Analytic morphomics, core muscle size, and surgical outcomes.
Englesbe Michael J,Lee Jay S,He Kevin,Fan Ludi,Schaubel Douglas E,Sheetz Kyle H,Harbaugh Calista M,Holcombe Sven A,Campbell Darrel A,Sonnenday Christopher J,Wang Stewart C
Annals of surgery
OBJECTIVE:Assess the relationship between lean core muscle size, measured on preoperative cross-sectional images, and surgical outcomes. BACKGROUND:Novel measures of preoperative risk are needed. Analytic morphomic analysis of cross-sectional diagnostic images may elucidate vast amounts of patient-specific data, which are never assessed by clinicians. METHODS:The study population included all patients within the Michigan Surgical Quality Collaborative database with a computerized tomography(CT) scan before major, elective general or vascular surgery (N = 1453). The lean core muscle size was calculated using analytic morphomic techniques. The primary outcome measure was survival, whereas secondary outcomes included surgical complications and costs. Covariate adjusted outcomes were assessed using Kaplan-Meier analysis, multivariate cox regression, multivariate logistic regression, and generalized estimating equation methods. RESULTS:The mean follow-up was 2.3 years and 214 patients died during the observation period. The covariate-adjusted hazard ratio for lean core muscle area was 1.45 (P = 0.028), indicating that mortality increased by 45% per 1000 mm(2) decrease in lean core muscle area. When stratified into tertiles of core muscle size, the 1-year survival was 87% versus 95% for the smallest versus largest tertile, whereas the 3-year survival was 75% versus 91%, respectively (P < 0.003 for both comparisons). The estimated average risk of complications significantly differed and was 20.9%, 15.0%, and 12.3% in the lower, middle, and upper tertiles of lean core muscle area, respectively. Covariate-adjusted cost increased significantly by an estimated $10,110 per 1000 mm(2) decrease in core muscle size (P = 0.003). CONCLUSIONS:Core muscle size is an independent and potentially important preoperative risk factor. The techniques used to assess preoperative CT scans, namely analytic morphomics, may represent a novel approach to better understanding patient risk.
Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index.
Martin Lisa,Birdsell Laura,Macdonald Neil,Reiman Tony,Clandinin M Thomas,McCargar Linda J,Murphy Rachel,Ghosh Sunita,Sawyer Michael B,Baracos Vickie E
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:Emerging evidence suggests muscle depletion predicts survival of patients with cancer. PATIENTS AND METHODS:At a cancer center in Alberta, Canada, consecutive patients with cancer (lung or GI; N = 1,473) were assessed at presentation for weight loss history, lumbar skeletal muscle index, and mean muscle attenuation (Hounsfield units) by computed tomography (CT). Univariate and multivariate analyses were conducted. Concordance (c) statistics were used to test predictive accuracy of survival models. RESULTS:Body mass index (BMI) distribution was 17% obese, 35% overweight, 36% normal weight, and 12% underweight. Patients in all BMI categories varied widely in weight loss, muscle index, and muscle attenuation. Thresholds defining associations between these three variables and survival were determined using optimal stratification. High weight loss, low muscle index, and low muscle attenuation were independently prognostic of survival. A survival model containing conventional covariates (cancer diagnosis, stage, age, performance status) gave a c statistic of 0.73 (95% CI, 0.67 to 0.79), whereas a model ignoring conventional variables and including only BMI, weight loss, muscle index, and muscle attenuation gave a c statistic of 0.92 (95% CI, 0.88 to 0.95; P < .001). Patients who possessed all three of these poor prognostic variables survived 8.4 months (95% CI, 6.5 to 10.3), regardless of whether they presented as obese, overweight, normal weight, or underweight, in contrast to patients who had none of these features, who survived 28.4 months (95% CI, 24.2 to 32.6; P < .001). CONCLUSION:CT images reveal otherwise occult muscle depletion. Patients with cancer who are cachexic by the conventional criterion (involuntary weight loss) and by two additional criteria (muscle depletion and low muscle attenuation) share a poor prognosis, regardless of overall body weight.
