The relationship between muscle strength and epicardial fat in healthy adults

Background: Muscular strength and muscle mass are considered key factors for healthy ageing. Modification of body composition and redistribution of adipose tissue has been described in advanced age. Muscle strength has an important predictive role for health outcomes. However, little is known regarding the relationship between muscle strength and epicardial fat. Methods and materials: In a cohort of healthy adults following physical capacity evaluations, anthropometric measurements, handgrip strength (HGS), echocardiography and bioimpedance analysis (BIA) were performed. Kruskal-Wallis test, Spearman's correlation and regression analysis adjusted for confounders were applied. Results: A total population of 226 adults, age range 18 – 83 years, were included. Epicardial fat thickness resulted significantly associated with age p < 0.001, HGS (p < 0.001). Regression analysis adjusted for confounders revealed an independent relationship between handgrip strength and epicardial fat thickness: regression coefficient: -1.34; R2 = 0.27 and p = 0.044. Conclusions: The relationship between epicardial fat and muscle strength is inverse and independent. Implementation of HGS measurement may be useful for the identification of subjects with excessive epicardial fat and cardiovascular risk. Measurement of epicardial fat could be helpful in the early detection of physical decline associated to ageing.


Introduction
In 2020 the population aged 60 years and older reached about one billion worldwide.One in 5 people will be 60 years of age or older by 2050 (WHO, and United Nations Department of Economic and Social Afairs, P. D, 2020).According to World Health Organization (WHO) healthy ageing is the process of maintaining the functional ability that enables well-being in older age (WHO, 2020, WHO, and United Nations Department of Economic and Social Afairs, P. D, 2020).Functional capacity reflects the environment where the people live, peopleenvironment interaction and the intrinsic capacity.Intrinsic capacity includes the physical and mental capacities of an individual and important domains are cognition, sensory, locomotor, psychological capacity and vitality.A growing body of evidence suggests that muscle function is an important component of intrinsic capacity (Arokiasamy et al., 2021).Hand grip strength (HGS) is a widely used method for the assessment of muscle strength and is considered as an indicator of vitality (McGrath et al., 2018).In early life muscle strength increases to a peak, remains constant during adulthood and follows a progressive decline with advancing age (McGrath et al., 2018;Huemer et al., 2023).Moreover, reduced HGS is considered an indicator of sarcopenia and predictor of health outcomes such as: disability, comorbidities and survival (Leong, Teo et al., 2015;Cruz-Jentoft, Bahat et al., 2019;Huemer et al., 2023).
Ageing is characterized by modifications in body composition.In older adults, muscle mass is reduced, fat mass is increased and accumulated in abdominal areas (Hughes et al., 2004;Goodpaster et al., 2006).Of note, gaining or maintaining muscle mass did not prevent ageassociated declines in muscle strength (Goodpaster et al., 2006).Agedependent modifications in body composition lead to the development of sarcopenia which has a bidirectional relationship with cardiovascular diseases (Damluji et al., 2023).Furthermore, visceral adipose tissue has been suggested as a significant risk factor for metabolic and cardiovascular diseases (Karlsson et al., 2019).
Epicardial fat is a visceral fat deposit of the heart that lies between the myocardium and the visceral layer of epicardium (Iacobellis and Willens, 2009), commonly found in the atrioventricular and intraventricular grooves.Epicardial fat is generally identified between the outer wall of the myocardium and the visceral layer of pericardium as the echo-free space (Iacobellis and Willens, 2009).The physiological function of epicardial fat is related to thermoregulation and myocardial energy hemostasis (Iacobellis and Bianco, 2011).Epicardial fat has also secretory properties in particular release of adipokines, adrenomedulline and pro-inflammatory cytokines (Iacobellis and Bianco, 2011).The endocrine profile of epicardial fat may lead to pro-atherosclerotic and pro-fibrotic effects which in turn favor the development of cardiovascular and metabolic diseases.Indeed, epicardial fat thickness (EFT) has been correlated to coronary artery disease, severity of aortic stenosis and occurrence of atrial fibrillation, all age-correlated diseases (Davin et al., 2019, Parisi et al., 2020, Cabaro et al., 2022).Furthermore, a significant association between age and EFT has been described (Karadag et al., 2011).EFT has been associated with exercise intolerance among diabetic patients with asymptomatic left ventricular structural and functional abnormalities (Sugita et al., 2020).In patients with chronic obstructive diseases, higher volume of epicardial fat was associated with worse 6-min walk test (Zagaceta et al., 2013).However, in older patients with heart failure with preserved ejection fraction epicardial fat was directly associated with peak VO2, 6-min walking distance leg power (Haykowsky et al., 2018).Therefore, the relationship between epicardial fat and vitality should be further explored.In this study we aimed to explore the relationship between muscle strength measured with HGS and epicardial fat in a population of healthy adults.

