HS-Omega-3 Index in Cardiology

The world’s most important cardiac scientific societies recommend two marine omega-3 fatty acids eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) for cardiovascular prevention, for secondary prevention, for treatment of cardiac arrhythmias, and for treatment of congestive heart failure (Perk et al, 2012; Smith et al, 2011; Zipes et al, 2006; McMurray et al, 2012). Nevertheless, many cardiologists do not recommend EPA plus DHA, because they consider EPA plus DHA ineffective. The opinion of the cardiologists is based on neutral results of large intervention trials with clinical endpoints, and their meta-analyses. However, scientific societies also consider other scientific data, like epidemiology, mechanisms, and results of intervention trials on surrogate (e.g. blood pressure, laboratory values) and intermediate parameters (e.g. changes in blood vessels).

Substantial amounts of data based on the HS-Omega-3 Index have been generated in the last ten years. This allows a clearer view on the field, and also allows to resolve the discrepancies between the results of the large trials with clinical endpoints, and the other results mentioned. This is supported by results of investigations on bioavailability and by results from measurements of levels of EPA plus DHA in other compartments. More detailed information can be found in current review articles (von Schacky, 2014a-d; Superko et al, 2013; Harris et al, 2013). In short: A low HS-Omega-3 Index is a cardiovascular risk factor. It is equivalent and sometimes even superior to conventional risk factors. A HS-Omega-3 Index in the target range of 8 – 11% is associated with lower total mortality, lower cardiovascular mortality, less sudden death, less fatal and non-fatal myocardial infarctions than a HS-Omega-3 Index below the target range.

Epidemiology

In a systematic review with meta-analysis of epidemiologic studies, a high intake of EPA plus DHA was associated with a lower rate of coronary events by 13%, than a low intake (RR 0.87, 95% Konfidenzintervall CI 0.78-0.97, Chowdury et al, 2014). Assessing diet is subject to substantial uncertainties (Archer et al, 2013). In the same meta-analysis, higher levels of EPA plus DHA in plasma or adipose tissue were associated with a lower rate of coronary events by 25%, than lower levels (RR 0.75, 95% CI .62-0.89, Chowdury et al, 2014). The biologic variability of omega-3 fatty acids in plasma is substantially larger than their biologic variability in erythrocytes (Harris & Thomas 2010). Moreover, the analytical variability of the HS-Omega-3 Index method is 3.9 rel.%, a very low value (Harris & Thomas 2010). Thus, the HS-Omega-3 Index method is probably the only analytical method for fatty acids conforming Clinical Chemistry. This explains, why epidemiologic studies based on the HS-Omega-3 Index have a higher discriminatory power than studies based on analyses of e.g. plasma or even nutrition (table 1). The data in table one are confirmed and expanded by as yet unpublished data from the LURIC study.

The HS-Omega-3 Index as a novel cardiovascular risk factor

According to US Preventive Service Task Force and American Heart Association, novel biomarkers for cardiovascular risk have to fulfill the following four criteria (Helfand et al, 2009; Hlatky et al, 2009):
1. standardized assessment
2. incremental information to conventional risk factors
3. improved risk classification
4. therapeutic consequence

1) As mentioned, the analytical method of the HS-Omega-3 Index conforms the quality management of Clinical Chemistry (constancy checks, plausibility checks, proficiency tests, asf.) (Harris & Thomas, 2009, von Schacky 2014a-d). This is in contrast to other biomarkers for cardiovascular risk, like measuring intima-media thickness with ultrasound, ankle-brachial index, or lipoprotein (a), all of which lack a standardized assessment. Therefore, use of these parameters should be restricted to investigational purposes (von Schacky 2014a-d).

2) In the US, the predictive value of a HS-Omega-3 Index based fatty acid profile for the acute coronary syndrome was bigger than the Framingham Risk Score (bigger area under the curve in c-statistic; Shearer et al, 2009). Similar data have been generated in other populations (von Schacky, 2014a-d).

3) Risk classification by the Framingham Risk Score was improved: Individuals, who were considered to have intermediary risk could be reclassified to high or low risk in a more precise manner (Shearer et al, 2009). In Korea, the Framingham Risk Score predicts poorly, and more pronounced data were generated there (Park et al, 2009). Current investigations in collaboration with Framingham, LURIC and others will add precision to this area.

