In this cross-sectional study, we revealed a linear relationship between HGS and the incidence of HF. The relationship was characterized as follows: a low HGS level was found to be associated with an elevated incidence of HF, independent of age, gender, race, income level, education level, BMI level, smoking status, drinking status, diabetes, hypertension and stroke. No interactive role was found in the association between HGS and HF, suggesting that the above conclusions remained stable in the different subgroups.
Given the sensitivity to physiological changes, HGS was used as a valid marker of muscle function25. Although HGS has been found to be associated with mortality and the incidence of some cardiovascular diseases, the relationship between HGS and HF remains unclear 26. Some studies have supported that HGS has no effect on the incidence of HF13,14. However, similar to our conclusion, a cohort study from England suggested that participants with a higher HGS had a lower incidence of HF. This conclusion was more obvious among participants aged > 65 years than among those aged ≤ 65 years in the subgroup analysis. However, the interaction between age and HGS for HF was not statistically significant 27. The results of other studies based on the UK Biobank and Swedish National Inpatient Registry also revealed that objective measurements of HGS are strongly and independently associated with a lower HF incidence28,29. These conflicting conclusions may be attributed to the heterogeneity among these studies, including differences in participant selection, study size, study designs, and controlled confounders. Based on previous literature, our study excluded groups with depression and cognitive impairment, fully considered confounding factors, and strictly limited the age of the included population, making the conclusion reliable and filling in the gaps of current research from different perspectives.
Currently, no conclusive statement can be made about how muscle function decline could lead to the incidence of HF. From the existing literature, we speculate that the possible mechanism is as follows.
First, inflammation and oxidative stress might be underlying mechanism for both muscle function decline and HF30. Inflammatory cytokines could alter blood vessel dynamics, which might result in alterations to muscle metabolism and muscle loss. For example, Wnt signaling pathway molecules were found play a critical role in tissue-specific stem cell aging and an increase in tissue fibrosis with age, involved in both calcification and loss of muscle mass, have been proposed as potential mediators31,32, In addition, the oxidative stress theory of aging suggested that age-associated functional losses was closely related to the accumulation of reactive oxygen and species (ROS)-induced damages26. The oxidative stress is involved in several age-related conditions including muscle function decline and HF33,34 The mechanism may be related to mitochondrial dysfunction leading to limited oxygen availability and subsequent reliance on anaerobic metabolism35,36.
Second, apoptosis may be another important underlying mechanism. Several apoptotic pathways have been linked with age-related muscle function37 and higher frequency of myonuclear apoptosis has also been found in the muscle of patients with HF relative to age-matched healthy controls38.
Thirdly, abnormal glucose metabolism may be a common risk factor for HF and muscle function decline. Considering that skeletal muscle is the main site for insulin-mediated glucose disposal and that insulin resistance is strongly associated with HF, it could be hypothesized that insulin resistance plays a main role in both HF and muscle function decline39. In addition, it has been reported that muscular strength was demonstrated to be associated with a reduced risk of long-term development of diabetes mellitus 40, which is known to be a major risk factor for the development of HF41,42.
Finally, muscle acted as a paracrine and exocrine organ, and the myokines may act in autocrine, paracrine, and endocrine manner. The release of myokines from skeletal muscle preserves or augments cardiovascular function, in the meanwhile, increased muscle strength may provide capabilities for more active lifestyles that are related to a lower HF risk29.
To the best of our knowledge, our study is the first to provide evidence that HGS is associated with the incidence of HF among American middle-aged and elderly adults. The data collection in the NHANES is carried out following standardized protocols, and the NHANES is designed to provide nationally representative estimates. Therefore, the current findings have ideal generalizability. It is helpful for clinicians to identify groups at high risk for HF.
There are also some limitations in our study. First, self-reported confounders might be susceptible to self-report bias. Second, limited by the cross-sectional study design, this study had less power regarding the determination of causal relationships between HGS and HF. Third, since the study was conducted in a population of middle-aged and elderly individuals, the findings are only generalizable to relatively healthy adults. Fourth, while we controlled for a broad range of lifestyle and health-related factors, correcting for possible confounders remains challenging. As we used questionnaires to estimate health status, residual confounding cannot be excluded.