A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults.
Morton Robert W,Murphy Kevin T,McKellar Sean R,Schoenfeld Brad J,Henselmans Menno,Helms Eric,Aragon Alan A,Devries Michaela C,Banfield Laura,Krieger James W,Phillips Stuart M
British journal of sports medicine
OBJECTIVE:We performed a systematic review, meta-analysis and meta-regression to determine if dietary protein supplementation augments resistance exercise training (RET)-induced gains in muscle mass and strength. DATA SOURCES:A systematic search of Medline, Embase, CINAHL and SportDiscus. ELIGIBILITY CRITERIA:Only randomised controlled trials with RET ≥6 weeks in duration and dietary protein supplementation. DESIGN:Random-effects meta-analyses and meta-regressions with four a priori determined covariates. Two-phase break point analysis was used to determine the relationship between total protein intake and changes in fat-free mass (FFM). RESULTS:Data from 49 studies with 1863 participants showed that dietary protein supplementation significantly (all p<0.05) increased changes (means (95% CI)) in: strength-one-repetition-maximum (2.49 kg (0.64, 4.33)), FFM (0.30 kg (0.09, 0.52)) and muscle size-muscle fibre cross-sectional area (CSA; 310 µm (51, 570)) and mid-femur CSA (7.2 mm (0.20, 14.30)) during periods of prolonged RET. The impact of protein supplementation on gains in FFM was reduced with increasing age (-0.01 kg (-0.02,-0.00), p=0.002) and was more effective in resistance-trained individuals (0.75 kg (0.09, 1.40), p=0.03). Protein supplementation beyond total protein intakes of 1.62 g/kg/day resulted in no further RET-induced gains in FFM. SUMMARY/CONCLUSION:Dietary protein supplementation significantly enhanced changes in muscle strength and size during prolonged RET in healthy adults. Increasing age reduces and training experience increases the efficacy of protein supplementation during RET. With protein supplementation, protein intakes at amounts greater than ~1.6 g/kg/day do not further contribute RET-induced gains in FFM.
Impact of sarcopenia on prognostic value of cirrhosis: going beyond the hepatic venous pressure gradient and MELD score.
Kang Seong Hee,Jeong Woo Kyoung,Baik Soon Koo,Cha Seung Hwan,Kim Moon Young
Journal of cachexia, sarcopenia and muscle
BACKGROUND:Sarcopenia has been reported as a prognostic factor. We evaluated the impact of sarcopenia to the conventional prognostic factors [Model for End-Stage Liver Disease (MELD) score, Child-Turcotte-Pugh (CTP) score, hepatic venous pressure gradient (HVPG)] in cirrhosis. METHODS:Overall, 452 patients with cirrhosis were stratified by MELD score (low < 15, high ≥ 15), CTP class, and HVPG [non-clinically significant portal hypertension (CSPH), 6-9 mmHg; CSPH, 10-19 mmHg; extremely severe PH, ≥20 mmHg]. L3 skeletal muscle index as marker of sarcopenia was subdivided into quartiles (47.01-52.25-58.22 cm /m ). RESULTS:Among the patients, 42% (190/452) presented with sarcopenia. During a median follow-up period of 21.2 months, sarcopenia was associated with mortality (adjusted hazard ratio = 2.253, P < 0.001) and specifically with compensated and early decompensated stages of cirrhosis, but not with advanced decompensated stages; low (P < 0.001) and high (P = 0.095) MELD scores; CTP classes A (P = 0.034), B (P < 0.001), and C (P = 0.205); and non-CSPH (P = 0.018), CSPH (P < 0.001), and extremely severe PH (P = 0.846). In quartiles of sarcopenia, MELD score, CTP class, and HVPG were independent predictors of mortality in non-sarcopenia, but not in severe sarcopenia (MELD, P = 0.182; CTP, P = 0.187; HVPG, P = 0.077). CONCLUSIONS:Sarcopenia is associated with mortality in compensated and early decompensated cirrhosis, and existing conventional prognostic factors had limited value in severe sarcopenia. Therefore, incorporating sarcopenia in the conventional prognostic factors had added value, particularly in compensated and early decompensated cirrhosis. Subclassification of prognostic factors according to sarcopenia may help to better assess the prognosis of cirrhosis.
