Despite the identification of traditional cardiovascular risk factors (CVRF) in the early 1960s, and many nontraditional factors in the following decades, atheromatous cardiovascular disease (ACVD) is the leading cause of mortality and disability in most countries, causing one third of deaths.1 Atheromatosis develops insidiously and is usually widespread by the time of symptom's occurrence. Thus, early detection of subclinical atheromatosis is of paramount importance. The most widely used system for cardiovascular risk assessment is the Framingham risk score.2 Nevertheless, there are significant differences with the European population that preclude its direct application to our population.3 Therefore, the use of the European Systematic Coronary Risk Evaluation (SCORE)4 and the Framingham-REGICOR (Registre Gironí del Cor) risk charts are recommended in Spain for stratifying cardiovascular disease risk.5 Based on the 2019 clinical guidelines, patients are classified according to their SCORE as very high risk (SCORE ≥ 10% for 10-year risk of fatal CVD), high risk (≥ 5% and <10%), moderate risk (≥ 1% and <5%), and low risk (< 1%). This stratification has clinical implications. Thus, the treatment goal for low-density lipoprotein cholesterol (LDL-C) in patients at high risk is 70mg/dL (1.8 mmol/L) and 55mg/dL (1.4 mmol/L) in patients at very high risk.4

Multiple clinical studies have analyzed atheromatosis in high-risk cardiovascular populations such as persons with diabetes,6 familiar hypercholesterolemia,7 and chronic kidney disease.8 However, there is a high prevalence of atheromatosis among individuals in the general population.9,10 Indeed, there is a mismatch between the number of traditional risk factors and cardiovascular events, and atheromatosis-related adverse events are frequent even in low-to-moderate cardiovascular risk individuals.11 Therefore, better risk stratification methods are urgently needed.

The association of atheroma plaque with cardiovascular events has been extensively confirmed.12 In addition, multiterritorial evaluation increases its predictive value in cardiovascular mortality.13

Therefore, new longitudinal population-based studies focused on subclinical atheromatosis addressing its prevalence, multiterritorial extent, and progression in low-to-moderate cardiovascular risk individuals could change the paradigm, namely to treat early subclinical disease instead of cardiovascular risk factors.

Based on the aforementioned data, the ILERVAS study was designed as a randomized, interventional, longitudinal clinical trial. The primary objectives were: a) to assess the prevalence, vascular distribution, severity, and progression of subclinical atheromatosis in a middle-aged population with low-to-moderate cardiovascular risk; b) to reveal potential predictor factors of generalized atheromatosis beyond traditional cardiovascular risk factors; c) to identify the prevalence of subclinical diseases with common risk factors such as occult chronic kidney disease, prediabetes, diabetes, respiratory diseases, and metabolic syndrome; and d) to assess the impact of subclinical atheromatosis detection on the incidence of cardiovascular events during a 10-year follow-up period. Here, baseline characteristics of the ILERVAS cohort focused on atheromatosis are shown. Subclinical atheromatosis assessed in 12 territories and plaque area were combined with clinical, anthropometric, lifestyle, and biochemical parameters.

The ILERVAS study is an ongoing randomized, interventional, longitudinal clinical trial with 2 arms: a) intervention group, hereafter called the mobile unit follow-up group, and b) no intervention group, hereafter called the electronic medical record follow-up group, in a low-to-moderate cardiovascular risk population of the province of Lleida, Spain (ClinicalTrials.gov identifier: NCT03228459).

In the mobile unit follow-up group, participants were enrolled between January 2015 and December 2018 from 32 primary basic health areas of the province of Lleida. The inclusion criteria were as follows: women aged 50 to 70 years and men aged 45 to 65 years with at least 1 of the following cardiovascular disease risk factors: hypertension, dyslipidemia, obesity (defined by body mass index [BMI] ≥ 30), smoking, and/or a first-degree relative who developed premature cardiovascular disease (with a threshold at age 55 years for men and 65 years for women). The exclusion criteria consisted of a clinical history of diabetes, chronic kidney disease, cardiovascular disease (angina, myocardial infarction, stroke, peripheral arterial disease, intestinal, or other ischemia), history of arterial surgery, active neoplasia, life expectancy less than 18 months, long-term home care, and/or institutionalized population. Participants will be reevaluated in the mobile unit after 4 years. A follow-up period of 10 years was established to monitor cardiovascular and noncardiovascular morbidity and mortality.

The study population was allocated to the groups by stratified sampling from the primary care electronic clinical history database of the Catalan Health Service (see supplementary data for further details). All patients provided signed informed consent. The protocol was approved by the Ethics Committee of The Catalan Health Service (Ref. CEIC-1410 Hospital Arnau de Vilanova, Lleida, Spain). The study was conducted according to the principles of the Declaration of Helsinki. A detailed description of methods is included in the supplementary data.

The most important findings of the present study are: a) the ILERVAS study identified several previously undiagnosed chronic diseases, such as dyslipidemia, hypertension, diabetes, obesity, and kidney disease in an otherwise healthy general population; b) subclinical atheromatosis was highly prevalent in otherwise healthy middle-aged population, and the most frequent localization was common femoral, followed by carotid bifurcation and internal carotid; c) one third of the participants, classified as low-to-moderate cardiovascular risk, had intermediate atheromatosis (2-3 territories with plaque out of 12), and one fifth had generalized atheromatosis (> 3 territories); and d) total plaque area rises as the number of cardiovascular risk factors increase.

