Association of Ideal Cardiovascular Health with Carotid Intima-Media thickness (cIMT) in a Young Adult Population: Tehran Lipid and Glucose Study (TLGS)


 Ideal cardiovascular health (CVH) is associated with a lower risk of developing cardiovascular diseases. This study aims to investigate the association of CVH metrics with carotid intima-media thickness (cIMT) as a marker of subclinical atherosclerosis in young adults. A cross-sectional study was performed on 1295 adults, average age of 29.7 ± 4.0 years, selected among the participants of the Tehran Lipid and Glucose Study (TLGS). The participants were divided into two CVH groups: Ideal CVH and poor/intermediate CVH. Multivariate-adjusted linear regression was used to determine the association of ideal CVH score with cIMT. Multivariate-adjusted odd ratios (ORs) were calculated for high cIMT (≥95%percentile). Also, the independent effects of each ideal CVH metric on cIMT were analyzed. The prevalence of ideal CVH was 9.3% in the studied population, and the mean of cIMT was 0.55±0.09 mm. A 1-point increase in CVH score was associated with a decrease of 0.128 mm (Beta [SE] = -0.128 [0. 002], p<0.001) in cIMT and rendered an odd ratio of 0.68 (OR = 0.68 [95% CI: 0.56-0.82], p<0.001) for having a high CIMT (≥95%percentile). Each ideal glucose, ideal blood pressure and ideal body mass index (BMI) had a significant inverse association with cIMT. There was a graded inverse association between ideal CVH score and cIMT among young adults, indicating that ideal CVH metrics are associated with better vascular health in this population. The low prevalence of ideal CVH highlighted the importance of implementing health promotion strategies.


Introduction
Cardiovascular diseases (CVD) are the leading causes of global mortality, with approximately 17.8 million deaths being reported due to diseases like coronary heart disease and stroke in just 2017 (1). More than three-quarters of CVD-related deaths occur in low-and middle-income countries (2). The American Heart Association presented the concept of ideal cardiovascular health (CVH) in 2010, intending to decrease CVD mortality by 20% in the following decade (3,4). Cardiovascular health metrics include seven items, of which four are related to health behaviors (i.e., smoking status, body mass index, physical activity, and diet), and the other three are important health indicators (i.e., total cholesterol, blood pressure, and fasting blood glucose). According to studies, achieving an ideal CVH status is associated with lower CVD-related mortality and morbidity and better cardiovascular outcomes (5)(6)(7).
Subclinical atherosclerosis is an important predictor of CVD beyond traditional risk factors (8,9). Carotid intima-media thickness (cIMT) is a common ultrasound-based measurement of arterial wall thickness used to evaluate atherosclerosis (10). This parameter has been shown to predict the risk of atherosclerotic plaque formation and CVD development in the future (11,12). Numerous epidemiological studies have shown an association between ideal CVH and a reduction in the risk of subclinical cardiovascular diseases characterized by changes in cIMT (6, [13][14][15][16]. Previously, evaluating the seven CVH metrics in Iranian men and women in the Tehran Lipid and Glucose Study (TLGS) indicated a low prevalence of ideal CVH in the adult population (17). Therefore, it is important to investigate a potential relationship between CVH metrics and the incidence of subclinical atherosclerosis to prevent cardiovascular events. Moreover, to our knowledge, there is no study in the Middle East and North Africa (MENA) region to assess the relationship between CVH metrics and cIMT.
This population-based study aimed to assess the association of the ideal CVH score and each of the seven CVH metrics, with the risk of developing subclinical atherosclerosis, de ned by increased cIMT, among Iranian young adults in the framework of the TLGS.

