Plasma Omega-3 Polyunsaturated Fatty Acids and Survival in Patients with Chronic Heart Failure and Major Depressive Disorder
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- Jiang, W., Oken, H., Fiuzat, M. et al. J. of Cardiovasc. Trans. Res. (2012) 5: 92. doi:10.1007/s12265-011-9325-8
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The omega-3 fatty acid (FA) concentration is low in patients with coronary heart disease (CHD). Supplement of omega-3 FA improves cardiovascular outcomes in patients with CHD and heart failure (HF). However, plasma omega-3 FA and its role for prognosis in HF patients have not been examined previously. In this study, we explore the prognostic value of omega-3 polyunsaturated FA in HF patients with major depressive disorder (MDD). Plasma was obtained from HF patients with MDD who participated in the Sertraline Against Depression and Heart Disease in Chronic Heart Failure trial. FA methyl esters were analyzed by the method of a flame ionization detector. Weight percent is the unit of the omega compounds. The primary outcome was survival which was analyzed using Cox proportional hazards regression modeling. A total of 109 depressed HF patients had adequate volume for completion of the FA assays. Plasma total omega-3 (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.43–0.98) and EPA_0.1 unit (HR 0.73, 95% CI 0.56–0.96) were significantly associated with survival of patients with HF and co-morbid MDD. The results suggest that low plasma omega-3 FA is a significant factor for reduced survival in HF patients with MDD.
KeywordsOmega-3 fatty acidsHeart failureDepressionPrognosis
Fish oil or omega-3 polyunsaturated fatty acid (FA) consumption has been shown to reduce the risk of major cardiovascular (CV) events and coronary heart disease (CHD) [1–5]. Supplement of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the main contents of fish oil, or omega-3 FA, have been found to reduce mortality [6–9] in CHD patients and patients with heart failure (HF) .
The role of plasma omega-3 FA in the prognosis of HF has not been examined. In a population of HF patients with major depressive disorder (MDD), we explored the relationship of plasma omega-3 FA with survival. We hypothesized that patients with lower levels of omega-3 FA would have increased risk of both CV events and death.
This study consisted of a subset of patients who were recruited from the cardiac inpatient service at Duke University Medical Center for participation in the Sertraline Against Depression and Heart Disease in Chronic Heart Failure (SADHART-CHF) trial [11, 12] and agreed to participate in the biomarker study of the SADHART-CHF trial. All the study participants had clinical HF, defined by left ventricular ejection fraction (LVEF) ≤ 45% (within the previous 6 months), and New York Heart Association (NYHA) classes II–IV heart failure symptoms and met the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria for MDD.
After providing written, voluntary, informed consent, HF patients were screened for depressive symptoms using the Beck Depression Inventory Scale  and the Diagnostic Interview Schedule [11, 12]. A separate consent was obtained to provide a blood sample for the biomarker study. A patient's decision to participate in the biomarker study did not affect his or her participation in the SADHART-CHF trial. The protocol was reviewed and approved by the Duke University Institutional Review Board.
Vital Status Follow-Up
The SADHART-CHF trial and results have been described previously [11, 12]. Briefly, these HF patients with MDD were randomized 1:1 to sertraline 50 mg/day or matched placebo for a 12-week active treatment phase. The dose of the study medication was titrated up weekly to a maximum of 200 mg/day according to the participant's tolerability and depression response. During the 12-week intervention, all participants also received nurse-facilitated support. Regardless of completion of the 12-week active treatment phase, all participants were contacted at 6 months, 12 months, and annually thereafter to evaluate clinical events and vital status until the last enrolled participant completed a 6-month follow-up. The National Death Index was used to ascertain vital status of participants who could not be contacted, which allowed for a 100% completion of the survival endpoint. Events resulting in a procedure or hospitalization due to CV causes according to predefined criteria were considered CV events. All CV events were adjudicated by three cardiologists with an HF subspecialty who were blinded to treatment assignment .