The ILERVAS study is the first study that exhaustively and globally screened atheromatosis, occult chronic kidney disease, diabetes, and prediabetes in a middle-aged asymptomatic population with at least 1 CV risk factor, representative of the general population. The mobile unit travelled across the entire province of Lleida, recruiting participants from all municipalities to obtain a representative sample of the whole population with the inclusion criteria.

Few cohort studies have investigated the prevalence and atheromatosis burden using vascular ultrasound across multiple vascular sites in middle-aged participants without a previous cardiovascular event. On the contrary, similar Spanish studies focused on atheromatosis, such as PESA and AWHS, only recruited employees of the Santander Bank in Madrid (Madrid, Spain) or General Motors automobile assembly plant in Figueruelas (Zaragoza, Aragón, Spain), respectively. Thus, a clear bias on age and even sex can affect the results of those cohorts. Our data showed a 71.4% of prevalence of subclinical atheromatosis in middle-aged population, a higher prevalence compared with the PESA study where 63% of participants showed atheromatosis.9 The higher prevalence of atheromatosis in our study could be due to the fact that our cohort is 12 years older in average, although women are more represented in our cohort (51% ILERVAS study vs 37% PESA study). On the other hand, the AWHS (Aragon Workers’ Health Study), with younger participants, but only men, showed a prevalence of 72%,14 slightly lower than the 79.7% present in our subpopulation of men, probably due to their older age.

Similar to PESA and AWHS14 studies, femoral artery was the most frequent affected vascular site; possibly due to shear stress and disturbed blood flow caused by the formal artery curvature.15 In femoral arteries, the association of atheromatosis with risk factors was stronger than in carotid or coronary arteries.14 Femoral atheroma plaques had similar predictive value for cardiovascular events; and increased plaque burden, with plaques in both carotid and femoral arteries increased the cardiovascular risk further.16 Thus, femoral artery evaluation could improve risk assessment.

Our work also confirmed the lack of correlation between the estimated 10-year cardiovascular risk assessment with clinical data and the actual presence subclinical atheromatosis.9,17,18 Up to 58% of individuals considered being at low risk in the PESA study and 57% in the AWHS study had atheromatosis. By contrast, the ILERVAS cohort showed that 71.4% of our low-to-moderate participants had subclinical atheromatosis. Regarding atheromatosis burden, one third of participants classified as low-to-moderate risk had intermediate atheromatosis (2-3 territories with plaque out of 12), and one fifth had generalized atheromatosis (> 3 territories). Similar results were obtained in the PESA study, where one third of participants with low risk had 2 sites affected. Traditionally, the absence of conventional CVRF was considered a reliable indicator of low atheromatosis risk. However, PESA investigators identified multiterritorial atheromatosis in nearly 30% of participants without CVRF. Therefore, atheromatosis is associated with factors not included in standard risk scales, an aspect that requires further investigation.19

In agreement with previous studies, the ILERVAS study revealed that atheroma plaque area was almost double in men than in women.20,21 The prevalence of atherosclerosis in carotid arteries had been reported to be low in women before menopause, and subsequently becoming similar to men.22 One possible explanation is that women benefit from protective effects of ovarian hormones and men possibly engage in more health-damaging behaviours such as smoking.23 Additionally, a higher area was observed in femoral arteries in both sexs, although plaque presence was more frequent in the femoral arteries in men, but in the carotid arteries in women. Similar results were obtained in the PESA study using 3D vascular ultrasound.21

The prevalence of intracranial stenosis was extremely low when compared with the Barcelona-AsiA study24 (1.72% ILERVAS study vs 8.6% Barcelona-AsiA study). Barcelona-AsiA cohort was an older moderate-to-high cardiovascular risk population from an urban ambient. Similar comparisons with Asian populations also showed a dramatic reduction when comparing elderly urban populations25 to younger rural,26 with prevalence dropping from 24.5% to 4.7%.

The 45.2% of participants showed a high risk of obstructive sleep apnoea (OSA) according to the Berlin questionnaire. This prevalence is higher than the previously reported in general population27–29. This difference could be due to older participants with at least one CVRF. OSA is a frequent sleep disorder associated with poor quality of life, cardiometabolic alterations, and high blood pressure that contributes to the pathogenesis of cardiovascular disease30.

In conclusion, our mobile unit detected several previously undiagnosed chronic diseases, such as dyslipidemia (21.1%), hypertension (15.3%), kidney disease (15.4%), obesity (10.6%), and diabetes (2.3%) in a cohort of middle-aged participants without a previous cardiovascular event. Subclinical atheromatosis was highly prevalent (71.4%) in this cohort, classified as low-to-moderate cardiovascular risk by current algorithms. The most frequent localization of atheroma plaques was common femoral, followed by carotid bifurcation and internal carotid, with one third of the cohort showing intermediate atheromatosis (2-3 territories with atheroma plaque), and one fifth generalized atheromatosis (> 3 territories). Atheroma plaque area was larger in femoral than in carotid arteries, and it increased with the number of CVRF and the number of affected vascular territories. Men showed larger plaques compared with women.

This work was supported by grants from the Diputació de Lleida, Instituto de Salud Carlos III (RETIC RD16/0009/0011) and Ministerio de Ciencia, Innovación y Universidades (IJC2018-037792-I).

None.