Study population
The participants have been recruited among individuals following physical capacity evaluation in Exercise and Sports Medicine Unit "Antonio Cardarelli Hospital", Department of Medicine and Health Sciences, University of Molise, Campobasso Italy.For the proposes of this study participants were considered eligible for enrollment if age was ≥18 years, and could provide a written informed consent.Exclusion criteria were: physical activity of vigorous intensity, participations in competitive sports, wheel-chaired individuals and inability to give written consent.Vigorous physical activity is characterized by an energy expenditure of ≥6 metabolic equivalents (METS).The perceived exertion during physical activity on scale of 0-10 points is 7-8 and examples of vigorous physical activity are: cycling ≥10 mph; running; tennis, basketball, football, swimming (Arnett et al., 2019, Bull et al., 2020).In our study the classification of physical activity intensity was based on the self-reported perceived exertion during physical activity and disciplines.The participants who reported at least 7 points on the perceived exertion scale and the above-mentioned disciplines were excluded.Anamnestic data regarding cardiovascular risk factors, comorbidities, therapy, were recorded as well.All procedures were approved by the Institutional Review Board of Department of Medicine and Health Sciences, University of Molise, and conducted in accordance with the declaration of Helsinki for studies on humans.All participants provided informed written consent for anonymous data collection prior to the study.The process of study selection is presented in Fig. 1.

Body composition analysis
Wunder SA.Bl. srl A 200 stadiometer was used to measure height in standing upright position bare feet.Waist circumference was measured by positioning a flexible anthropometric tape parallel to the floor, at the midpoint between the last rib and the upper edge of the iliac crest (World Health Organisation, 1995).Body mass, fat-free mass, fat-free mass percentage, muscle mass, muscle mass percentage, fat mass, fat mass percentage were estimated by the electrical impedance body composition analyzer TANITA BC-420MA (Tanita Corporation, Tokyo, Japan), as indicated by the manufacture.Body mass index (BMI) was calculated as well.

Handgrip strength measurement
Hand grip strength was evaluated with handheld dynamometer DynX (MD Systems, Inc., Ohio, USA) (Shechtman et al., 2005).Measurements were performed as described elsewhere (Roberts et al., 2011).In brief, the participant in a seating position performed a maximal effort for three times both in the right and left sides.Participants were asked to squeeze maximally for about 5 s and the higher measurement was recorded in kilograms (kg).

Echocardiography
All measurements were performed according to the European Society of Cardiology Recommendations (Lang et al., 2015) by a trans-thoracic echocardiography Alpinion ultrasound system with cardiac sector transducer sampling at 1-5 MHz.Left Ventricular (LV) size end-diastolic and end-systolic diameter, volume and wall thickness were measured.Simpson's biplane method was used for the evaluation of the LV Ejection Fraction (LVEF), four and two chamber views.Epicardial fat thickness was measured as indicated by Iacobellis et al. (Iacobellis et al., 2003a).In brief, participants laid at the left lateral decubitus position and epicardial fat thickness was measured at the end of the systole on the free wall of the right ventricle in two-dimensional long heart axis view.

Statistical analysis
Shapiro-Wilk test was performed for the assessment of data K. Komici et al. normality distribution.The population was categorized into the following age quartiles: Q1 = 18-20 years; Q2 = 21-27 years; Q3 = 28-46 years; and Q4 = 47-83 years.Categorical variables were expressed in numbers and percentage and continues variables as medians and interquartile ranges (IQRs) or mean and standard deviation (SD).Kruskal-Wallis test with pairwise comparison, One-way ANOVA with Bonferroni correction and multiple chi-squared test were performed to compare qualitative and quantitative variables as appropriate.Epicardial fat thickness was expressed also as z score and categorized into epicardial fat thickness quartiles.Spearman's correlation coefficient was used to test the correlations between age, epicardial fat, HGS and body composition parameters.The relationship between HGS and epicardial fat thickness was also tested with linear regression analysis and multivariate regression analysis adjusted for confounders.The statistical significance was p ≤ 0.05 and data were analyzed by STATA SE 16.1 (StataCorp LLC, College Station, TX, USA).