Sarcopenia: A Time for Action. An SCWD Position Paper.
Bauer Juergen,Morley John E,Schols Annemie M W J,Ferrucci Luigi,Cruz-Jentoft Alfonso J,Dent Elsa,Baracos Vickie E,Crawford Jeffrey A,Doehner Wolfram,Heymsfield Steven B,Jatoi Aminah,Kalantar-Zadeh Kamyar,Lainscak Mitja,Landi Francesco,Laviano Alessandro,Mancuso Michelangelo,Muscaritoli Maurizio,Prado Carla M,Strasser Florian,von Haehling Stephan,Coats Andrew J S,Anker Stefan D
Journal of cachexia, sarcopenia and muscle
The term sarcopenia was introduced in 1988. The original definition was a "muscle loss" of the appendicular muscle mass in the older people as measured by dual energy x-ray absorptiometry (DXA). In 2010, the definition was altered to be low muscle mass together with low muscle function and this was agreed upon as reported in a number of consensus papers. The Society of Sarcopenia, Cachexia and Wasting Disorders supports the recommendations of more recent consensus conferences, i.e. that rapid screening, such as with the SARC-F questionnaire, should be utilized with a formal diagnosis being made by measuring grip strength or chair stand together with DXA estimation of appendicular muscle mass (indexed for height2). Assessments of the utility of ultrasound and creatine dilution techniques are ongoing. Use of ultrasound may not be easily reproducible. Primary sarcopenia is aging associated (mediated) loss of muscle mass. Secondary sarcopenia (or disease-related sarcopenia) has predominantly focused on loss of muscle mass without the emphasis on muscle function. Diseases that can cause muscle wasting (i.e. secondary sarcopenia) include malignant cancer, COPD, heart failure, and renal failure and others. Management of sarcopenia should consist of resistance exercise in combination with a protein intake of 1 to 1.5 g/kg/day. There is insufficient evidence that vitamin D and anabolic steroids are beneficial. These recommendations apply to both primary (age-related) sarcopenia and secondary (disease related) sarcopenia. Secondary sarcopenia also needs appropriate treatment of the underlying disease. It is important that primary care health professionals become aware of and make the diagnosis of age-related and disease-related sarcopenia. It is important to address the risk factors for sarcopenia, particularly low physical activity and sedentary behavior in the general population, using a life-long approach. There is a need for more clinical research into the appropriate measurement for muscle mass and the management of sarcopenia. Accordingly, this position statement provides recommendations on the management of sarcopenia and how to progress the knowledge and recognition of sarcopenia.
Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study.
