Long-Chain Monounsaturated Fatty Acids and Incidence of Congestive Heart Failure in 2 Prospective CohortsClinical Perspective
Background—Decades-old animal experiments suggested that dietary long-chain monounsaturated fatty acids (LCMUFAs) caused cardiotoxicity, leading, for example, development of Canola oil (Canadian oil low in erucic acid) from rapeseed. However, potential cardiotoxicity in humans and contemporary dietary sources of LCMUFAs are unknown.
Methods and Results—We prospectively investigated the associations of plasma phospholipid LCMUFAs (20:1, 22:1, and 24:1), assessed as objective biomarkers of exposure, with incidence congestive heart failure in 2 independent cohorts: 3694 older adults (mean age, 75.2±5.2 years) in the Cardiovascular Health Study (CHS; 1992–2006) and 3577 middle-aged adults (mean age, 54.1±5.8 years) in the Atherosclerosis Risk in Communities Study, Minnesota subcohort (ARIC; 1987–2008). We further examined dietary correlates of circulating LCMUFAs in CHS and ARIC and US dietary sources of LCMUFAs in the 2003–2010 National Health and Nutrition Examination Survey (NHANES). In CHS, 997 congestive heart failure events occurred during 39 238 person-years; in ARIC, 330 events congestive heart failure events occurred during 64 438 person-years. After multivariable adjustment, higher levels of 22:1 and 24:1 were positively associated with greater incident congestive heart failure in both CHS and ARIC; hazard ratios were 1.34 (95% confidence interval, 1.02–1.76) and 1.57 (95% confidence interval, 1.11–2.23) for highest versus lowest quintiles of 22:1, respectively, and 1.75 (95% confidence interval, 1.23–2.50) and 1.92 (95% confidence interval, 1.22–3.03) for 24:1, respectively (P for trend ≤0.03 each). A variety of foods were related to circulating LCMUFAs in CHS and ARIC, consistent with food sources of LCMUFAs in NHANES, including fish, poultry, meats, whole grains, and mustard.
Conclusions—Higher circulating levels of 22:1 and 24:1, with apparently diverse dietary sources, were associated with incident congestive heart failure in 2 independent cohorts, suggesting possible cardiotoxicity of LCMUFAs in humans.
In the 1960s to 1980s, feeding experiments in rodents, pigs, and nonhuman primates suggested that consumption of erucic acid (22:1n9) and cetoleic acid (22:1n11) caused cardiac steatosis.1–4 Although potential effects in humans were never studied, mechanistic studies suggest that exposure to long-chain monounsaturated fatty acids (LCMUFAs; 20:1, 22:1, and 24:1 fatty acids) might impair myocardium. The heart preferentially uses fatty acids as fuel.5–7 Long-chain fatty acids, including LCMUFAs, are predominantly oxidized in peroxisomes rather than mitochondria, which lack membrane-transporting enzymes for long-chain fatty acids.3,8 Peroxisomal fatty acid oxidation produces reactive oxygen species and various cytosolic lipid metabolites8 that stimulate several signaling pathways, thereby inhibiting mitochondrial fatty acid oxidation, synthesizing cardiac lipid droplets, inhibiting glycolysis, and inducing apoptosis.5–7 In sum, such effects can cause cardiotoxicity.5–7
Clinical Perspective on p 1521
This decades-old evidence led Canadian farmers to modify rapeseed oil, a major source of erucic acid (≈30% to 60% of fatty acids), and market it as Canola oil (Canadian oil low in erucic acid),9 as well as some governments to limit content of erucic acid in rapeseed oil.9,10 Thereafter, the potential cardiotoxicity and dietary sources of LCMUFAs have been largely forgotten and, to the best of our knowledge, never studied in humans. However, food composition data indicate that LCMUFAs remain present in mustard oils (20%–50%) and related products, some fish species (5%–30%), and meat and poultry products (0%–5%).2,11 Given experimental induction of cardiac fibrosis and steatosis, key risk factors for congestive heart failure (CHF),12–14 we hypothesized that LCMUFA exposure may increase the incidence of CHF. To address this hypothesis, we investigated prospective associations between LCMUFA exposure, assessed as objective biomarkers in plasma phospholipids, and incident CHF in 2 independent US cohorts: the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities Study (ARIC). We further characterized dietary factors related to LCMUFA biomarker levels and evaluated potential dietary sources of LCMUFA consumption based on the US National Health and Nutrition Examination Survey (NHANES) and the US Department of Agriculture food composition database.11
Design and Population
In 1989 to 1990, CHS recruited 5201 ambulatory, noninstitutionalized adults ≥65 years of age who were randomly selected from Medicare lists in 4 US communities; an additional 687 black participants were similarly recruited in 1992 to 1993.15,16 ARIC recruited 15 792 adults 45 to 64 years of age in 4 US communities in 1987 to 1989 from multiple databases, including driver’s license listings, community lists, local health Census lists, and area sampling.17 In CHS and ARIC, 57% and 60% of eligible adults, respectively, agreed to enroll and gave informed consent.
