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American Journal of Clinical Nutrition, Vol. 88, No. 3, 722-729, September 2008
© 2008 American Society for Nutrition

ORIGINAL RESEARCH COMMUNICATION

Long-chain n–3 fatty acids and mortality in elderly patients1,2,3

Morten Lindberg, Ingvild Saltvedt, Olav Sletvold and Kristian S Bjerve

1 From the Department of Medical Biochemistry, St Olavs Hospital, Trondheim University Hospital and Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway (ML and KSB), and Section of Geriatrics, Department of Internal Medicine, St Olavs Hospital, Trondheim University Hospital and Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway (IS and OS)

See corresponding editorial on page 595.

2 Supported in part by grants from The Research Council of Norway, The Norwegian Cancer Society and The Cancer Fund at St Olavs Hospital.

3 Reprints not available. Address correspondence to M Lindberg, Department of Medical Biochemistry, St Olavs Hospital, N-7006 Trondheim, Norway. E-mail: morten.lindberg{at}stolav.no.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Long-chain n–3 fatty acids may favorably modulate many diseases. The evidence is firm for coronary heart disease, less certain for stroke, and only speculative for other diseases. The impact of these fatty acids on mortality among acutely sick elderly patients is unknown.

Objective: The objective was to investigate the relation between long-chain n–3 fatty acids and overall mortality in acutely sick elderly patients.

Design: Frail, elderly patients (n = 254) acutely admitted to St Olavs Hospital in central Norway were examined. The plasma phospholipid concentration of eicosapentaenoic acid (EPA) was used as a surrogate marker for dietary intake of marine fatty acids. Mortality rates were evaluated after 3 y of follow-up. Cox proportional hazard analysis was used to calculate hazard ratios adjusted for important biochemical and clinical covariates.

Results: The hazard ratio of overall mortality was significantly higher in patients with EPA concentrations in the lowest quartile than in patients in the upper 3 quartiles (adjusted hazard ratio: 0.52; 95% CI: 0.35, 0.77). The upper 3 quartiles were not significantly different from one another (P = 0.94).

Conclusions: Overall mortality in frail, elderly, acutely sick patients was inversely and nonlinearly associated with EPA concentrations. Approximately 25% of the population had EPA concentrations below the indicated threshold for maximal protection, suggesting that only this part of the population might have benefited from additional EPA intake.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Long-chain n–3 fatty acids are essential in human nutrition (1). They play an important role in the development and function of several organs (eg, brain, heart, and reproduction organs) as well as in the immune system. Since the first observations of the low frequency of coronary heart disease among Eskimos exposed to a diet rich in fish oil (2), these substances have received great interest from medical researchers. Dietary n–3 fatty acids favorably modulate many diseases (3). The evidence is strongest for coronary heart disease and stroke (4-7), but reports of the relation between long-chain n–3 fatty acids and other conditions, such as autoimmune disorders (8), hypertension (9), and certain cancers (10), are abundant. There is little controversy concerning the beneficial effect of these fatty acids, but the mechanisms through which they exhibit their effects are only partly understood. The antiarrhythmic properties of long-chain n–3 fatty acids and their modulation of platelet activity are considered the main mechanisms responsible for reducing the incidence of fatal cardiac arrest (11, 12).

Data concerning long-chain n–3 fatty acid dietary intake on overall mortality in populations consisting of elderly people are limited (13-16). The present study focused on frail, elderly, acutely sick patients admitted to a general medical ward, where they often represent a substantial proportion of the patients. The proportion of elderly people in the general population is increasing. It is therefore important to establish factors that influence their morbidity and mortality.

We investigated whether n–3 fatty acid nutritional status at admission was associated with survival rate in elderly patients admitted acutely to a general medical ward. The n–3 fatty acid nutritional status was indirectly assessed by analyzing plasma total phospholipid fatty acid concentrations (17).


