Prevalence of Early Ischemic Heart Disease and Its Associations with Risk Factors and Socioeconomic Variables in the 25–44-year Age Group in Western Siberia

The aim of this study was to investigate the prevalence of early ischemic heart disease (IHD) in accordance with standardized epidemiological criteria in the 25–44-year age group in Novosibirsk (Russia) and to identify associations with some risk factors and socioeconomic factors. Materials and methods. A cross-sectional populational medical examination was conducted on a random sample of the 25–44-year age group in Novosibirsk. A total of 1457 people were analyzed (653 males and 804 females). Epidemiological IHD diagnosis was made according to validated epidemiological (cardiological Rose questionnaire) and functional criteria (recording of an ECG interpreted via the Minnesota Code). The “denite IHD” diagnosis was made in the presence of the following criteria: a history of large-focal myocardial infarction (ECG), tension angina pectoris (Rose questionnaire), ischemic changes on ECG without left ventricular hypertrophy (ECG). Further, the diagnosis of "denite IHD" was conrmed by conducting an ECG test with physical activity. The evaluated IHD modiable risk factors were cigarette smoking, elevated body mass index, elevated waist circumference, the presence of arterial hypertension, low physical activity, and elevated blood levels of low-density lipoprotein cholesterol, non– high-density lipoprotein cholesterol, and triglycerides. Socioeconomic factors were assessed too: marital status, occupation type, education, health self-rating, and economic status. Results. The prevalence of denite IHD in the study population was found to be 3.36% (49 subjects): 2.8% (18 subjects) among males and 3.9% (31 subjects) among females. All quantitative data on IHD risk factors were higher in males than in females. The prevalence of IHD risk factors (except for elevated waist circumference) was higher among males than females. The prevalence of IHD risk factors (except for cigarette smoking) was not different between IHD and no-IHD groups in the study population. Smoker prevalence was 1.66-fold higher (p = 0.031) in the no-IHD group than in the


Introduction
According to data from the World Health Organization (WHO), ischemic heart disease (IHD) continues to be the leading cause of morbidity and mortality in industrially developed and developing countries and is responsible for ~ of all deaths among people older than 35 years [1,2].
The IHD is considered early or premature if it develops before age 55 years in males and before age 65 in females [3]. Other terminology may be used in various studies (IHD at a young age, IHD at a very young age, or premature development of IHD), whereas the age limit of the study population varies from 35 to 65 years, thus complicating comparisons of the ndings [4][5][6][7].
In recent years, IHD prevalence among the young has been increasing, and this is an important socioeconomic problem because of early disability and early deaths. Patients presenting with IHD at a younger age differ from elderly IHD patients in the structure of risk factors (RFs), clinical manifestations, and in the prognosis. Virtually all young patients with IHD have at least one traditional RF of this disease [8,9].
The present study was aimed at investigating the prevalence of IHD according to standardized epidemiological criteria in the age group of 25-44-year-oldsin Novosibirsk and at identifying associations of IHD with some of its RFs.

Ethics approval and consent to participate
The study protocol was approved by the local Ethics Committee of the Institute of Internal and Preventive Medicine (a branch of the Institute of Cytology and Genetics, the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia). All methods were performed in accordance with the relevant guidelines and regulations. Written informed consent to the medical examination and analysis of personal data was obtained from each patient.