Circulating fatty acid concentrations were measured in 3941 CHS participants using blood samples from 1992 to 1993 and in 3705 ARIC participants in the Minneapolis subcohort using blood samples from1987 to 1989. These years of fatty acid measurement were considered the baseline for all analyses. Sociodemographic characteristics, lifestyle behaviors, dietary consumption, and laboratory measures were assessed as previously described15–17 (see the online-only Data Supplement for details). After the exclusion of participants with prevalent CHF in CHS (n=247) and ARIC (n=128) and without circulating fatty acid measures, the present analyses included 3694 CHS and 3577 ARIC participants.
Phospholipid Fatty Acids
Methods for assessing plasma phospholipid fatty acids in CHS and ARIC slightly differed, as described in the online-only Data Supplement. In CHS, 42 known individual fatty acids were quantified; in ARIC, 29 fatty acids. In this study, we evaluated LCMUFAs as the main exposure variables: gadoleic acid (20:1; the first number referring to the number of carbons and the second referring to the number of double bonds in the fatty acid), erucic acid (22:1), and nervonic acid (24:1). Intra-assay coefficients of variation were <5% for 20:1 and 24:1 and 15% for 22:1. We assessed reproducibility of LCMUFA levels potentially affected by both measurement error and biological variation over time that would attenuate findings toward the null, evaluating serial measures from blood samples drawn in 1992 to 1993, 1998 to 1999, and 2005 to 2006 in a subset (n=100) of CHS participants. Within-individual correlations were highest for 24:1 (r=0.66 at 6 years and 0.43 at 13 years) and lower for 22:1 (r=0.26 and 0.18) and 20:1 (r=0.26 and 0.26). This reproducibility for 24:1 was comparable or superior to the reproducibility for major cardiovascular risk factors such as blood pressure.18
Cardiovascular Risk Factors and Incident CHF
In each cohort, we evaluated cross-sectional associations of LCMUFA levels with cardiovascular risk factors (see the online-only Data Supplement for the assessments) and longitudinal associations of LCMUFAs with incident CHF. In CHS, potential CHF events were identified from annual examinations, interim 6-month phone contacts, and hospital discharge records, with review and classification by a centralized committee of physicians.16,19 A CHF event was confirmed when all 3 criteria were met: (1) CHF symptoms (shortness of breath, fatigue, orthopnea, paroxysmal nocturnal dyspnea) and signs (edema, rales, tachycardia, gallop, displaced apical impulse) or clinical findings from echocardiography, ventriculography, or chest radiography; (2) diagnosis of CHF by a treating physician; and (3) CHF medical therapy (a diuretic plus either digitalis or a vasodilator). In ARIC, potential CHF events were first identified by annual phone contacts, review of hospital discharge codes, and death certificates and then ascertained by either a hospitalization including a CHF discharge diagnosis (International Classification of Diseases, Ninth Revision, code 428) or a death certification listing CHF.20 In CHS, CHF events with sufficient information were further subclassified as due primarily to ischemic or nonischemic causes and to valvular or nonvalvular causes.19
To determine whether LCMUFA-CHF associations were myocardium specific, we analyzed incident stroke as a prespecified negative-control outcome.21 We selected stroke because it shares many risk factors with CHF (eg, hypertension) but should be unaffected by any causal processes specific to cardiac steatosis, ie, the hypothesized cardiotoxicity of LCMUFAs. Each cohort defined stroke as a neurological deficit of rapid onset lasting >24 hours or as a subarachnoid hemorrhage confirmed by computed tomography or magnetic resonance imaging when available.22,23
Dietary Correlates of Circulating LCMUFAs and Estimated US LCMUFA Consumption
To examine independent dietary correlates to circulating LCMUFA levels, we assessed cross-sectional associations of habitual food consumption with phospholipid LCMUFA levels. We evaluated 43 food groups in CHS and 41 food groups in ARIC derived from interviewer-administered validated food-frequency questionnaires (mustard consumption and fried fish were available only in CHS). In CHS, we related averaged dietary intakes over the 2 questionnaires in 1989 to 1990 and 1996 to 1997 to LCMUFA levels in 1992 to 1993, as previously performed.24 In ARIC, dietary intakes were related to LCMUFA levels at the same data collection cycle in 1987 to 1989.
