Rachel A. Murphy

Cancer Cachexia in the Age of Obesity: Skeletal Muscle Depletion Is a Powerful Prognostic Factor, Independent of Body Mass Index

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.

Dietary and Supplemental Calcium Intake and Cardiovascular Disease Mortality: The National Institutes of Health–AARP Diet and Health Study

IMPORTANCE Calcium intake has been promoted because of its proposed benefit on bone health, particularly among the older population. However, concerns have been raised about the potential adverse effect of high calcium intake on cardiovascular health. OBJECTIVE To investigate whether intake of dietary and supplemental calcium is associated with mortality from total cardiovascular disease (CVD), heart disease, and cerebrovascular diseases. DESIGN AND SETTING Prospective study from 1995 through 1996 in California, Florida, Louisiana, New Jersey, North Carolina, and Pennsylvania and the 2 metropolitan areas of Atlanta, Georgia, and Detroit, Michigan. PARTICIPANTS A total of 388 229 men and women aged 50 to 71 years from the National Institutes of Health-AARP Diet and Health Study. MAIN OUTCOME MEASURES Dietary and supplemental calcium intake was assessed at baseline (1995-1996). Supplemental calcium intake included calcium from multivitamins and individual calcium supplements. Cardiovascular disease deaths were ascertained using the National Death Index. Multivariate Cox proportional hazards regression models adjusted for demographic, lifestyle, and dietary variables were used to estimate relative risks (RRs) and 95% CIs. RESULTS During a mean of 12 years of follow-up, 7904 and 3874 CVD deaths in men and women, respectively, were identified. Supplements containing calcium were used by 51% of men and 70% of women. In men, supplemental calcium intake was associated with an elevated risk of CVD death (RR>1000 vs 0 mg/d, 1.20; 95% CI, 1.05-1.36), more specifically with heart disease death (RR, 1.19; 95% CI, 1.03-1.37) but not significantly with cerebrovascular disease death (RR, 1.14; 95% CI, 0.81-1.61). In women, supplemental calcium intake was not associated with CVD death (RR, 1.06; 95% CI, 0.96-1.18), heart disease death (1.05; 0.93-1.18), or cerebrovascular disease death (1.08; 0.87-1.33). Dietary calcium intake was unrelated to CVD death in either men or women. CONCLUSIONS AND RELEVANCE Our findings suggest that high intake of supplemental calcium is associated with an excess risk of CVD death in men but not in women. Additional studies are needed to investigate the effect of supplemental calcium use beyond bone health.

n-3 polyunsaturated fatty acids: the potential role for supplementation in cancer.

Purpose of reviewn-3 polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid have been implicated as potential mediators in pathways involved in cancer cachexia. This review summarizes recent findings on the n-3 fatty acid status of patients with cancer, the effects of n-3 fatty acid supplementation on weight and lean body mass and the potential role of supplementation during antineoplastic therapy. Recent findingsDue to suboptimal intakes and possible metabolic disturbances, physiological concentrations of n-3 fatty acids are low in patients with cancer. Low n-3 fatty acids are associated with loss of skeletal muscle, suggesting a need for supplementation. Recent trials have shown an effect of n-3 supplementation throughout antineoplastic therapy on weight, lean body mass and treatment outcomes. Attenuation or gain of weight and lean body mass was reported and the first clinical trials of n-3 fatty acids as an adjuvant to chemotherapy treatment suggest improved efficacy and milder treatment toxicity with n-3 fatty acid supplementation. SummaryRecent evidence appears to favour providing n-3 fatty acids early in the disease trajectory, during antineoplastic therapy for preservation of muscle and also to improve treatment tolerance. Additional, larger trials are needed to define these relationships further but it appears that fish oil has broad therapeutic potential in patients with cancer.

Association between Objectively Measured Physical Activity and Mortality in NHANES.