Study Participants and Design
In this cross-sectional study, we used the data available from the TLGS, a cohort study initiated in 1998, to identify the risk factors of non-communicable diseases in Tehran urban populations. The details of this population-based study have been reported elsewhere (18). In the present study, we used the data collected in phase VI (2015-2018) of the TLGS. Among the subjects aged 20-40 years old and had already undergone routine evaluations in phase VI (n = 2641), a number of the participants were recruited for cIMT measurement (n=1455). After excluding those with a BMI < 20 kg/m 2 at baseline (n=77), the subjects using corticosteroids (n=38), pregnant women (n=13), those with a history of malignancies (n=4), and individuals with distorted cIMT measurement (n=5), a total number of 1295 participants were recruited for the current study ( Figure 1).

Measurements And De nitions
Trained interviewers used standard questionnaires to obtain demographic data, smoking status, dietary intake, physical activity, medical history, and drug consumption history. Also, trained personnel performed anthropometric examinations. A digital electronic weighing scale (range: 0·1-150 kg, Seca 707, Hanover, MD, USA) was used to measure weight that was recorded to the nearest of 100 g with the participants being shoeless and minimally clothed. A tape meter was used to measure height in the standing position, and BMI was calculated as weight (in Kg) divided by height (in squared meters) (kg/m 2 ). Duplicate measurements (15-minute apart) of systolic and diastolic blood pressure were done by a quali ed physician using a standard mercury sphygmomanometer applied on the seated participant's right arm. The mean of the two measurements was calculated and regarded as the subject's blood pressure. Venous blood samples were taken after overnight fasting of 12-14 h, centrifuged within 30-45 min of collection, and nally analyzed at the TLGS research laboratory. Details of measuring serum biochemistry parameters, FPG, and lipids have been reported elsewhere (18).

Determining Cimt
The participants underwent ultrasound examination using a linear 7.5-10 MHz transducer (Samsung Medison SonoAceR3 Ultrasound, South Korea). Two radiologists performed the examinations in the supine position with the neck extended and slightly rotated to the opposite side of the examination. The initial carotid scan was performed in the transverse plane throughout the artery to evaluate its anatomy, locate any atherosclerotic plaque, and determine the site of maximal wall-thickening. Measurements were done in plaque-free arterial segments ful lling the optimal B-mode imaging criteria described below. A clear vision of the far arterial wall interface with a completely anechoic luminal content was considered to be an optimal greyscale carotid artery image and was saved for cIMT measurement. The IMT was de ned as a hypoechoic band between the arterial wall's echogenic intimal and adventitial surfaces. The distance between the leading edge of the rst and second echogenic lines of the far walls of the distal segment of the common carotid artery on both sides was measured at three locations, and the average was regarded as the nal measurement of that side. Left common carotid artery (LCCA) far wall measurements were used for de ning high cIMT. The degree of CIMT measures agreement between the two radiologists was evaluated by using an interclass correlation coe cient (ICC). ICC estimates and their 95% con dent intervals were calculated using SPSS statistical package version 20 based on 2-way mixed-effects model and reported ICC results as ICC = 0.79 with 95% con dent interval = 0.55-0.90. The ICC is a value between 0 and 1, where values between 0.75 and 0.9 indicates good reliability (19). Moreover, the mean (SD) difference regarding between-rate ICC was 0.08 (0.12).