To evaluate the validity of dietary correlates to LCMUFA biomarkers in CHS and ARIC and to consider current consumption levels in the United States, we assessed major food sources of LCMUFAs, evaluating food-composition databases and food intakes in the 2003–2010 NHANES (n=20 150 adults) that implemented two 24-hour dietary recalls per person (see the online-only Data Supplement for the analytical methods). Food consumption data were available for 20:1 and 22:1 but not for 24:1.
We assessed independent dietary correlates to circulating LCMUFA levels by multivariable-adjusted stepwise linear regression (P<0.05 to retain and P>0.1 to remove) as performed previously,24 relating food groups (servings per week) to LCMUFA levels that were standardized to a standard deviation after log transformation to improve normality.
To assess cross-sectional associations of LCMUFAs with cardiovascular risk factors, we evaluated LCMUFA levels as independent variables and cardiovascular risk factors as dependent variables by multivariable-adjusted linear regression. Prospective relationships of phospholipid LCMUFAs with incident CHF were examined by multivariable-adjusted Cox proportional hazards in each cohort separately, and then estimates for quintile category scores were pooled by random-effects meta-analysis. The proportionality assumption was not rejected by examining cross-product terms of follow-up time by exposure (P>0.3). Time at risk was from time of blood draw to the first CHF (or stroke) diagnosis, death, loss of follow-up, or administrative censoring (2006 in CHS; 2008 in ARIC). Loss of follow-up was ≤2% of person-times in both CHS and ARIC.
To minimize confounding, we adjusted for covariates based on previously published associations or clinical relevance, including demographics, clinical histories, and lifestyle factors. We recognized that numerous dietary factors and circulating fatty acids could be confounders. Consumption of both generally healthful foods such as plant oils and fish could influence circulating levels of LCMUFAs, other fatty acids, and incident CHF. Importantly, fish consumption has been associated with lower CHF incidence in CHS and ARIC.20,25 To select and control for potential confounders of diet and circulating fatty acids, we adopted a confounder selection strategy developed previously.26 Briefly, we selected covariates when their removal caused >5% change in the measure of association of LCMUFA levels with CHF.
To assess whether the associations between LCMUFAs and incident CHF were independent of traditional cardiovascular risk factors or potential mediators, we further adjusted for body mass index, waist circumference, blood lipids, inflammatory markers, and incident CHD during follow-up as a time-varying covariate. We tested multiplicative interactions by prespecified factors of age, sex, race, and prevalent CHD by evaluating the Wald test for a cross-product term of exposure and covariate in the model. We also evaluated interaction by prevalent diabetes mellitus post hoc.
In longitudinal analyses, time-dependent misclassification in both exposures and covariates causes regression dilution bias and residual confounding. We performed sensitivity analyses to correct for this bias by means of multivariate regression calibration based on within-individual correlations of serial measures of physical activity, dietary habits, and phospholipid fatty acids (in a subset) in CHS.18 Because comparable serial measures were unavailable in ARIC, we extended regression dilution ratios in CHS to analysis in ARIC, recognizing the limited generalizability and thus considering these corrected risk values in ARIC as only estimates. We examined nonlinear associations in each cohort using 4-knot restricted cubic splines. Statistical analyses were performed with STATA 10.0 (2-tailed α=0.05).
Participants in CHS were older at baseline (age, 75.2±5.2 years) than participants in ARIC (age, 54.1±5.8 years), with concomitantly higher prevalence of chronic diseases (Table I in the online-only Data Supplement). The majority were white: 88% in CHS and 100% in ARIC. Both cohorts included broad mixtures of sex, education, and smoking. Lifestyle habits were relatively similar in both cohorts.