4) Increasing the HS-Omega-3 Index decreased heart rate, increased heart rate variability, lowered blood pressure and platelet aggregability, lowered triglycerides and various pro-inflammatory cytokines, lowered atherogenic small dense LDL, and increased anti-atherogenic large buoyant LDL(Harris et al Am J Cardiol 2006; 98:1393-5, Carney et al Psychosom Med 2010;72:748; Dewell et al J Nutr Res 2011;141:2166; Skulas-Ray et al Ann Behav Med 2012;44:301. Larson et al, Thromb Haemost 2008;100: 634, Harris et al, Lipids 2008;43:805, Duda et al Cardiovasc Res 2009;81:319,Dewell et al J Nutrition 2011;141:2166, Blocket al World J Cardiovasc Dis2012;2:14, Skulas-Ray Am J Clin Nutr 2011;93:243, Schuchardt et al PLEFA 2011;85:381, Shearer et al J Lipid Res. 2012;53:2429, Maki et al J Clin Lipidol 2011;5:483). Taken together, a large number of surrogate parameters for cardiovascular disease were improved by an increase of the HS-Omega-3 Index.

In our own randomized controlled intervention trial with EPA and DHA, progression of coronary lesions was reduced, and regression increased by an increase of erythrocyte EPA plus DHA from <4% to >8%. The fatty acid analytical method was different at the time, and therefore cannot be directly compared to data generated with the HS-Omega-3 Index method. However, clearly the “natural” course of coronary atherosclerosis was mitigated by increasing erythrocyte EPA plus DHA (von Schacky et al, 1999). This mid-sized intervention trial demonstrated a positive effect on an intermediary parameter of coronary artery disease.

As mentioned, large intervention trials did not demonstrate a reduction in clinical events by increased ingestion of EPA plus DHA (discussed in more detail in von Schacky, 2014). Two issues in the design of these studies are likely to be responsible for these neutral results:
– bioavailability: without an accompanying high-fat meal, bioavailability of EPA in capsules is minimal (Schuchart & Hahn, 2013). In almost all large intervention trials, participants were advised to take the study capsules with breakfast, a low-fat meal in most countries (von Schacky, 2014).
– Trial design: For all large intervention trials, participants were recruited irrespective of baseline levels of EPA plus DHA (von Schacky, 2014). In every population studied so far, the HS-Omega-3 Index had a statistically normal distribution (von Schacky, 2014). The response of the HS-Omega-3 Index to increased intake of EPA plus DHA varies from Person to Person by a factor of up to 13 (Köhler et al, 2011). In combination, both facts lead to overlapping levels of EPA plus DHA during the trial – as already demonstrated in a large intervention trial (Muhlhausler et al, 2014). A trial, where Verum and Placebo or control group are no different in terms of the intervention will not demonstrate a difference in outcome.
A new generation of trials, recruiting participants with a low baseline HS-Omega-3 Index, and using variable doses of EPA plus DHA to reach a predefined treatment goal (e.g. a HS-Omega-3 Index of 8 – 11%) is likely to have clearer results.

The HS-Omega-3 Index needs to be compared to other novel biomarkers for cardiovascular risk. In the European guidelines for cardiovascular prevention, imaging procedures like coronary calcium scoring, assessment of carotid intima-media thickness or the ankle brachial index are suggested as a means for further risk stratification, while laboratory parameters like hs-CRP, Fibrinogen or homocysteine are seen more critically (Perk et al, Eur Heart J 2012;33:1635;). Rarely is coronary calcium measured in a standardized way in clinical routine, rather in studies, and pertinent intervention trials have not yet been performed. Similar things can be said about assessing intima-media thickness, or the ankle-brachial index. The standardized analytical procedure and the existing intervention trial rather support hs-CRP. However, practical problems hamper its use in clinical routine. If the authors of the guidelines would apply the criteria of the American Heart Association and/or of the US Preventive Service Task Force anwenden (Helfand et al, 2009, Hlatky et al, 2009), use of the HS-Omega-3 Index would have to be recommend, because it fulfills almost all those criteria completely.

