Cardiac visceral fat and cardiometabolic risk in the elderly| JOURNAL OF GERONTOLOGY AND GERIATRICS

Abstract

Aging is characterized by several changes in body mass composition with loss of muscle mass and increase in
fat mass, particularly visceral fat. Visceral fat is represented mainly by abdominal and cardiac depots and it is
directly related to chronic low-grade inflammation, insulin-resistance and metabolic syndrome. Unfavourable
outcomes as cardiovascular death are also associated with the amount of visceral fat depots. In this scenario,
the cardiac visceral fat seems to play an important role in increasing the cardiometabolic risk. This review aims
to provide a literature revision about the role of cardiac visceral fat on cardiometabolic risk in elderly.

INTRODUCTION

The relationship between body fat and the risk of morbidity and mortality changes with changing age. Indeed, overweight or obese middle-aged adults present with an increased risk of morbidity and mortality, while a body mass index (BMI) included between 25 and 30 kg/m² shows a potential protective effect in aged people ¹. Body fat redistribution associated with age may be the underlying factor of the “obesity paradox”, according to which overweight is associated with an increased risk – but decreased mortality – for cardiovascular disease (CD) ². Several mechanisms have been proposed to explain the protective role of increased body fat and BMI in older people, such as a greater metabolic reserve, a different cytokine profile secerned by fat, a lower activation of the sympathetic nervous system, and a reduced concentration of plasmatic natriuretic peptides ². Aging is associated with progressive changes in body composition characterized by a loss of fat free mass and an increase in fat mass, particularly referred as visceral fat (VF) ³. The increase in VF, a key factor for the development of insulin-resistance, is a hallmark of metabolic syndrome (MetS) ^4-6. MetS is a clinical condition characterized by several abnormalities in lipid and glucose metabolism ⁷. In aged subjects, MetS associates with a higher risk for acute coronary events, myocardial infarction, heart failure, and cardiovascular mortality ⁸. MetS includes several cardiovascular risk factors such as increased fasting glucose, low HDL cholesterol, hypertriglyceridemia and hypertension ⁹. In sight of this, body fat distribution rather than BMI is suggested to be a better predictor factor of morbidity and mortality in older people ¹.

For many years, intra-abdominal fat has been considered the main representative of visceral fat. However, in recent times cardiac visceral fat (CVF) has been shown to play an important role in cardiometabolic risk ¹⁰.

Cardiac visceral fat is closely associated with the body mass index (BMI), since it increases during weight gain, and it decreases after weight loss ¹¹.

This review aims to present the current evidence related to the clinical importance of cardiac visceral fat as marker of metabolic dysfunction and cardiovascular disease risk in old people. Since most studies were not specifically performed on aged patients (and other investigations excluded old subjects, focusing on adults), we will try to summarize the available data in the geriatric population.

THE DIFFERENT DEPOTS OF ADIPOSE TISSUE IN THE HEART

The nomenclature used to differentiate cardiac visceral fat depots is often misleading, with several discrepancies and ambiguities among different Authors ¹². Cardiac visceral fat includes both intra- and extra-pericardial fat. Intra-pericardial fat is represented by depots situated between the myocardium and the visceral pericardium, in direct contact with the surface of myocardium and coronary vessels. This fat layer has been referred as epicardial fat (EF) ¹³ (Fig. 1). Fat depots localized between the visceral and the parietal pericardium, or just external but attached to the parietal pericardium, are named pericardial fat (PF) ¹³. The fat layer surrounding arteries and arterioles is defined as perivascular fat (PVF). Extra-pericardial fat (EPF) (or intrathoracic or paracardial fat) is referred to thoracic adipose tissue external to the parietal pericardium ^13-15. In this review we will refer to this nomenclature.

Another classification of cardiac visceral fat identifies three types of depot: the EF, located within the pericardial sac; the PF, located between the external surface of the parietal pericardium and medial face of mediastinum; the pericoronary fat (PCF), represented by the adipose tissue surrounding the coronary arteries within the visceral epicardium ¹⁶.

EF and PF can be assessed by cardiac CT, MRI and echocardiography. Ultrasonography is a very safe and reliable technique to identify EF and PF. EF is visualized as echo-free space between the myocardium surface and the visceral layer of pericardium, whereas PF appear as a hypoechoic space anterior to the EF and the parietal pericardium ¹⁷.