Mean±SD levels of 24:1 were 1.96±0.44% and 0.57±0.17% of total fatty acids in CHS and ARIC, respectively. The interdecile ranges (10th and 90th percentiles) of 24:1 were 1.21% in CHS and 0.41% in ARIC. Levels of 20:1 and 22:1 were much lower than 24:1 levels; in ARIC, 43% of adults exhibited 22:1 levels lower than the detection limit (0.01%). Levels of the 3 LCMUFAs were interrelated moderately in CHS (Pearson correlation coefficient, r=0.25–0.63) and weakly in ARIC (r=0.10–0.27). In both cohorts, LCMUFA levels were also weakly or moderately correlated with levels of other phospholipid fatty acids: 20:0, 22:0, and 24:0 (r=0.16–0.67); 20:3n3 and 22:6n3 (r=0.21–0.49); 18:3n6 and trans-18:2n6 (r=−0.17 to −0.36); 16:1n7 and 18:1n9 (r=−0.13 to −0.15), and most strongly 20:0 (with 24:1) (r=0.54 in CHS and r=0.67 in ARIC).
Cross-sectional Associations of Circulating LCMUFAs With Cardiovascular Risk Factors
Higher levels of 24:1 were independently associated with several cardiovascular risk factors in directions toward both favorable and unfavorable associations with cardiovascular disease risks (Table 1). These included greater adiposity (body mass index and waist circumference) and higher levels of C-reactive protein, fibrinogen, and leukocyte counts, but also a trend toward lower diastolic blood pressure, higher high-density lipoprotein cholesterol, and substantially lower triglycerides. Results were concordant across the 2 cohorts. Levels of 20:1 were associated with generally healthier profiles of adiposity and physiological measures, and 22:1 showed either weaker or null results (Table II in the online-only Data Supplement).
Prospective Associations of Circulating LCMUFAs With the Incidence of CHF
In CHS, 997 CHF events were documented during 39 238 person-years; and in ARIC, 330 CHF events were documented during 64 438 person-years. In multivariable-adjusted analyses, higher levels of both 22:1 and 24:1, but not 20:1, were significantly associated with higher CHF incidence (Ptrend=0.01 and 0.004, respectively; Table 2). As expected, adjustment for other individual phospholipid fatty acids strengthened the associations. In CHS, individuals in the highest quintile of 22:1 had 34% higher CHF incidence (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.02–1.74; Ptrend=0.01) compared with those in the lowest quintile; in ARIC, 57% higher incidence (HR, 1.57; 95% CI, 1.11–2.23; Ptrend=0.03); and when pooled together, 42% higher incidence (HR, 1.42; 95% CI, 1.15–1.76; Ptrend=0.001). Results were more robust for 24:1, with 75% higher CHF incidence comparing the top and bottom quintiles in CHS (HR, 1.75; 95% CI, 1.23–2.50; Ptrend<0.001); 92% higher incidence in ARIC (HR, 1.92; 95% CI, 1.22–3.03; Ptrend=0.002); and 82% higher incidence when pooled (HR, 1.82; 95% CI, 1.37–2.40; Ptrend<0.001).
Further adjustment for potential mediators, including body mass index, waist circumference, high-density lipoprotein cholesterol, fibrinogen, C-reactive protein (CHS only), and leukocyte counts, partly attenuated the associations. In CHS, the extreme-quintile HRs were 1.27 (95% CI, 0.96–1.67; Ptrend=0.04) for 22:1 and 1.62 (95% CI, 1.12–2.34; Ptrend=0.003) for 24:1; and in ARIC, 1.55 (95% CI, 1.09–2.20; Ptrend=0.06) for 22:1 and 1.53 (95% CI, 0.96–2.42; Ptrend=0.04) for 24:1. We examined incident CHD (n=471 in CHS, n=349 in ARIC) as a potential mediator. Adjusted for the incident events as time-varying variables, results were generally similar. In CHS, the extreme-quintile HR was 1.39 (95% CI, 1.11–1.74) for 22:1 and 1.44 (95% CI, 1.06–1.94) for 24:1 (Ptrend<0.002 each); in ARIC, these HRs were 1.72 (95% CI, 1.21–2.45) and 1.43 (95% CI, 0.89–2.28; Ptrend=0.01 and 0.11), respectively. We assessed multiplicative interaction for association of circulating LCMUFAs with incident CHF in each cohort according to age, sex, race, prevalent CHD, and prevalent diabetes mellitus. None of these factors appeared to be significantly modified the associations (Pinteraction>0.05 each).