Sudden cardiac death

Sudden cardiac death is responsible for some 15% of all deaths (Zipes et al, 2006). Mostly individuals, who consider themselves in good health, die from sudden cardiac death. Risk factors either define a small population, like the MADIT-criteria, the basis for implantation of a cardioverter-defibrillator (Zipes et al, 2006). Results from mechanistic studies indicate that EPA plus DHA inhibit the conversion of ventricular tachycardia (hemodynamically frequently tolerated) to ventricular fibrillation (usually not tolerated) (von Schacky, 2012). In a case-control study, the erythrocyte fatty acid composition of victims of sudden cardiac death was analyzed, and compared to the erythrocyte fatty acid composition of healthy controls (Siscovick et al. 1995). The probability for sudden cardiac death increased with decreasing percentages of EPA plus DHA in erythrocytes, and a 10 fold difference was observed between the highest and the lowest quartile (Siscovick et al, 1995). Similar findings were reported from the Physicians’ Health Study (Albert et al, 2002). Of note, little relation was found between intake of EPA plus DHA and sudden cardiac death (Siscovick et al, 1995). This puts the neutral findings of the only intervention trial aiming at prevention of sudden cardiac death with EPA plus DHA into perspective (Rauch et al, 2010). A low HS-Omega-3 Index was associated with increased risk for ventricular fibrillation during acute ischemia in a myocardial infarction (Aarsetøy et al, 2008), and a low HS-Omega-3 Index was associated with sudden cardiac death (Aarsetøy et al, 2011). Interestingly, an increase of the HS-Omega-3 Index by 1% was associated with a 58% lower risk for ventricular fibrillation during a myocardial infarction ((95% CI: 0.25–0.76%)( Aarsetøy et al, 2011). Current guidelines of the American and European cardiac societies mention EPA plus DHA as a therapeutic possibility in patients with ventricular arrhythmias and coronary artery disease (Level of Evidence B, Grade of recommendation IIb, Zipes et al, 2006). Currently, more data is being generated in collaboration with various registries. Nevertheless, the data so far supports the conclusion that risk for ventricular fibrillation depends on the HS-Omega-3 Index, and that a HS-Omega-3 Index based supplementation with EPA plus DHA is an option for prevention of sudden cardiac death.

Atrial fibrillation

Epidemiology, mechanisms of action an some clinical trials support the notion that EPA plus DHA prevent atrial fibrillation (von Schacky, 2012). Low levels of EPA plus DHA in plasma phospholipids are associated with a high likelihood to develop atrial fibrillation, as compared to high levels of EPA plus DHA (Wu et al, 2012). This indicates that a low HS-Omega-3 Index is associated with subsequent development of atrial fibrillation; this is currently investigated.

Congestive Heart failure

Low levels of EPA plus DHA in plasma phospholipids are associated with a 50% increased risk for subsequent development of congestive heart failure, as compared to high levels (HR 0.52; 95%CI 0.38 – 0.72]; p for Trend <0.001) (Mozaffarian et al, 2011). Our own unpublished data indicate that patients with congestive heart failure have a low HS-Omega-3 Index (mean < 4%). In a large randomized intervention trial with clinical endpoints in patients with congestive heart failure, EPA plus DHA reduced total mortality and re-hospitalizations (GISSI-HF, 2008). Therefore, EPA and DHA are recommended in the pertinent European guidelines (levels of evidence B, level of recommendation IIb, McMurray et al, 2012). In our opinion, although a pertinent trial has not yet been conducted, EPA plus DHA should be used in congestive heart failure with the aim of a HS-Omega-3 Index of 8 – 11%.