Determining Cvh Status
The AHA 2020 impact goals (3) were used to de ne cardiovascular health (CVH). Four ideal health behaviors (no smoking within the last year, ideal BMI, ideal physical activity, and an ideal diet) and three ideal health factors (untreated total cholesterol <200 mg/dL, untreated blood pressure <120/80 mm Hg, and untreated glucose <100 mm Hg) were considered to determine the CVH status of each individual. The number of ideal CVH metrics summarized the participants' CVH scores. An ideal CVH status was de ned as having six or seven CVH metrics; intermediate CVH was de ned as having 3-5 metrics, and poor CVH was regarded as having 0-2 of the metrics. To ensure the presence of a su cient number of participants within each group, we categorized them into two groups: those with six or more ideal CVH metrics vs. those with less than six ideal CVH metrics.
A checklist for dietary habits, a qualitative Food Frequency Questionnaire (FFQ), and two 24-hour dietary recall scales was used to assess the dietary status. The validity and reliability of the Persian translated version of FFQ had already been veri ed for evaluating the food intake status of the participants of the TLGS (20). In the present study, after excluding individuals with an extreme energy intake (±3SD), ve AHA's ideal CV health components were used to calculate the participants' dietary scores (≥4.5 cups per day of fruits and vegetables; ≥2 to 3.5 oz serving of sh per week; ≥3 1-oz equivalents serving per day of whole grains; <1500 mg per day sodium; and ≤36 oz per week of sugar-sweetened beverages [≤450 kcal The Modi able Activity Questionnaire (MAQ) was used to assess physical activity. The validity and reliability of the Persian translated version of MAQ had already been con rmed for evaluating the physical activity of TLGS participants (21). According to the minutes of vigorous or moderate physical activity, patients were classi ed into ideal (≥1500 min/week), intermediate (600-1500 min/week), and poor (<600 min/week) groups.

Statistical Analysis
The number of ideal CVH metrics was described for the participants. Normally distributed and skewed continuous variables were illustrated as Mean±SD and median (IQ 25-75), respectively. Categorical variables were reported by the frequency (percentage) statistic. Quantitative variables with normal distribution were analyzed by the independent t-test, and quantitative variables with skewed distribution were analyzed using the Mann-Whitney U test. Qualitative variables were analyzed using the Chi-square test, when appropriate. Multiple linear regression was used to assess the independent effects of the ideal CVH metrics on cIMT, adjusting for age, sex, and each metric separately, and then in a mutually adjusted model for all seven ideal CVH metrics. Odds for having a signi cantly high cIMT (cIMT > 95 percentile) were also estimated using logistic regression models. To handle missing values, the multiple imputations by chained equations (MICE) method was employed. All the analyses were performed in STATA version 12 SE (STATA Inc., TX, USA), considering a two-tailed P value of <0.05 as statistically signi cant.

Results
The study participants (n=1295) aged 29.7±4.0 years old, and 51.7% of them were men. The means of BMI and cIMT were 26.2±4.8 kg/m 2 and 0.55±0.09 mm, respectively. Other characteristics of the studied population have been illustrated in Table 1. Regarding the CVH status, the participants were divided into three distinct groups (Figure 2). The majority of the participants had intermediate CVH (n=1039, 80.2%), followed by poor CVH (n=135, 10.4%), and then ideal CVH (n=121, 9.3%).