Subtypes of CHF
We separately evaluated CHF subtypes centrally adjudicated in 857 cases (86%) in CHS, including ischemic CHF, valvular CHF, and nonischemic nonvalvular CHF. There was no evidence of substantial differences in associations of LCMUFAs with CHF overall and CHF subtypes (Table III in the online-only Data Supplement). For example, the multivariable-adjusted HR across the interdecile range (90th–10th percentile) of 24:1 was 1.65 (95% CI, 1.19–2.29) for overall CHF, 1.70 (95% CI, 1.06–2.71) for ischemic CHF, 1.83 (95% CI, 0.93–3.60) for valvular CHF, and 1.85 (95% CI, 1.04–3.30) for nonischemic nonvalvular CHF.
Regression Dilution Bias
In sensitivity analyses, we evaluated the associations of 22:1 and 24:1 with incident CHF after correcting for regression dilution bias (measurement error over time) in both LCMUFA levels and time-varying covariates. In multivariable-adjusted models (as in Table 2, fully adjusted model) further corrected for the bias, the observed associations were estimated to be 4.0-fold stronger for 20:1, 4.2-fold stronger for 22:1, and 3.0-fold stronger for 24:1. For example, the multivariable-adjusted HR comparing the top with the bottom quintile of 22:1 was 3.37 (95% CI, 1.19–9.52) in CHS and 6.58 (95% CI, 1.74–24.8) in ARIC; and of 24:1, 5.44 (95% CI, 1.81–16.3) in CHS and 7.14 (95% CI, 1.75–29.1) in ARIC.
Dose-response relationships between circulating LCMUFA levels and incident CHF were evaluated by restricted cubic splines. Although nonlinear associations of 22:1 levels were suggested in CHS (Pcurve=0.01), higher levels of LCMUFAs, in particular 24:1 levels, appeared to be monotonically associated with a higher incidence CHF in both cohorts (Plinear<0.001 in CHS and Plinear=0.003 in ARIC; Figure 1).
Given the many shared risk factors for CHF and stroke, we evaluated whether LCMUFAs were associated with stroke as a prespecified negative control, that is, to evaluate the specificity for CHF. None of the LCMUFAs were associated with incident stroke when evaluated separately in both cohorts and when pooled by meta-analysis (Table III in the online-only Data Supplement). The multivariable-adjusted pooled HRs per an interdecile range were 1.13 (95% CI, 0.94–1.36) for 20:1, 0.96 (95% CI, 0.75–1.25) for 22:1, and 1.12 (95% CI, 0.78–1.63) for 24:1.
Dietary Correlates of Circulating LCMUFAs and Estimated US LCMUFA Consumption
A variety of foods were positively associated with LCMUFA levels consistently between CHS and ARIC (Figure 2 and Figure I in the online-only Data Supplement). These included both generally more healthful foods such as seafood and whole grains and generally less healthful foods such as meat products.
In NHANES 2003 to 2010, mean±SD intakes of 20:1 and 22:1 were 239±23 and 34±15 mg/d, respectively. Many of the food sources of LCMUFA consumption in the United States were similar to those seen to be associated with circulating phospholipid LCMUFA levels in CHS and ARIC, including seafood, poultry, meats, and mustard (Figure 3). Because 24:1 consumption was not reported in NHANES, we assessed the US Department of Agriculture nutrient database to identify possible sources of LCMUFAs.11 Reported sources included mustard, seafood, and edible oil products (Table IV and V in the online-only Data Supplement), although only 6% of all items indexed 24:1 food contents.
In 2 independent community-based prospective cohorts, we found higher circulating levels of 22:1 and 24:1 to be associated with a higher incidence of CHF. Each plasma phospholipid LCMUFA, in particular 24:1, was also associated with specific physiological risk factors. In both cohorts, we identified diverse dietary correlates of circulating LCMUFA concentrations, including fish, poultry, nuts, mustard, and meat products. These findings were broadly consistent with the current major food sources of estimated LCMUFA consumption in the United States.
