|
Identification of risks associated
with arrhythmic death remains a great challenge.
Although great progress
has been made in the prevention of cardiovascular diseases, the
mortality remains high for patients after myocardial infarction or
heart failure who often die without previous symptoms. Almost half of
all cardiovascular deaths can be attributed to this unexpected and not
yet predictable cause. Sudden cardiac death (SCD) as a consequence of
coronary heart disease has been rated the most important cause of death
in the adult population in industrialized societies.
Mechanisms of
action of omega-3 fatty acid ethyl esters in heart dysfunction.
Myocardial infarction and severity of coronary artery disease
are associated with a higher risk of SCD. In fact, coronary artery
disease is known to be present in about 80% of patients who suffer from
SCD, whereby the proportion of deaths that are sudden is higher in mild
to moderate heart failure (HF). Like in the MERIT-HF study, the
incidence of SCD was 64% in New York Heart Association (NYHA)
functional class II, 59% in class III
and was reduced to 33% in class IV. Preventing SCD is thus particularly
important for patients during early progression of heart failure when
their
pump function is still associated with good quality of life.
Irrespective of the underlying pathophysiology (ischemic or
non-ischemic heart failure), SCD is very often caused by ventricular
tachycardia that
degenerates to ventricular fibrillation. However, the majority of
patients
who die suddenly during progression of heart failure cannot be
identified
by current risk stratification. Since the protective action of
implantable
cardioverter-defibrillators (ICDs) and highly purified EPA+DHA ethyl
esters
(Omacor) depends on the risk of SCD in a given patient population,
efforts
should be made to better understand the pathophysiology of HF.
Particularly,
mechanisms inferred from depressed pump function often monitored by
reduced
ejection fraction (EF) remain unresolved. EF is a composite of various
physiological
factors with major contributions from:
i. Remodeling of the hypertrophied cardiocyte and the extracellular
matrix leading to depressed "contractility". While fibrosis has long
been alleged as contributing factor to malignant arrhythmias, the
dysregulated gene expression of hypertrophied cardiocytes (e.g. lack in
upregulation of the sarcoplasmic reticulum Ca2+ pump gene, SERCA2,
partially corrected by the FOXIB/PPARalpha
etomoxir (1,2)) leading to diastolic Ca2+ overload and electric
instability has only recently been explored and is not targeted by
current therapy. Thus, SCD not only
occurs in patients with systolic heart failure but is also not uncommon
in patients with diastolic heart failure. Based on the many defects in
cardiocyte
gene expression and extracellular matrix remodeling, left ventricular
hypertrophy (LVH) emerged as a major risk for SCD. LVH occurs as a
result of a hemodynamic overload (e.g. surviving myocardium after MI or
hypertension). Thus, the
anti-arrhythmogenic intervention with Omacor is expected to have a
protective
action not only in post-MI but also during progression of HF associated
with
LVH irrespective of its etiology.
ii. The “compensated” stage of concentric hypertrophy can often not be
maintained and enlargement of the LV occurs, i.e. dilatation. A
deleterious consequence is the rise in wall stress (according to
LaPlace, wall stress is increased by an increase in intraventricular
pressure and radius and decreased when wall thickness is increased,
i.e. as in LVH). Wall stress reflects the tension a cardiocyte has to
develop during systole. Since the LVH response is limited e.g. by
coronary blood and energy supply, LV dilatation is often not adequately
compensated by LVH and a rise in wall stress ensues. A high wall stress
has various adverse effects including an increased opening probability
of stretch-activated cation channels which raises the risk of ectopic
activity. A reduction of diastolic Ca2+ through partial inhibition of
the late and fast
Na+ current and the L-type Ca2+ current by EPA+DHA would, therefore, be
useful.
Wall stress is also the major determinant of oxygen consumption of the
heart
and, thereby, can aggravate latent ischemia. Myocardial stretch can
also
trigger afterdepolarisations and extrasystoles. Furthermore, the
conduction
system is often impaired by mechanical stretch resulting in ventricular
dysynchrony
(a target for resynchronization
therapy). While wall stress has been calculated in the past from
echocardiography data, it was only recently shown by Alter et al. that
the actual wall stress is underestimated and that only volumetric data
derived from cardiac magnetic resonance imaging (MRI) permit accurate
wall stress assessment (3). The
MRI-based wall stress was correlated with raised serum brain
natriuretic
peptide (BNP), a marker of cardiocyte stretch (4). MRI-based wall
stress is expected to have a greater specificity compared with BNP
which
nonetheless has a positive predictive value for SCD. The MRI-based wall
stress calculation provides the long-sought tool for monitoring
progression
of heart failure in terms of LV dilatation and LVH (5). It became also
possible
to predict the LV afterload reduction required for returning wall
stress
into the normal range. Using “isostress” curves, the systolic pressure
had,
however, to be reduced in some patients to a level which is too low for
maintaining
adequate organ perfusion (3).
iii. a reduced endogenous production of long-chain desaturated fatty
acids by an altered activity of delta-6 and delta-5 desaturase. By this
mechanism, EPA+DHA is expected to be reduced which can be viewed as
“lipid remodelling”. Particularly crucial is in this respect marked
cardiac dilatation. (Rupp
et al. unpublished). Any protective action of Omacor or also ICDs will
depend on the impact of these factors, whereby an increased wall stress
appears
to be the most crucial one. Thus, after myocardial infarction, LV
dilatation occurs in about 20-30% of patients which appears not to be
adequately compensated by LVH resulting most probably in a markedly
raised wall stress and thus
high risk of SCD. It would thus also be of great interest to examine
whether in HF patients with high wall stress the benefit of ICDs is
greater and
whether a high wall stress can account for the greater benefit of ICDs
in
ischemic versus non-ischemic HF. It is thus proposed to assess
anti-arrhythmogenic effects of EPA+DHA ethyl esters in patients in
terms of MRI-based wall stress and the “EPA+DHA level” (6).