Prado Carla M M,Lieffers Jessica R,McCargar Linda J,Reiman Tony,Sawyer Michael B,Martin Lisa,Baracos Vickie E
The Lancet. Oncology
BACKGROUND:Emerging evidence on body composition suggests that sarcopenic obesity (obesity with depleted muscle mass) might be predictive of morbidity and mortality in non-malignant disease and also of toxicity to chemotherapy. We aimed to assess the prevalence and clinical implications of sarcopenic obesity in patients with cancer. METHODS:Between Jan 13, 2004, and Jan 19, 2007, 2115 patients with solid tumours of the respiratory or gastrointestinal tract from a cancer treatment centre serving northern Alberta, Canada, were identified. Available lumbar CT images of the obese patients were analysed for total skeletal muscle cross-sectional area; these values were also used to estimate total body fat-free mass (FFM). FINDINGS:Of the 2115 patients initially identified, 325 (15%) were classified as obese (body-mass index [BMI] > or =30). Of these obese patients, 250 had CT images that met the criteria for analysis. The remaining 75 patients were recorded as without assessable scans. Obese patients had a wide range of muscle mass. Sex-specific cut-offs that defined a significant association between low muscle mass with mortality were ascertained by optimum stratification analysis: 38 (15%) of 250 patients who had assessable CT images that met the criteria for analysis were below these cut-offs and were classified as having sarcopenia. Sarcopenic obesity was associated with poorer functional status compared with obese patients who did not have sarcopenia (p=0.009), and was an independent predictor of survival (hazard ratio [HR] 4.2 [95% CI 2.4-7.2], p<0.0001). Estimated FFM showed a poor association with body-surface area (r(2)=0.37). Assuming that FFM represents the volume of distribution of many cytotoxic chemotherapy drugs, we estimated that individual variation in FFM could account for up to three-times variation in effective volume of distribution for chemotherapy administered per unit body-surface area, in this population. INTERPRETATION:This study provides evidence of the great variability of body composition in patients with cancer and links body composition, especially sarcopenic obesity, to clinical implications such as functional status, survival, and potentially, chemotherapy toxicity.
Obesity and Energy Balance in GI Cancer.
Brown Justin C,Meyerhardt Jeffrey A
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
The prevalence of overweight (body mass index [BMI], 25 to 29.9 kg/m) and obesity (BMI ≥ 30 kg/m) have increased dramatically in the United States. Because increasing BMI is associated with the development of multiple different cancer types, including most GI cancers, providers will frequently encounter patients with GI cancer who are overweight or obese. Mounting evidence associates overweight and/or obesity with worsened prognosis in multiple GI cancers, including esophageal, gastric, hepatocellular, pancreatic, and colorectal. However, these data are observational and may be subject to bias and/or confounding. Furthermore, in some cancer types, the associations between BMI and outcomes is not linear, where overweight and class I obese patients may have an improvement in outcome. This report provides a brief highlight of existing studies that have linked overweight and/or obesity to prognosis in GI cancer; provides recommendations on best management practices; and discusses limitations, controversies, and future directions in this rapidly evolving area. There are multiple areas of promise that warrant continued investigation: What are the comparative contributions of energy balance, including weight, dietary patterns, and physical activity on cancer prognosis? What are the specific physiologic pathways that mediate the relationship between energy balance and prognosis? What is the relationship between low muscle mass (sarcopenia) or sarcopenic obesity and cancer prognosis? Are there subsets of patients for whom purposefully altering energy balance would be deleterious to prognosis? This area is rich with opportunities to understand how states of energy (im)balance can be favorably altered to promote healthy survivorship.
Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty.
Ferrucci Luigi,Fabbri Elisa
Nature reviews. Cardiology
Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Potential mechanisms of inflammageing include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic infections. Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal. Inflammageing is also a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial. This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty - which affect clinical manifestations, prognosis, and response to treatment - and are associated with inflammation by mechanisms similar to those in CVD. The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans. Whether early modulation of inflammageing prevents or delays the onset of cardiovascular frailty should be tested in clinical trials.
Muscle Wasting Diseases: Novel Targets and Treatments.
Furrer Regula,Handschin Christoph
Annual review of pharmacology and toxicology
Adequate skeletal muscle plasticity is an essential element for our well-being, and compromised muscle function can drastically affect quality of life, morbidity, and mortality. Surprisingly, however, skeletal muscle remains one of the most under-medicated organs. Interventions in muscle diseases are scarce, not only in neuromuscular dystrophies, but also in highly prevalent secondary wasting pathologies such as sarcopenia and cachexia. Even in other diseases that exhibit a well-established risk correlation of muscle dysfunction due to a sedentary lifestyle, such as type 2 diabetes or cardiovascular pathologies, current treatments are mostly targeted on non-muscle tissues. In recent years, a renewed focus on skeletal muscle has led to the discovery of various novel drug targets and the design of new pharmacological approaches. This review provides an overview of the current knowledge of the key mechanisms involved in muscle wasting conditions and novel pharmacological avenues that could ameliorate muscle diseases.
