Intramuscular and Intermuscular Adipose Tissue in Older Adults

Over the last 20 years, obesity has been consistently associated with an increased risk for heart failure (HF). Although earlier studies reported that obesity increased all forms of HF, more recent data suggest that this association is stronger for heart failure with preserved ejection fraction (HFpEF) compared with heart failure with reduced ejection fraction (HFrEF). The exact mechanisms leading to the increased risk of HF remain elusive; however, increased fat mass (ie, adipose tissue [AT]) has been proposed to contribute to the risk of HF by its ability to reduce cardiorespiratory fitness (CRF),¹ which is defined as the cardiovascular, respiratory, and muscular responses to exercise and typically assessed as peak oxygen consumption (VO₂). Of note, CRF also remains a strong prognosticator in those with established HF. Although cardiac dysfunction, also in the presence of a preserved left ventricular ejection fraction, remains a central contributor to reduced CRF following the Fick equation: peak VO₂ = CO_max × (C[a-v]O₂)_max, where CO indicates cardiac output and C[a-v]O₂ indicates arteriovenous oxygen difference, individuals with obesity present severely reduced CRF² associated with significant noncardiac peripheral limitations to exercise.

FAT MASS DEPOTS: FOCUS ON INTRAMUSCULAR AND INTERMUSCULAR AT

Fat mass is far from being exclusively an energy storage tissue, and it can be divided into subcompartments with markedly different effects on metabolism and cardiovascular system. In the presence of excess adiposity that impairs health, individuals are diagnosed with obesity, more commonly defined using a body mass index (BMI) ≥30 kg/m².

The characteristics of the adipocytes allow classification of AT between white, brown, and beige (or “brite”). White AT is composed for ~90% of one lipid droplet in the presence of limited mitochondria, and physiologically composes ~30%–40% of the human body in women and ~15%–25% in men. Brown AT presents numerous lipid droplets as well as several large mitochondria, which are characterized by the presence of uncoupling protein-1 that allows chemical energy to dissipate into heat through uncoupling of the oxidative phosphorylation, and it only accounts for ~0.1%–0.5% of total body mass. Beige (or “brite”) AT is characterized by white AT in presence of brown or brown-like adipocytes. In addition, AT is classified depending on its location: briefly, below the skin (subcutaneous AT), in the trunk (visceral AT), around the muscle (intermuscular AT), and inside the muscle (intramuscular AT). Although a detailed distinction of AT subcompartments provides prognostic information, it requires advanced imaging technique to be assessed, such as computed tomography scan and cardiac magnetic resonance. Other techniques, such as dual-energy x-ray absorptiometry (DEXA) and bioelectrical impedance analysis, are also valid tools to measure whole and segmental body composition; however, to date, they are unable to accurately assess intermuscular and intramuscular AT.

In patients with established HFpEF, intermuscular AT predicts reduced CRF measured as peak VO₂,³ whereas intramuscular AT does not,⁴ and intramuscular AT predicts CRF and long-term outcomes in HFrEF.⁵ However, little is known about the role of intermuscular AT and intramuscular AT in the development of HF in those at risk for it, such as older adults.

SKELETAL MUSCLE COMPOSITION ABNORMALITIES AND THE RISK FOR HF

In this issue of JACC: Heart Failure, using the population cohort Health ABC (Health, Aging and Body Composition) study, Huynh et al⁶ investigated the role of computed tomography–measured thigh skeletal muscle composition, namely intermuscular and intramuscular AT, in 2,399 nondisabled older adults (70–79 years of age), in whom HF remains the leading cause of hospitalizations; 53% were women, and 40% were Black. Individuals were followed for a median time of 12.2 years, during which 455 HF events were reported (172 HFrEF, 154 HFpEF, and 129 unclassified).⁶

As expected, greater intramuscular and intermuscular AT were associated with higher BMI, DEXA-measured visceral AT, subcutaneous AT, and lean mass as well as worse metabolic control and markers of systemic inflammation, such as tumor necrosis factor-α, C-reactive protein, and interleukin-6. Individuals in the highest tertile of intramuscular and intermuscular AT were more likely to identify as Black compared with those in the lowest tertile.