Schematic presentation
of pathophysiological events raising the risk of SCD. Various vicious
cycles raise the risk of SCD and HF. The risk of SCD can be reduced by
prophylactic ICD implantation or by prescription omega-3 fatty acids
(based on GISSI-P, Omacor) where a low peroxide and p-anisidine value
(marker of adverse oxidation of EPA and DHA) is certified which can be
monitored also by SPME-GC/ion
trap MS in terms of volatile aldehydes/ketones (pungent “fishy” odour;
Rupp,
unpublished). The ICD indication is given here for the dilated heart of
high wall stress where EF is expected to be <35%. However, SCD risk
is
also high in patients with EF in between 35% and 50% (mild to moderate
heart
failure) which is considered an important therapeutic target for Omacor.
EPA+DHA ethyl esters
(Omacor) in heart failure
The value of adding
1g/day EPA-DHA ethyl esters (Omacor) to standard therapy for heart
failure has
been established by the results of the recent GISSI-HF
trial (7). This randomized, double-blind, placebo-controlled trial,
conducted
at 357 cardiology or internal medicine centres in Italy under the
direction
of the GISSI group recruited 7046 patients with heart failure. Omacor therapy was associated with
statistically
significant benefits on both the co-primary endpoints: time to death
from
any cause – the adjusted hazard ratio was 0.91 (95.5% CI 0.833–0.998; P
=
0.041). For time to all-cause mortality or admission to hospital for
any
cardiovascular reason the adjusted hazard ratio was 0.92 (99% CI
0.849–0.999;
P = 0.009). The effects were consistent across a wide range of
prespecified
subgroups, including EF > or <40%, aetiology of heart failure
(ischemic
vs non-ischemic), baseline NYHA grade, diabetes at baseline or age.
The effects of Omacor on the GISSI-HF primary endpoints can also be
expressed as the
number of patients that have to be treated for the time of the
follow-up to prevent one endpoint event, i.e. number-needed-to-treat (NNT). For
all-cause mortality, NNT for Omacor was 56; for all-cause mortality or
hospitalization for a cardiovascular cause, the NNT was 44. Said in
other words, when 1000 patients are treated with Omacor for ~4 years,
18 lives
were saved and 17 cardiovascular hospitalizations were prevented.
It has been pointed out by Gregg C. Fonarow (Ahmanson-UCLA Cardiomyopathy
Center, Los Angeles) in the Comment "Statins and n-3 fatty acid
supplementation
in heart failure" to the GISSI-HF study: "...Whilst questions remain
about
mechanisms of action, optimum dosing, and formulation, supplementation
with
n-3 polyunsaturated fatty acids should join the short list of
evidence-based
life-prolonging therapies for heart failure." (Lancet. Online 2008 Aug
29)
Evidence-based
therapies for systolic heart failure (from G C Fonarow, Lancet. Online 2008 Aug 29)
Therapy
|
Relative-risk
reduction in all-cause
mortality
|
Angiotensin-converting-enzyme
inhibitors
or angiotensin-receptor antagonists
|
17–25%
|
β
blockers
|
34–35%
|
Aldosterone
antagonists*
|
15–30%
|
Hydralazine-isosorbide
dinitrate*
|
43%
|
Implantable
cardioverter defibrillator*
|
23%
|
Cardiac
resynchronisation therapy*
|
36%
|
n-3 polyunsaturated fatty acid
supplementation
|
9%
|
*For patients with
specific indications.
The results of
GISSI-HF mandate, therefore, in our opinion the use of Omacor 1 g/day
in
heart failure patients. Heart failure guidelines should be amended to
reflect
this fact.
It shoud be pointed out that a specific medication was used in the
GISSI trials, i.e. Omacor and it is unscientific to infer that regular
fish oil capsules could be a substitute. It is also not justified to
simplify this medication by referring to it as "n-3 polyunsaturated fatty acid
supplementation". It is hoped that this aspect will be corrected in the
guidelines. On the
other hand, manufacturers of fish oils are encouraged to initiate
trials
and to assess efficacy or lack of efficacy of their preparations.
1. Turcani M,
Rupp H. Etomoxir improves left ventricular performance of
pressure-overloaded
rat heart. Circulation. 1997;96:3681-3686.
2. Rupp H, Rupp TP, Maisch B. Fatty acid oxidation inhibition with
PPARalpha activation (FOXIB/PPARalpha) for normalizing gene expression
in heart failure? Cardiovasc Res. 2005;66:423-426.
3. Alter P, Rupp H, Rominger MB, Vollrath A, Czerny F, Figiel JH, Adams
P, Stoll F, Klose KJ, Maisch B. B-type natriuretic peptide and wall
stress in dilated human heart. Mol Cell Biochem. 2008;314:179-191.
4. Alter P, Rupp H, Rominger MB, Vollrath A, Czerny F, Klose KJ, Maisch
B. Relation of B-type natriuretic peptide to left ventricular wall
stress as assessed by cardiac magnetic resonance imaging in patients
with dilated cardiomyopathy. Can J Physiol Pharmacol. 2007;85:790-9.
5. Alter P, Rupp H, Rominger MB, Klose KJ, Maisch B. A new
methodological approach to assess cardiac work by pressure-volume and
stress-length relations in patients with aortic valve stenosis and
dilated cardiomyopathy. Pflugers Arch. 2008;455:627-36.
6. Rupp H, Wagner D, Rupp T, Schulte LM, Maisch B. Risk stratification
by the "EPA+DHA level" and the "EPA/AA ratio" focus on
anti-inflammatory and
antiarrhythmogenic effects of long-chain omega-3 fatty acids. Herz.
2004;29:673-85.
7.GISSI-HF Investigators. 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;372:1223-1230.