Selection and Description of Participants
During 2014-2015, a cross-sectional populational medical examination was conducted on a random sample of people from a typical borough of Novosibirsk, which is a capital of Western Siberia. To compile the population sample, we used a database of the Novosibirsk Territorial Fund of mandatory health insurance, from which (by means of a random number generator) 2500 subjects of both sexes aged 25-44 years were selected. It is known that young age groups are among the least responsive to invitations to a medical examination; therefore, methods of gradual epidemiological stimulation were employed: postal invitations, telephone calls, and announcements in mass media. The response rate was 58.3%. At our Screening Center, 1457 people underwent the medical examination: 653 males (45%) and 804 females (55%). All the participates provided informed consent to the medical examination and analysis of personal data. The screening was carried out by a team of physicians, who had been trained in standardized epidemiological methods of medical-examination-based screenings.
The medical-examination program included collection of demographic and social data, questions about cigarette-smoking and alcohol-drinking habits, a socioeconomic questionnaire, nutritional survey, collection of chronic-disease and medication history, the cardiological Rose questionnaire, anthropometric-data collection, three-time measurement of arterial blood pressure (BP), spirometry, ECG recording with interpretation in accordance with the Minnesota Code (MC), and assessment of other parameters.
The BP measurement was performed thrice with a 2 min interval on the right arm in a sitting position after a 5 min rest by means of a digital BP monitor, and the average of the three measurements was recorded. The body mass index (BMI) was determined via the following formula: body weight (kg) divided by the height squared (m 2 ). Participants were assumed to be smokers if they smoked at least one cigarette a day.
One-time blood collection from the medial cubital vein was carried out in the morning after a 12 h fast.
Indicators of lipid metabolism were measured by the enzymatic method using standard reagents from TermoFisher on a KoneLab 30i automatic biochemical analyzer (Finland).
The following socioeconomic factors were evaluated: marital status (married, single, divorced, or widowed), the occupation type (sedentary job, standing work, manual labor, or heavy manual labor), education level (grammar school, a high school diploma, or a college degree), health self-rating (good, fair, or bad), and economic status (employed, student, or unemployed).
The epidemiological diagnosis of IHD was made via validated epidemiological (using the Rose questionnaire) and functional criteria (ECG recording with interpretation using the MC). The diagnosis of "de nite IHD" was made in the presence of the following criteria: a history of large-focal myocardial infarction (MI) (ECG with MC), tension angina pectoris (Rose questionnaire), ischemic changes on ECG without left ventricular hypertrophy (ECG with MC). Further, the diagnosis of "de nite IHD" was con rmed by conducting an ECG test with physical activity.

Statistics
Statistical analysis was carried out in the SPSS software for Windows (version 17) with evaluation (for each variable) of the mean, median, standard deviation, con dence intervals (CIs), and lower and upper quartiles. The following methods of group comparison were used: the Mann-Whitney U test for a comparison of medians, Wilcoxon's test, one-way ANOVA with Dunnett's test for a multigroup comparison, calculation of the odds ratio (OR) by means of contingency tables, OR calculation in a logistical regression model, the χ 2 test, and t-test. The 95% level of statistical signi cance was assumed.
Among 653males, IHD was detected in 18 subjects (2.8%), and among 804 females, in 31 subjects (3.9%). No signi cant difference in IHD prevalence was found between males and females (р=0.247). No statistically signi cant association of the IHD family history with the presence of early IHD was found (р = 0.229).
As shown in Table 1, there were no signi cant differences in age between the males and females. All quantitative data on the analyzed IHD modi able RFs were higher in males than in females. BMI -body mass index; BP -arterial blood pressure; LDL-C -low-density lipoprotein cholesterol; Mmean; Me -median; non-HDL-C -non-high-density lipoprotein cholesterol; SD -standard deviation; TG -triglyceride; WC -waist circumference As depicted in Table 2, the prevalence of the studied IHD modi able RFs (except for elevated WC) was higher among males than among females. We analyzed quantitative data on the studied RFs depending on the presence of IHD in the study population (25-44-year-olds in Novosibirsk; Table 3). Signi cant differences between the two groups (with and without IHD) were not found. There were no signi cant differences in the quantitative data on the analyzed RFs depending on the presence of IHD either in the male subpopulation or in the female subpopulation. BMI -body mass index; BP -arterial blood pressure; IHD -ischemic heart disease; LDL-C -low-density lipoprotein cholesterol; M -mean; Me -median; non-HDL-C -non-high-density lipoprotein cholesterol; SD -standard deviation; TG -triglyceride; WC -waist circumference As presented in Table 4, in the study population, the prevalence of the studied IHD RFs (except for cigarette smoking) was not different between the subjects with and without IHD. The prevalence of smokers was 1.66-fold higher (p = 0.031) in the group without IHD than in the group with IHD. Having analyzed this result, we found that in the male population (653 subjects), the prevalence of smoking was 1.6-fold higher (without signi cance, р = 0.113) among people without IHD (635 subjects) than among those with IHD (18 subjects), whereas in the female population (773 subjects), the prevalence of smoking was 1.55-fold higher (without signi cance, р = 0.184) among people without IHD (773subjects) than among those with IHD (31subjects). Thus, the prevalence of smokers among males and females with IHD, albeit statistically insigni cantly, was somewhat lower than that in the groups without IHD.  Table 5). This "paradoxical result" can be explained by an above-mentioned nding ( Table 4) that it was the IHD group where the prevalence of smoking was statistically signi cantly lower 1.66-fold relative to the no-IHD group. AH -arterial hypertension; BMI -body mass index; CI -con dence interval; IHD -ischemic heart disease; LDL-C -low-density lipoprotein cholesterol; non-HDL-C -non-high-density lipoprotein cholesterol; OR -odds ratio; RF -risk factor; TG -triglyceride; WC -waist circumference Because none of the analyzed RFs (except for smoking) manifested an evident correlation with the relative risk of IHD, and because cigarette-smoking analysis yielded the "paradoxical" result, next we studied the relation of IHD with socioeconomic factors. The multivariate logistical regression analysis of socioeconomic factors was performed in relation to the risk of de nite IHD in the study population (25-44-year-olds in Novosibirsk) and in its male and female subpopulations. Statistically signi cant results were obtained only in the male population. We noted age-independent correlations of the occupation type and of marital status (which are associated with cigarette smoking: OR = 0.202, CI 0.060-0.672, р=0.009) with the relative risk of de nite IHD among 25-44-year-old males. For instance, among divorced nonsmoking males, the probability of IHD presence was 5-fold higher (OR = 4.976, CI 0.944-26.228, р=0.058), whereas among non-smoking males occupationally engaged in heavy manual labor, it was 3.5-fold higher (OR = 3.495, CI 1.306-9.353, р=0.013).
Therefore, among 25-44-year-old males in Novosibirsk, the relative risk of IHD (namely, early IHD, manifesting itself before 45 years of age) is directly associated with heavy manual labor and unfavorable marital status but inversely correlates with smoking.

