criteria did not always appear to be associated with cardiovascular disease (Sakurai et al., 2010) . In the present study, PS of older subjects was significantly higher than middle-aged subjects. In multiple regression analysis, determinant of PS were age, BMI, Met-S and hs-CRP in middle-aged subjects. On the other hand, in spite of correlation with hs- CRP and sLDL-C, age, and Met-S were not included as significant determinants of PS in older subjects. Furthermore, not only Met-S but also DM was not affected PS in older subjects.

There are two reasons that we speculated. First, frequency of dyslipidemia in middle-aged subjects were smaller than older subjects. Therefore, sLDL-C was not an explanatory variable in middle-aged subjects. Second, BMI in older subjects was lower than middle-aged subjects. Hence, Met-S could not be an explanatory variable for PS older subjects.

There were two study limitations. First, eating habit of subjects were not monitored in the present study. Second, the present study was only a cross-sectional. Therefore, a randomized control trial may be essential for determining whether intervention is obligatory for the prevention of subclinical atherosclerosis within older type 2 diabetes mellitus subjects with metabolic syndrome.

In conclusion, Met-S is an important factor for progression of subclinical atherosclerosis, but it can no longer be a significant determinant of PS if the subjects are limited within an older group. An association of hs CRP and sLDL-C may be a more powerful determinant of PS of older people than the presence of metabolic syndrome; therefore, it can be a matter of debate whether an aggressive intervention for Met-S still must be obligatory for older subjects from the standpoint of progression of subclinical atherosclerosis.

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