Cachexia, muscle wasting, and frailty in cardiovascular disease.
Bielecka-Dabrowa Agata,Ebner Nicole,Dos Santos Marcelo Rodrigues,Ishida Junishi,Hasenfuss Gerd,von Haehling Stephan
European journal of heart failure
The last several years have seen increasing interest in understanding cachexia, muscle wasting, and physical frailty across the broad spectrum of patients with cardiovascular illnesses. This interest originally started in the field of heart failure, but has recently been extended to other areas such as atrial fibrillation, coronary artery disease, peripheral artery disease as well as to patients after cardiac surgery or transcatheter aortic valve implantation. Tissue wasting and frailty are prevalent among many of the affected patients. The ageing process itself and concomitant cardiovascular illness decrease lean mass while fat mass is relatively preserved, making elderly patients particularly prone to develop wasting syndromes and frailty. The aim of this review is to provide an overview of the available knowledge of body wasting and physical frailty in patients with cardiovascular illness, particularly focussing on patients with heart failure in whom most of the available data have been gathered. In addition, mechanisms of wasting and possible therapeutic targets are discussed.
Microvascular Dysfunction in Diabetes Mellitus and Cardiometabolic Disease.
Horton William B,Barrett Eugene J
This review takes an inclusive approach to microvascular dysfunction in diabetes mellitus and cardiometabolic disease. In virtually every organ, dynamic interactions between the microvasculature and resident tissue elements normally modulate vascular and tissue function in a homeostatic fashion. This regulation is disordered by diabetes mellitus, by hypertension, by obesity, and by dyslipidemia individually (or combined in cardiometabolic disease), with dysfunction serving as an early marker of change. In particular, we suggest that the familiar retinal, renal, and neural complications of diabetes mellitus are late-stage manifestations of microvascular injury that begins years earlier and is often abetted by other cardiometabolic disease elements (eg, hypertension, obesity, dyslipidemia). We focus on evidence that microvascular dysfunction precedes anatomic microvascular disease in these organs as well as in heart, muscle, and brain. We suggest that early on, diabetes mellitus and/or cardiometabolic disease can each cause reversible microvascular injury with accompanying dysfunction, which in time may or may not become irreversible and anatomically identifiable disease (eg, vascular basement membrane thickening, capillary rarefaction, pericyte loss, etc.). Consequences can include the familiar vision loss, renal insufficiency, and neuropathy, but also heart failure, sarcopenia, cognitive impairment, and escalating metabolic dysfunction. Our understanding of normal microvascular function and early dysfunction is rapidly evolving, aided by innovative genetic and imaging tools. This is leading, in tissues like the retina, to testing novel preventive interventions at early, reversible stages of microvascular injury. Great hope lies in the possibility that some of these interventions may develop into effective therapies.
Definition and classification of cancer cachexia: an international consensus.
Fearon Kenneth,Strasser Florian,Anker Stefan D,Bosaeus Ingvar,Bruera Eduardo,Fainsinger Robin L,Jatoi Aminah,Loprinzi Charles,MacDonald Neil,Mantovani Giovanni,Davis Mellar,Muscaritoli Maurizio,Ottery Faith,Radbruch Lukas,Ravasco Paula,Walsh Declan,Wilcock Andrew,Kaasa Stein,Baracos Vickie E
The Lancet. Oncology
To develop a framework for the definition and classification of cancer cachexia a panel of experts participated in a formal consensus process, including focus groups and two Delphi rounds. Cancer cachexia was defined as a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Its pathophysiology is characterised by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. The agreed diagnostic criterion for cachexia was weight loss greater than 5%, or weight loss greater than 2% in individuals already showing depletion according to current bodyweight and height (body-mass index [BMI] <20 kg/m(2)) or skeletal muscle mass (sarcopenia). An agreement was made that the cachexia syndrome can develop progressively through various stages--precachexia to cachexia to refractory cachexia. Severity can be classified according to degree of depletion of energy stores and body protein (BMI) in combination with degree of ongoing weight loss. Assessment for classification and clinical management should include the following domains: anorexia or reduced food intake, catabolic drive, muscle mass and strength, functional and psychosocial impairment. Consensus exists on a framework for the definition and classification of cancer cachexia. After validation, this should aid clinical trial design, development of practice guidelines, and, eventually, routine clinical management.