Webcast:
New
perspectives for an evidence-based therapy with omega-3 fatty acid
ethyl esters
Malignant arrhythmias and
sudden
cardiac death in myocardial infarction.
The major pathophysiological cause of SCD is seen in the electrical
instability of the infarct zone and the non infarcted muscle. Because
of the loss of
contractile tissue, the surviving hypertrophied myocardium is subjected
to
various adverse neuroendocrine influences. A consequence is an
unfavorable
cellular and molecular restructuring of the extracellular matrix and
the
cardiomyocyte. The fibrosis also worsens coronary blood supply and thus
amplifies
the risk of reinfarction. In approximately one third of post-MI
patients, dilatation of the left ventricle occurs. Since dilated hearts
exhibit an
increased wall stress favouring also the opening of stretch-activated
ion
channels (1), the resulting electrical instability contributes to the
increased
risk of ventricular tachyarrhythmias. All these adverse processes
contribute
to worsening of pump function which is reflected in a reduced EF which
is
the most often used predictor of malignant arrhythmias. Conventional
therapy
is, however, only partially directed against mechanisms which promote
electrical
instability. The remaining electrical instability after MI can be
counteracted
by modulating the activity of membrane ion channels through
incorporation
of long-chain omega-3 fatty acids, particularly DHA, in their
microenvironment.
The administration of Omacor should, therefore, also be seen in the
context
of the implantable cardioverter defibrillator (ICD) therapy
SCD
prevention by ICDs and Omacor
ICDs are implanted in patients with EF <35-40, whereby the number of
patients needed to treat (NNT) to prevent a sudden death was 11 in
MADIT-II and 14 in SCD-HeFT. Only in MADIT-I, the NNT was 4 when
EF<35% was combined with the presence of non-sustained ventricular
tachycardia. Nonetheless, a
substantial proportion of patients will die suddenly despite ICD
implantation (2). ICD therapy is associated with a relative risk
reduction of SCD of approximately 60%, far less than the greater than
90% efficacy that many expect (2). Reducing the incidence of
ICD-unresponsive SCD would substantially improve survival and
cost-effectiveness related to ICD therapy. Alternatives for reducing
SCD risk are thus required. Pharmacological interventions proved not to
be successful. Proarrhythmic and negative inotropic effects of class Ia
and Ic
antiarrhythmics are more pronounced during progression of heart
failure. The
class III antiarrhythmic D-sotalol which lacks beta-blocking action
even increased
mortality in post-MI patients with reduced pump function (3). For
amiodarone,
no significant mortality reduction was observed in chronic HF or after
MI
and on prognostic terms represents, therefore, no alternative for an
ICD.
The need of alternatives for SCD prevention is demonstrated also by the
fact
that in post-MI patients the risk of SCD is increased already at
EF<50%.
In the GISSI-Prevenzione study, 86% of patients had EF>40% and only
2.5%
EF<30%. In the light of ICD guidelines, one would therefore expect
only
a very limited effect for interventions targeting SCD. This was,
however,
not the case as seen in the comparison of trials with ICD therapy (2)
and
the GISSI-Prevenzione study (4-6) with Omacor administration.
Anti-arrhythmogenic effects of DHA+EPA ethyl esters
In the studies of the GISSI group, 1g omega-3 fatty acids was
administered, whereby the relevance of the particular formulation has
been underrated
particularly in guidelines
i. Ethyl esters but not triglycerides commonly present in fish oils
were used. Ethyl esters result in a retarded and sustained uptake of
DHA and
EPA. After intestinal absorption, long-chain fatty acids reach the
coronaries
via the thoracic duct and bypass the liver (contrary to amino acids and
sugars). It appears that ethyl esters have the advantage of providing a
sustained
increase in lymphe DHA and EPA levels (7) which are expected to
contribute
to the critical rise in DHA and EPA required for the antiarrhythmogenic
action.
ii. Omacor used in the GISSI trials contains min 84% of the long-chain
omega-3 fatty acids DHA and EPA, whereby the ratio of DHA:EPA was
38:46%. An exchange of DHA for EPA or short-chain fatty acids
(alpha-linolenic acid) is expected to reduce the antiarrhythmogenic
action. In rats with low dose intake of omega-3 fatty acids, DHA but
not EPA inhibited ischemia-induced cardiac arrhythmias (8). In the
Japan EPA lipid intervention study (JELIS), hypercholesterolaemic
patients were treated with daily 1.8g EPA (9). While a 19% relative
reduction in major coronary events occurred, the (low) risk of SCD was
not reduced further. One should, therefore, not refer in guidelines to
1g omega-3 fatty acids in general when referring to the GISSI trials
but to specify the DHA:EPA ratio and to point out that ethyl esters
were used. To demonstrate that Omacor differs markedly from regular
fish oil preparations, representative gas chromatograms of the
constituent fatty acids are given. The high concentration of EPA and
DHA and the virtual absence of saturated and omega-6 fatty acids can be
achieved only by transesterification of fish oils with ethanol
resulting in ethyl esters with subsequent purification of
the respective DHA and EPA ethyl esters.
iii. During preparation of ethyl esters more purification steps are
involved than in the extraction of triglycerides present in fish oils
which is expected to reduce the contamination particularly with methyl
mercury which has been associated with an increased risk of MI (10).
Body mercury was correlated with omega-3 fatty acids, indicating that
omega-3 fatty acids were derived from fish or fish oils contaminated
with mercury. It appears, therefore,
mandatory to use in post-MI patients DHA+EPA preparations with a
minimum
of methyl mercury and other environmental pollutants such as PCBs and
dioxins.
Work is ongoing to determine such pollutants in various DHA+EPA
preparations
and to assess whether they influence the incidence of dilative
cardiomyopathy.
iv. In post-MI patients on standard care (anti-platelet drug,
beta-blocker, ACE-inhibitor, statin) a preparation with 1g DHA+EPA in 1
capsule (Omacor) is required. In a number of non positive, i.e.