Particularly, several recent studies have been currently focusing on EF ¹⁸. Nevertheless, in many studies EF and PF are used indifferently ¹⁶. For instance, reports from the Framingham Heart Study did not differentiate between EF and PF, since the biomolecular properties of these two fat depots were supposed to be similar ^{19 20}. Nevertheless, the inappropriate use of EF and PF is misleading and is incorrect according to the main literature ²¹.

On the contrary, studies on the association between extra-pericardial fat and cardiovascular risk are lacking. Chen et al. found an association between EPF and MetS, even though this study is characterized by a reduced number of the sample and a short follow-up time ²².

EPICARDIAL FAT AND CARDIOMETABOLIC RISK

EF origins from the splanchnic-pleural mesoderm associated with the gut, similarly to the mesenteric and omental fat ¹⁴. EF is mainly localized on the right ventricle surface and anterior wall of the left ventricle as well as on atrioventricular grooves and great coronary vessels, reaching the main thickness at the anterior and lateral walls of the right atrium. Normally, about 80% of the heart surface is covered by the epicardial adipose tissue, EF contributing for the 20% to the whole heart mass ¹⁵.

Two-dimensional echocardiography can be used to visualize and measure EF. Parasternal long-axis and short-axis views allow the most accurate measurement of EF thickness overlying the right ventricle. EF thickness ranges from 1 to 23 mm ²³.

EF and myocardium are not divided by muscle fascia, sharing the same microcirculation ²⁴. Taking into account that fat accumulation in the epicardial space is limited - especially in obese individuals - the largest ectopic depots as body weight increases are located in the visceral abdominal area and in the extra-pericardial area ¹⁰.

EF is characterized by a wide individual variability which is dependent on the instrumental methodology but also on different clinical and demographic features such as age, obesity, gender, and ethnicity ²⁵. Indeed, EF tends to increase with age ^{25 26}. No consensus exists about the impact of gender on the EF thickness. The amount of EF increases with the increase of total body fat ²⁷ and seems to be related to male gender and high body mass index (BMI) ²⁶. On the other hand, a recent study showed that in old age EF thickness was greater in women than in men ²⁸.

Based on data from the Framingham study, some Authors described a higher association between EF and female gender, but this observation was not confirmed by other studies ^{20 25 29 30}. Postmenopausal women with MetS showed a greater amount of EF with respect to those without MetS ³¹. Concerning ethnicity, African-American men present with less EF depots than non-Hispanic white men, but these data may be also related to the high frequency of central obesity reported in the first group ^{25 32}.

Patients with Mets present with higher EF thickness compared to patients without Mets, and the presence of MetS is an independent predictor of increased EF ³³. Iacobellis et al. described that values of EF of 9.5 mm in men and 7.5 mm in women may predict accurately the presence of Mets ³⁴. However, this study enrolled subjects aged 40.8 ± 11.5 years old.

Another study showed how in old patients EF, but not intra-abdominal fat, was associated with MetS, while both were closely related with hepatic steatosis ³⁵.

Normally, epicardial adipocytes exert several physiological function for the myocardium at metabolic, thermogenic, mechanic and textural level ³⁶. However, this positive role is lost in particular conditions associated with an augmented amount of EF, such as obesity ³⁷.

EF presents with the most intensive metabolic activity as compared to pericardial and other visceral fat ^{14 24}. In fact, EF produces higher levels of free fatty acids (FFA), with increased release of FFA after catecholamine stimulation; moreover, high lipolysis activity in EF could be associated with lower insulin sensitivity and a larger number of β3-adrenoreceptors ³⁸.

EF is also associated to the pro-inflammatory state, and it is characterized by unique physiological and metabolic profile. Indeed, with respect to visceral fat in other body sites, EF presents with small adipocyte size, characterized by low reduction during weight loss, and several metabolic features such as different fatty acid composition, high protein content and fatty acid synthesis, reduced glucose utilization, and high level of adipokine secretion ²⁶. Moreover, compared to the sub-cutaneous, the epicardial adipose tissue is able to produce higher level of chemokines and inflammatory cytokines such as interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor (TNF-α), interacting with numerous cardiovascular pathways via vasocrine and paracrine signalling ^{39 40}. Increased EF deposits are associated with higher serum level of C-reactive protein (PCR) and low-grade systemic inflammation ³³. These proinflammatory properties are independent of clinical conditions such as the presence of diabetes or obesity ³⁹. Nevertheless, EF may produce anti-inflammatory and antiatherogenic adipokines, but the regulation of this balance is still unknown ²³. Adiponectin and adrenomedullin represent the most important adipokines secerned by EF, particularly in the coronary circulation. Adiponectin plays a role in the modulation of insulin sensitivity, and it exerts anti-inflammatory and antiatherogenic effects, whereas adrenomedullin acts as vasodilator, anti-inflammatory and anti-vasogenic ²³. Moreover, EF presents with the highest percentage of lipogenesis and free fatty acid metabolism as compared to other visceral fat depots ⁴¹.