Omega FA Assessment
Blood samples were collected using a Vacutainer system (Becton, Dickinson and Company, NJ 07417) containing clot activator and gel serum separator and centrifuged at a g-force of 1,864 (3,000 rpm for 10 min at a fixed angle of 34° using a Sorvall Model RT 7 Plus Centrifuge). The resulting plasma was stored in Vacutainer tubes (Becton, Dickinson and Company, NJ 07417) containing ethylenediaminetetraacetic acid (EDTA) and frozen at −80°C. Once all plasma samples were collected, the tubes were coded in a blinded fashion and sent to the Martek Biosciences Clinical Laboratory for assay.
Plasma Phospholipid Extraction and FA Analysis
The methods for plasma phospholipid extraction and FA analysis have been described previously by Bailey-Hall et al. .
The FA profiles were expressed as a percent of the total μg of FA (weight percent). The plasma mean values of phospholipid α-linolenic acid (ALA) (C18:3n-3), DHA (C22:6n-3), and EPA (C20:5n-3) were calculated. The omega-3 proportion was computed from plasma phospholipid mean weight percent using the following equation: 100 × (C20:5n-3 + C22:5n-3 + C22:6n-3)/(C20:3n-6 + C20:4n-6 + C22:4n-6 + C22:5n-6 + C20:5n-3 + C22:5n3 + C22:6n-3). The total omega-3 includes the following fatty acids: 18:2n-6, 18:3n-6, 20:2n-6, 20:3n-6, 20:4n-6, 22:4n-6, and 22:5n-6. The total omega-6 includes the following fatty acids: 18:3n-6, 20:5n-6, 22:5n-6, and 22:6n-6. The ratio of omega-6 to omega-3 was calculated by dividing the total omega-6 by the total omega-3. The total omega-3 (ALA, DHA, EPA) total omega-6, and the ratio of omega-6 to omega-3 are the focus of the survival analyses.
Baseline characteristics and omega-3 FA distributions were presented by a median and interquartile range for continuous variables and by a percentage for categorical variables. The primary endpoint of this analysis was mortality, and the secondary endpoint was a composite of CV events or death. Cox proportional hazards regression models were used to evaluate the relationship between omega FA with (a) time to death and (b) time to initial CV event or death. The association of age, sex, baseline LVEF, NYHA class, ischemic etiology of HF, baseline Hamilton Depression Rating Scale (HDRS) scores, treatment assignment (sertraline vs. placebo), or remission status with survival was assessed by Cox proportional hazards regression models as well. Because of the modest sample size and a low number of deaths, we elected to adjust for age, sex, and baseline ejection fraction (EF) in a multivariate analysis of the omega FA measures that were found to be significantly associated with survival. A P value < 0.05 was considered statistically significant. Statistical analyses were performed by statistical personnel within Duke University Medical Center, using statistical software, SAS, version 9.1 (SAS Incorporated, Cary, NC).
Characteristics (N = 109)
60 (53, 68)
History of myocardial infarction (MI)
Baseline Beck Depression Inventory Scale
Total omega-3 (wt.%)
4.73% (3.93, 5.43)
Omega-3 proportion (wt.%)
0.23% (0.19, 0.29)
3.07% (2.37, 3.73)
0.45% (0.33, 0.59)
Total omega-6 (wt.%)
39.91% (38.21, 40.80)
8.37% (7.28, 10.34)
Omega Fatty Acids and Survival Status
Overall, the population had low omega-3, reflected by the omega-3 proportion (Table 1). The majority of the participants (79.8%) had their omega-3 proportion value <22%, which is considered a risk factor for sudden cardiac death and CHD . There were only three patients (2.8%) that had an omega-3 proportion value equal or greater than 37%, which is an indicator for low risk of sudden cardiac death and CHD .
Survival analysis (univariate)
Total omega 3
Total omega 6
Omega 6/omega 3
History of myocardial infarction
Baseline ejection fraction
Baseline Hamilton Depression Rating Scale
Event-free survival analysis
Total omega 3
Total omega 6
Omega 6/omega 3
Coronary artery disease
History of myocardial infarction
Baseline ejection fraction
Baseline Hamilton Depression Rating Scale (HDRS)
Age, sex, baseline LVEF, NYHA class, ischemic etiology of HF, baseline HDRS scores, treatment assignment (sertraline vs. placebo), or remission status at the end of 12-week intervention were not significantly associated with either survival or CV-event-free survival (Tables 2 and 3).