Age-related and disease-related muscle loss: the effect of diabetes, obesity, and other diseases.
Kalyani Rita Rastogi,Corriere Mark,Ferrucci Luigi
The lancet. Diabetes & endocrinology
The term sarcopenia refers to the loss of muscle mass that occurs with ageing. On the basis of study results showing that muscle mass is only moderately related to functional outcomes, international working groups have proposed that loss of muscle strength or physical function should also be included in the definition. Irrespective of how sarcopenia is defined, both low muscle mass and poor muscle strength are clearly highly prevalent and important risk factors for disability and potentially mortality in individuals as they age. Many chronic diseases, in addition to ageing, could also accelerate decrease of muscle mass and strength, and this effect could be a main underlying mechanism by which chronic diseases cause physical disability. In this Review, we address both age-related and disease-related muscle loss, with a focus on diabetes and obesity but including other disease states, and potential common mechanisms and treatments. Development of treatments for age-related and disease-related muscle loss might improve active life expectancy in older people, and lead to substantial health-care savings and improved quality of life.
Sarcopenic obesity in older adults: aetiology, epidemiology and treatment strategies.
Batsis John A,Villareal Dennis T
Nature reviews. Endocrinology
The prevalence of obesity in combination with sarcopenia (the age-related loss of muscle mass and strength or physical function) is increasing in adults aged 65 years and older. A major subset of adults over the age of 65 is now classified as having sarcopenic obesity, a high-risk geriatric syndrome predominantly observed in an ageing population that is at risk of synergistic complications from both sarcopenia and obesity. This Review discusses pathways and mechanisms leading to muscle impairment in older adults with obesity. We explore sex-specific hormonal changes, inflammatory pathways and myocellular mechanisms leading to the development of sarcopenic obesity. We discuss the evolution, controversies and challenges in defining sarcopenic obesity and present current body composition modalities used to assess this condition. Epidemiological surveys form the basis of defining its prevalence and consequences beyond comorbidity and mortality. Current treatment strategies, and the evidence supporting them, are outlined, with a focus on calorie restriction, protein supplementation and aerobic and resistance exercises. We also describe weight loss-induced complications in patients with sarcopenic obesity that are relevant to clinical management. Finally, we review novel and potential future therapies including testosterone, selective androgen receptor modulators, myostatin inhibitors, ghrelin analogues, vitamin K and mesenchymal stem cell therapy.
Cruz-Jentoft Alfonso J,Sayer Avan A
Lancet (London, England)
Sarcopenia is a progressive and generalised skeletal muscle disorder involving the accelerated loss of muscle mass and function that is associated with increased adverse outcomes including falls, functional decline, frailty, and mortality. It occurs commonly as an age-related process in older people, influenced not only by contemporaneous risk factors, but also by genetic and lifestyle factors operating across the life course. It can also occur in mid-life in association with a range of conditions. Sarcopenia has become the focus of intense research aiming to translate current knowledge about its pathophysiology into improved diagnosis and treatment, with particular interest in the development of biomarkers, nutritional interventions, and drugs to augment the beneficial effects of resistance exercise. Designing effective preventive strategies that people can apply during their lifetime is of primary concern. Diagnosis, treatment, and prevention of sarcopenia is likely to become part of routine clinical practice.