General characteristics of the population based on age quartiles division
The final study population was 226 participants.The median age was 27 years range 18-83 years, and most of the population were men 79.65 %.Hypertension, smoking and dyslipidemia were present respectively in 4.42 %, 15.04 % and 11.50 % of the overall population, with a higher prevalence in Q4 (Table 1).The time spend in physical training in the overall population was 4.85 ± 1.5 h weekly, and age quartiles did not differ significantly (p = 0.399).

Correlations between EFT and characteristics of population
The Spearman's correlation coefficient showed that EFT was positively correlated with age (p < 0.001) and fat mass percentage (p < 0.01).The correlation between EFT and muscle mass percentage was inverse and significant (p < 0.01).HGS and EFT resulted negatively correlated (p < 0.01).HGS showed a positive and significant correlation with muscle mass percentage (p < 0.01), and a negative correlation with fat mass percentage (p = 0.01).The correlation between WC and HGS (see Table 2) did not reach the significance level (p = 0.07).WC resulted significantly correlated with age, and body composition parameters (p < 0.001).The correlation matrix is presented in Table 2.

EFT and HGS relationship
Kruskal-Wallis test revealed that HGS differed across EPT quartiles: p = 0.038 (Fig. 2).Pairwise analysis showed a significant difference between the first and the fourth EFT quartile (p = 0.005).
Univariate regression analysis revealed a significant and inverse association between HGS and z EFT: regression coefficient: − 2.24 p = 0.001.A separate analysis for female and male gender was conducted.The association was significant for both genders, female: regression coefficient: -2.47 R2: 0.13 p = 0.011; male: regression coefficient: -2.35 R2: 0.05 p = 0.002.Multivariate regression analysis adjusted for confounders such as: age, gender, BMI, and fat mass percentage revealed a significant and independent association between HGS and z EFT: regression coefficient: -1.34; R2 = 0.27 and p = 0.044 (Fig. 3).