The major finding from this study is that lower total omega-3 and EPA concentrations were significantly associated with reduced survival for HF patients with MDD. The results suggest that every one unit lower in the total omega-3 or every 0.1 unit lower in EPA increases the risk of dying by 27–35% among HF patients with MDD over a median of 16 months. The association of total omega 3 and EPA with HF survival is independent of age, sex, and baseline EF. Furthermore, the majority of the study population has low omega-3.
Previous studies have suggested that blood and/or tissue proportions of specific FAs may stratify risk for a variety of diseases, especially CHD [16–19]. In a review of 25 studies that examined the role of tissue FA and risk of CHD, Harris et al. demonstrated that DHA, among several other omega-3 FAs, was significantly reduced in patients who died of CHD . Patients who experienced non-fatal CV events also had lower DHA or lower DHA + EPA combination, although it was not significant . Because low DHA was the most common finding across all the studies reviewed, these authors  and others  concluded that DHA was more cardioprotective than EPA. There was only one study involving HF patients that tested the relationship between omega-3 FA and ventricular arrhythmia. This study found that 102 HF patients with implantable cardioverter-defibrillators (ICDs), compared with 25 control subjects, had higher red blood cell omega-3 FA, measured as omega-3 index, indicative of an association of higher omega-3 FA and increased risk for ventricular arrhythmia . Our study focused on assessing the relationship of omega FAs with survival and did not measure heart rhythm irregularities during the follow-up. Furthermore, the omega-3 index was not calculated in our study, as the omega FAs were derived from plasma, not red blood cells.
Low concentrations of DHA and EPA have been reported in depressed patients without medical co-morbidity in peripheral tissues such as plasma , red blood cell phospholipids [24, 25], cholesterol esters , adipose tissue , and in the brain . Similar to studies conducted in the cardiac population, the components of omega FAs and tissues tested for omega-3 levels are not consistent across studies. Conversely, fewer studies have examined the relationship of tissue omega concentration and depression. The major omega-3 FAs (ALA, EPA, and DHA) have been found to be low in cholesterol esters or red blood cells in depressed patients [23, 24, 26, 29]. Two larger sample studies [30, 31] demonstrated that depressed patients have lower DHA and EPA compared to normal controls.
There are several potential mechanisms  by which omega-3 FAs reduce the risk of CV diseases, such as stabilizing cell membranes, inhibiting production of thromboxane A2 and inflammatory cytokines [33–35], increasing heart rate variability , etc. An echocardiographic study found omega-3 polyunsaturated FAs had a small but significant improvement in left ventricular ejection fraction in patients with HF . Another recent mechanistic investigation demonstrated that 2 g omega-3 polyunsaturated FA of 11 months after a 5 g omega-3 polyunsaturated FA 1 month, compared to placebo, resulted in significant improvement in LVEF (increased by 10.4% and decreased by 5.0%, respectively); peak VO2 (increased by 6.2% and decreased by 4.5%, respectively); exercise duration (increased by 7.5% and decreased by 4.8%, respectively); and reduction of NYHA class (decreased from 1.88 ± 0.33 to 1.61 ± 0.49 and increased from 1.83 ± 0.38 to 2.14 ± 0.65, respectively) among 133 patients with non-ischemic HF. The intervention also resulted in lower re-hospitalization for HF vs. in placebo (6% vs. 30%, p = 0.0002) .
The understanding of the role of omega-3 FA in depression is evolving as well and evidence by far indicates that the vital roles of DHA and EPA in depression may be quite different. DHA is commonly believed to be the key element for mental health as it is an essential component of neuronal membranes and thus critical to the structure of the brain and nervous system, while EPA is believed to have direct interactions with cyclo-oxygenases, lipoxygenases, phospholipases, acylating systems, ion channels, mitochondria, and the peroxisome proliferator activated receptors. It is also thought to exert regulatory influences on gene expression [39–41]. Nevertheless, more studies are needed to better understand the role of these FAs in CV disease and mental health.
