|
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 /
Lovaza). 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
/
Lovaza) 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
/
Lovaza) 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
/
Lovaza) 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
/
Lovaza.
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
/
Lovaza, 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
herzzentrum.online.uni-marburg.de
|