Discussion
There is evidence of high prevalence of IHD (according to epidemiological criteria) and its RFs in the population of Novosibirsk, a capital of Western Siberia. In this city, a young population (25-44 years of age) was last analyzed during the WHO project MONICA in the1990s [11][12][13].
Our results were obtained via a medical examination of the 25-44-year-old age group in Novosibirsk during 2014-2015. The results showed that at present, the prevalence of de nite IHD in the study population (3.36%) and in its male (2.8%) and female (3.9%) subpopulations is not high.
It is known that more than half of young adults even at the age of 18-24 years have at least one RF of IHD [14].
We studied quantitative data on IHD RFs and data on the prevalence of IHD RFs, such as smoking, elevated BMI, elevated WC, AH presence, low physical activity, and elevated blood levels of LDL-C, non-HDL-C, and TG sin older subjects: 25-44 years. The prevalence of the aforementioned RFs in the study population ranged from 25-85%. All quantitative data on the analyzed RFs of IHD were higher in males than in females. In addition, the prevalence of the studied IHD RFs turned out to be higher among males than females, except for the "elevated WC" RF (indicating abdominal obesity), whose prevalence was not signi cantly different between males (42%) and females (45%). As for the excess body weight in general, it was found to be 1.3-fold higher among males than among females.
While discussing this result, we should point out that obesity occurs more often among patients with early development of IHD and is an independent predictor of coronary atherosclerosis at a young age, as revealed in some studies. In particular, this pattern was demonstrated in a comparison of the prevalence of RFs among patients hospitalized with acute MI at age younger and older than 50, in a registry containing 1199 patients [15]. The link of obesity with atherosclerosis at a young age was demonstrated in a study on autopsies of 3 000 subjects aged 15-34 years who died of non-cardiological causes [16]. In the Framingham study, it was shown that the contribution of obesity to the development of IHD in middleaged people may be as high as 23% of the cases among males and 15% of the cases among females [17].
In our study population, the prevalence of the analyzed IHD RFs (except for cigarette smoking) was found to be not different between the groups with and without IHD. The prevalence of smokers was 1.7-fold higher in the no-IHD group than in the group with IHD. Our multivariate logistical regression analysis also uncovered an inverse association of smoking (independent of age, sex, and other analyzed RFs) with the relative risk of de nite IHD in the study population (25-44-year-olds in Novosibirsk). We explain this nding, which contradicts known classical data, by the insu cient number of IHD cases (a total of 49 subjects, 18 males and 31 females) in our study.
Indeed, all the data from the international literature point to a rather signi cant role of smoking in IHD development and complications. It is believed that smoking is the most prevalent RF of early IHD. According to Cole J.H. and coworkers, the number of smokers among IHD patients under 45 years ranges from 60%to 90%, whereas among patients older than 45 years, from 24%to 56% [18].
In a meta-analysis including 14 international randomized studies on IHD, among76716 MI patients with ST segment elevation, 35527 patients with unstable angina pectoris/MI without ST segment elevation, and 10215 patients who underwent percutaneous coronary interventions, researchers analyzed the prevalence of 4 RFs (smoking, diabetes mellitus, AH, and hyperlipidemia) depending on sex and age. In the majority of younger patients, at least one RF was noted, with the most frequent one being smoking: 72% frequency among subjects younger than 45 years, both in males and in females [8].
In a study on a registry intended for observation of 892 patients with acute MI with ST segment elevation who underwent their rst percutaneous coronary intervention, there were 78% of smokers among the patients aged 18 to 34 years, and 23% of smokers in the whole study population; the percentage of smokers decreased with the increasing age at MI diagnosis [19].
Kafadar D. and colleagues have examined 235 patients with coronary-angiography-veri ed coronary atherosclerosis. Active smokers showed the highest mean levels of TGs in the blood, whereas nonsmokers were reported to have the highest mean HDL-C concentrations [20].
Christus T. and coworkers have examined 200 males younger than 35 years with IHD diagnosed by coronary angiography and concluded that the main RFin this population is cigarette smoking [5].
