Plasma-Free Fatty Acids and Mortality in Older Adults
Editor's Note: Commentary based on Miedema MD, Maziarz M, Biggs ML, et al. Plasma-free fatty acids, fatty acid-binding protein 4, and mortality in older adults (from the Cardiovascular Health Study). Am J Cardiol 2014;114:843-8.
The association between plasma-free fatty acids (FFAs) and insulin resistance/type 2 diabetes,1 hypertension (HTN),2 cardiovascular disease (CVD),3 stroke,4 and atrial fibrillation5 is well-known. Fatty acid-binding protein (FABP4) is a carrier protein for FFAs and, like FFA, FABP4 has also been associated with CVD, including heart failure6 and sudden cardiac death.7 Even with this background, there is limited data on the association of FFA and FABP4 with mortality, and studies to date have shown mixed results.8-10 In this study, Meidema et al. evaluated the association of FFA and FABP4 with total and cause-specific mortality in older individuals.11
FFA and FABP4 were measured from plasma samples collected from 4,707 subjects enrolled in the Cardiovascular Health Study (CHS), a prospective cohort of subjects aged >65 years, recruited in 1992-93 from a random sample of Medicare-eligible residents. Subjects were followed prospectively for all-cause, CV, and non-CV mortality.
The mean age of the study population was 75 years with 58% females and the majority Caucasians. The median follow-up time was close to 12 years, during which time over 75% of subjects died. Mortality rates per 1,000 person-years for quartiles of FFA were 61.6, 62.9, 67.4, and 71.3, respectively. Similarly, the corresponding mortality rates per 1,000 person-years for quartiles of FABP4 were 65.7, 65.4, 61.1, and 70.7, respectively. No significant interaction was found between FFA and FABP4 and mortality (p = 0.45). In multivariable-adjusted models, increasing FFA [hazard ratio (HR): 1.14, (1.09 to 1.18)], but not FABP4 [HR: 1.04 (0.98 to 1.09)], was associated with total mortality. The authors, however, did find a gender-specific association between FABP4 and mortality in men [HR= 1.17 (1.08 -1.26)] but not in women [HR= 1.02 (0.96-1.07); interaction p value <0.001). Furthermore, higher levels of FFA were also associated with cause-specific death: CV death [HR=1.08 (1.01-1.15), p=0.02], dementia related death [HR=1.32 (1.20-1.44), p<0.001], infection related death [HR= 1.25 (1.10-1.41, p= 0.001], respiratory death [HR=1.23 (1.06-1.43), p=0.007), and other causes of death [HR=1.16 (1.03, 1.31), p=0.02].
In this large prospective study of elderly community dwellers with a follow up of almost 12 years, higher levels of FFA, but not FABP4, were associated with mortality from multiple causes, even after adjusting for multiple chronic medical conditions, including diabetes. The authors postulated that mechanisms other than adiposity and insulin resistance may have contributed to mortality in patients with high circulating FFA levels. Elevated FFA levels may simply be a marker of poor overall health, leading to an increased risk of both CV and non-CV mortality. Previously, studies have shown that high FFA levels are associated with dementia and stimulate polymerization of the dysfunctional proteins in Alzheimer's disease.12 In addition, FFAs have also been associated with inflammatory states,13 which may partially explain the association with increased mortality.
In addition, it is known that increased lipolysis is a part of catabolic process associated with several chronic diseases as well as aging. Thus, FFA levels may be a byproduct of a larger general process of aging and/ or chronic debility associated with old age or chronic medical diseases. Nevertheless, a causative role of FFA in certain chronic conditions cannot be ruled out. It is known that high FFA levels can lead to vascular endothelial disorders, insulin resistance, and diabetes.13 Similarly, high FFA concentration has been shown in studies to affect gene expression with possible carcinogenic effects in predisposed individuals.
The study has several strengths. It included a large cohort with an adequate number of deaths over a long follow-up period. Both genders were equally represented. In the end, the authors were able to show a significant association between elevated FFA levels and CV and non-CV mortality. However, no association was seen between FABP4 and mortality. This is inconsistent with previous studies.6,7 Reason for this differential association of FFA and FABP4 on mortality in the same cohort is not entirely clear. The gender-specific association of FABP4 with mortality in men but not women was an interesting finding, which may be related to differential fat distribution in men and women, even more so in older subjects.
