While major developments have been made in the etiology and diagnosis of sarcopenia in the last 20 years, variability persists in definition criteria and clinical assessment. The Asian Working Group for Sarcopenia (AWGS), European Working Group on Sarcopenia in Older People 2 (EWGSOP2), and Sarcopenia Definitions and Outcomes Consortium (SDOC) have each independently determined defining criteria for sarcopenia. All three groups utilize low grip strength and low physical performance as markers for sarcopenia in some way, though cut-off points and testing batteries vary. The Global Leadership Initiative in Sarcopenia was formed in 2019 to create an internationally consistent definition of sarcopenia, and while they have created a conceptual definition, they have yet to operationalize it into universally accepted clinical criteria. Still today, many cases of sarcopenia will go undiagnosed.

Frailty and sarcopenia are related but distinct conditions. Frailty is defined as a multidimensional, clinically significant state of diminished physiological reserve and increased vulnerability arising from a cumulative decline across multiple physiological systems. While both may predict adverse outcomes for geriatric populations, frailty is a broader, multifactorial disorder, while sarcopenia is a specific, muscular condition. Evidence from the Toledo Study of Healthy Aging shows that while sarcopenia and frailty frequently coexist, the overlap is incomplete, with the prevalence of sarcopenia among frail patients ranging from 40.27% to 65.3% depending on which definition of sarcopenia was applied. Muscle wasting is another related but distinct condition that generally refers to atrophy of muscle tissue, but does not necessarily involve diminished function or physical performance. Sarcopenia may be one manifestation of the physical phenotype of frailty, but frailty encompasses wider systemic vulnerability that can be present without muscle loss, while muscle wasting fails to encompass the functional changes associated with sarcopenia.

Sarcopenia is primarily initiated by aging-related biological changes, leading to a gradual, progressive loss of skeletal muscle mass, strength, and function. The disease is a manifestation of hormonal changes, chronic inflammation, mitochondrial dysfunction, metabolic imbalance, and neuromuscular degeneration ( Figure 1 ). The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) activates the Nuclear Factor KB (NF-κB) pathway, inducing reactive oxygen species production via NADPH oxidase expression, which mediates muscle catabolism and promotes proteolysis. TNF-α has been shown to upregulate Atrogin1 and MuRF1 expression, both atrophy-related ubiquitin E3 ligases, which further contribute to skeletal muscle and protein degradation. Another proinflammatory cytokine, interleukin-6 (IL-6), also induces Atrogin1 and MuRF1 expression, promoting muscle atrophy primarily through activation of the JAK/STAT3 signaling pathway, which under normal conditions plays an important role in skeletal muscle homeostasis. Age-related declines in growth hormone, testosterone, estrogen, and Insulin Like Growth factor 1 (IGF-1) further contribute to decreased anabolic signaling. The AMPK/SIRT1/PGC-1α pathway, critical for mitochondrial biogenesis and autophagy, and the mTOR pathway, which promotes protein synthesis and muscle growth, both become dysregulated with age, contributing to muscle catabolism and oxidative stress. ^, Concurrently, there is a shift toward catabolic pathways via increased ubiquitin-proteosome system and autophagy-lysosome pathway signaling, degrading muscle protein. Degeneration at the neuromuscular junction also contributes to loss of motor units and fast-twitch muscle fibers.

Important contributory factors in the pathogenesis of sarcopenia.

Lifestyle factors play a significant role in the development and progression of sarcopenia. Low physical activity is one of the strongest modifiable risk factors for sarcopenia, accelerating muscle loss and functional decline. Inadequate or poor nutrition with low protein intake impairs muscle maintenance and regeneration, contributing to sarcopenia. The oxidative stress and inflammation triggered by smoking and alcohol use are other modifiable risk factors for sarcopenia. Studies have identified cardiovascular disease as another risk factor for sarcopenia. While initiated primarily by age-dependent intrinsic biological changes, lifestyle factors, many of which overlap directly with those implicated in cardiovascular disease, are critical contributors to the pathogenesis of sarcopenia and important targets for prevention or treatment.

Several tools are routinely used clinically to assess diagnostic markers of sarcopenia ( Table 1 ), although they have yet to be routinely integrated into preoperative assessment for cardiac surgery candidates. Muscle strength measurement is typically the primary indicator of sarcopenia, followed by a confirmatory muscle mass assessment, and then a physical performance battery is used to determine severity. While no gold standard diagnostic tool exists, handgrip strength, as measured by a handheld dynamometer, remains the cornerstone of sarcopenia assessment, with cut-offs ranging from <27 to 35.5 kg for men and <16 to 18 kg for women, depending on which definition of sarcopenia is applied. Clinically, low muscle mass is typically assessed with dual-energy X-ray absorptiometry or bioimpedance analysis to calculate appendicular lean mass or appendicular skeletal muscle index. CT or MRI scans may also be used to assess muscle mass, although these approaches are less common clinically, with utility primarily for research purposes. Physical performance, commonly evaluated using tests such as gait speed (≤0.8 m/s), is next used to determine the severity of sarcopenia. Self-reported questionnaires have emerged as practical screening tools for sarcopenia. The SARC-F questionnaire has been validated as a clinically useful measure, with one study of hospitalized chronic heart failure patients reporting a specificity of 96%. While questionnaires are not substitutes for diagnostic criteria, they have become one feasible method for clinicians to screen high-risk patients.