PURPOSE We examined total activity, light activity, and moderate-to-vigorous physical activity (MVPA) as predictors of mortality in a nationally representative sample of older adults. Then we explored the theoretical consequences of replacing sedentary time with the same duration of light activity or MVPA. METHODS Using accelerometer-measured activity, the associations between total activity, light activity (100-2019 counts per minute), and MVPA (>2019 counts per minute) counts and mortality were examined in adults age 50 to 79 yr in the National Health and Nutrition Examination Survey, 2003-2006 (n = 3029), with mortality follow-up through December 2011. Cox proportional hazard models were fitted to estimate mortality risks. An isotemporal substitution model was used to examine the theoretical consequences of replacing sedentary time with light activity or MVPA on mortality. RESULTS After adjusting for potential confounders, including age, sex, race/ethnicity, education, BMI, and the presence of comorbid conditions, those in the highest tertile of total activity counts had one fifth the risk of death of those in the lowest tertile (hazard ratio [HR] = 0.21, 95% confidence interval [CI] = 0.12-0.38), and those in the middle tertile had one third the risk of death (HR = 0.36, 95% CI = 0.30-0.44). In addition, replacing 30 min of sedentary time with light activity was associated with significant reduction in mortality risk (after 5 yr of follow-up: HR = 0.80, 95% CI = 0.75-0.85). Replacing 30 min of sedentary time with MVPA was also associated with reduction in mortality risk (HR = 0.49, 95% CI = 0.25-0.97). CONCLUSIONS Greater total activity is associated with lower all-cause mortality risk. Replacing sedentary time with light activity or MVPA may reduce mortality risk for older adults.

Changes in daily activity patterns with age in U.S. men and women: National Health and Nutrition Examination Survey 2003-04 and 2005-06.

To compare daily and hourly activity patterns according to sex and age.

Adipose Tissue Density, a Novel Biomarker Predicting Mortality Risk in Older Adults

BACKGROUND Knowledge of adipose composition in relation to mortality may help delineate inconsistent relationships between obesity and mortality in old age. We evaluated relationships between abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) density, mortality, biomarkers, and characteristics. METHODS VAT and SAT density were determined from computed tomography scans in persons aged 65 and older, Health ABC (n = 2,735) and AGES-Reykjavik (n = 5,131), and 24 nonhuman primates (NHPs). Associations between adipose density and mortality (4-13 years follow-up) were assessed with Cox proportional hazards models. In NHPs, adipose density was related to serum markers and tissue characteristics. RESULTS Higher density adipose tissue was associated with mortality in both studies with adjustment for risk factors including adipose area, total fat, and body mass index. In women, hazard ratio and 95% CI for the densest quintile (Q5) versus least dense (Q1) for VAT density were 1.95 (1.36-2.80; Health ABC) and 1.88 (1.31-2.69; AGES-Reykjavik) and for SAT density, 1.76 (1.35-2.28; Health ABC) and 1.56 (1.15-2.11; AGES-Reykjavik). In men, VAT density was associated with mortality in Health ABC, 1.52 (1.12-2.08), whereas SAT density was associated with mortality in both Health ABC, 1.58 (1.21-2.07), and AGES-Reykjavik, 1.43 (1.07-1.91). Higher density adipose tissue was associated with smaller adipocytes in NHPs. There were no consistent associations with inflammation in any group. Higher density adipose tissue was associated with lower serum leptin in Health ABC and NHPs, lower leptin mRNA expression in NHPs, and higher serum adiponectin in Health ABC and NHPs. CONCLUSION VAT and SAT density provide a unique marker of mortality risk that does not appear to be inflammation related.

Weight change, body composition, and risk of mobility disability and mortality in older adults: a population-based cohort study.

To examine associations between weight change, body composition, risk of mobility disability, and mortality in older adults.

Dietary sodium content, mortality, and risk for cardiovascular events in older adults: the Health, Aging, and Body Composition (Health ABC) Study.