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
St Olavs Hospital serves as the regional hospital of central Norway as well as the local hospital for 160 000 inhabitants in the city of Trondheim. Frail, elderly patients admitted acutely to The Department of Internal Medicine were eligible for the study. To target frail patients eligible for inclusion, Winograd et al's (18) targeting criteria were applied. These have been shown to predict patients most at risk of nursing home placement and death (18, 19). Briefly, eligible patients had to meet at least one of the following targeting criteria: acute impairment of single activity of daily life, imbalance or dizziness, impaired mobility, chronic disability, weight loss, a fall during the previous 3 mo, confusion, vision or hearing impairment, depression, malnutrition, mild or moderate dementia, urinary incontinence, social or family problems, polypharmacy (≥5 drugs/d), and prolonged bed rest. The included patients met a median of 4 (interquartile range: 3–5) of the Winograd targeting criteria.

After admission, the patients were evaluated clinically. If included, the patients were randomly assigned to further treatment at either one of the general medical wards or at a newly established Geriatric Evaluation and Management Unit (GEMU). Details of the clinical evaluation and inclusion criteria are published elsewhere (20). During the period from October 1994 to November 1995, a total of 254 patients were included. Date and causes of death were collected from death certificates. Patients were followed for 3 y, and none were lost during follow-up.

Activities of daily living functionality were assessed by using the Barthel Index (BI) (21), as described by Colin et al (22). The BI is a validated measure of disability and is a representative measure of activities of daily living indexes. The index was reclassified into group 1 (poor, BI = 1–4), group 2 (BI = 5–9), group 3 (BI = 10–14), and group 4 (good, BI = 15–20) before being entered into the proportional hazard analysis.

Smoking status was through interviews and the measurement of serum cotinine concentrations (Immulite2000 Nicotine Metabolite; Diagnostic Products Corporation, Los Angeles, CA) on the basis of a cutoff value of 25 mg/L to distinguish smoking status. Eleven percent of the study subjects were current smokers.

Blood samples were collected at admission and after 3 and 6 mo. Serum and plasma samples were stored at –80 °C until analyzed, if not analyzed immediately. LDL cholesterol was estimated by using the Friedewald formula, ie, LDL-cholesterol = total cholesterol –HDL cholesterol –(0.45 x triacylglycerols) if triacylglycerols were <4.5 mmol/L. Total cholesterol, HDL cholesterol, triacylglycerol, hemoglobin, glucose, C-reactive protein, alanine aminotransferase, creatinine, sodium, potassium, calcium, and ferritin concentrations were measured by using routine laboratory methods. Albumin, retinol binding protein, and prealbumin were measured by nephelometry using calibrators and reagents from Dade Behring (Marburg, Germany). Zinc was analyzed by using atomic absorption spectrometry, and {alpha}-carotene, β-carotene, {alpha}-tocopherol, {gamma}-tocopherol, and {delta}-tocopherol were analyzed by HPLC, essentially as described by Nierenberg and Nann (23). Plasma phospholipid fatty acid concentrations were measured as milligrams phospholipid fatty acids per liter of plasma using capillary gas chromatography as previously described (17) and recalculated to a percentage by weight (% by wt) on the basis of 22 identified fatty acids.

Participation in the trial was voluntary and in accordance with the Helsinki Declaration. Written informed consent was obtained from all patients, except from those who were not able to write, in which case oral consent was accepted. If the patient was cognitively impaired, relatives also gave their written consent. The regional ethical committee approved the protocol.

Statistical analysis
For baseline characteristics, means, SDs, or medians (interquartile ranges) and proportions were calculated. The significance of the association was tested with the chi-square statistic for categorical variables and with Wilcoxon's rank-sum test for continuous variables. The reported P values are 2-sided, and the CIs were computed at the 95% level.

The Kaplan-Meier method was used to create unadjusted survival curves. To test for differences in survivor functions among quartiles of eicosapentaenoic acid (EPA) concentrations, the SAS Lifetest procedure was used with the strata statement to calculate Wilcoxon's statistics. This is also referred to as the Gehan test or the Breslow test and allows comparison of the 4 quartiles simultaneously.

