ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies

In the paper

“No significant differences in associations of ω-3 PUFA biomarkers with incident CHD events were observed by age, sex, ω-6 PUFA (LA or AA) concentrations, type 2 diabetes status, statin use, regular aspirin use, year of biomarker sampling, or (for ALA) EPA, DPA, and DHA concentrations (P for heterogeneity >.05 for each)”

In the paper

“The 19 studies comprised 16 countries, 45 637 unique individuals, and 7973 total CHD, 2781 fatal CHD, and 7157 nonfatal MI events, with ω-3 measures in total plasma, phospholipids, cholesterol esters, and adipose tissue.”

In the paper

“Median age at baseline was 59 years (range, 18–97 years), and 28 660 (62.8%) were male.”

In the paper

“Compared with the main findings, no appreciable differences were observed after excluding cases identified in the first 2 years after biomarker sampling, censoring participants at the first 6 years of follow-up, excluding retrospective studies, or excluding studies with self-reported events”

In the paper

“Across biomarker types, inverse associations were generally stronger in the phospholipid and total plasma compartments (Table 2); heterogeneity decreased when adipose tissue and cholesterol ester estimates were excluded from meta-analyses.”

In the paper

“Across these diverse studies, findings were consistent by age, sex, ω-6 PUFA LA and AA levels, year of biomarker sampling, presence or absence of diabetes, statin use, and aspirin use.”

In the paper

“Our findings suggest generally stronger inverse associations with CHD for EPA, DPA, and DHA in phospholipids and total plasma, although fewer estimates and cases were available for adipose and cholesterol esters compartments, decreasing precision.”

In the paper

“Compared with priorwork,42 we also took advantage of a far larger number of events (eg, >4-fold larger for fatal CHD)”

What the sources say

• Not checked yetcites [42] Chowdhury R Warnakula S Kunutsor S Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis Ann Intern Med 2014 160 6 398 406 24723079 source

In the paper

“most prior research11 has focused on seafood-derived long-chain ω-3 PUFAs, and potential CHD effects of plant-derived α-linolenic acid (ALA; 18:3ω-3) are far less understood.”

What the sources say

• Not checked yetcites [11] Pan A Chen M Chowdhury R α-Linolenic acid and risk of cardiovascular disease: a systematic review and meta-analysis Am J Clin Nutr 2012 96 6 1262 1273 23076616 PMC3497923 source

In the paper

“most trials provided supplements for a few years or less and were conducted in patients with preexisting CHD or at high risk for CHD and taking multiple cardiovascular drugs.”

What the sources say

• Not checked yetcites [2] Bucher HC Hengstler P Schindler C Meier G N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials Am J Med 2002 112 4 298 304 11893369 source
• Not checked yetcites [3] Hooper L Thompson RL Harrison RA Omega 3 fatty acids for prevention and treatment of cardiovascular disease Cochrane Database Syst Rev 2004 4 CD003177 15495044 PMC4170890 source
• Not checked yetcites [4] León H Shibata MC Sivakumaran S Dorgan M Chatterley T Tsuyuki RT Effect of fish oil on arrhythmias and mortality: systematic review BMJ 2008 337 a2931 10.1136/bmj.a2931 19106137 PMC2612582 source
• Not checked yetcites [5] Marik PE Varon J Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review Clin Cardiol 2009 32 7 365 372 19609891 PMC6653319 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [6] Trikalinos TA Lee J Moorthy D Effects of Eicosapentanoic Acid and Docosahexanoic Acid on Mortality Across Diverse Settings: Systematic Review and Meta-analysis of Randomized Trials and Prospective Cohorts Rockville, MD Agency for Healthcare Research and Quality 2012 22479722
• Not checked yetcites [7] Kwak SM Myung SK Lee YJ Seo HG Korean Meta-analysis Study Group Efficacy of ω-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials Arch Intern Med 2012 172 9 686 694 22493407 source
• Not checked yetcites [8] Rizos EC Ntzani EE Bika E Kostapanos MS Elisaf MS Association between ω-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis JAMA 2012 308 10 1024 1033 22968891 source

In the paper

“A previous review1 also found that a handful of studies have measured objective circulating or tissue ω-3 PUFA levels, but such findings could be limited by publication bias.”