Existing evidence from animal experiments of LCMUFA-rich oil feeding and human studies on cardiac steatosis supports our observations, providing plausible biological pathways whereby LCMUFA exposure increases CHF risk, including CHF with both preserved and reduced ejection fraction. In studies in rodents, pigs, and nonhuman primates, experimental feeding of LCMUFAs caused cardiac steatosis and fibrosis,1–4 which relate to both systolic and diastolic dysfunction in humans.12–14 For example, among patients with aortic valve disease and healthy volunteers without known cardiac diseases, the presence of greater cardiac fibrosis and greater myocardial lipid content, as quantified by cardiac biopsy or magnetic resonance imaging, are independently associated with lower ejection fraction, greater passive ventricular stiffness, and other indexes of impaired early and late diastolic function.27–29
The potential cardiotoxicity of LCMUFAs may relate to their oxidative metabolism, to which the heart is likely to be especially susceptible because of its preferential use of fatty acids for energy.5–7 Experimental studies suggest that, in contrast to most other fatty acids, long-chain fatty acids, including LCMUFAs, are poorly oxidized in mitochondria as a result of a lack of mitochondrial membrane-transporting enzymes.3,8 Consequently, long-chain fatty acids predominantly undergo peroxisomal oxidation, which generates reactive oxygen species, including H2O2, and releases various lipid metabolites into the cytosol.8 Accumulated lipids include malonyl-CoA, which could inhibit mitochondrial fatty acid transport mediated by carnitine palmitoyltransferase-1; other acyl-CoAs that could stimulate lipogenic signals, suppressing glycolysis and forming lipid droplets linked to cardiac steatosis; ceramides, which serve as a second messenger for apoptotic signaling; and phospholipids and diacylglycerols, which alter membrane lipid composition and electrophysiological homeostasis, enhancing calcium overload linked to apoptosis, as well as contractile dysfunction and arrhythmia.5–7 These exacerbations have been partly demonstrated by research in transgenic animals.6,7 For example, mice with myocardium-specific overexpression of peroxisome proliferator-activated receptor-α exhibited interrelated phenotypes,30 including greater peroxisomal fatty acid oxidation; greater cytosolic lipid accumulation; inhibition of pyruvate dehydrogenase, a rate-limiting enzyme of glycolysis; greater left ventricular size and wall thickness; and reduced systolic function. Other evidence supports the notion of links between mitochondrial dysfunction and cardiac steatosis and heart failure. In cardiomyocytes biopsied from patients with aortic regurgitation,28 cardiac steatosis was associated with greater systolic dysfunction and overexpression of lipogenic enzymes, including sterol-regulatory element binding protein-1c.
As described above, a potential mechanism of cardiotoxicity is malonyl-CoA accumulation, resulting in inhibition of carnitine palmitoyltransferase-1. However, in animal studies and small clinical studies, antianginal drugs include carnitine palmitoyltransferase-1 inhibitors, which block mitochondrial oxidation, activating glycolysis and resulting in lower myocardial oxygen consumption.6,31 Thus, our findings highlight the need for better understanding of the potential mechanisms that might underlie the observed toxicity of LCMUFAs, including investigation of pathways related to mitochondrial function and energetic changes induced by fatty acids of all types.
When we evaluated subtypes of incident CHF in CHS, 24:1 appeared similarly associated with all subtypes. Conversely, 22:1 appeared most strongly related to ischemic CHF; however, we cannot rule out the possibility that the associations for CHF subtypes were similar because the 95% CIs were broad and associations for different CHF subtypes were not significantly different. Potential harms of LCMUFAs for diverse mechanisms of CHF onset are consistent with the multiple pathophysiologic pathways implicated in experimental studies, which together could lead to both systolic and diastolic dysfunction, both in the setting of ischemia and in the absence of ischemia. Interestingly, we also found that higher LCMUFA levels were associated with substantially lower triglyceride levels and higher inflammatory biomarkers, consistent with hepatic mitochondrial toxicity exhibiting hepatic inflammation and impaired hepatic lipid secretion.32 Our findings demonstrate the need for future studies to better characterize associations of LCMUFA exposure with differing origins of CHF and with measures of steatosis, fibrosis, and function of both cardiac and noncardiac tissues, for example, as assessed by cardiac and hepatic magnetic resonance imaging.