The research protocol defined EPA concentration as the surrogate variable for effective long-chain marine fatty acid dietary intake. There was considerable correlation among the n–3 fatty acids (a complete correlation matrix was calculated). To investigate the significance of different fatty acids on overall mortality, we performed a stepwise selection including 18:3n–3, 20:5n–3, 22:6n–3, and the sum of n–3 fatty acids using P = 0.25 for entering the model and P = 0.05 for staying. EPA (20:5n–3) was the only n–3 fatty acid entering this model. To further investigate possible contributions from other biologically relevant fatty acids, hazard ratios (HRs) were calculated for linoleic acid (18:2n–6), dihomo {gamma}-linolenic acid (20:3n–6), arachidonic acid (20:4n–6), {alpha}-linolenic acid (18:3n–3), EPA (20:5n–3), and docosahexaenoic acid (DHA, or 22:6n–3).

Cox proportional hazards models were used to estimate risk, with censoring at death or 3 y of follow-up. Trend was assessed by assigning ordinal values for categorical variables. In building the regression model, covariates were selected on the basis of clinical relevance and known major risk factors of death in the elderly. In addition to the unadjusted model, 2 multivariate models were built: model 1 was adjusted for age, sex, assignment to GEMU treatment, BI, residence (private home or sheltered housing), and model 2 was further adjusted for current smoking status, history of cardiovascular disease (CVD; defined as patients who received a diagnosis of CVD before inclusion, received a diagnosis of CVD during the index stay, or were treated with medication prescribed for CVD), HDL cholesterol, LDL cholesterol, prealbumin, and {alpha}-tocopherol. Data analysis was performed by using SAS/STAT software version 9.1.3 (SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Baseline plasma phospholipid fatty acid concentrations and characteristics of the total population at baseline are given in Table 1Go and Table 2Go, respectively. The mean age of the total population was 82.1 y (range: 72.5–97.7 y). Baseline characteristics are given for the total population, for the low-EPA group (which consisted of subjects in the lowest EPA quartile; n = 63), and for the high-EPA group (which consisted of subjects in the upper 3 quartiles; n = 191) because the subsequent statistical data analysis indicated that the low-EPA group differed from the high-EPA group. Quartiles 1 through 4 were defined as follows on the basis of % by wt of EPA: quartile 1, ≤1.25; quartile 2, >1.25 to ≤1.69; quartile 3, >1.69 to ≤2.25; and quartile 4, >2.25. A correlation matrix of all fatty acid concentrations is presented in Table 3Go. As expected, many fatty acids were significantly correlated. In the present context, EPA was highly and positively correlated with 22:6n–3 (r = 0.61) and negatively correlated with 18:2n–6 and 20:4n–6 (r = –0.50 and r = –0.22, respectively). However, neither changes in 22:6n–3, 20:4n–6, nor 18:2n–6 affected the risk of death (Table 4Go). Common dietary sources and metabolic pathways as well as competition between dietary sources and metabolic pathways contributed to the observed correlations between fatty acids concentrations. However, EPA was the only fatty acid significantly associated with risk of death in this population, suggesting that a major part of the observed correlations between fatty acid concentrations are due to factors other than those determining risk of death.


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  		TABLE 1 Baseline characteristics of the subjects1

 

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  		TABLE 2 Baseline plasma phospholipid concentrations1

 

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  		TABLE 3 Matrix of Pearson correlation coefficients for fatty acid concentrations (% by wt) in plasma phospholipids (n = 254)

 

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  		TABLE 4 Risk of death according to quartile (Q) of fatty acids in plasma phospholipids1

 
After 3 y, the low-EPA group experienced 46 (73%) deaths, whereas the high-EPA group experienced 55 (40%) deaths. The median survival time was 1.5 y (95% CI: 0.7, 2.3) in the low-EPA group and 2.4 y (95% CI: 1.8, 2.9) in the high-EPA group. The most frequent diagnosis at discharge was CVD in both the high- and low-EPA groups.