What the sources say

• Not checked yetcites [1] Mozaffarian D Wu JHY Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events J Am Coll Cardiol 2011 58 20 2047 2067 22051327 source

In the paper

“the background dietary intake in these trials was not usually measured, and many participants may have had adequate intake from diet alone.”

What the sources say

• Not checked yetcites [2] Bucher HC Hengstler P Schindler C Meier G N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials Am J Med 2002 112 4 298 304 11893369 source
• Not checked yetcites [3] Hooper L Thompson RL Harrison RA Omega 3 fatty acids for prevention and treatment of cardiovascular disease Cochrane Database Syst Rev 2004 4 CD003177 15495044 PMC4170890 source
• Not checked yetcites [4] León H Shibata MC Sivakumaran S Dorgan M Chatterley T Tsuyuki RT Effect of fish oil on arrhythmias and mortality: systematic review BMJ 2008 337 a2931 10.1136/bmj.a2931 19106137 PMC2612582 source
• Not checked yetcites [5] Marik PE Varon J Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review Clin Cardiol 2009 32 7 365 372 19609891 PMC6653319 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [6] Trikalinos TA Lee J Moorthy D Effects of Eicosapentanoic Acid and Docosahexanoic Acid on Mortality Across Diverse Settings: Systematic Review and Meta-analysis of Randomized Trials and Prospective Cohorts Rockville, MD Agency for Healthcare Research and Quality 2012 22479722
• Not checked yetcites [7] Kwak SM Myung SK Lee YJ Seo HG Korean Meta-analysis Study Group Efficacy of ω-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials Arch Intern Med 2012 172 9 686 694 22493407 source
• Not checked yetcites [8] Rizos EC Ntzani EE Bika E Kostapanos MS Elisaf MS Association between ω-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis JAMA 2012 308 10 1024 1033 22968891 source

In the paper

“Heterogeneity by prespecified subgroups was evaluated by pooling individual study results based on defined strata”

In the paper

“We excluded soft CHD end points (eg, angina, revascularization) to minimize bias in ascertainment of these events.”

In the paper

“with coefficients of variation less than 10% for most fatty acids and biomarkers”

In the paper

“In randomized clinical trials, long-chain ω-3 PUFAs benefit multiple major cardiovascular risk factors, including triglyceride levels, blood pressure, heart rate, heart rate variability, endothelial function, and myocardial oxygen demand.1,10”

What the sources say

• Not checked yetcites [1] Mozaffarian D Wu JHY Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events J Am Coll Cardiol 2011 58 20 2047 2067 22051327 source
• Not checked yetcites [10] Mozaffarian D Wu JH (n-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J Nutr 2012 142 3 614S 625S 22279134 PMC3278271 source

In the paper

“Several sensitivity analyses were performed.”

In the paper

“Our findings are consistent with prior experimental evidence that long-chain ω-3 PUFAs may have membrane stabilizing actions in the setting of ischemia-induced ventricular fibrillation1,38 and observational evidence indicating that benefits of fish consumption are most related to arrhythmic events39 and fatal CHD.40”

What the sources say

• Not checked yetcites [1] Mozaffarian D Wu JHY Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events J Am Coll Cardiol 2011 58 20 2047 2067 22051327 source
• Not checked yetcites [38] Siscovick DS Lemaitre RN Mozaffarian D The fish story: a diet-heart hypothesis with clinical implications: n-3 polyunsaturated fatty acids, myocardial vulnerability, and sudden death Circulation 2003 107 21 2632 2634 12782612 source
• Not checked yetcites [39] Siscovick DS Raghunathan TE King I Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest JAMA 1995 274 17 1363 1367 7563561 source

In the paper

“Covariates were standardized across studies based on prespecified, harmonized definitions and categorizations”

In the paper

“a previous study10 suggests that DPA may inhibit ex vivo collagen-stimulated platelet aggregation, thromboxane production, and cyclooxygenase 1 activity.”