Discussion
The main result of the present study is that epicardial fat evaluated by transthoracic echocardiography is independently associated with muscle strength.Higher age quartiles compared to lower ones are characterized by reduced HGS and increased EFT.Measurement of muscle strength may identify subjects with excessive epicardial fat and increased cardiovascular risk.Furthermore, considering the importance of muscle strength on health outcomes evaluation of epicardial fat may be useful in the early detection of age-related physical decline.Body composition changes significantly with advancing age.Muscle mass decreases from 3 to 8 % after 30 years of age and this trend is more pronounced after 60 years (Melton 3rd et al., 2000, Volpi et al., 2004).On the other hand, fat mass is increased and a redistribution of adipose tissue with decreased subcutaneous fat and increased visceral fat is present (Ou et al., 2022).Epicardial fat is a component of visceral fat which displays white, brown and beige adipose tissues (Iacobellis, 2021).In line with the above-mentioned assumptions, in our study body composition parameters such as: fat mass, muscle mass, and waist circumference were modified by age, and pairwise analysis reported significant differences comparing older to younger age groups.Furthermore, epicardial fat differed significantly across age groups, reflecting higher values among the oldest participants of our study (p < 0.001).It should be mentioned that data regarding the relationship between age and epicardial fat are inconsistent: some studies failed to show a correlation (Iacobellis et al., 2003b, Willens et al., 2007), whilst other studies report a significant relationship (Jeong, Jeong et al., 2007, Natale et al., 2009, Mazzoccoli et al., 2012, Castanheira et al., 2020).Important heterogeneity regarding sample size, methods and clinical setting may be possible explanations related to this inconsistency.Indeed, most of the studies are focused on cardiovascular risk factors, metabolic syndrome, and coronary artery disease (Jeong et al., 2007, Natale et al., 2009, Karadag et al., 2011).Whether comorbidities, age alone or a combination of both lead to modification of epicardial fat is not clarified and needs further investigations (Iacobellis, 2021).In our population we verified an inverse relationship between age epicardial fat in a healthy population, as demonstrated by the low prevalence of hypertension, dyslipidemia and other cardiovascular risk factors.This is of importance considering that with increasing age the function of adipose progenitor stem cells declines leading to low adipogenesis (Ou et al., 2022).In addition, accumulation of senescent cells and abnormal activation of immune cells may further contribute to modification of visceral adipose tissue and epicardial fat accumulation (Iacobellis, 2021;Ou et al., 2022).Of note, adiponectin is expressed by epicardial fat and lower adiponectin levels were detected among patients with severe coronary artery disease compared to patients without coronary artery disease (Iacobellis et al., 2005).Modification of adiponectin gene expression was observed in experimental models of ageing (Fei et al., 2010).
In addition, in a previous meta-analysis study we reported that sarcopenia was associated to increased circulating levels of adiponectin (Komici et al., 2021).Future research should investigate the relationship between the secretome profile of epicardial fat and age-related modifications of body composition.
In obese women fat mass negatively affected muscle strength (Otten et al., 2017) and higher abdominal adiposity was associated with lower HGS in Chilean adults (Palacio et al., 2022).In our population body composition parameters such as muscle mass and fat mass resulted significantly correlated to muscle strength.Visceral adiposity did not reach statically significance but this may be influenced by the number of participants included in our study.A significant correlation between epicardial fat and muscle strength resulted from our data (p < 0.001).Increased EFT values were associated with reduction in HGS and this relationship was significant even in the analysis adjusted for age, gender and body composition parameters: one SD increase in EFT was associated with a 1.34 kg reduction in HGS.The negative impact of epicardial fat on muscle strength in our population may be explained by the chronic low-grade inflammation generated by the epicardial fat.Epicardial fat may enhance the production of pro-inflammatory   mediators, such as IL-1β, IL-6, TNFα (Parisi et al., 2015).Inflammation was associated with reduction in HGS in non-critical ill patients (Norman et al., 2014).A longitudinal study revealed that ageing is associated by an increase of intramuscular fat thickness regardless of weight modifications (Delmonico, Harris et al., 2009).Of note a recent study reported a positive correlation between epicardial fat and insulin resistance (Kalmpourtzidou et al., 2024).From the other side, insulin resistance has been associated to significant reduction in HGS in women (Abbatecola et al., 2005).In our study the relationship between EPFT and HGS resulted significant in both genders.Low HGS and insulin resistance resulted independent risk factors for aggravated glycemic control in elderly with diabetes mellitus (Koo et al., 2021).Future studies should clarify the mechanistic insight involved in a possible connection between epicardial fat and muscle strength which may be important for a healthy ageing process.Physical performance and muscle strength have been associated with disability, cognitive decline, cardiovascular diseases, and all-cause mortality (Cesari et al., 2005;Stessman et al., 2017;Landi et al., 2018;Coelho-Junior et al., 2024).Measurement of muscle mass by handgrip test is characterized by high feasibility, reliability, characteristics that make HGS suitable for clinical application as well (Patrizio et al., 2021).Excessive accumulation of epicardial fat has emerged as a risk factor for metabolic and cardiovascular diseases (Iacobellis and Bianco, 2011).While, echocardiography, magnetic resonance imaging or computed tomography are used to measure epicardial fat, HGS may be useful for the screening of subjects with excessive epicardial fat also as a time-saving and not expensive alternative, especially in primary care setting.In addition, muscle strength measurement may serve for monitoring of possible interventions, aimed at reducing excessive epicardial fat.Meta-analysis studies of the effects of exercise on epicardial fat concluded that physical exercise interventions appear as an effective strategy for reducing epicardial fat (Colonetti et al., 2021;Saco-Ledo et al., 2021).A recent randomized controlled study in patients with hypertensive metabolic syndrome reported that high intensity interval training compared to moderate-intensity continuous training is better for the reduction of EFT (Jo et al., 2020).Bariatric surgery and diet significantly reduced epicardial fat (Rabkin and Campbell, 2015).In type 2 diabetic patients combination of caloric restriction with physical activity provided a greater reduction of EFT than caloric restriction alone (Leroux-Stewart et al., 2021).
On the other hand, cardiovascular diseases are conditions frequently associated to ageing and echocardiography examination is necessary for this population.In this context measurement of EFT could be helpful in the early detection of the muscle strength decline, which in turn may negatively impact the clinical outcome.Indeed, in patients with cardiac disorders reduced muscle strength was associated with increased hospital admission for heart failure and mortality (Pavasini et al., 2019).

Study limitation
This study is a single-center experience and the number of the participants is not high.The frequency of female participants is lower compared to male participants.The cause-effect relationship cannot be explored considering the cross-sectional analysis of our data.

Conclusions
The relationship between epicardial fat and muscle strength is inverse and independent.Implementation of HGS measurement may be useful for the identification of subjects with excessive epicardial fat and cardiovascular risk.On the other hand, measurement of epicardial fat could be helpful in the early detection of physical decline associated to ageing.Future studies should clarify the mechanistic insight involved in a possible connection between epicardial fat and muscle strength which may be important for a healthy ageing process.

Table 1
Characteristics of population divided in age quartiles.