Kaplan-Meier survival plots corresponding to the 4 quartiles of EPA concentration are shown in Figure 1Go. There was a significantly higher mortality rate in the lowest EPA quartile than in the upper 3 quartiles (P = 0.003, Breslow test). There was no significant difference between the upper 3 quartiles (P = 0.94), suggesting that EPA has a threshold concentration above which the survival functions do not change further. Most of the difference in mortality between groups was observed within the first 3 mo. Plasma phospholipid fatty acid concentrations were also measured after 3 mo in 162 of the 205 surviving patients. Spearman correlation coefficients between concentrations measured at inclusion and after 3 mo were 0.48, 0.61, 0.64, 0.59, 0.69, 0.65, and 0.71 for 18:2n–6, 20:3n–6, 20:4n–6, 20:5n–3, 22:6n–3, sum of n–6 fatty acids, and sum of n–3 fatty acids, respectively (P < 0.0001 for all). Correspondingly, 143 patients (88.3%) were found in the same or the neighboring initially defined quartile also after 3 mo. Only 19 patients (11.7%) changed quartile by 2 or 3 groups. It is therefore unlikely that the difference in mortality seen during the initial 3 mo was due to changes in n–3 fatty acid nutritional status after inclusion and indicates that the dietary intake of marine n–3 fatty acids was stable over this time period.


Figure 1
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  		FIGURE 1. Kaplan-Meier curves for eicosapentaenoic acid (EPA) quartiles. P = 0.03 for survival differences across all quartiles (Breslow test), adjusted for multiple comparisons defining the quartile variable as strata in the Lifetest procedure of the SAS statistical package. Patients were divided into 4 equally large groups based on increasing concentrations of EPA at inclusion, and survival curves were constructed for each group.

 
The unadjusted and adjusted Cox HRs according to quartiles of linoleic acid (18:2n–6), dihomo {gamma}-linolenic acid (20:3n–6), arachidonic acid (20:4n–6), {alpha}-linolenic acid (18:3n–3), EPA (20:5n–3), and docosahexaenoic acid (22:6n–3) are shown in Table 4Go. EPA was the only fatty acid showing a statistically significant association with the risk of death across all quartiles, both before and after adjustment for available confounders. In addition, the association of EPA with risk of death showed a threshold whereby all 3 upper quartiles (quartiles 2, 3, and 4) had similar adjusted HRs and 95% CIs: 0.53 (0.33, 0.86), 0.48 (0.29, 0.79), and 0.57 (0.34, 0.96) respectively, compared with the lowest quartile. When quartile 1 was compared with the upper 3 quartiles combined, the HR was 0.52 (95% CI: 0.35, 0.77; model 2). Dihomo {gamma}-linolenic acid showed a statistically significant association in the highest quartile before, but not after, adjustment for confounders. The trend analysis, although less sensitive to nonlinear effects, suggests EPA as the most important prognostic factor of these fatty acids. The overall likelihood ratio test of model 2 without fatty acids had a chi-square of 26.9 (P = 0.0048). The corresponding chi-squares for model 2 with the fatty acids 18:2n–6, 20:3n–6, 20:4n–6, 18:3n–3, and 22:6n–3 were 27.9, 28.3, 27.4, 27.2, and 27.5, respectively. In comparison, EPA increased the chi-square to 31.7 (P = 0.0015), confirming that EPA is the most important prognostic factor of these fatty acids. Women had a 31% lower risk of death than did men after adjustment for EPA, GEMU, age, current smoking status, CVD, and BI (HR: 0.69; 95% CI: 0.48, 0.98).

