Age-dependent effect of metabolic phenotypes on carotid atherosclerotic disease in coronary heart disease patients (CORDIOPREV study)

Aging can be defined as a natural process in which the chances of survival of an organism gradually decline. It is a multifactorial process involving genetic and environmental factors [22, 30]. Aging is associated with an increased risk of suffering age-related diseases such as diabetes, cancer, neurodegenerative diseases or dementia, and is also widely considered as a cardiovascular risk factor [25]. It is common knowledge that body weight tends to increase with age, except in the elderly, while the prevalence of metabolic disease is higher among older individuals, particularly those with obesity [3, 17].

Obesity, defined as abnormal or excessive body fat accumulation, is related to an increased risk of cardiometabolic diseases [21, 31]. Over the past decades, it has increased worldwide as is now considered a pandemic, not only in the middle-aged or pediatric population, but also in the elderly [7, 29]. There is increasing evidence to suggest that not all individuals in obese populations display metabolic disorders and a high cardiovascular risk associated with obesity and, conversely, not all normal-weight individuals are in a favorable metabolic condition [10]. In fact, our current knowledge suggests that it is not obesity itself, but certain clinical or metabolic phenotypes associated with it, which are linked to an increase of the cardiovascular risk [12, 15, 28]. In this context, the so-called metabolically healthy obese phenotype is characterized by increased body fat and a favorable cardiovascular profile (high levels of HDL-cholesterol, normal glucose and triglyceride levels and good insulin sensitivity) [11, 26]. However, normal-weight individuals with metabolic disease show early signs of insulin resistance, hyperinsulinemia, atherogenic dyslipidemia and hypertension, with a high susceptibility to develop diabetes and cardiovascular disease (CVD) [11, 15]. However, to date, it is not known whether the associated cardiovascular risk with metabolic phenotypes could be modified by age.

Taking all the above into account, the aim of the present study was to establish whether age influences the cardiovascular risk associated with metabolic phenotypes (the presence/or absence of obesity and/or metabolic disease), measured by intima-media thickness of both the common carotid arteries (IMT-CC), as marker of carotid atherosclerosis, in a large cohort of coronary heart disease (CHD) patients. The identification of these potential associations would provide evidence to allow the use of more intensive medical interventions and prevention strategies aimed at reducing CVD risk and delay an age-related decline in health.

This study provides new findings about risk factors for carotid atherosclerosis associated with metabolic status and obesity, defined by metabolic phenotypes, and its relationship with age in patients with CHD. Our data highlights the age-dependency of this association and suggests that the relative importance of metabolic parameters and obesity differ in patients below and over 60 years old. Therefore, in patients aged< 60 years, there is an increased risk of carotid atherosclerosis among the MSO, MSNO and MHO groups compared to MHNO, where IFG seems to be the most influential metabolic parameter. However, in patients aged≥60 years, those classified as MSO showed the highest risk for the disease, being hypertension, hsCRP and WHTR (a biomarker of fat visceral deposit) [24] the metabolic parameters that more contributed to the risk for carotid atherosclerosis. In the study of predictive and earlier biomarkers for CVD, IMT-CC is considered a surrogate marker that allows the anatomical changes in the arterial wall to be explored and quantified [14, 16] and can be used as an indicator of the presence of carotid atherosclerosis [5, 13]. Among risk factors studied regarding the development of carotid atherosclerotic disease, weight is considered an independent risk factor for CVD and is associated with higher mortality [1]. Obesity, and particularly central obesity, increases the risk of CVD and is associated with diabetes, hypertension and dyslipidemia, as well as other lifestyle risk factors such as physical inactivity and poor diet [20]. In this area, Choi et al. found that older MSNO adults showed a markedly higher risk of all-cause mortality, whereas overweight or obese subjects without metabolic disease had a comparatively lower risk of death [4].