The Gruppo Italiano Di Studio Della Sopravvivenza Nella Insufficienza Cardiac-Heart Failure (GISSI-HF) trial has demonstrated that, compared with placebo, omega-3 FA supplementation of DHA + EPA (850 to 882 mg/capsule), improved survival (adjusted HR 0.91, 95% CI 0.83–1.00) and reduced CV re-hospitalizations (adjusted HR 0.92, 95% CI 0.85–1.00) over an average of 3.9 years of intervention among 6,975 HF patients . The findings of our present study further support the importance of omega-3 FA supplements for HF patients, as lower omega-3 FA is associated with shortened survival of HF patients. A large number of studies have examined whether an omega-3 supplement may improve depression; however, the results are not as consistent [39, 55]. Results of meta-analyses indicate that omega-3 FA supplement is beneficial for patients who have a formal diagnosis of depression . Variation of dosing and proportion of omega-3 FA supplement have been speculated to be responsible, at least partially, for the inconsistent findings of benefits in depression and many other conditions [39, 40, 55]. While Lovaza (similar EPA to DHA concentrations) failed to demonstrate antidepressant effects , an almost pure EPA supplement demonstrated antidepressant efficacy . EPA has been argued to be the main component of omega-3 to alleviate depression [39, 40], but no definitive conclusions have been drawn . Guiding omega-3 FA supplement therapy by using DHA and EPA concentrations may improve the outcome and reduce the heterogeneity of these trials.
The study is limited by the origin of the sample to test if the same relationship of omega-3 and HF survival exists in HF patients without depression, and by the small sample size to fully evaluate confounders or mediators with the negative association of low omega-3 and high mortality. Recruitment for the biomarker study from depressed HF patients was challenging, reflected by the fact that only about half of the parent trial participants were willing to give blood. The study population was not large enough to fully assess the prognostic role of omega FAs for event-free survival. Further study is needed to examine the associations of omega-3 FA with occurrence of CV events or event-free survival in HF patients.
In conclusion, our study suggests that omega-3 FA has a significant association with survival in HF patients with MDD. Whether a supplement of omega-3 FA may improve depression as well as survival and other CV outcomes in these patients needs to be studied. The interplay between omega-3 and conventional risk factors as well as other biomarkers in patients with HF also warrants future study.
Results of this study suggest omega-3 FA plays a significant role in the survival of patients with HF and MDD. Studies testing whether omega-3 supplement may improve depression and survival in this population are in demand.
The authors would like to thank Eileen Bailey-Hall of Martek Biosciences Corporation, Columbia, MD and the Martek Biosciences Corporation for the significant contribution in regards to processing plasma samples and the FA analysis. We would also like to thank Dr. Steve Rozen of the Duke-NUS Graduate Medical School Singapore in Singapore for his contribution of data analysis and interpretation.
The study was funded by the SADHART-CHF study (R01-MH063211) and R21 MH076178 by the National Institute of Mental Health (NIMH) Bethesda, Maryland.
• Dr. Jiang received salary support through the NIMH research grant, and a minority supplement award for the biomarker study affiliated to the SADHART-CHF grant.
• Dr. O'Connor has received salary support through the NIMH research grant and is a consultant for Martek Biosciences Corporation.
• Dr. Kuchibhatla received salary support through the NIMH research grant.
• Dr. Cuffe has received salary support through the NIMH research grant.
• Dr. Krishnan has received salary support through the NIMH research grant.
• Dr. Martsberger has received salary support from the NIMH research grant.
• Linda Shaw: nothing to disclose for this study.
• Dr. Fiuzat: nothing to disclose for this study.
• Dr. Oken is a consultant to the Martek Biosciences Corporation.
• Dr. Kaddurah-Daouk: nothing to disclose for this study.
• Dr. Steffens has received salary support from NIMH for the metabolomic study.
• Dr. Baillie: nothing to disclose for this study.
All authors had access to the data. The preliminary result of the omega fatty acid study was presented at the 2010 American College of Cardiology Annual Meeting in March 2010 in Atlanta, GA.