"neutral" studies on patients with ICD (sometimes mislabeled as
“negative studies”), the number of capsules was higher than in the
GISSI trials which was associated with poor patient compliance. In the
Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) by
Brouwer et al. (7), ICD patients were enrolled for assessing the effect
of 2 g of "purified fish oil" (4 capsules/day) vs. placebo (olive oil)
on life-threatening arrhythmias. Judged by capsule count, 76% of
patients took more than 80% of the fish oil capsules. The primary
endpoint (appropriate ICD intervention for ventricular tachycardia or
fibrillation or all-cause death) occurred in 30% of patients taking
fish oil vs. 33% patients taking placebo (not significant difference).
In the study by Leaf et al. (11), ICD
patients were randomized to 2.6g EPA and DHA ethyl ester (daily four 1g
capsules)
or olive oil as placebo for 12 months. Why in this study capsules with
only
65% DHA+EPA instead of 84% as in the case of Omacor and the trials of
the
GISSI group were used, remains intriguing. Compliance with the
double-blind treatment was similar in the two groups; however, the
noncompliance rate
was high (35% of all enrollees). The primary end point, time to first
ICD
event for ventricular tachycardia or fibrillation confirmed by stored
ECG
or death from any cause was borderline significant (risk reduction of
28%;
P=0.057). For those who stayed on protocol for at least 11 months, the
antiarrhythmic benefit of DHA+EPA ethyl esters was improved for those
with confirmed events (risk reduction of 38%; P=0.034). This study also
argues against the use
of capsules with a lower DHA and EPA content, e.g. the approximately
30%
DHA+EPA of regular fish oil. The known low compliance with multiple
capsule intake (e.g. 32% permanent noncompliance for beta-blocker use
in COMET (12)) was also one of the reasons for the production of ethyl
esters using transesterification of fish oil triglycerides resulting in
the highly concentrated preparation of Omacor. The critical impact of
noncompliance can be derived also from the observation that already 2
days after Omacor intake, the serum DHA+EPA level has reached again
baseline (Rupp, unpublished). Thus, DHA+EPA has to be released from
membranes during an ischemic event which would obviously be more
pronounced in MI than in HF or even an ICD event.
In sum, although great
progress has been made in elucidating the antiarrhythmogenic action of
DHA+EPA and the trials of the GISSI group have provided clear evidence
on the clinical effectiveness in arrhythmic event prevention also when
compared with ICD
therapy, one should be very careful when referring to the active
ingredients
of Omacor which are ethyl esters and not triglycerides as in fish oils.
It
is not justified to extrapolate to omega-3 fatty acids in general
implicating
the use of short-chain omega-3 fatty acids such as alpha-linolenic
acid.
Also substitution of EPA for DHA is expected to result in a different
therapeutic
profile. To avoid further confusion, it is suggested to clearly specify
the
actual ingredients particularly in guidelines and to adhere to the
accepted
chemical nomenclature.
(1) Franz MR, Cima R, Wang D, Profitt D, Kurz R.
Electrophysiological effects of myocardial stretch and mechanical
determinants of stretch-activated arrhythmias. Circulation 1992;
86:968-978.
(2) Anderson KP. Sudden cardiac death unresponsive to implantable
defibrillator therapy: an urgent target for clinicians, industry and
government. J Interv Card Electrophysiol 2005; 14:71-78.
(3) Doggrell SA, Brown L. D-Sotalol: death by the SWORD or deserving of
further consideration for clinical use? Expert Opin Investig Drugs
2000; 9:1625-1634.
(4) GISSI-Prevenzione Investigators. Dietary supplementation with n-3
polyunsaturated fatty acids and vitamin E after myocardial infarction:
results
of the GISSI- Prevenzione trial. Gruppo Italiano per lo Studio della
Sopravvivenza
nell'Infarto miocardico. Lancet 1999; 354:447-55.
(5) Marchioli R, Avanzini F, Barzi F, Chieffo C, Di Castelnuovo A,
Franzosi MG, Geraci E, Maggioni AP, Marfisi RM, Mininni N, Nicolosi GL,
Santini M, Schweiger C, Tavazzi L, Tognoni G, Valagussa F. Assessment
of absolute risk of death after myocardial infarction by use of
multiple-risk-factor assessment equations: GISSI- Prevenzione mortality
risk chart. Eur Heart J 2001; 22:2085-103.
(6) Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio
R, Franzosi MG, Geraci E, Levantesi G, Maggioni AP, Mantini L, Marfisi
RM, Mastrogiuseppe G, Mininni N, Nicolosi GL, Santini M, Schweiger C,
Tavazzi L, Tognoni G, Tucci C, Valagussa F. Early protection against
sudden death by n-3 polyunsaturated fatty acids after myocardial
infarction: time-course analysis of the results of the Gruppo Italiano
per lo Studio della Sopravvivenza nell'Infarto Miocardico
(GISSI)-Prevenzione. Circulation 2002; 105:1897-1903.
(7) Rupp H, Rupp TP, Wagner D, Alter P, Maisch B. Microdetermination of
fatty acids by gas chromatography and cardiovascular risk
stratification by
the "EPA+DHA level". Herz 2006; 31 (suppl 3):30-49.
(8) McLennan P, Howe P, Abeywardena M, Muggli R, Raederstorff D, Mano
M, Rayner T, Head R. The cardiovascular protective role of
docosahexaenoic
acid. Eur J Pharmacol 1996; 300:83-89.
(9) Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa
Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A,
Nakaya N, Sakata T, Shimada K, Shirato K. Effects of eicosapentaenoic
acid on major coronary events in hypercholesterolaemic patients
(JELIS): a randomised
open-label, blinded endpoint analysis. Lancet 2007; 369:1090-1098.
(10) Guallar E, Sanz-Gallardo MI, van't Veer P, Bode P, Aro A,
Gomez-Aracena J, Kark JD, Riemersma RA, Martin-Moreno JM, Kok FJ.