As compared with the total number of publications about the adverse impact of cigarette smoking on the development of CVDs in the world literature, there are only a few papers where the results defy the traditional ndings, for example, the study by Li G. and colleagues [21]. They examined a Chinese population aged 20-80 years (1248 subjects) and concluded that sex-and age-adjusted BP is lower in smokers than in nonsmokers or former smokers. There was no signi cant dose-dependent in uence of smoking on sex-and age-adjusted BP. Furthermore, smoking cessation was signi cantly associated with a higher risk of hypertension.
Because none of the RFs analyzed by us, except for smoking, manifested an apparent association with the relative risk of IHD, and because the cigarette smoking analysis yielded the "paradoxical" result, we then investigated the link of IHD with socioeconomic factors whose in uence on IHD development has been actively discussed in the last decades [22].
We performed a multivariate logistical regression analysis of the socioeconomic factors in relation to the risk of de nite IHD in our study population (25-44-year-olds in Novosibirsk) and in its male and female subpopulations. Statistically signi cant results were obtained only in the male subpopulation. We identi ed age-independent associations of the occupation type and marital status (which correlated with smoking), with the relative risk of early IHD in males aged 25-44 years. It was found that among divorced males aged 25-44 years, the probability of the presence of early IHD is 5-fold higher, whereas among males occupationally engaged in heavy manual labor, it is 3.5-fold higher.
Our results are consistent with data from other studies. For example, the in uence of marital status on the frequency of CVDs and prognosis after CVD was assessed in a meta-analysis of 34 studies involving more than 2 million participants. In comparison with married participants, the absence of marriage (never married, divorced, or widowed) correlated with a higher risk of CVDs, IHD, death from IHD, and death from stroke. Divorce was associated with a higher risk of IHD both in males and in females [23].
Leisure time physical activity is a widely recognized protective factor against cardiovascular mortality.
Participants of a prospective epidemiological study on MI (PRIME; n = 9758; age 50 to 59 years), who did not have IHD at the beginning of the study, were observed for 5 years: the researchers registered 167 cases of severe IHD and 154 cases of tension angina pectoris. A bene cial effect of leisure time physical activity was noted among the subjects who did not report high-intensity activity, in France and Northern Ireland. By contrast, increasing the level of leisure time physical activity was associated with a higher risk of tension angina pectoris in both countries [24].
In the CORDIS study, investigators analyzed the in uence of leisure time physical activity and of heavy physical activity associated with one's job (occupational heavy manual labor) on cardiovascular mortality among males (4819 subjects) during 22-year prospective observation. It was occupational heavy manual labor that posed the highest risk of death, including IHD-related mortality. Those authors concluded that heavy manual labor at one's job is bad for health [25].
Thus, our data suggest that among 25-44-year-old males in Novosibirsk, the relative risk of IHD (namely, early IHD, manifesting itself before 45 years of age) directly correlates with occupational heavy manual labor and unfavorable marital status but is inversely associated with smoking. In our opinion, these results undoubtedly require further research.

Conclusion
Early detection of IHD, especially early IHD, presenting before 45 years of age, is highly important for programs on secondary prevention of IHD. Nevertheless, earlier detection of IHD RFs is even more important for programs on the primary prevention of this disease. In a young population at 25-44 years of age, owing to the high employment rate at this age, there is insu cient self-rating of health and not enough effort aimed at the risk assessment and prevention of IHD. Consequently, it is crucial to motivate the young population to undergo timely screening (medical exam) to prevent CVDs and their RFs, i.e., mostly conventional RFs, such as the social ones.

Consent for publication
All the authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given nal approval to the version to be published.

Availability of data and material
The datasets before and after analysis in this study are available from the corresponding author on reasonable request.

Funding
The medical-examination-based screening was performed within the framework of a government-funded research topic in State Assignment No. АААА-А17-117112850280-2. The biochemical and functional analyses were nancially supported by a Russian Federation President grant for leading scienti c schools, No. НШ-2595.2020.7.