Association between metabolic syndrome and left ventricular geometric change including diastolic dysfunction

Abstract Background We investigated the association between individual components of metabolic syndrome (MetS) and left ventricular (LV) geometric changes, including diastolic dysfunction, in a large cohort of healthy individuals. Methods Overall, 148 461 adults who underwent echocardiography during a health‐screening program were enrolled. Geographic characteristics on echocardiography and several markers of LV relaxation function were identified according to individual MetS components. Univariate linear regression analysis and a multivariate regression model adjusted for factors known to influence LV relaxation function were conducted. Results The prevalence of LV diastolic dysfunction (LVDD) was higher in the MetS group than in the non‐MetS group (0.56% vs. 0.27%, p < .001). In univariate and multivariate analyses, E/A ratio, e′ velocity, and left atrial volume index were significantly associated with each component of MetS and covariates (all p ≤ .001). In the age‐ and sex‐adjusted model, MetS was significantly associated with LVDD (odds ratio [95% confidence interval], 1.350 [1.103, 1.652]). However, subjects with more MetS components did not have a significantly higher risk of LVDD. As the analysis was stratified by sex, the multivariate regression model showed that MetS was significantly associated with LVDD only in men (1.3 [1.00, 1.68]) with higher risk in more MetS component (p for trend < .001). In particular, triglyceride (TG) and waist circumference (WC) among MetS components were significantly associated with LVDD in men. Conclusions MetS was associated with the risk of LVDD, especially in men, with a dose‐dependent association between an increasing number of components of MetS and LVDD. TG and WC were independent risk factors for LVDD in men.

To the 158 422 individuals for whom echocardiography and associated data were initially available, we applied the following exclusion criteria: history of malignancy (n = 4674), history of heart surgery (n = 7), history of heart disease (n = 1651), history of coronary disease (n = 1641), and history of stroke (n = 830). Finally, a total of 148 461 participants were eligible for inclusion in our study (102 416 men and 46 045 women; mean age, 40.3 ± 8.8 years). This study was approved by the Institutional Review Board of Kangbuk Samsung Hospital (IRB No: 2020-03-049). As anonymized and deidentified data were used for analysis, the need for informed consent was waived. Data supporting the findings of this study are available from the corresponding author upon request. Height, weight, waist circumference (WC), and body composition were measured by well-trained nurses with participants wearing lightweight gowns. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. The WC was measured in the standing position, at the midpoint between the top of the anterior iliac crest and the lower border of the last palpable rib margin. Blood pressure and heart rate were measured using an automated oscillometric device (53000, Welch Allyn) by trained nurses while participants were in a sitting position with their arm supported at heart level after a 5-min rest. Blood pressure and heart rate were measured three times in a row, and we used the average of the second and third readings for our analysis. The fat mass was measured using a multifrequency bioimpedance analyzer (Inbody 3.0, Inbody 720, Biospace Co.). As a marker of insulin resistance, the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated using equation 14  Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, selfreported history of hypertension, or current use of antihypertensive medications. 15 Diabetes mellitus was defined based on the diagnostic F I G U R E 1 Flowchart summarizing the study population. criteria of the American Diabetes Association, a selfreported history of diabetes, or current use of antidiabetic medications. 16 19 MetS was defined as the presence of any three or more of the following five criteria: (a) WC ≥ 90 cm in men or ≥80 cm in women; (b) TG level ≥ 150 mg/dl or drug treatment; (c) HDL-C < 40 mg/dl in men or <50 mg/dl in women or drug treatment;

| Echocardiographic data
Transthoracic echocardiography with a 4 MHz, sector-type transducer probe (Vivid 7 and E9, General Electric) was performed by a trained sonographer following the guidelines. 6

| Statistical analyses
Categorical variables are expressed as numbers (%) and compared using the χ 2 test. Continuous variables were expressed as mean (standard deviation) or median (interquartile range) according to their distribution. We used Student's t-test or Mann-Whitney test to compare the two groups according to the presence/absence of MetS and LVDD, and analysis of variance (ANOVA) or Kruskal-Wallis tests to compare the four groups according to MetS and LV diastolic dysfunction. Linear regression and stepwise multiple regression analyses were performed to determine the association between diastolic measurement (E/A ratio, e′ velocity, and LA volume index) and potential variables, including clinical parameters, other echocardiographic parameters, and components of MetS. Odds ratios (ORs) and 95% confidence intervals (CIs) for LVDD according to MetS risk were estimated using multivariable logistic regression analysis. In our analyses, we used three models to adjust for confounding factors:

| Baseline characteristics of the study population
In this study, 148 461 participants were included; 69% were male with a mean age of 40.3 ± 8.8 years. The prevalence of MetS was 16.8%. Table 1 shows the clinical, anthropometric, and echocardiographic characteristics of the study population, divided by comparing those with and without MetS. Participants with MetS were older (43.9 ± 9.5 vs. 39.6 ± 8.5 years), more obese (BMI, 27.3 ± 3.2 vs. 23.3 ± 3.4 kg/m 2 ; WC, 93.1 ± 7.7 vs. 81.5 ± 8.5 cm) and more likely to be men (85.1% vs. 65.8%). They were more likely to be current or former smokers, more likely to drink, and less likely to exercise regularly. All metabolic values were significantly higher in the MetS group than in the MetS group. In addition, the proportions of current and former smokers and alcohol consumption were higher in the MetS group, and the proportion of those who exercised regularly was lower. Regarding echocardiographic parameters that reflect the cardiac structure, people with MetS showed statistically significant differences compared to those without MetS. In the MetS group, the ratio of LVDD was higher than in the group without MetS (0.56% vs. 0.27%, p < .001), and in detail, larger LA

| DISCUSSION
In this cross-sectional cohort study, we showed that MetS was associated with LV geometric changes and diastolic dysfunction using The exact pathophysiological mechanisms by which MetS induces the development of LVDD are unknown, but it is generally known that MetS is significantly associated with LVDD in several studies. 9,10,12,21 In two studies of subjects with normal LV function, MetS was associated with diastolic dysfunction regardless of LV hypertrophy, 9,21 and diastolic dysfunction occurred even in the pre-MetS state. 9 A Multi-Ethnic Study of Atherosclerosis study using cardiac MRI for 1582 subjects showed that insulin resistance was associated with diastolic function, but MetS without type 2 DM could also develop diastolic dysfunction. 10 A study of 684 Portuguese people showed a stepwise association between an increasing number of components of MetS and diastolic dysfunction. 12 The mechanism by which the components of MetS induce LVDD is multifactorial and does not induce LVDD via different mechanisms. As a result, MetS is known to be a risk factor in the development of LVDD, but also to develop synergistically through the interaction of each component of MetS. 11 Our results seem to be consistent with those of previous studies but showed some differences. The strength of our study and the distinction from other studies is that, through a large number of participants, MetS increased the risk of LVDD, especially in men, and that WC and TG could play an important role.
Waist circumference (abdominal obesity) is a well-known cause of LVDD among the components of MetS, which can affect multiple metabolic and neurohormonal pathways due to accumulation of adipose tissue, causing abnormalities in the renin-angiotensin system and myocardial oxidative stress. 22 In addition, obesity causes cardiomyocyte apoptosis and cardiac structural remodeling due to an increase in lipotoxicity resulting from an increase in free fatty acid use, which can lead to diastolic dysfunction. [23][24][25] Hyperglycemia causes an increase in oxidative stress by increasing fatty acid metabolism and reducing glucose metabolism, 26 leading to contractile dysfunction, 27 mitochondrial dysfunction, 28 and endothelial dysfunction of cardiomyocytes. 29 As TG levels increase, myocellular lipid accumulation increases, which is known to trigger lipoapoptosis and cause diastolic dysfunction. 30 The combination of TG-rich lipoprotein secretion and clearance impairment leads to abdominal obesity, 31 and changes in TG levels could affect diastolic dysfunction by increasing the risk of diabetes. 32 (Table S2).
A recent study of 57 449 subjects suggested that physical activity may reduce the risk of impaired LV relaxation. 39 Since the limitation of cross-sectional studies is that the effects of differences in morbidity of each disease, changes in the condition of the disease due to drug use, and the causal relationship of exercise to the disease are difficult to elucidate, it is necessary to clarify our results through additional research.

| STUDY LIMITATIONS
The results of this study should be interpreted in the context of several