IMPORTANCE Additional information is needed about the role of dietary sodium on health outcomes in older adults. OBJECTIVE To examine the association between dietary sodium intake and mortality, incident cardiovascular disease (CVD), and incident heart failure (HF) in older adults. DESIGN, SETTING, AND PARTICIPANTS We analyzed 10-year follow-up data from 2642 older adults (age range, 71-80 years) participating in a community-based, prospective cohort study (inception between April 1, 1997, and July 31, 1998). EXPOSURES Dietary sodium intake at baseline was assessed by a food frequency questionnaire. We examined sodium intake as a continuous variable and as a categorical variable at the following levels: less than 1500 mg/d (291 participants [11.0%]), 1500 to 2300 mg/d (779 participants [29.5%]), and greater than 2300 mg/d (1572 participants [59.5%]). MAIN OUTCOMES AND MEASURES Adjudicated death, incident CVD, and incident HF during 10 follow-up years. Analysis of incident CVD was restricted to 1981 participants without prevalent CVD at baseline. RESULTS The mean (SD) age of participants was 73.6 (2.9) years, 51.2% were female, 61.7% were of white race, and 38.3% were black. After 10 years, 881 participants had died, 572 had developed CVD, and 398 had developed HF. In adjusted Cox proportional hazards regression models, sodium intake was not associated with mortality (hazard ratio [HR] per 1 g, 1.03; 95% CI, 0.98-1.09; P = .27). Ten-year mortality was nonsignificantly lower in the group receiving 1500 to 2300 mg/d (30.7%) than in the group receiving less than 1500 mg/d (33.8%) and the group receiving greater than 2300 mg/d (35.2%) (P = .07). Sodium intake of greater than 2300 mg/d was associated with nonsignificantly higher mortality in adjusted models (HR vs 1500-2300 mg/d, 1.15; 95% CI, 0.99-1.35; P = .07). Indexing sodium intake for caloric intake and body mass index did not materially affect the results. Adjusted HRs for mortality were 1.20 (95% CI, 0.93-1.54; P = .16) per milligram per kilocalorie and 1.11 (95% CI, 0.96-1.28; P = .17) per 100 mg/kg/m2 of daily sodium intake. In adjusted models accounting for the competing risk for death, sodium intake was not associated with risk for CVD (subHR per 1 g, 1.03; 95% CI, 0.95-1.11; P = .47) or HF (subHR per 1 g, 1.00; 95% CI, 0.92-1.08; P = .92). No consistent interactions with sex, race, or hypertensive status were observed for any outcome. CONCLUSIONS AND RELEVANCE In older adults, food frequency questionnaire-assessed sodium intake was not associated with 10-year mortality, incident CVD, or incident HF, and consuming greater than 2300 mg/d of sodium was associated with nonsignificantly higher mortality in adjusted models.

The QT interval and risk of incident atrial fibrillation

BACKGROUND Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine. OBJECTIVE To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF. METHODS We examined a prolonged QT interval corrected by using the Framingham formula (QT(Fram)) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by using other formulas. RESULTS Among 14,538 ARIC study participants, a prolonged QT(Fram) predicted a roughly 2-fold increased risk of AF (hazard ratio [HR] 2.05; 95% confidence interval [CI] 1.42-2.96; P < .001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in Cardiovascular Health Study and Health, Aging, and Body Composition study and were similar across various QT correction methods. Also in the ARIC study, each 10-ms increase in QT(Fram) was associated with an increased unadjusted (HR 1.14; 95% CI 1.10-1.17; P < .001) and adjusted (HR 1.11; 95% CI 1.07-1.14; P < .001) risk of AF. Findings regarding a short QT interval were inconsistent across cohorts. CONCLUSIONS A prolonged QT interval is associated with an increased risk of incident AF.

Associations of BMI and adipose tissue area and density with incident mobility limitation and poor performance in older adults

BACKGROUND Obesity is a risk factor for disability, but risk of specific adipose depots is not completely understood. OBJECTIVE We investigated associations between mobility limitation, performance, and the following adipose measures: body mass index (BMI) and areas and densities of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and intermuscular adipose tissue (IMAT) in older adults. DESIGN This was a prospective population-based study of men (n = 1459) and women (n = 1552) initially aged 70-79 y and free from mobility limitation. BMI was determined from measured height and weight. Adipose tissue area and density in Hounsfield units were measured in the thigh and abdomen by using computed tomography. Mobility limitation was defined as 2 consecutive reports of difficulty walking one-quarter mile or climbing 10 steps during semiannual assessments over 13 y. Poor performance was defined as a gait speed <1 m/s after 9 y of follow-up (n = 1542). RESULTS In models adjusted for disability risk factors, BMI, and areas of VAT, abdominal SAT, and IMAT were positively associated with mobility limitation in men and women. In women, thigh SAT area was positively associated with mobility limitation risk, whereas VAT density was inversely associated. Associations were similar for poor performance. BMI and thigh IMAT area (independent of BMI) were particularly strong indicators of incident mobility limitation and poor performance. For example, in women, the HR (95% CI) and OR (95% CI) associated with an SD increment in BMI for mobility limitation and poor performance were 1.31 (1.21, 1.42) and 1.41 (1.13, 1.76), respectively. In men, the HR (95% CI) and OR (95% CI) associated with an SD increment in thigh IMAT for mobility limitation and poor performance were 1.37 (1.27, 1.47) and 1.54 (1.18, 2.02), respectively. CONCLUSIONS Even into old age, higher BMI is associated with mobility limitation and poor performance. The amount of adipose tissue in abdominal and thigh depots may also convey risk beyond BMI.