Mercury, fish oils,
and the risk of myocardial infarction. N Engl J Med 2002; 347:1747-1754.
(11) Leaf A, Albert CM, Josephson M, Steinhaus D, Kluger J, Kang JX,
Cox B, Zhang H, Schoenfeld D. Prevention of fatal arrhythmias in
high-risk subjects by fish oil n-3 fatty acid intake. Circulation 2005;
112:2762-2768.
(12) Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P,
Komajda M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp-Pedersen C,
Scherhag A, Skene A. Comparison of carvedilol and metoprolol on
clinical outcomes in
patients with chronic heart failure in the Carvedilol Or Metoprolol
European Trial (COMET): randomised controlled trial. Lancet 2003;
362:7-13.
How
does EPA and DHA work?
Recent emphasis has been placed on malignant arrhythmia risks
associated with a low abundance of EPA and DHA in the body. Since free
acids of EPA
and DHA are required for most of their biological effects including
their
antiarrhythmogenic action, it appears essential not only to build up
stores
in the body for their release, but also to provide a sustained uptake
of
EPA and DHA in the form of ethyl esters rather than dietary triglycerides
which
are present in fish or fish oils.
The triglyceride on the left contains 2 saturated fatty acids (C16:0,
palmitic acid) and a long-chain polyunsaturated omega-3 fatty acid
(C20:5,
EPA, eicosapentaenoic acid, at the bottom) which have a different chemical structure. On average,
triglycerides
("triacylglycerols" in biochemistry textbooks) from fish contain 1 EPA
or
DHA and 2 other fatty acids. The EPA+DHA concentration of simple
extracts
of fish, i.e. fish oils, does, therefore, not exceed one third on
average.
A high concentration can be achieved by breaking up the triglyceride
structure
via transesterification with ethanol leading to ethyl esters. On a
small
scale, the transesterification is used
for
preparing fatty acid methyl esters for gas chromatography. On the right: the ethyl ester of
EPA which is a major (48%) component of Omacor
Ethyl
esters provide a retarded and sustained uptake of EPA and DHA in the
duodenum
Whether the free EPA and DHA level is raised sufficiently for
antiarrhythmic action, depends not only on the fatty acid release from
membrane phospholipids involving particularly phospholipase A2 but also
on the absorption of orally administered EPA and DHA. In fish, EPA and
DHA occur as triglycerides. Regular fish oils contain up to 30% EPA+DHA
triglycerides. If a once daily administration of one capsule is
required for achieving an intake of 1g EPA+DHA, Omacor
has to be used. Triglycerides are transesterified with ethanol
resulting
in a mixture of saturated and unsaturated ethyl esters. After
purification,
nearly homogeneous EPA and DHA ethyl esters can be prepared (Omacor). The corresponding
ethyl esters should not be referred to as fish oils simply because they
contain EPA and DHA. They
are also not 'refined' or 'concentrated' fish oils. It is thus
unscientific to refer to the omega-3 preparation used in the trials of
the GISSI group as "cheap and simple fish oil". There is also no
evidence available that Omacor can be substituted with fish oils. This
point should be made clear in guidelines. Fish oil is also not a
"generic" of Omacor.
The type of ester bond has important consequences for the absorption
kinetics of EPA and DHA. Duodenal uptake rates differ between
triglycerides and ethyl esters. Triglycerides are rapidly degraded by
pancreatic lipase and, in
the case of polyunsaturated fatty acids, by carboxylester hydrolase.
Compared with triglycerides, the ethyl esters of EPA and DHA are
absorbed more slowly. This
has been shown in rats when EPA and DHA were administered by gavage
either as triglycerides or
ethyl esters (2).
Within 3 h after administration, the recovery in the lymph of the
respective fatty acids was greater in the case of triglycerides (2).
After 15 h, the recovery from ethyl esters was approximately doubled
compared with triglycerides. One of the consequences is that the lymph
EPA and DHA level is maintained at a higher level in the second half of
a 24-h period which could be of importance, since malignant ventricular
arrhythmias are more abundant in the early morning hours (3).
Lymph EPA and DHA levels arising from fish consumption during the
preceding day would thus be expected to be lower than in the case of an
ethyl ester administration. The different absorption kinetics seen in
the rat appear
to hold also for humans. Thus, the recovery of EPA in the blood was
lower
within an 8-h period when compared with triglycerides (4),
while there was no difference in the long-term incorporation of EPA and
DHA
involving time periods up to 28 days (5). Although the absorption of
ethyl
esters is increased by co-ingestion with a high-fat meal, the
absorption of EPA ethyl ester was still lower (6).
Ethyl esters are taken
up more slowly than triglycerides but nonetheless are absorbed within
24-h to the same extent as triglycerides.
The
slowed uptake of ethyl esters results in a "dual mechanism of action"
of EPA
and DHA:
1. Sustained uptake
A sustained uptake of EPA+DHA into blood which is expected to be
beneficial in ischemic events before EPA+DHA can be released. This
could be crucial, since in the case of severe arrhythmias there is
little time left for the release of fatty acids from tissue stores.
EPA+DHA should already be in
the blood. In contrast
to EPA and DHA ethyl esters, EPA and DHA triglycerides present in
fish are more rapidly absorbed and are expected to provide less
protection
in the early morning hours when the risk of sudden death is high and
the
triglycerides were consumed the day before. The slowed recovery of
ethyl
esters in the lymph has been shown by Ikeda et al. (2)
in rats where fatty acids were either given as triglycerides or ethyl
esters.
These data suggest,
therefore, that the "retard" formulation of ethyl esters has the
advantage of providing increased non-membrane bound EPA and DHA levels
which are expected to contribute to the critical rise in EPA and DHA
required for an antiarrhythmogenic action. In the case of EPA and DHA
triglycerides, a greater amount had to be released from membranes by
ischemic events.