Circulating levels of 22:1 and 24:1 were robustly and consistently associated with CHF in both cohorts. Findings for 22:1 are consistent with animal experimental evidence of cardiotoxicity resulting from consumption of oil rich in 22:1. In addition, dietary 22:1 appears to be elongated to 24:1 in humans,33 which, together with our findings, suggests that experimentally observed cardiotoxicity of dietary 22:1 could be partly attributable to effects of its metabolite 24:1. In contrast to 22:1 and 24:1, we did not find significant associations of 20:1 with incident CHF. Evidence from cellular studies suggests that 20:1 undergoes mitochondrial oxidation to a greater extent than 22:1,3 which could limit its cardiotoxicity and explain our findings. Additionally, why the potential cardiotoxicity of 22:1 and 24:1 may be greater than for other long-chain fatty acids is unknown. One study suggested that peroxisomal oxidation of 24:1 is faster than that of 24:0,34 supporting greater toxicity of the former.
Animal experimental evidence of cardiotoxicity resulting from LCMUFA consumption stimulated Canadian farmers to develop Canola oil, which became commercially available during the 1960s.9 Thereafter, governmental regulations in Canada (1975), the United Kingdom (1977), and the United States (1985), as well as recommendations by Food and Agriculture Organization of the United Nations/World Health Organization (1982), were instituted to lower the content of 22:1n9 in rapeseed-derived oils.9,10 For instance, the US Food and Drug Administration mandated producers to reduce the 22:1n9 content in rapeseed oil from the original 30% to 60% to <2% by weight.10 Although these steps might reduce the population exposure to LCMUFAs in these countries, our findings indicate remaining dietary exposure to LCMUFAs in the United States. Additionally, in other countries, LCMUFA exposure could be even higher because of habitual consumption of unaltered rapeseed oil and mustard oil.35
We found that many different foods could influence LCMUFA exposure, including generally more healthful foods (fish, mustard seeds and oil, salad oils, poultry) and less healthful foods (processed meats and mixed meals, eg, pizza and meat sandwiches). This indicates that the potential cardiotoxicity of LCMUFAs cannot be attributed to any single dietary source and depends on overall exposure to LCMUFAs. As a corollary of this, the net effects of any food would depend not just on its LCMUFA content but also on other constituents in the food. For example, in the case of fish, which has been inversely associated with incident CHF in these cohorts,20,25 potential benefits of long-chain omega-3 polyunsaturated fatty acids in fish36 would plausibly outweigh any harmful effects of LCMUFA content. This does not obviate the suggestion of our findings that LCMUFA exposure itself increases the risk of CHF compared with the absence of such exposure. Our results support the need for interventional studies to determine whether lowering LCMUFAs in foods could reduce their harms or, in the case of beneficial foods such as fish, further increase their benefits. Although diet clearly influences circulating LCMUFA levels, the contribution of metabolic pathways remains uncharacterized. Few studies suggest that both diet and metabolism may influence circulating LCMUFA levels. For example, in a small (n=29) 2-year intervention among patients with inherited peroxisomal disorder (X-linked adrenoleukodystrophy) to reduce circulating levels of long-chain saturated fatty acids, 22:1 feeding (0.3 g/kg/d) elevated levels of both circulating 22:1 and 24:1 by 3-fold.33 These findings suggest that dietary 22:1 directly influences circulating 22:1 levels and is elongated to 24:1.