What the sources say

• Not checked yetcites [10] Mozaffarian D Wu JH (n-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J Nutr 2012 142 3 614S 625S 22279134 PMC3278271 source

In the paper

“Our prespecified primary analysis used inverse-variance weights.”

In the paper

“A standardized analysis protocol was developed and provided to each participating study, including harmonized definitions of populations, exposures, outcomes, covariates, effect modifiers, and methods for pooling across studies.”

In the paper

“A key strength of our analysis was the prespecified, harmonized analytic plan using individual-level data within each study, which allowed consistent assessment of how ALA relates to CHD.”

In the paper

“Our results support use of phospholipids or total plasma for long-chain ω-3 PUFA exposure and a need for further investigation of optimal biomarkers for assessing ALA.”

In the paper

“few studies were available with African American (n = 2 studies: CHS and MESA) and Chinese subgroups (n = 2 studies: SCHS and MESA).27,33”

What the sources say

• Not checked yetcites [27] Bild DE Bluemke DA Burke GL Multi-Ethnic Study of Atherosclerosis: objectives and design Am J Epidemiol 2002 156 9 871 881 12397006 source
• Not checked yetcites [33] Hankin JH Stram DO Arakawa K Singapore Chinese Health Study: development, validation, and calibration of the quantitative food frequency questionnaire Nutr Cancer 2001 39 2 187 195 11759279 source

In the paper

“Randomized clinical trials of fish oil supplements have found mixed effects, although overall pooled findings indicate a benefit in lowering risk of cardiac death,8 consistent with our findings.”

What the sources say

• Not checked yetcites [8] Rizos EC Ntzani EE Bika E Kostapanos MS Elisaf MS Association between ω-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis JAMA 2012 308 10 1024 1033 22968891 source

In the paper

“Because our findings reflect habitual ω-3 exposure for primary CHD prevention, our results do not imply that fish oil supplementation will necessarily reduce CHD events, particularly in the context of short-term treatment or in those with preexisting CHD.”

In the paper

“All cohorts assessed ω-3 PUFA exposure once at baseline, and changes over time would attenuate findings toward the null, causing underestimation of associations.”

In the paper

“Because we analyzed observational studies, biomarkers and risk factors were not evenly distributed by randomization of study participants; hence, unmeasured or residual confounding cannot be excluded, and ω-3 biomarker measures may in part be markers of a long-term healthy lifestyle.”

In the paper

“The best compartment for assessing ALA has also been unclear, with possible advantages to adipose tissue16 but relatively little prior evaluation of other compartments.”

What the sources say

• Not checked yetcites [16] Baylin A Kim MK Donovan-Palmer A Fasting whole blood as a biomarker of essential fatty acid intake in epidemiologic studies: comparison with adipose tissue and plasma Am J Epidemiol 2005 162 4 373 381 16014782 source

In the paper

“Most studies18–25,27–35 used centralized adjudication processes or registry linkage rather than self-report alone in ascertaining events, reducing information bias.”