These considerations
are based on a once daily administration which is relevant in patients
after
MI being on standard therapy with beta-blocker, ACE inhibitor,
anti-platelet drug and statin or patients with HF on beta-blocker, ACE
inhibitor, diuretic and aldosterone antagonist.
2.
Increased tissue stores
An increased EPA+DHA intake results in a higher EPA+DHA tissue store
for release during ischemic events. The size of the tissue store is
measured
by the "EPA+DHA level". The released free fatty acids EPA and DHA are
incorporated in the microenvironment of ion channels and modulate their
activity. This is associated with an increased electrical stability as
shown by a greater refractory period or hyperpolarisation in
cardiomyocytes (10).
For the administration
of 1 g/day highly purified EPA+DHA ethyl esters (Omacor) to healthy
volunteers, it
has been shown that whole blood EPA is increased from 0.6% to 1.4%
within 10 days while DHA is increased from 2.9% to 4.3%. After
withdrawal, EPA
and DHA approach baseline values within 10 days (data from Rupp et al. (1)).
A gas chromatographic procedure was established which requires only 10
µl of whole blood for the identification of more than 35 fatty
acids. A gas
chromatogram of Omacor
demonstrating its high purity is given here.
A low “EPA+DHA level” represents a
risk for sudden cardiac death
The important study by CM Albert et al (11)
showed that low whole blood levels of the long-chain omega-3 fatty
acids EPA (C20:5n-3) and DHA (C22:6n-3) but not of the long-chain
docosapentaenoic acid (C22:5n-3) and not of the short-chain alpha-linolenic acid
(C18:3n-3) were associated with an increased risk of sudden death:
Fatty
acid
|
GROUP
WITH SUDDEN DEATH FROM
CARDIAC CAUSES
|
CONTROL
GROUP
|
P
VALUE
|
EPA (eicosapentaenoic
acid),
long-chain n-3
|
1.72±0.59
|
1.84±0.53
|
0.06
|
DHA (docosahexaenoic acid),
long-chain n-3
|
2.12±0.65
|
2.38±0.78
|
0.005
|
DPA
(docosapentaenoic acid), long-chain
n-3
|
0.98±0.23
|
1.01±0.21
|
0.25
|
alpha-Linolenic
acid, short-chain n-3
|
0.39±0.16
|
0.37±0.15
|
0.28
|
Based on this study, we proposed the term “EPA+DHA
level” for assessing the risk of sudden death (1).
In healthy volunteers, administration of 840 mg/day of
EPA+DHA ethyl esters (Omacor) raised the “EPA+DHA level” in whole blood to approx.
6% (1). In the GISS-P trial, this dose of EPA and DHA ethyl
esters was associated with a marked protection from sudden death.
Interrelationship between the
EPA+DHA level and risk of SCD. Data are adapted from the
epidemiological studies
of (open squares) Albert et al. (11)
and (open circles) Siscovick et al. (12).
The data of Albert et al. (11)
include also docosapentaenoic acid and are, therefore, by estimated
0.98 percentage points higher than in our study where docosapentaenoic
acid was not included. As in our study involving 840 mg/d EPA+DHA ethyl
ester (Omacor)
administration, whole blood was analyzed in the study of Albert et al. (11).
Data of Rupp et al. (2003) are from (1).
The predicted
reduction in the risk of SCD can account in part for the reduced
mortality observed in the GISSI-Prevention Study with 840 mg/day EPA+DHA ethyl esters (7,
8,
9). One has, however, to take into
account that the above epidemiological studies cannot identify the
mechanisms which result in high EPA+DHA levels in particular patients.
In our opinion, certain variations occur in the endogenous EPA+DHA
production (altered activities of the corresponding desaturases). It
appears less likely that the high
EPA+DHA levels observed in the US in a subset of the patients arise
from
a very high fish intake.
In the GISSI Prevention
(Prevenzione) Study (7,
8,
9), patients
who survived a myocardial infarction were treated with 1g/day Omacor.
Mortality risk was reduced by 20%, cardiovascular mortality risk by 30%
and sudden
cardiac death risk by 45%. Since the risk of re-infarction was
not
affected by Omacor, it
appears
that the EPA+DHA ethyl esters had a specific action on mechanisms
leading
to SCD, i.e. an anti-arrhythmogenic action. The patients received
standard care (anti-platelet drug, beta-blocker, ACE-inhibitor and at
the end of
the study also a statin). Noteworthy is that the patients consumed on
average
approx. 1 fish meal per week and that Omacor exhibited a protection on
top
of the dietary fish intake.
Further support for
antiarrhythmogenic effects of omega-3 fatty acids was provided in the
study of Calo et al.
(14).
Two 1 g capsules of EPA and DHA ethyl esters were administered during
hospitalization in patients undergoing coronary artery bypass graft
surgery (CABG). Postoperative atrial fibrillation developed in 27
patients of the control group (33.3%) and in 12 patients of the EPA and
DHA ethyl ester group (15.2%) (P = 0.013). There was no significant
difference in the incidence of nonfatal postoperative complications,
and postoperative mortality was similar in the EPA and DHA ethyl ester
treated patients (1.3%) versus controls (2.5%). After CABG,
the EPA and DHA ethyl ester treated patients were hospitalized for
significantly fewer days than controls (7.3 ± 2.1 days vs. 8.2
± 2.6 days, P = 0.017).
In view of the present
evidence, it is suggested to include the determination of fatty acid
profile in the list of investigated parameters in patients with
cardiovascular disease, particularly in patients after MI. This would
strengthen the rationale of therapeutic regimens with EPA and DHA ethyl
esters, as specified in current guidelines (15,16).
