Targeting Cardiac and Cerebrovascular Risks of Sarcopenia: Is it time to Screen for Muscle Health?

As healthcare providers, we recognize the critical importance of screening patients for cardiovascular disease (CVD) risk factors like hypertension, hyperlipidemia, and diabetes. Yet, an emerging condition with CVD implications and shared pathophysiology is often overlooked - sarcopenia, defined as the loss of skeletal muscle mass and strength. With the aging global population, sarcopenia is rising in prevalence (1). However, sarcopenia is not simply a geriatric condition. Muscle wasting and weakness can begin earlier, accelerated by sedentary lifestyles, malnutrition, and chronic diseases like obesity and diabetes (Figure 1) (1). Beyond its shared pathophysiology with CVD, sarcopenia itself has negative cardiovascular consequences. Loss of muscle mass depletes protective myokines, disrupts glucose utilization, and reduces energy expenditure, leading to worse inflammation, insulin resistance, and fat deposition, respectively (2). The diminished strength also causes physical inactivity, deconditioning, and accelerated muscle loss (3). This creates a vicious cycle of muscle wasting, metabolic dysregulation, oxidative stress, and endothelial dysfunction that, if not intervened upon, can lead to adverse clinical outcomes (2).

Figure 1.

The aging process is a significant risk factor for the development of sarcopenia and cardiovascular disease, with both conditions exacerbating each other. This figure highlights the intricate interplay between these health factors, emphasizing the need for comprehensive approaches to address their impact on overall health. MACCE, major adverse cardiac and cerebrovascular event.

Past evidence has shown that low muscle mass is associated with markers of subclinical atherosclerosis, including higher coronary artery calcium scores, arterial stiffness, and carotid wall thickness (4,5). Others have linked sarcopenia to elevated inflammatory markers as predictors of CVD (6). Two Mendelian randomization studies utilizing the UK Biobank and other datasets also found individual components of sarcopenia, such as low appendicular lean mass (ALM) and handgrip strength (HGS), to be independent causal risk factors for coronary artery disease and myocardial infarction (MI), though findings were less consistent for stroke (7,8). Despite the associations with surrogate markers and the intuitive pathophysiology, studies on the direct association of sarcopenia with cardiovascular events have shown mixed results. For example, a 2020 UK Biobank study found sarcopenia, defined by low muscle mass and strength using the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria, not to be associated with incident CVD (MI or stroke) (9). However, another 2021 UK Biobank study showed the combination of sarcopenia and frailty, defined by EWGSOP2 criteria and modified Fried criteria, respectively, to be associated with incident CVD (ischemic heart diseases, heart failure, and cerebrovascular diseases) (10). Also, a 2022 China Health and Retirement Longitudinal Study found possible sarcopenia (low muscle strength or physical performance) and sarcopenia (low muscle mass plus low muscle strength or physical performance), defined using the Asian Working Group for Sarcopenia 2 criteria, to be associated with self-reported incident CVD (any heart disease or stroke) among middle-aged and older Chinese adults; for the individual components, stroke remained significant while heart disease did not (11). These discrepancies are likely due, in part, to differing sarcopenia definitions and outcome measures, highlighting the need for more rigorous studies using consistent definitions.

To this end, the article by Jauffret et al. in this issue of the journal examines the association of pre-sarcopenia and sarcopenia with the risk of incident major adverse cardiac and cerebrovascular events (MACCEs) in the UK Biobank (12). The authors utilize the widely used 2018 EWGSOP2 criteria and cutoffs to define sarcopenia as low muscle mass and strength (1). Pre-sarcopenia, a term not used by EWGSOP2, was defined as either low muscle mass or strength alone. They used bioelectrical impedance analysis (BIA) and the Janssen equation to estimate ALM, adjusted by height², to obtain what they termed skeletal muscle index (SMI) (9,10). Muscle strength was quantified using HGS. The study included 406,411 middle-aged and older Caucasian adults, median age of 58.0 years, free of MACCEs at baseline. They identified 0.3% of the participants as sarcopenic, 2.1% as pre-sarcopenic by low SMI, and 4.3% as pre-sarcopenia by low HGS. Over a median follow-up of 12.1 years, there were 28,300 participants with incident MACCEs, which were composed of fatal or non-fatal cardiovascular events (acute MI, angina pectoris, and cardiac arrest) or fatal or non-fatal cerebrovascular events (ischemic and hemorrhagic stroke, and TIA); outcomes were obtained from International Classification of Diseases-10th Revision (ICD-10) codes and self-reported data. Compared to non-sarcopenic participants, those with pre-sarcopenia and sarcopenia had a significantly higher risk of MACCEs after maximal multivariate adjustment (hazard ratio [HR] 1.25, 95% confidence interval [95%CI] 1.19–1.31 for pre-sarcopenia using low HGS; HR 1.33, 95%CI 1.23–1.45 for pre-sarcopenia using low SMI; and HR 1.62, 95%CI 1.34–1.95 for sarcopenia). Secondary analyses of the cardiovascular or cerebrovascular events, considered independently, showed pre-sarcopenia definitions and sarcopenia were associated with 24–26% and 60% higher risks of incident cardiovascular events, respectively. However, for incident cerebrovascular events, pre-sarcopenia definitions showed a 26–37% increased risk, whereas sarcopenia did not. The authors also assessed sarcopenic obesity (1.4%), defined as those in either the pre-sarcopenia or sarcopenia groups with obesity; the participants in these groups were combined due to the limited number with concomitant obesity. They found that participants with pre-sarcopenia or sarcopenia with obesity had 2.16 times higher MACCEs risk than participants without these conditions; pre-sarcopenia or sarcopenia alone also showed 1.29 times higher risk, whereas obesity alone did not.