Adjusted HRs for all-cause death as a function of EPA concentrations at admission are shown in Figure 2Go. The risk of death decreased to the same extent in all 3 upper quartiles in this population. We also examined the cause of death among those who died during the first year after inclusion. Cardiac disease was the major cause of death in both groups and was responsible for 13 (20.6%) cases in the low-EPA group and for 24 (12.6%) cases in the high EPA-group (P = 0.15, Fisher's exact test). The other major causes of death were infection, cancer, and stroke.


Figure 2
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  		FIGURE 2. Hazard ratios (HRs) for all-cause death given as a function of EPA concentrations at inclusion. The model was controlled for age, sex, assignment to GEMU treatment, Barthel Index, residence (private home or sheltered housing), current smoking status, history of cardiovascular disease, HDL cholesterol, LDL cholesterol, prealbumin, and {alpha}-tocopherol. The first-quartile HR was defined as 1.0 and used as referent, the second-quartile HR was 0.53 (95% CI: 0.33, 0.86), the third quartile HR was 0.48 (95% CI: 0.29, 0.79), and the fourth quartile HR was 0.57 (95% CI: 0.34, 0.96). Patients were categorized in quartiles according to EPA concentration, as described in Figure 1Go, and HRs of all-cause death among EPA groups were calculated using multivariate Cox analysis.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this prospective study of elderly patients admitted to the hospital because of acute illness, the concentration of the long-chain marine fatty acid EPA in plasma phospholipids at admission was used as a surrogate variable for dietary intake of marine n–3 fatty acids. Of the fatty acids analyzed, EPA showed the highest association with all-cause mortality. Increasing concentrations of EPA were associated with a decreased risk of death. However, the association was nonlinear and had reached a plateau at the second concentration quartile. Compared with patients in the lowest quartile, patients in the upper 3 quartiles had a 48% lower risk of all-cause mortality after the known confounders were controlled for. The upper 3 quartiles were not significantly different from each other. The results suggest that a low dietary intake of marine fatty acids is a risk factor in this patient group and that only {approx}25% of the study population might have benefited from an additional dietary supply of marine fatty acids before the acute incident.

Data on the association between dietary intake of long-chain n–3 fatty acids and overall mortality in the elderly are limited. On the basis of nutritional interview data on fish consumption, a small amount of fish was reported to protect against coronary heart disease mortality in an elderly population followed for 17 y (14). A case-control study originating from the Cardiovascular Health Study reported that the concentration of DHA plus EPA in plasma phospholipids was linearly and inversely associated with the risk of fatal ischemic heart disease in adults aged ≥65 y (15). After 12 y of follow-up of 4475 elderly (range: 65–98 y), the Cardiovascular Health Study also reported an inverse association between stroke and dietary intake of tuna or other broiled fish assessed using a food-frequency questionnaire (16).

There is strong supporting evidence from primary and secondary prevention studies that long-chain n–3 fatty acids protect against myocardial infarction, sudden CVD death, and stroke (5, 6, 24), which are major causes of death in an elderly population. This conclusion is also supported by systematic reviews and meta-analyses (25-27). However, a recent Cochrane review found that n–3 fats showed no association with mortality, CVD, or cancer (28). This review was later criticized (29, 30) because its conclusion rests entirely on the inclusion of one large, negative trial (31). Systematic reviews and meta-analysis in this field are difficult because of heterogeneity in the studies with respect to the methods used to estimate fish or n–3 FA intakes, background diets, background risks for heart disease, settings, and the methods of reporting results.

Experimental data from cell cultures, animal models, and humans have shown several possible mechanisms for the beneficial effects of long-chain n–3 fatty acids. The antiarrhythmic properties of n–3 fatty acids and their modulation of platelet activity are considered the main mechanisms for reducing fatal cardiac arrest, whereas their antithrombotic effect and their ability to lower heart rate, lower plasma lipids, and stabilize atherosclerotic plaques possibly also contributes to their protective effect (11, 12, 32-36).