To the best of our knowledge, this is the first investigation to evaluate LCMUFAs and any health outcome in humans. Despite our findings and the prior animal experimental evidence, any single study should not alter dietary guidelines or clinical practice. Policy makers and clinicians should recognize the potential cardiotoxicity of LCMUFA exposure and be supportive of and watchful for further investigations. Our findings highlight the clear need to understand how LCMUFAs may influence health. This includes research to characterize details of dietary sources of LCMUFAs in various populations, as well as intervention studies to explore possible benefits of lowering LCMUFA exposure in populations having or at risk for CHF, examining end points such as cardiac imaging metrics, left ventricular systolic and diastolic function, symptoms and exercise tolerance, and clinical CHF.12–14,27–29
Potential limitations deserve consideration. Methods for assessing study variables were somewhat different in each cohort. Methodological differences in fatty acid measurements could partly explain the observed differences in absolute levels of 24:1 in the 2 cohorts. Despite these differences, the consistency of our findings between the 2 cohorts increases confidence in the validity and generalizability of our findings. Our findings should be interpreted cautiously because causality is unknown owing to confounding and exposure misclassification. Lesser reproducibility over time could partly explain weaker associations for 20:1 and 22:1 compared with 24:1. Although we performed multivariate adjustment and regression dilution correction, such methods are imperfect, and remaining residual errors could bias our results toward or away from the null. In examinations of potential confounding, circulating LCMUFAs were not associated with incident stroke, which shares many CHF risk factors. Moreover, both generally healthful and unhealthful foods were associated with LCMUFA exposure. These results, together with the magnitude and consistency of our findings, suggest that residual confounding could not entirely explain the observed associations. Our analysis was based on cohorts generally made up of white Americans, stimulating future research on LCMUFA exposure and CHF events and causes in other races/ethnicities.
Our observations indicate that higher circulating LCMUFA levels are associated with a greater incidence of CHF. Our findings in 2 cohorts, together with prior animal experiments, support the need to better characterize dietary sources of LCMUFAs, to further elucidate molecular mechanisms of effects, and to design and implement interventions to test the effects of reducing LCMUFA exposure.
Sources of Funding
This study was funded by the National Heart, Lung, and Blood Institute (NHLBI) with cofunding from the Office of Dietary Supplements (R01-HL085710), as well as an Administrative Supplement Award (3R01-HL085710-03S1). CHS was supported by the NHLBI (N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, and HL080295), with additional contributions from the National Institute of Neurological Disorders and Stroke and the National Institute of Aging (AG-023629, AG-15928, AG-20098, and AG-027058). A Searle Scholar Award additionally supported CHS fatty acid assessment. ARIC was supported by the NHLBI (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C).
Dr Mozaffarian reported support from GlaxoSmithKline, Sigma Tau, and Pronova for a trial of fish oil and postsurgical complications; ad hoc travel reimbursement and/or honoraria for presentations from Aramark, Unilever, SPRIM, and Nutrition Impact; ad hoc consulting fees from Foodminds and McKinsey Health Systems Institute; and royalties from UpToDate. The other authors reported no conflicts of interest.
Guest Editor for this article was Gregory Y.H. Lip, MD.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.112.001197/-/DC1.
- Received September 19, 2012.
- Accepted March 4, 2013.
- © 2013 American Heart Association, Inc.
- Bremer J,
- Norum KR
- Lopaschuk GD,
- Ussher JR,
- Folmes CD,
- Jaswal JS,
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Decades ago, animal experiments demonstrated that feeding of long-chain monounsaturated fatty acids (LCMUFAs) such as erucic acid (22-carbon fatty acid, 22:1) caused cardiotoxicity, including cardiac lipid accumulation. In the 1970s, this evidence stimulated Canadian farmers to modify rapeseed oil, a major source of LCMUFA, to lower its 22:1 content and rename it Canola oil (Canadian oil low in erucic acid). Potential health effects and dietary sources of LCMUFAs (20:1, 22:1, and 24:1) were never studied in humans and subsequently largely forgotten. To elucidate both potential cardiotoxicity and dietary sources, we evaluated blood LCMUFA biomarkers in relation to incident congestive heart failure in 2 independent cohorts and LCMUFA dietary consumption in both cohorts and in the 2003–2010 US National Health and Nutrition Examination Survey. In multivariable-adjusted analyses, compared with the bottom quintiles, individuals in the highest quintile of 22:1 levels experienced ≈50% greater incident congestive heart failure and those in the highest quintile of 24:1 levels experienced 2-fold greater incidence, with consistent results in both cohorts. On the basis of both biomarkers and food composition data, major food sources of LCMUFAs were mustard, salad oils, poultry, fish, processed meats, and mixed meals (eg, pizza). No single food contributed >35% of LCMUFA consumption. In summary, blood LCMUFAs were significantly associated with incident congestive heart failure in 2 cohorts. Diverse identified dietary sources suggest that potential cardiotoxicity cannot be attributable to any single food, for which net health effects might depend on both LCMUFAs and other constituents. Our findings demonstrate the need for additional experimental, observational, and interventional studies to characterize the cardiovascular effects of LCMUFAs and their implications for clinical and public health guidelines.