As previously cited, EF is closely related to MetS as well as its main several components such as endothelial dysfunction, blood pressure, insulin-resistance, high fasting glucose, presence of diabetes or hypertension, high serum levels of LDL-cholesterol and triglycerides, and increased risk of cardiovascular disease ^{23 42 43}. The study by Yorgun et al. demonstrated that EF and pericoronary fat thickness are associated with the presence of MetS ⁵. Particularly, the Authors found that subjects presenting with MetS were older than those without, highlighting a progressive relationship between the growing number of MetS components and EF thickness ⁵. Of note, in this study age was reported as an independent risk factor associated with mean EF thickness ⁵.

With respect to visceral abdominal fat (VAT), EF is also associated with coronary atherosclerosis, probably mediated by paracrine pathways which induce the progression of coronary vessel inflammation and atherosclerosis ^{5 16}. In this context, EF measurement may be useful to evaluate coronary artery disease (CAD) risk and to predict the extent and activity of CAD ^{7 44}.

Another evidence from the Framingham Heart Study identified how fat deposits around the heart are an independent predictor of CVD risk 29. Mahabadi et al. demonstrated the role of EF as an independent predictive factor of future major adverse cardiac events (MACE) beyond traditional cardiovascular risk factors in the general population ^{45 46}. Of note, the statistical models used in this study were all adjusted for age.

Even though cardiac visceral fat has been recently proposed as a new marker of cardiometabolic risk ¹⁰, in a recent observational study on 113 subjects, some Authors did not find any independent association between EF and metabolic components such as blood pressure, plasma triglycerides, and insulin resistance ¹⁰. The evidence of this study suggests how the isolated increase of EF is not necessarily associated with higher metabolic or CV risk ¹⁰. Nevertheless, people enrolled in this investigation were from 18 to 74 years old, but data were not stratified for age classes.

In the last years, several pieces of evidence have been highlighted about the association between EF and hypertension. Cardiac fat has been found expanded in patients with hypertension compared to healthy controls ⁴⁷. Dicker et al. found a higher EF thickness in hypertensive patients rather than patient without hypertension, as well as in hypertensive patients with non-dipper profile ^48-50. Of note, in this study hypertensive patients were older than controls, and EF thickness was associated with age ⁴⁸. A positive correlation was also found between EF thickness and blood pressure among prehypertensive patients (even though no older subjects were enrolled) ^51-53. In untreated adult patients, high values of EF thickness may be independently associated with diastolic dysfunction and atrial dilatation; EF thickness results as a stronger predictive factor than abdominal obesity ⁵⁴.

Data about the relationship between EF and serum triglyceride levels are discordant through studies, showing a large degree of variability. Some studies did not show any association between serum triglycerides and EF thickness, while other Authors highlighted a low degree of correlation ^{5 55-58}. This heterogeneity could be linked to the difference in age, weight and morbidity of the different study populations.

Recently, Calabuig et al. have shown how EF thickness was independently associated with high-density lipoprotein cholesterol and high level of serum triglycerides ⁵⁹. This study also demonstrated that EF thickness increases with age even in subjects without MetS ⁵⁹.

Both EF and extra-pericardial fat are associated with insulin resistance. Particularly, a positive association was found between EF and insulin-resistance or glucose tolerance in patients without diabetes and normal cardiac function ^{11 60}. Insulin resistance, age and blood glucose level after 2 hours of oral tolerance test were found independent predictor factors of high EF thickness in non-diabetic patients ⁶¹. Similarly, Narumi et al. highlighted that increased values of EF thickness were independently associated with IR in non-obese and non-diabetic patients ⁶². Furthermore, patients with morbid obesity showed higher EF thickness values associated with insulin resistance, inappropriate high left ventricular mass, and left ventricular dysfunction ⁶³. In addition, Iacobellis et al. found a significant association between EF thickness and obesity-related insulin resistance ⁶⁴.