At univariate analysis, both intramuscular and intermuscular AT were positively associated with the risk for HF; however, after adjustment for age, sex, race, education, blood pressure, fasting blood sugar, current smoking, prevalent coronary artery disease, and creatinine first, and then additionally for percent total AT, abdominal visceral AT, indexed muscle strength, and thigh muscle area, only intramuscular AT remained significantly associated with the risk of HF. When adjusted for inflammatory biomarkers, however, the association between intramuscular AT and the risk of HF was also attenuated, suggesting that some of the effects of intramuscular AT on the risk for HF may be mediated by systemic inflammation. Interestingly, when HF phenotypes were investigated, intramuscular AT only predicted the risk for HFrEF, but not HFpEF.

The findings of the study are exceptionally novel and somewhat surprising; yet, they need to be taken in the context of HF prevention rather than treatment. Considering the prognostic role of intermuscular AT, and particularly of intermuscular AT/skeletal muscle mass ratio of the thigh in patients with established HFpEF,³ one would expect that such AT depot would also predict its incidence, which was not the case after adjustments for confounders. These results suggest that the role of intramuscular and intermuscular AT might be different depending on whether an individual is at risk for HF or has established HF (Figure 1).

FIGURE 1. The Effects of Intramuscular and Intermuscular AT on the Risk of Heart Failure, Mortality, and CRF.

Elevated intramuscular adipose tissue (AT) (red) predicts the risk for heart failure with reduced ejection fraction (HFrEF), but not heart failure with preserved ejection fraction (HFpEF) in older adults. Moreover, intramuscular AT is associated with increased mortality and worse cardiorespiratory fitness (CRF) in patients with established HFrEF, although it does not appear to affect CRF in those with HFpEF, with long-term data on mortality currently lacking in this population. Intermuscular AT (green) does not predict the risk for HFrEF nor HFpEF in older adults. Although no data on survival exist in either forms of HF, intermuscular AT predicts worse CRF in HFpEF, whereas it is unknown whether it affects CRF in HFrEF. Blue = subcutaneous adipose tissue. Modified with permission from Kumar et al.¹⁰ Created with BioRender.com.

QUANTITY VS QUALITY OF INTRAMUSCULAR AT: MECHANISTIC INSIGHTS

Mechanistically, intramuscular AT, particularly when resulting from accumulation of saturated fatty acids, which is influenced by dietary intake,⁷ is a major contributor to reduced insulin sensitivity. Saturated fatty acid–induced insulin resistance in the skeletal muscle appears to be mediated by proinflammatory pathways within the skeletal muscle itself, which can be reversed by monounsaturated fatty acids, like oleic acid,⁷ that can be found in the largest amount in food like olive oil, canola oil, and avocado, among others. Similarly, sodium-glucose cotransporter-2 inhibitors, which can prevent HF in individuals at risk and improve clinical outcomes in those with established disease, at least in preclinical studies can also improve the composition of intramuscular AT by reducing its content of saturated fatty acids, particularly palmitic acid, and increase the content of monosaturated fatty acids, particularly oleic acid.⁸ These results suggest that the quality of intramuscular AT might also play an important role and could be targeted by therapeutic strategies.

Consistent with the inflammatory hypothesis, in the study by Huynh et al,⁶ the effect of intramuscular AT on the risk of HF was attenuated after adjustment for markers of systemic inflammation,⁶ proposing that perhaps targeting inflammation using anti-inflammatory strategies might prevent HF in those with elevated intramuscular AT. Of note, targeted anti-inflammatory strategies against interleukin-1 can prevent HF and HF-related hospitalizations in patients with coronary heart disease,⁹ further confirming the potential causative role of inflammation on the risk for HF in individuals at elevated risk for it.

The study by Huynh et al⁶ assessed the effects of AT depots in a specific population of older adults; therefore, the results should not be extrapolated to younger individuals, highlighting the need of similar analyses across different age subgroups. The BMI of the investigated population was also lower than what is typically reported in patients with HFpEF,³ and whether these results are confirmed at higher classes of obesity requires further investigation. Finally, the study was cross-sectional in nature, which cannot prove causality; therefore, future studies targeting intramuscular AT and its related metabolic abnormalities to confirm whether its reduction can prevent HF are strongly encouraged.

CONCLUSIONS

Huynh et al⁶ should be congratulated for providing novel evidence that noncardiac body composition compartments, particularly intramuscular AT, can predict the risk for HF in a diverse population of older adults. Studies testing novel modalities of exercise training, intentional weight loss, diet quality improvements with and without weight loss (ie, increase of dietary monounsaturated fatty acids, such as oleic acid), as well as pharmacological anti-inflammatory strategies should be encouraged in this population to test whether the reduction in intramuscular AT or improvements of its quality can ultimately reduce the risk for HF in this population.