Since only 10 µl of whole blood are required, it does rarely
require additional blood sampling. By monitoring the EPA+DHA level,
patients could be identified who are at an increased risk of SCD
irrespective of their
underlying disease. Furthermore, longitudinal changes in the EPA+DHA
incorporation
can be monitored and it can thus be assessed whether a required EPA+DHA
level has been reached.
For reducing
pro-inflammatory eicosanoids and cytokines, a higher “EPA+DHA level” is
required which can be achieved with an intake of 2 - 4 g/day of 84%
EPA+DHA ethyl esters. For assessing influences from pro-inflammatory
eicosanoids and cytokines, the EPA/arachidonic acid ratio (“EPA/AA
ratio”) appears as a useful diagnostic parameter and deserves further
investigation
Avoid misconceptions:
EPA+DHA level and Omega-3 level are not
the same
If we want to
specify the percentage of the long-chain omega-3 fatty acids EPA and
DHA, then we use the term EPA+DHA level. Why do we not use the term
"Omega-3 level"?
There is a simple answer: omega-3 includes also other omega-3 fatty
acids.
There are conditions where the Omega-3 level changes not, however, the
EPA+DHA level. In one of our experiments, rats were fed linseed oil
which is rich in the omega-3 alpha-linolenic acid. The Omega-3 level
markedly increased, but not the EPA+DHA level. Why should we say, the
omega-3 level did not increase
because we (contrary to textbook knowledge) defined omega-3 level as
sum
of only EPA+DHA?
Fish meals are not a substitute for Omacor
To assess the role of dietary EPA+DHA intake, fatty acids were
determined in fish dishes of the cafeteria
of the Philipps University Marburg. The EPA+DHA content of the
popular Alaska Pollock was 125±70 mg/100 g (1).
A
once daily fish dish can thus not provide the 840 mg/day EPA+DHA
administered
in the GISSI trials in the form of ethyl ester which markedly reduced
the
risk of SCD in post-MI patients. Nonetheless, at least two preferably
oily
fish meals per week should be consumed as preventive measure by persons
without coronary artery disease. With documented coronary heart
disease, it was
advised to consume approximately 1 g/day of EPA+DHA (16).
Fish oils must not be
substituted for Omacor
Great progress has been made in prevention of cardiovascular diseases.
A major contribution came from randomized double blind clinical trials.
Therapy is based on the outcome of these trials and we are privileged
to
live in the age of evidence-based medicine. Why do we mention this in
the context of omega-3 fatty acids? In contrast to the nomenclature of
pharmaceuticals,
the term "omega-3 fatty acids" is often used in an unscientific manner.
While
in the trials of the GISSI group Omacor was administered, the
impression
is often generated that "omega-3 fatty acids or "omega-3 PUFAs" were
administered.
It is implicated that it does not matter whether Omacor or other
preparations
of "omega-3 fatty acids" are used. Incidentally, the other preparations
are cheaper (less costly to prepare because of less stringent
regulations
in case of OTC nutrition supplements). So this misconception is readily
accepted. But do these other "omega-3" preparations work? The answer
is: we don't
know, there is no evidence available at all. So in this respect we turn
away from evidence-based medicine. A patient who survived an MI should
be
treated based on the outcome of the trials of the GISSI group and not
on
the basis of assumptions. Obviously, manufacturers of fish oil capsules
are invited to do clinical trials and to prove the efficacy of their
products.
In view of the huge sales of fish oils, it should not be a financial
burden
for the companies to support these trials. If physicians prescribe Omacor and
pharmacists recommend substitution with fish oils, they are - in our
opinion
- in breach of their own ethical guidelines. Pharmacists must be aware of the
differences
and cannot mislead patients. Pharmacists have to give customers proper
information.
The ethical code states that pharmacists "must assist patients in
making
informed decisions" by providing them with "necessary and relevant
information"
(see also the recent discussion on homeopathic
remedies. Put in simple terms: fish oils
are
not "generics" of Omacor. It has been argued that the level
of EPA+DHA is some type of surrogate endpoint and as long as a
specified (high) level is reached, it does not matter how it is
reached. What is the evidence for this? There is no evidence!
"Any" brand of ethyl ester must
not be substituted for Omacor
Fish oils are different
from Omacor, so clearly they cannot be substituted for Omacor. But what
about "omega-3 ethyl esters" in general? Again the same situation: in
the GISSI
trials, Omacor was used but not "any" brand of ethyl esters. There are
indeed
major differences in the preparations. This is exemplified by the
comparison
of two ethyl ester preparations, referred to as preparation A and
preparation
B. Although preparation A and preparation B contain 90% omega-3 fatty
acids,
preparation B contains only 20% DHA and 60% EPA while preparation A
contains
38% DHA and 46% EPA. Furthermore, by including various minor omega-3
fatty
acids, the total omega-3 fatty acid content is raised in preparation B
to
90%, although the biological role of these minor (including also
short-chain)
omega-3 fatty acids remains unresolved. Therefore, preparation B is
clearly
not a substitute for preparation A. Since no clinical trials have been
done
with preparation B, we consider it unethical to come up with a
substitution
simply because preparation B is cheaper than preparation A (Omacor).
Again
the argument comes up that the EPA+DHA level might be a good enough
surrogate
endpoint or predictor of sudden death. Too often we have learned that
predictions
for cardiovascular endpoints turned out to be wrong. A very recent
example
is the lack of efficacy of a statin in heart failure despite its
pleiotropic
actions.
(1)
Rupp H, Wagner D, Rupp T, Schulte L, Maisch B. Risk stratification by
the "EPA+DHA Level" and the "EPA/AA Ratio". Focus on anti-inflammatory
and antiarrythmogenic effects of long-chain omega-3 fatty acids. Herz
2004; 29:673-685. Also available as PDF
(2)
Ikeda I, Imasato Y, Nagao H, et al. Lymphatic transport of
eicosapentaenoic and docosahexaenoic acids as triglyceride, ethyl ester
and free acid, and their effect on cholesterol transport in rats. Life
Sci 1993;52:1371–9.