Literature

Aarsetoey H, Pönitz V, Nilsen OB, Grundt H, Harris WS, Nilsen DW. Low levels of cellular omega-3 increases the risk of ventricular fibrillation during the acute ischaemic phase of a myocardial infarction. Resuscitation 2008;78:258-64
Aarsetøy H, Aarsetøy R, Lindner T, Staines H, Harris WS, Nilsen DWT. Low Levels of the Omega-3 Index are Associated with Sudden Cardiac Arrest and Remain Stable in Survivors in the Subacute Phase. Lipids 2011;46:151-61.
Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, Willett WC, Ma J. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N. Engl. J. Med. 2002;346:1113-8.
Archer E, Hand GA, Blair SN. Validity of U.S. nutritional surveillance:National Health and Nutrition Examination Survey caloric energy intake data, 1971-2010. PLoS One. 2013;8:e76632
Block RC, Dier U, Calderonartero P, Shearer GC, Kakinami L, Larson MK, Harris WS, Georas S, Mousa SA. The Effects of EPA+DHA and Aspirin on Inflammatory Cytokines and Angiogenesis Factors. World J Cardiovasc Dis. 2012;2:14-19
Carney RM, Freedland KE, Stein PK, Steinmeyer BC, Harris WS, Rubin EH, Krone RJ, Rich MW. Effect of Omega-3 Fatty Acids on Heart Rate Variability in Depressed Patients with Coronary Heart Disease. Psychosom Med 2010;72:748-54.
Chowdhury R, Warnakula S, Kunutsor S, Crowe F, Ward HA, Johnson L, Franco OH, Butterworth AS, Forouhi NG, Thompson SG, Khaw KT, Mozaffarian D, Danesh J, Di Angelantonio E. Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis. Ann Intern Med. 2014 Mar 18;160:398-406
Dewell A, Marvasti FF, Harris WS, Tsao P, Gardner CD. Dose-Dependent Effects of Plant and Marine Omega-3 Fatty Acids on Inflammatory Markers in Insulin Resistant Adults. A Randomized Controlled Trial. J Nutrition 2011;141:2166-71
Duda MK O’Shea KM, Tintinu A, Xu W, Khairallah RJ, Barrows BR, Chess DJ, Azimzadeh AM, Harris WS, Sharov VG, Sabbah HN, Stanley WC. Fish oil but not flaxseed oil decreases inflammation and prevents pressure-overload induced cardiac dysfunction. Cardiovasc Res 2009;81:319-27.
Gissi-HF Investigators, Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, Lucci D, Nicolosi GL, Porcu M, Tognoni G. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9645):1223-30
Harris WS, Gonzales M, Laney N, Sastre A, Borkon AM. Effects of Omega-3 Fatty Acids on Heart Rate in Cardiac Transplant Recipients. Am J Cardiol 2006;98:1393-5.
Harris WS, Lemke SL, Hansen SN, Goldstein DA, DiRienzo MA, Su H, Nemeth MA, Taylor ML, Ahmed G, George C. Stearidonic Acid-Enriched Soybean Oil Increased the Omega-3 Index, an Emerging Cardiovascular Risk Marker. Lipids 2008;43:805-11.
Harris WS, Dayspring TD, Moran TJ. Omega-3 Fatty Acids and Cardiovascular Disease. New Developments and Applications. Postgrad Med 2013;125:100-113
Harris WS, Thomas RM. Biological variability of blood omega-3 biomarkers. Clin Biochem 2010;43:338-40,
Helfand M, Buckley DI, Freeman M, Fu R, Rogers K, Fleming C, Humphrey LL. Emerging risk factors for coronary heart disease: a summary of systematic reviews conducted for the U.S. Preventive Services Task Force. Ann. Intern. Med. 2009;151:496-507
Hlatky MA, Greenland P, Arnett DK, Ballantyne CM, Criqui MH, Elkind MS et al; American Heart Association Expert Panel on Subclinical Atherosclerotic Diseases and Emerging Risk Factors and the Stroke Council. Circulation 2009;119:2408-16.
Köhler A, Bittner D, Löw A, von Schacky C. Effects of a convenience drink fortified with n-3 fatty acids on the n-3 index. Br J Nutr 2010; 104:729-36.
Larson MK, Ashmore JH, Harris KA, Vogelaar JL, Pottala JV, Sprehe M, Harris WS. Effects of Omega-3 Acid Ethyl Esters and Aspirin, Alone and in Combination, on Platelet Function in Healthy Subjects. Thromb Haemost 2008;100:634-41.
Maki KC, Bays HE, Dicklin MR, Johnson SL, Shabbout M. Effects of prescription omega-3-acid ethyl esters, coadministered with atorvastatin, on circulating levels of lipoprotein particles, apolipoprotein CIII, and lipoprotein-associated phospholipase A2 mass in men and women with mixed dyslipidemia. J Clin Lipidol. 2011;5:483-92.
McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al; ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur. Heart J. 2012;33:1787-847.
Mozaffarian D, Lemaitre RN, King IB, Song X, Spiegelman D, Sacks FM, et al. Circulating long-chain ω-3 fatty acids and incidence of congestive heart failure in older adults: the cardiovascular health study: a cohort study. Ann. Intern. Med. 2011;155:160-70
Mühlhäusler BS, Gibson RA, Yelland LN, Makrides M. Heterogeneity in cord blood DHA concentration: towards an explanation.Prostaglandins Leukot Essent Fatty Acids. 2014;91:135-40
Park Y, Lim J, Lee J, Kim SG. Erythrocyte fatty acid profiles can predict acute non-fatal myocardial infarction. Br J Nutr. 2009;102:1355-6.
Perk J, de Backer G, Gohlke H, et al. European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012;33:1635–1701.
Rauch B, Schiele R, Schneider S, Diller F, Victor N, Gohlke H, et al; OMEGA Study Group. OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation. 2010;122:2152-9.
Schuchardt JP, Neubronner J, Kressel G, Merkel A, von Schacky C, Hahn A. Moderate doses of EPA and DHA from re-esterified triacylglycerols but not from ethyl-esters lower fasting serum triacylglycerols in statin-treated dyslipidemic subjects: Results from a six month randomized controlled trial. Prostaglandins Leukot Essent Fatty Acids 2011;85:381-6
Schuchardt JP, Hahn A. Bioavailability of long-chain omega-3 fatty acids. Prostaglandins Leukot Essent Fatty Acids 2013;89:1-8.
Shearer GC, Chen J, Chen Y, Harris WS. Myocardial infarction does not affect fatty acid profiles in rats. Prostaglandins Leukot Essent Fatty Acids 2009; 81:411-6.
Shearer GC, Pottala JV, Hansen SN, Brandenburg V, Harris WS. Effects of prescription niacin and omega-3 fatty acids on lipids and vascular function in metabolic syndrome: a randomized controlled trial. J Lipid Res. 2012;53:2429-35.
Siscovick DS, Raghunathan TE, King I, Weinmann S, Wicklund KG, Albright J, et al. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. J. Am. Med. Assoc. 1995;275:836-7.
Skulas-Ray AC, Kris-Etherton PM, Harris WS, Vanden Heuvel JP, Wagner PR, West SG. Dose response effects of omega-3 fatty acids on triglycerides, inflammation, and endothelial function in healthy people with moderate hypertriglyceridemia. Am J Clin Nutr 2011;93:243-
Skulas-Ray AC, Kris-Etherton PM, Harris WS, West SG. Effects of Marine-Derived Omega-3 Fatty Acids on Systemic Hemodynamics at Rest and During Stress: a Dose-Response Study. Ann Behav Med. 2012;44:301-8
Smith SC Jr, Benjamin EJ, Bonow RO, et al.; World Heart Federation and the Preventive Cardiovascular Nurses Association. AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation. 2011;124:2458-2473
Superko HR, Superko SM, Nasir K, Agatston A, Garrett BC. Omega-3 fatty acid blood levels: Clinical significance and controversy. Circulation 2013;128:154–161.
von Schacky P, Angerer P, Kothny W, Theisen K, Mudra H. The effect of dietary omega-3 fatty acids on coronary atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 1999;130:554-62
von Schacky C. Omega-3 fatty acids: anti-arrhythmic, pro-arrhythmic, or both? Frontiers in Cardiac Electrophysiology, 2012;3: 98
von Schacky C. Omega-3 Index for Cardiovascular Health. Nutrients 2014;6:799-814
von Schacky C. Der HS-Omega 3 Index®: klinische Wertigkeit standardisierter Fettsäureanalytik. J Lab Med 2014;38:167-78
von Schacky C. Nahrungsergänzung mit Omega-3 Fettsäuren? Herzmedizin 2014:31(3):6-10
von Schacky C. Omega-3 Fatty Acids in Cardiovascular Disease – an Uphill Battle. PLEFA e-pub 2014 May 28
Wu JH, Lemaitre RN, King IB, Song X, Sacks FM, Rimm EB. Association of plasma phospholipid long-chain omega-3 Fatty acids with incident atrial fibrillation in older adults: the cardiovascular health study. Circulation. 2012;125:1084-93
Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al; American College of Cardiology/American Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114; e385-484