The MHO phenotype has been described as an intermediate stage between a healthy and sick status, producing the same risk of suffering a cardiovascular event as MHNO [2]. Although this has been noted in most published studies, in the present study we observed a higher association with carotid atherosclerosis for the MHO phenotype than for MHNO. However, when we analyzed patients according to age, MHO patients aged< 60 years showed no link to a higher prevalence of carotid atherosclerosis. Moreover, the MSNO and MSO phenotypes showed a higher prevalence than MHNO. Indeed, an increasing prevalence of carotid atherosclerosis can be seen between MHNO and MSO.

Recent data from a 20-year follow up suggest that cumulative incidence rates for CHD, stroke and survival probability in individuals with suboptimal health (≤two metabolic diseases factors) were intermediate between the healthy and unhealthy subgroups, which was not affected by the BMI [8]. In contrast to our results, accordance exists in the whole population and in patients aged< 60 years, but not aged≥60 years, suggesting that, with the progression of age, there may be a loss in metabolic flexibility, where the presence of obesity could trigger, a loss in the capacity for lipogenesis with an increase of visceral fat depots coming from a dysfunctional adipose tissue, transforming the metabolically healthy obese in a phenotype associated with a higher risk for carotid atherosclerosis. In fact, the measure of fat visceral depots, through the WHTR, depicts how those age ≥ 60 years had more than 0.6 which determines a high risk of fat visceral contributing to the development of metabolic inflexibility.

Hamer M et al. reported, in a stability study regarding the healthy obese phenotype, that unstable healthy obese (those who develop unhealthy status at the following 8 years) showed greater increases in central adiposity and impaired glycaemic control with slightly elevated levels of HbA1c [9]. In agreement with this study, in the multiple logistic regression analysis, we found that the impairment of glycaemic control, such as IFG, was associated with the presence of the disease, but only in patients aged<60 years. However, we showed that in those aged≥60 years, the association appeared for hypertension, increased hsCRP and WHTR. Here, therefore, our results showed up the evident different importance of these parameters in the high risk for carotid atherosclerosis observed among the metabolic phenotypes according to age. In a previous study from our group in this population, we demonstrated how certain types of the metabolic phenotypes are less favorable modulating phenotypic flexibility [19]. This fact suggests us that one of the mechanisms behind these effects, described above, could be related to the loss of capacity for lipogenesis with increasing adipose tissue and the gaining weight that occurs in adulthood. In those aged<60, these moderate changes in weight could be mitigated by maintaining these capacities which do not increase the numbers of risk factors. Surprisingly, smoking status (non-smoker, current smoker and ex-smoker) is kept out from all the models. Despite the fact that smoking is considered as an influential variable which is widely described in the literature, we must take into account the characteristics of our population, who are patients with CHD who have suffered a cardiovascular event, of which the percentage of active smokers is extremely low (< 10%) since they have all been previously recommended to give up smoking.

One of the limitations found in our study is that it is cross-sectional, which offers no evidence of causal effects, but instead provides a link between the diseases and the variables studied. On the other hand, this analysis could provide the basis for future approaches in longitudinal studies in order to clarify the influence of metabolic phenotypes in the development of carotid atherosclerosis and CVD measured by IMT-CC. In this context,

it is therefore important to identify the potential risk factors associated to the CVD risk and monitor them in the change from adulthood to old age. According to that, our study is focused on the analysis of this association, by assessing atherosclerotic disease, which is behind and preceding the development of cardiovascular events, so it could provide practitioners with information about their patients to act preventing the event or even mortality. It seems clear that high cardiovascular risk groups, such as MHO and, especially, those age ≥ 60 years, would benefit from risk factor stratification to identify obese individuals who may gain most from modifying specific metabolic parameters, with the subsequent benefits for their metabolic health profile and a reduction in development of cardiometabolic disease.

In conclusion, our results suggest that in CHD patients, there is an age-dependent effect of metabolic phenotypes on carotid atherosclerotic disease. CHD patients aged≥60 years lose their metabolic flexibility compared to patients aged< 60 years. This fact indicates the need to focus on therapeutic strategies in order to modify those parameters related to obesity and metabolic inflexibility in patients with CHD before entering old age.