Operationalizing these different tests into accurate, efficient clinical batteries that could be employed during preoperative assessments of valve patients remains challenging. While a low BMI is associated with increased risk of sarcopenia and was once used as a proxy for it, sarcopenic obesity, when low strength and muscle mass coexist with high adiposity, limits the utility of body mass index (BMI) as a diagnostic marker. One study of 5,888 older adults showed that 2.2% had confirmed sarcopenia, and 5.0% of those had sarcopenic obesity. Given BMI’s inability to detect sarcopenic obesity, calf circumference has emerged as a better predictor of sarcopenia and has begun to replace BMI as a clinically actionable alternative to quickly assess muscle mass.

Several blood biomarkers have been investigated as potential indicators of sarcopenia with mixed results. The potential utility of a diagnostic biomarker for sarcopenia that can be identified through routine preoperative bloodwork during cardiac surgery evaluation is significant. Creatinine to cystatin C (Cr/CysC) ratio and aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT) ratios have emerged as the most promising markers of sarcopenia. Studies have demonstrated that a low Cr/CysC ratio is associated with lower muscle mass and weak grip strength. Cr/CysC is only a moderately accurate diagnostic criterion for sarcopenia, and its clinical utility remains limited as a sarcopenia screening tool for elderly patients unable to undergo direct muscle mass or strength evaluation. An elevated AST/ALT ratio is typically used as an indicator of alcoholic liver disease, though several studies have demonstrated an association with sarcopenia risk. Elevated AST/ALT ratio was found to have a pooled sensitivity of 62% and a pooled specificity of 66% for sarcopenia. Further research is needed to discover and validate novel biomolecules associated with sarcopenia ( Figure 2 ).

Timeline of notable advancements in the treatment of valvular heart disease ( blue ) and sarcopenia diagnosis ( yellow ).

Although no direct causal pathway has been demonstrated between sarcopenia and the molecular progression of valvular disease, the two conditions share several upstream biological mechanisms that may create a convergent environment favoring tissue vulnerability. Sarcopenia is characterized by chronic low-grade inflammation, with elevated proinflammatory cytokines TNF-α and IL-6 driving activation of NF-κB signaling, proteolysis, and impaired myocyte regeneration. In myxomatous mitral valve disease, these same cytokines contribute to profibrotic signaling in valvular interstitial cells, including stimulation of TGF-β-dependent extracellular matrix production and promotion of myofibroblast activation. Oxidative stress and mitochondrial dysfunction, hallmark features of skeletal muscle catabolism, also appear in myxomatous and degenerative valve tissue, where reactive oxygen species generation accelerates cellular aging, disrupts mitochondrial dynamics, and alters valvular interstitial cell phenotype. Aging-related hormonal dysregulation, including reductions in IGF-1, growth hormone, and sex steroids, further contributes to impaired anabolic signaling. Similar hormonal decline has been associated with diminished valve matrix turnover and susceptibility to fibrotic remodeling. These shared inflammatory, metabolic, and endocrine pathways suggest parallel biological stressors affecting both skeletal muscle and valvular tissue. However, current evidence supports these mechanisms as convergent rather than causative, underscoring that sarcopenia primarily modifies physiological reserve and clinical risk rather than directly driving leaflet degeneration.

The relationship between sarcopenia and cardiovascular disease is bidirectional due to shared biomolecular causes and lifestyle factors: sarcopenia increases the risk and severity of cardiovascular disease, and cardiac conditions accelerate the development of sarcopenia. The prevalence of sarcopenia is significantly higher among patients with cardiovascular disease. A meta-analysis published in 2023 showed sarcopenia had a pooled prevalence of 32% among patients with chronic heart failure and 61% in patients with acute decompensated heart failure. In a bidirectional Mendelian randomization study, low appendicular lean muscle mass was shown to have a negative causal effect on coronary heart disease, stroke, and myocardial infarction. Cardiac disease, especially chronic conditions like heart failure and advanced valvular disease, can exacerbate loss of skeletal muscle mass through complex pathophysiological overlap and reduced physical activity.

Sarcopenia is independently associated with worse outcomes following several cardiac procedures. In a study involving 479 patients undergoing coronary artery bypass grafting sarcopenia was associated with higher rates of reintubation, sternal wound infection, acute kidney injury requiring hemodialysis, 30-day mortality, and mortality after 1 and 2 years. Sarcopenia is also a strong predictor of poor outcomes following transcatheter aortic valve replacement (TAVR), associated with increased long-term mortality.

While sarcopenia is not routinely screened for before most cardiac procedures, frailty screening is increasingly being integrated into preprocedural evaluation before cardiac procedures, recognizing functional decline as an important predictor of poor outcomes. The American College of Cardiology now recommends that frailty assessment be conducted as part of a comprehensive preprocedural evaluation for TAVR. The ACC also advises frailty screening for elderly patients over the age of 65 or younger patients with suspected frailty before high-risk cardiac surgery. The 2024 EACTS/STS guidelines recommend assessment of sarcopenia via CT imaging of the psoas muscle mass as part of comprehensive frailty evaluation before aortic procedures, while no guidelines exist specifically for valvular pathologies.