What the sources say

• Not checked yetcites [18] ARIC Investigators The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives Am J Epidemiol 1989 129 4 687 702 2646917
• Not checked yetcites [19] Campos H Bailey SM Gussak LS Siles X Ordovas JM Schaefer EJ Relations of body habitus, fitness level, and cardiovascular risk factors including lipoproteins and apolipoproteins in a rural and urban Costa Rican population Arterioscler Thromb 1991 11 4 1077 1088 2065029 source
• Not checked yetcites [20] Fried LP Borhani NO Enright P The Cardiovascular Health Study: design and rationale Ann Epidemiol 1991 1 3 263 276 1669507 source
• Not checked yetcites [21] Day N Oakes S Luben R EPIC-Norfolk: study design and characteristics of the cohort: European Prospective Investigation of Cancer Br J Cancer 1999 80 1 suppl 1 95 103 10466767 source
• Not checked yetcites [22] Kardinaal AF van ‘t Veer P Kokl FJ EURAMIC Study: antioxidants, myocardial infarction and breast cancer: design and main hypotheses Eur J Clin Nutr 1993 47 2 suppl 2 S64 S72 8262023
• Not checked yetcites [23] Rimm EB Giovannucci EL Willett WC Prospective study of alcohol consumption and risk of coronary disease in men Lancet 1991 338 8765 464 468 1678444 source
• Not checked yetcites [24] Bartali B Benvenuti E Corsi AM Changes in anthropometric measures in men and women across the life-span: findings from the InCHIANTI study Soz Praventivmed 2002 47 5 336 348 12512227 source
• Not checked yetcites [25] Vanharanta M Voutilainen S Lakka TA van der Lee M Adlercreutz H Salonen JT Reduced risk of acute coronary events at high levels of mammalian lignan, enterolactone: a prospective population-based cohort study Lancet 1999 354 2112 2115 10609816 source
• Not checked yetcites [27] Bild DE Bluemke DA Burke GL Multi-Ethnic Study of Atherosclerosis: objectives and design Am J Epidemiol 2002 156 9 871 881 12397006 source
• Not checked yetcites [28] Norberg M Wall S Boman K Weinehall L The Västerbotten Intervention Programme: background, design and implications Global Health Action website 2010 http://www.globalhealthaction.net/index.php/gha/article/view/4643/5514 Accessed May 30, 2016 PMC2844807 20339479 source

In the paper

“Our inclusion of all available studies substantially reduces the potential for publication bias.”

In the paper

“In addition, whereas circulating and tissue levels of EPA and DHA are strongly influenced by dietary seafood consumption, DPA concentrations appear to be mainly derived from endogenous elongation of EPA; interconversion between DPA and DHA is very limited.10”

What the sources say

• Not checked yetcites [10] Mozaffarian D Wu JH (n-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J Nutr 2012 142 3 614S 625S 22279134 PMC3278271 source

In the paper

“Use of biomarkers provided measures of exposure free of recall error and allowed separate evaluation of different ω-3 PUFAs and different circulating and tissue lipid compartments.”

In the paper

“However, a meta-analysis11 of prior reports of dietary and biomarker ALA and CHD risk revealed inconsistency, perhaps owing to methodologic and analytic differences in these investigations.”

What the sources say

• Not checked yetcites [11] Pan A Chen M Chowdhury R α-Linolenic acid and risk of cardiovascular disease: a systematic review and meta-analysis Am J Clin Nutr 2012 96 6 1262 1273 23076616 PMC3497923 source

In the paper

“Adipose tissue has been suggested for measurement of fatty acids because it reflects long-term dietary intake (approximately 1 year).56”

What the sources say

• Not checked yetcites [56] Dayton S Hashimoto S Dixon W Pearce ML Composition of lipids in human serum and adipose tissue during prolonged feeding of a diet high in unsaturated fat J Lipid Res 1966 7 1 103 111 5900208 source

In the paper

“However, our findings were independent of a range of major cardiovascular risk factors, and the relative specificity for fatal CHD and known biologic effects of ω-3 PUFAs also argue against residual confounding as the sole explanation for our findings.”

In the paper

“However, EPA and DHA are more highly concentrated in phospholipids than other compartments, and phospholipids also respond rapidly to dietary changes57,58 and may best reflect effects on membrane receptors.1”

What the sources say

• Not checked yetcites [57] Arterburn LM Hall EB Oken H Distribution, interconversion, and dose response of n-3 fatty acids in humans Am J Clin Nutr 2006 83 6 suppl 1467S 1476S 16841856
• Not checked yetcites [58] Conquer JA Holub BJ Effect of supplementation with different doses of DHA on the levels of circulating DHA as non-esterified fatty acid in subjects of Asian Indian background J Lipid Res 1998 39 2 286 292 9507989
• Not checked yetcites [1] Mozaffarian D Wu JHY Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events J Am Coll Cardiol 2011 58 20 2047 2067 22051327 source

In the paper

“The studies included both sexes, multiple races, and a range of socioeconomic statuses across 16 countries, increasing generalizability.”