Discussion
In this population-based study that was conducted in the framework of the TLGS, the association of the ideal CVH score and each of the seven CVH metrics with cIMT was evaluated. The participants in this study had a mean age of 30 years, and the prevalence of ideal CVH among them was 9.3%. A 1-point increase in the CVH score was associated with a decrease of 0.128 mm in cIMT and decreased the probability of presenting with a high cIMT (>95 percentile) by 32%. Each ideal glucose, ideal blood pressure, and ideal BMI had a signi cant inverse association with cIMT. Also, having ideal blood pressure and ideal BMI factors reduced the chances of developing high cIMT by 69% and 53%, respectively. Cardiovascular health metrics introduced by the AHA in the past decade to predict cardiovascular events consist of seven metrics (3). Based on studies, an ideal CVH status correlates with better cardiovascular outcomes (5,7). The low prevalence of ideal CVH is an important global concern, especially in the middleand low-income countries (22). In our study, the prevalence of ideal CVH in a young adult Iranian population was 9.3%. The prevalence of the ideal CVH status varies among studies, depending on populations' age and gender distribution and geographic variances (23). A systematic review of 88 studies reported that the prevalence of having ve or more ideal CVH metrics was 19.6 % (95% CI: 15.2 % 23.9 %), and a poor CVH status was about twice in the elderly than in the young population (23). Previous studies have reported a low prevalence (0.3-4%) of ≥ 6 ideal CVH metrics in developing countries (5).
Similarly, in the STEPwise study in Iran, although the prevalence of ideal CVH metrics among the population aged 20 to 65 years old reached about 7.2% in 2011, it again decreased to <4% in 2016 (24).
The results of our study supported earlier studies demonstrating an inverse relationship between ideal CVH and cIMT (13)(14)(15)(16). This is important as cIMT is a subclinical marker of atherosclerosis and a factor predisposing people to cardiovascular diseases (5,11). We found that a 1-point increase in the CVH score was associated with a decline of 0.128 mm in cIMT and decreased the probability of presenting with a high cIMT after adjustment for age and sex. Nevertheless, the association of ideal CVH with cIMT did not change after further adjustments for the family history of premature CVD and educational level. The age range of our participants was between 20 and 40 years old. To our knowledge, there is only one crosssectional study on a similar population, in which ve different cohorts of western populations were assessed, reporting that cIMT was 0.006 mm (95% CI: 0.012-0.003 mm) thinner for each additional ideal CVH score (14). Likewise, other studies investigating the association between ideal CVH score and cIMT in adult populations in Spain, USA, and Africa revealed that a 1-point increase in the ideal CVH score was associated with 0.011, 0.04, and 0.005 mm cIMT reduction, respectively (13,15,16). It is important to note that to our knowledge, there is only one longitudinal study conducted in China that evaluates the association between CVH metrics and cIMT. Wang et al. (25) after excluding individuals with elevated cIMT at the baseline, examined the association of CVH metrics with cIMT changes over approximately four years and showed that ideal CVH score were signi cantly and inversely related to the risk of developing subclinical atherosclerosis.
Ideal glucose, ideal blood pressure, and ideal BMI had a signi cant inverse association with cIMT. Similarly, Nonterah et al. (13) demonstrated an inverse association between the same ideal CVH metrics and cIMT in populations from four African countries. On the other hand, Oikonen et al. (14) indicated that the ideal status of each of blood pressure, BMI, cholesterol, and diet was independently and inversely associated with cIMT, whereas physical activity was directly associated with cIMT. According to these ndings, differences in the weight of each of the seven metrics on cIMT should be considered when evaluating the effectiveness of the metrics.
The ndings of this report are subjected to at least two limitations. First, it should be kept in mind that the observed inverse associations between ideal CVH metrics and cIMT were based on cross-sectional data, precluding the analysis of causal associations. The second limitation was that based on a previous study (16), the two groups of CVH were merged into one group due to sample size restrictions. As the main strength, this study is the rst population-based report on the association of CVH metrics with cIMT in a young adult population in the MENA region. Also, various CVH metrics were measured by trained individuals instead of being based on self-reports.
In conclusion, in this population-based study on young adults, the prevalence of ideal CVH was 9.3 %. An inverse graded association was observed between ideal CVH score and cIMT, which also decreased and the probability of presenting a high cIMT by 32%. Moreover, cIMT was signi cantly and inversely associated with each ideal glucose, ideal blood pressure, and ideal BMI. It is suggested that future studies with larger sample sizes; investigating the relationship between ideal CVH metrics and cIMT and other surrogate markers of subclinical atherosclerosis; are needed in the MENA region. It is also necessary to conduct longitudinal studies to evaluate cIMT changes over time and assess its relationship with ideal CVH metrics, considering the weight of each of the seven CVH metrics on cIMT.

Declarations
Ethical approval and consent to participate: Ethical approval for the TLGS study was obtained from the Ethics Committee of the Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences. All the participants provided written informed consent. All the methods were carried out in accordance with relevant guidelines and regulations. Approval for undertaking the current project was also obtained from the Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran (IR.SBMU.MSP.REC.1399.759).
Consent for publication: Not Applicable.
Availability of data and materials: The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Competing interest: The authors declare that they have no nancial or non-nancial competing interests. The ow chart of the study population.

Figure 2
The distribution of study participants into three distinct CVH categories.