The study population consisted of predominantly Caucasian subjects. Whether the association of FFA with mortality also exists in other ethnicities is not entirely clear. Although there were adequate numbers of deaths for statistical power, the high mortality rate in the study due to the age of the study population, on the order of 60 per 1,000 person/years across all quartiles of the FFA levels may have, by itself, diluted the statistical significance of association of FFA and FABP4 with mortality. Dysfunction in lipid handling with age and an age‐associated abnormality in fat metabolism have been described in animal models.14 It would be a reasonable to assume that such changes in lipid handling would also be seen in humans.15
The blood sample was drawn during the index visit, but serial measurements were not obtained. Whether serial changes in the levels of FFA and FABP4 affect long term mortality is not known. Lastly, stability of FFA and FABP4 after prolonged storage is not known.
In conclusion, the study shows an association of elevated plasma FFA levels with CV and non-CV mortality in an older population. However, the small effect size of the association with mortality as well as its non-specific association with different causes of mortality does limit its use for risk stratification in an asymptomatic population. Nevertheless, it does highlight, once again, that abnormalities in fat metabolism may be at the heart of age-related, all-cause mortality.
- Pankow JS, Duncan BB, Schmidt MI, et al. Fasting plasma free fatty acids and risk of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes Care 2004;27:77-82.
- Fagot-Campagna A, Balkau B, Simon D, et al. High free fatty acid concentration: an independent risk factor for hypertension in the Paris Prospective Study. Int J Epi 1998;27:808-13.
- Matteo P, Mauriège P, Tchernof A, et al. Plasma free fatty acid levels and the risk of ischemic heart disease in men: prospective results from the Québec Cardiovascular Study. Atherosclerosis 2002;160:377-84.
- Khawaja O, Maziarz M, Biggs ML, et al. Plasma free fatty acids and risk of stroke in the Cardiovascular Health Study. Int J Stroke 2014;9:917-20.
- Khawaja O, Bartz TM, Ix JH, et al. Plasma free fatty acids and risk of atrial fibrillation (from the Cardiovascular Health Study). Am J Cardiol 2012;110:212-6.
- Fernández-Real JM, Broch M, Vendrell J, Ricart W. Insulin resistance, inflammation, and serum fatty acid composition. Diabetes Care 2003;26:1362-8.
- Djoussé L, Bartz TM, Ix JH, et al. Fatty acid-binding protein 4 and incident heart failure: the Cardiovascular Health Study. Eur J Heart Fail 2013;15:394-9.
- Djoussé L, Maziarz M, Biggs ML, et al. Plasma fatty acid binding protein 4 and risk of sudden cardiac death in older adults. Cardiol Res Pract 2013;2013:181054.
- Pilz S, Scharnagl H, Tiran B, et al. Free fatty acids are independently associated with all-cause and cardiovascular mortality in subjects with coronary artery disease. J Clin Endocrinol Metab 2006;91:2542-7.
- Charles MA, Fontbonne A, Thibult N, et al. High plasma nonesterified fatty acids are predictive of cancer mortality but not of coronary heart disease mortality: results from the Paris Prospective Study. Am J Epidemiol 2001;153:292-8.
- Miedema MD, Maziarz M, Biggs ML, et al. Plasma-free fatty acids, fatty acid-binding protein 4, and mortality in older adults (from the Cardiovascular Health Study). Am J Cardiol 2014;114:843-8.
- Wilson DA, Binder LI. Free fatty acids stimulate the polymerization of tau and amyloid beta peptides. In vitro evidence for a common effector of pathogenesis in Alzheimer's disease. Am J Pathol 1997;150:2181-95.
- Tripathy D, Mohanty P, Dhindsa S, et al. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes 2003;52:2882-7.
- Donato AJ, Henson GD, Hart CR, et al. The impact of ageing on adipose structure, function and vasculature in the B6D2F1 mouse: evidence of significant multisystem dysfunction. J Physiol 2014;592:4083-96.
- Adams KF, Leitzmann MF, Ballard-Barbash R, et al. Body mass and weight change in adults in relation to mortality risk. Am J Epidemiol 2014;179:135-44.
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