Mitral and tricuspid valve diseases are structural or functional abnormalities of the valve, resulting in stenosis or regurgitation, which can be categorized as degenerative or primary and functional or secondary. Primary mitral or tricuspid regurgitation is a result of intrinsic abnormalities of the valve itself (leaflets, chordae, and annulus), most often caused by valve prolapse. Sarcopenia is a well-established risk factor for adverse outcomes following valvular surgery, but the literature describing its impact on the mitral or tricuspid valves remains scarce.

Chronic mitral regurgitation can lead to progressive left ventricular dilation, heart failure, atrial fibrillation, and increased mortality if left untreated. In one study of 378 participants (88 of whom had sarcopenia), patients with sarcopenia had significantly smaller left ventricle sizes, reduced left ventricle masses, and lower left atrial volume, with left ventricle mass linearly correlated with handgrip strength. Smaller left atrial and ventricular sizes can significantly affect the pathophysiology and progression of mitral valve disease, particularly by limiting the heart’s ability to compensate for volume overload. In acute or severe mitral regurgitation, a small left atrium cannot accommodate excess regurgitant volume, leading to rapid increases in left atrial pressure and a higher risk of pulmonary edema and symptomatic decompensation. In chronic mitral regurgitation, the left atrium and ventricle will enlarge to buffer against elevated pressures and delay symptoms, but sarcopenia may limit this compensatory ability, posing a risk for abrupt decompensation if regurgitation worsens suddenly. Several studies have also shown that sarcopenia is a significant risk factor for left ventricular diastolic dysfunction. Left ventricular diastolic dysfunction exacerbates the hemodynamic burden of mitral valve regurgitation, leading to higher left atrial pressures and pulmonary congestion, and is thus associated with more severe regurgitation and higher rates of heart failure or other adverse outcomes. Sarcopenia is clearly linked to the progression of mitral regurgitation, given its association with a smaller size of the left chambers and poor diastolic function.

In cardiac surgery generally, sarcopenia has been shown to significantly increase mortality and major morbidity, and also prolong intensive care unit stays. The body of literature describing the effect of sarcopenia on patients with isolated tricuspid pathology remains limited. In one study of 163 transcatheter tricuspid valve repair patients, patient with lower psoas muscle area (as measured by CT scan) were found to have similar rates of operative success and in-hospital mortality, though a higher incidence of a composite outcomes measure, defined as all-cause mortality or heart failure hospitalization within one year. Another study of an isolated tricuspid valve surgery cohort demonstrated significantly higher of major 30-day postoperative complications (including mortality, renal complications, prolonged ventilation, major adverse cardiovascular or cerebrovascular events, and reoperations, among others) in a sarcopenic cohort, defined by skeletal muscle mass index below the 50th sex-specific percentile measures using chest CT scan. The generalizability of these findings is restricted by the heterogeneous approaches to sarcopenia assessment and definition, by the limited available literature and patient populations, as well as by the retrospective, non-randomized nature of these studies, with further research needed to validate the effects of sarcopenia on patients with isolated tricuspid valve pathology.

Sarcopenia is emerging as an important predictor of poorer outcomes for patients undergoing mitral valve surgery. In a study that stratified mitral valve patients by age (319 patients: 40–59 years old, 795 patients: 60–74 years old, and 513 patients: ≥75 years old), it was noted that BMI decreased with age, which authors associated with an increase in sarcopenia, concomitant with the development of critical illness, longer hospitalization, and increased mortality risk. While once accepted as a marker of sarcopenia in geriatric populations, the relationship between low-weight and sarcopenia is complicated by the prevalence of sarcopenic obesity. Reduced muscle mass diminishes physiologic resilience, delays mobilization, and weakens respiratory mechanics, all key determinants of postmitral intervention outcomes, making it essential to identify sarcopenia to ensure optimal procedural decision-making.

Using preprocedural CT evaluation of 238 TEER patients, sarcopenia assessed using psoas muscle area as a diagnostic indication was associated with worse clinical outcomes. The 1-year incidence of heart failure hospitalization and 1-year cumulative incidence of all-cause death and heart failure hospitalization were both significantly higher in the low psoas muscle index cohort. Another study of 192 patients who underwent isolated minimally invasive mitral valve surgery found that major morbidity, mortality, and 1-year mortality rate did not differ significantly for sarcopenic patients, defined as those in the lowest gender-specific quartile of psoas area muscle index. A minimally invasive approach to the mitral valve may be optimal for sarcopenic patients with limited physiological reserve, for whom recovery from an open procedure may be especially challenging. While psoas muscle area as measured by CT imaging is a reliable tool for diagnosing sarcopenia, its widespread clinical utility for mitral valve patients is hindered by cost and time constraints, though can be more easily integrated into the assessment of minimally invasive mitral valve patients who routinely undergo CT scans preoperatively.