Overall, the authors are commended for a sophisticated study of a large prospective cohort dataset with strong methodology to broaden our understanding of the impact of muscle health on CVD risk. They particularly expand upon prior studies by separately assessing the predictive potential of muscle wasting and weakness. However, the study is not without inherent limitations. The use of ICD-10 codes and self-reported data allows for capturing many events but may not reflect a true diagnosis compared to clinician adjudication. Furthermore, the generalizability of the findings is limited given the white European cohort and the risk for “healthy volunteer” bias from lower rates of sarcopenia risk factors, like smoking, alcohol, and multimorbidity, within the UK Biobank (13). However, the significant findings, despite a healthier cohort, do raise concern for even greater risks in the general population, shedding light on the importance of this topic. Another limitation is regarding the findings with sarcopenic obesity. Given the global obesity epidemic and an aging population, this syndrome has emerged as an important cardiometabolic risk factor. Unfortunately, the evidence surrounding it has been plagued by vastly heterogeneous diagnostic criteria demonstrating 19- to 26-fold variations in its sex-specific prevalence (14). Moving forward, following the first consensus algorithm for sarcopenic obesity introduced in 2022 by the European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) will be key to advance understanding of this syndrome (15). Studies using these new criteria are limited but have already shown the ESPEN/EASO definition to better identify sarcopenic obesity than EWGSOP2 (16).

These limitations aside, the authors are applauded for drawing attention to the distinction between sarcopenia and low muscle mass - a key concept as we seek to understand skeletal muscle across the lifespan. Although sarcopenia was initially defined as loss of muscle mass, subsequent research highlighted the importance of incorporating muscle strength into the definition (17). The current definitions focus more on muscle strength, but identifying low muscle mass alone remains valuable. Muscle wasting can occur at any age, is associated with metabolic dysregulation, and may provide an opportunity for early intervention and sarcopenia prevention if caught early. Although the recent Sarcopenia Definition and Outcomes Consortium criteria exclude muscle mass evaluation (18), evidence like this should urge future consensus criteria to keep low muscle mass (rather than relying predominantly on handgrip definitions that may reflect a more advanced phenotype) and define it as a high-risk condition in itself. However, questions remain on whether the CVD risk of muscle wasting depends on a threshold of low muscle mass or a degree of longitudinal decline (19). Further research using consistent diagnostic criteria (with ethnic- and disease-based cutoffs) and clinical endpoints is needed to clarify optimal prevention and treatment strategies for cardiovascular risk reduction.

The prevention and treatment of sarcopenia to lower CVD risk depends on its etiologic mechanisms and requires a multifaceted approach. Regular resistance exercise helps maintain muscle mass and strength (17). Adequate dietary protein is also crucial (17). Some emerging pharmacological options like anabolic hormones, vitamin D, and angiotensin-converting enzyme inhibitors show potential, but more research on their optimization and CVD effects is needed (17). Improved screening tools can help identify at-risk patients for early intervention, particularly given the plastic nature of skeletal muscles with responsiveness to targeted therapy (20). Future work should clarify optimal exercise regimens, dietary patterns, and drug therapies to manage sarcopenia and CVD risk jointly. Studies are also needed on whether improving sarcopenia directly lowers CVD events. As the biological mechanisms are elucidated, targeted therapies may emerge.

In summary, the study by Jauffret et al. provides compelling evidence for an association between sarcopenia and incident CVD and highlights the importance of incorporating muscle mass alone into current diagnostic criteria. As the global population ages, this calls for a multidisciplinary approach to prevent sarcopenia before it develops to prevent downstream adverse CVD outcomes. With greater awareness and collaboration among specialties, sarcopenia screening and management may soon become vital to cardiovascular risk assessment and care.