(3)
Kozak M, Krivan L, Semrad B. Circadian variations in the occurrence of
ventricular tachyarrhythmias in patients with implantable cardioverter
defibrillators.
Pacing Clin Electrophysiol 2003;26:731–5.
(4)
Lawson LD, Hughes BG. Human absorption of fish oil fatty acids as
triacylglycerols, free acids, or ethyl esters. Biochem Biophys Res
Commun 1988;152:328–35.
(5) Luley C, Wieland H, Grünwald J. Bioavailability of omega-3
fatty acids: ethylester preparations are as suitable as triglyceride
preparations. Akt Ernährungsmed 1990;15:123–5.
(6)
Lawson LD, Hughes BG. Absorption of eicosapentaenoic acid and
docosahexaenoic acid from fish oil triacylglycerols or fish oil ethyl
esters co-ingested
with a high-fat meal. Biochem Biophys Res Commun 1988;156:960–3.
(7)
GISSI-Prevenzione Investigators. Dietary supplementation with ω-3
polyunsaturated fatty acids and vitamin E after myocardial infarction:
results of the
GISSI-Prevenzione Trial. Gruppo Italiano per lo Studio della
Sopravvivenza nell’Infarto miocardico. Lancet 1999;354:447–55.
(8)
Marchioli R, Avanzini F, Barzi F, et al. Assessment of absolute risk of
death
after myocardial infarction by use of multiple-risk-factor assessment
equations:
GISSI-Prevenzione mortality risk chart. Eur Heart J 2001;22:2085–103.
(9).
Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden
death by ω-3 polyunsaturated fatty acids after myocardial infarction:
time-course
analysis of the results of the Gruppo Italiano per lo Studio della
Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation
2002;105: 1897–903.
(10)
Leaf A, Xiao YF, Kang JX, et al. Prevention of sudden cardiac death by
ω-3 polyunsaturated fatty acids. Pharmacol Ther 2003;98:355–77.
(11)
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; 346:1113-1118.
(12)
Siscovick DS, Raghunathan TE, King I, Weinmann S, Wicklund KG, Albright
J,
Bovbjerg V, Arbogast P, Smith H, Kushi LH. Dietary intake and cell
membrane levels of long-chain n-3 polyunsaturated fatty acids and the
risk of primary cardiac arrest. JAMA 1995; 274:1363-1367.
(13)
Leaf A, Albert
CM, Josephson M, Steinhaus D, Kluger J, Kang JX, Cox B, Zhang H,
Schoenfeld
D. Prevention of fatal arrhythmias in high-risk subjects by fish oil
n-3
fatty acid intake. Circulation 2005;112:2762-2768
(14)
Calo L, Bianconi L, Colivicchi F, Lamberti F, Loricchio ML, de Ruvo E,
Meo A, Pandozi C, Stai-bano M, Santini M. N-3 Fatty acids for the
prevention
of atrial fibrillation after coronary artery by-pass surgery: a
randomized,
controlled trial. J Am Coll Cardiol 2005;45:1723-1728.
(15) Kris-Etherton PM, Harris WS, Appel
LJ; American Heart Association. Nutrition Committee. Fish consumption,
fish
oil, omega-3 fatty acids, and cardiovascular disease. Circulation.
2002;106:2747-57.
(16)
Van de Werf F, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KA,
Julian D, Lengyel M, Neumann FJ, Ruzyllo W, Thygesen C, Underwood SR,
Vahanian
A, Verheugt W, Wijns W.
Management of acute myocardial infarction in patients presenting with
ST-segment elevation. The Task Force on the Management of Acute
Myocardial Infarction of the European Society of Cardiology. Eur Heart
J 2003;24:28-66.
|
Omega-3-Forum
"Make everything as simple as possible, but not
simpler."
Be more precise:
the "EPA+DHA level"
Not all omega-3 fatty acids are the same (see textbooks of
biochemistry) and their protective effects depend on the chain length
and number of double bonds. Only long-chain omega-3 fatty acids
(EPA+DHA) but not the short-chain omega-3 alpha-linolenic acid have
been shown to reduce risk of sudden death (Albert
CM et al.).
If e.g. the "omega-3 level" is calculated, obviously also the omega-3
alpha-linolenic acid has to be included (or you redefine what you mean
with
omega-3 and simply ignore textbook knowledge). Thus, terms like
"omega-3
level" are too broad and not appropriate when referring to benefits
observed
in the GISSI-Prevention and GISSI-HF trials.
There is also a discrepancy between the design of well-controlled
trials and the inprecise specification of the medication used. To our
knowledge, the ratio of DHA:EPA in the GISSI trials was 1: 1.2 and not
the reverse. This ratio is found in Omacor, i.e. 38% DHA and 46% EPA.
These prescription omega-3 fatty acid ethyl esters must not be
referred to as "cheap and simple fish oil" and also not as "highly
purified fish oil". Fish oil contains
triglycerides whereas Omacor contains ethyl esters. Triglycerides but
not
ethyl esters are split by pancreatic lipase and thus rapidly absorbed.
Ethyl
esters result in a retarded sustained EPA and DHA absorption. It should
not be tolerated that the public is misled in this respect.
Recent
questions:
Monitoring beyond omega-3 fatty acids?
The arachidonic acid:EPA ratio needs to be re-evaluated.
Gas
chromatography
How to work safely with hydrogen: use a hydrogen generator.
Sample
preparation and standardization
Use alkaline conditions in the transesterification with methanol. The
typical BF3/method results in a loss of EPA and DHA. Details are given
in Rupp
et al.
Alternative
tests
Are the "fast" GC methods an alternative?
Other sites maintained by us:
www.cleverfood.com
www.cardiorepair.com
www.carditis.com
www.herzzentrum-marburg.de
web.uni-marburg.de/herzzentrum
|