Several publications have reported that blood lipid fatty acid composition correlates with the dietary intake of marine n–3 fatty acids (37-39). Correlation coefficients range from {approx}0.3 up to 0.9, suggesting that several factors modify the pharmacokinetics of the dietary marine fatty acids and how they are incorporated into plasma and cell membrane phospholipids. Also, dietary and lifestyle factors affect the pharmacokinetics. Corpeleijn et al (40) reported that exercise changes desaturase expression, and Montanaro et al (41) reported that both peroxisome proliferator–activated receptor-{alpha} and Liver X receptor increase both the expression and the activity of {Delta}5- and {Delta}6-desaturases. Measurement of lipid fatty acid concentrations does not have the methodologic inaccuracies and bias inherent in dietary assessment methods. Analyzing the attained concentration of the active substance in the body might also eliminate or reduce potential confounding effects of individual or genetic differences in the pharmocokinetics of EPA and DHA.

The threshold phenomenon we observed for changes in HRs with increasing EPA concentrations agreed with several other prospective observational studies and clinical trials (42), indicating that most or all beneficial effects of long-chain n–3 fatty acids are not linear. In populations in whom the majority already has a nutritional intake or cell concentration of long-chain n–3 fatty acids above the thresholds for protection, a further increase in the intake cannot be expected to provide any additional clinical effect. The Norwegian population, especially the elderly, traditionally has a high intake of fish. This is a characteristic we share with other populations throughout the circumpolar north, where fish is abundant and is an important part of the diet. Most of our patients, therefore, already have a dietary intake sufficient to achieve the protection offered by these oils.

Our low EPA group has a mean % by wt of EPA and DHA of 1.01 and 7.09, respectively. The corresponding values found by Harris et al (43) were 0.55 and 3.02. Crowe et al (44) and Welch et al (45) reported EPA concentrations of 1.02 and 1.26 mol% and DHA concentrations of 2.64 and 5.2 mol%, respectively. The corresponding values in our low-EPA group are 0.96 and 6.17 mol%. Data from the study by Harris et al (43) and Crowe et al (45) were recalculated by combining their subpopulation data to reflect their total study population. This suggests that the lowest quartile in our population is in the same range as the mean of other populations. Comparison of different studies, however, is difficult because of the lack of standardized methods and available calibrators. We report a DHA-EPA ratio of 7.0, whereas the corresponding ratios found by Harris et al (43), Crowe et al (44), and Welch et al (45) are 5.5, 2.6, and 4.1, respectively, suggesting either population differences in the intake and metabolism of EPA and DHA or difference in analytic methods. To facilitate study comparison, we analyzed 23 fatty acids in a commercially available calibrator (see Supplemental Table 1 under "Supplemental data" in the online issue).

Although the present study did not adjust for all known confounders, the results suggest that a moderate dietary intake of n–3 fatty acids in the elderly (age >65 y) reduces their overall mortality if they become acutely ill and hospitalized. The results also suggest that {approx}25% of this Norwegian population might have benefited from an increased dietary intake before the acute incident. The reported differences in EPA and DHA concentrations (43-45) suggest that this proportion might be considerably higher in other populations. In future intervention studies, baseline status of marine n–3 fatty acids should be established in eligible study participants and entered in the inclusion criteria to include only participants who are likely to benefit from intervention.


   ACKNOWLEDGMENTS
 
The skilled technical assistance of Merete Mack (Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology) and of Unni Sirum, Erling Sagen, and Kirsti Brechan (Department of Medical Biochemistry, St Olavs Hospital, Trondheim University Hospital) is gratefully acknowledged.

The authors' responsibilities were as follows—OS, IS, and KSB: designed the study; OS and IS: recruited the subjects and collected the data; ML and KSB: collected and analyzed the data; and ML: prepared the first draft of the manuscript. All authors refined the subsequent drafts and provided consultation on the final draft. None of the authors had any conflicts of interest.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication November 8, 2007. Accepted for publication April 24, 2008.


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n-3 Fatty acids and health: DaVinci's code
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