Based on multiple large sample GWAS datasets, our Mendelian randomization analysis revealed a significant causal association between Sarcopenia, as indicated by Appendicular lean mass, Hand grip strength, and Usual walking pace, and the risk of CHD and MI. The alignment of our findings with prior observational studies further enhances the robustness of our results. These findings have implications for identifying potential targets for prevention and intervention strategies aimed at reducing the burden of these cardiovascular diseases.
While the precise mechanisms linking sarcopenia to CHD and MI are currently under investigation, there is a growing belief that the reduction in muscle mass and function could play a role in the onset of atherosclerosis, impaired myocardial function and vascular dysfunction. A recent meta-analysis of 42 observational studies found that lower handgrip strength, a component of possible sarcopenia, independently predicted increased risks of cardiovascular diseases, stroke, and coronary heart disease in community-dwelling populations, with hazard ratios (HRs) of 1.21 (1.14–1.29), 1.09 (1.05–1.14), and 1.07 (1.03–1.11) per 5-kg decrease in grip strength, respectively16. In a Chinese cross-sectional analysis, sarcopenia assessed using the AWGS 2019 criteria, was independently and positively associated with higher CVD risk among middle-aged and older adults17. Xia et al. demonstrated that sarcopenia was positively associated with increased risk of carotid atherosclerosis, myocardial infarction and atrial fibrillation among 2432 middle-aged and elderly adults18. Park et al. reported that CVD prevalence was positively associated with sarcopenia, and men aged ≥ 50 years with sarcopenia showed elevated prevalence of cardiovascular diseases, especially stroke19. A study from Korean population data from the Korea National Health and Nutrition Examination Survey (KNHANES) showed that sarcopenia measured by appendicular skeletal muscle mass (ASM) was associated with CVD independent of other well-documented risk factors, renal function and medications (OR, 1.768; 95% CI, 1.075–2.909, P = 0.025)20. Gill et al. found that slower walking speed, which may indicate sarcopenia, was linked to a higher risk of self-reported cardiovascular disease and mortality (men and women, respectively; HR, 0.62; 95% CI, 0.50–0.76 and HR, 0.80; 95% CI, 0.73–0.88), compared to those with a brisk walking pace21. These cross-sectional findings are largely consistent with our results, although the criteria for diagnosis of sarcopenia differ markedly.
Previous Mendelian randomization studies have also explored the causal relationship between muscle strength and cardiac disease5,6. Xu's and Willems's analysis utilized genetic variants associated with handgrip strength in a European population to investigate their impact on coronary artery disease and MI in a diverse population comprising various ethnicities. Xu's analysis indicated that a stronger handgrip is associated with a reduced risk of CAD, while Willems's analysis did not find a causal link between handgrip strength and CAD. The limited genetic variants (2 SNPs in Xu’s study and 20 SNPs in Willems's study) restricted the accuracy and reliability of the MR study, which may account for the discrepancies in the results between these two studies. Furthermore, the inconsistent results may be attributed to the different ancestry of the individuals regarding the exposure (handgrip strength, European ethnicity) and the outcome (CAD/MI, Mix ethnicity). Compared to these two TSMR analyses5,6, Liu's research confirmed that decreased muscle strength but not decreased muscle mass leads to the increased risk of CAD in sarcopenia, employing a greater number of selected IVs to improve the interpretation of exposures, despite the variation in individuals' ancestry in different GWAS data7. Liu's study utilized body lean mass instead of appendicular lean mass to measure muscle mass, which may not be entirely appropriate, as it could be influenced by other components of non-fat soft tissue, while our analysis, which employed appendicular lean mass, is more suitable7. In our study, we increased the exposure database sample size by obtaining GWAS summary statistics for body lean mass (n = 450,243) and handgrip strength (left hand, n = 461,026; right hand, n = 461,089) from the UK Biobank study, and we also examined the Usual walking pace as an important feature of sarcopenia (n = 459,915). Moreover, we focused on specific outcomes of CHD and MI using a more stringent definition, which allowed us to improve the reliability and specificity of our findings.
The exact mechanisms linking sarcopenia to CHD and MI remain elucidated. In our study, we preliminarily revealed that sarcopenia might exert effects on several conventional risk factors of CVD, like BMI, HDL-C, LDL-C, TC, TG, and WHR. Kouvari’s study22 indicated that increased Skeletal Muscle Mass Index and reduced abdominal obesity are independently associated with lower rates of coronary artery disease, and these two factors interact as significant determinants of cardiovascular disease. And Kim’s study23 revealed that promoting purposeful weight loss while increasing muscle mass offers numerous benefits to cardiovascular health. Regular exercise that focuses on building muscle mass, coupled with weight loss, can lead to reductions in total blood volume, stroke volume, preload, left ventricular filling pressure, and consequently, improved cardiac output24. On a microscopic level, myokines released from skeletal muscle exert anti-inflammatory effects25. Body lean mass, handgrip strength, and usual walking pace directly reflect an individual's physical function, muscle strength, and overall health status, potentially influencing the occurrence of cardiovascular diseases, including myocardial infarction26–28. Individuals with Sarcopenia tend to exhibit higher rates of cardiovascular risk factors, such as obesity, insulin resistance, and inflammation, which are known to contribute to the development of CHD and MI. Moreover, Sarcopenia may impact cardiovascular health through its effects on physical function and metabolic abnormalities29. Sarcopenia-related reductions in muscle strength and physical performance can result in decreased physical activity, impaired mobility, and a sedentary lifestyle, all of which serve as additional risk factors for CHD and MI30,31.
There are some potential limitations in this study. Firstly, although our use of appendicular lean mass to measure muscle mass may be more precise than body lean mass, as it could be influenced by other components of non-fat soft tissue, relative muscle mass (appendicular lean mass/height2) might be a more suitable measure compared to absolute muscle mass32. Further research is needed to improve the study with a proper GWAS database. Secondly, we believe that stratified analysis based on sex and age could be useful, as sarcopenia and CHD/MI incidence rates differ among different age groups and genders. However, since we only had summary statistics and not individual data, conducting sex- and age-specific analysis might be challenging. However, age and sex adjustments were made in the genetic association data from the original GWAS database, which should have minimized any related issues. Thirdly, like previous MR analysis, as we only used summary statistics and had no access to the original individual measures, CHD and MI with mixed ethnicity used in this study might be not exactly appropriate and it may affect our results. Therefore, we need to be cautious and prudent when drawing conclusions.
In summary, given the growing evidence linking Sarcopenia with CHD and MI, it is important to consider the assessment and management of Sarcopenia as part of cardiovascular disease prevention and management strategies. Early identification and interventions to improve muscle mass and function may have the potential to reduce the risk of CHD and MI in individuals with Sarcopenia. Further research is needed to better understand the underlying mechanisms and establish the effectiveness of interventions targeting Sarcopenia in reducing the risk of CHD and MI.