Despite the associative results, the exact pathogenesis between EF and insulin resistance is not yet clear ⁶⁵.

Diabetes is an important perturbing factor in the normal homeostasis of glucose metabolism in the heart. In fact, diabetic patients show that peripheral insulin resistance and low insulin stimulated myocardial glucose uptake with a range of reduction up to 40% ¹¹. In a study performed on a geriatric population, diabetic patients showed higher EF thickness compared to non-diabetic subjects ⁶⁶. Recently, Yagi et al. have confirmed that the amount of EF is greater in patients with diabetes, regardless of type 1 or 2 diabetes mellitus and of EF measured method used, suggesting that an augmented EF could be an independent predictor of newly-diagnosed diabetes mellitus ⁶⁷. A strong correlation between fasting plasma glucose and EF measured with echocardiography and CT has also been lately highlighted ⁶⁸.

Recent investigations suggest that EF may represent a more reliable measure of visceral adiposity. In fact, although visceral fat correlates with the waist circumference, this can be modified by numerous factors such as the amount of subcutaneous fat, especially in older people ^{7 18 69}.

EF measured by ultrasonography is associated with anthropometric and clinical parameters of MetS (as body mass index, BMI) so that EF may be a useful index of MetS 5. Echocardiographic measure of EF is more and more often considered as a new parameter to evaluate cardiac and visceral obesity ⁷.

PERICARDIAL FAT AND CARDIOMETABOLIC RISK

Pericardial fat originates from the division of primitive thoracic mesenchyme, which gives rise to the parietal pericardium and the external thoracic wall ²³.

Data from the Framingham Heart Study Offspring and Third Generation showed that, as compared with other ectopic fat depots (including abdominal subcutaneous adipose tissue, abdominal visceral adipose tissue, intramuscular fat, intrathoracic fat, thoracic periaortic fat, intrahepatic fat, and renal sinus fat), pericardial fat presented with the great magnitude of correlation with intrathoracic and abdominal visceral fat ^{26 70}. However, the metabolic activity of EF and PF is different ²¹. Unlike EF, PF has not yet shown an association with metabolic syndrome, visceral adiposity, heart morphology, insulin resistance, and other features ²¹. Moreover, the term “pericardial” used in several studies is referred to fat in the pericardium without any distinction between EF and PF ^{20 71 72}. Recent pieces of evidence – even though on adult subjects – indicate that PF appears strongly associated with obesity and hypertension ^{17 47}. Sicari et al. studied EF and PF separately and found how PF – rather than EF – is related to parameters of metabolic syndrome, such as serum triglyceride and glucose concentrations, blood pressure, insulin sensitivity, and BMI ⁷³. Notably, in this study the PF thickness detected by echocardiography, but not that detected by MRI, was correlated with age ⁷³. Another correlation between PF and cardiovascular risk was found considering the 10-year CHD Framingham risk score ⁷³. Dabbah et al. investigated the association between EF and PF, and diastolic filling, finding a low correlation among PF and diastolic indices ⁷⁴. Definitely, despite several studies suggesting that PF could play an active role as a cardiovascular risk factor, its role still needs to be studied ⁷⁵.

CONCLUSIONS

Among the cardiac visceral fat depots, the EF presents with peculiar metabolic features. Indeed, the EF is characterized by differences in fatty acid composition, higher protein content and dissimilar metabolic profile, such as higher production of FFA, high levels of lipolysis activity, and reduced glucose utilization. Moreover, the EF shows active endocrinal properties as compared to the PF, and a close association with a low-grade pro-inflammatory state favoured by sharing the microcirculation with the myocardium. While a few studies on the association between the PF and cardiometabolic risk are available, there is strong evidence supporting the close association between the EF and cardiometabolic risk. Beyond the CV risk factors, EF is also an independent predictor factor of MACE. However, the available literature on cardiac visceral fat and cardiovascular risk includes only a small number of studies specifically targeting the old population. Future investigations are needed to address many questions in the geriatric field of research.

Figures and tables

Figure 1.Transthoracic echocardiographic measurement of epicardial adipose tissue (white arrow), that appears as an echo-free space. EF: epicardial fat.

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