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Omega3 PUFA and Cardiac Arrhythmias

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Omega-3 PUFA and Cardiac Arrhythmias. Dalit Weisman R.D, Msc, ... ?????-9 - 40 oleic acid) - ?'?( ?????? 2- E?'?. ????? ?????? ?????? ???: ?????? (??'?) - 10 ... – PowerPoint PPT presentation

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Title: Omega3 PUFA and Cardiac Arrhythmias


1
Omega-3 PUFA and Cardiac Arrhythmias Dalit
Weisman R.D, Msc, PhD student Electrophysiology
Unit Heart Institute Sheba Medical Center
2
WILLIAM S. HARRIS, PhD. CLEVELAND CLINIC JOURNAL
OF MEDICINE VOLUME 71 NUMBER 3 MARCH 2004
3
Breaking News on Food Beverage Development -
Europe
The inventor of omega-3
27/11/2007- It all started with a trip to
Greenland in 1970. Three Danes, a couple of
dogsleds, and several years of study later and
the omega-3 was born. Since then, awareness and
understanding of marine omega-3 has sky-rocketed.
Dr. Jörn Dyerberg
The science explosion has been followed by
consumer and product blast-off. Different ratios
for EPA (C205 n-3) to DHA (C226 n-3) are being
marketed, or DHA alone, or products containing
alpha-linolenic acid (ALA, C183 n-3), a shorter
long-chain omega-3 from plants. It's all a bit
confusing"The ratios of EPA and DHA are not
important," said Dr. Dyerberg, "as they can be
interconverted.""But consumption should include
both, and a decent combination is 32
EPADHA."So what about docosapentaenoic acid
(DPA), labelled by some as "underrated" amongst
the omega-3 fatty acids? "I don't know any
specific effects of DPA," he said. "But it is an
intermediate in the conversion of EPA to DHA, so
it will be present in the body all the time."As
for ALA, an omega-3 from plants that is converted
in the body to EPA and subsequently DHA, he was
unconvinced. In terms of biological effects of
DHA and EPA, Dr. Dyerberg said there are many.
"We don't know of any specific biological effects
of ALA," he said.
If we want the benefits of omega-3, we have to
eat them as long chain," he said, referring to
EPA and DHA.
4
Mozaffariam D et al. JAMA. 20062961885-99.
5
  • Circulation. 2007116e320-e335.

6
  • Efforts to better understand the links between
    diet and cardiac rhythm have the potential to
    improve public health and welfare and to reduce
    the ballooning costs associated with treating
    cardiovascular disease.
  • That omega-3 fatty acids have an impact on the
    fundamental elements (ion channels, exchangers,
    and modulators) of cardiac electric activity is
    now indisputable. However, the translation of
    this understanding into evidence-based public
    policy guidelines that can decrease the incidence
    of arrhythmias and SCD still requires significant
    additional efforts.

Circulation. 2007116e320-e335.
7
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9
  • 6 medical USA centers.
  • N 200 (parallel group design).
  • 100 fish-oil.
  • 100 placebo.
  • 2 year follow-up.
  • Intervention dose
  • 1.8 g fish-oil 1.3 g EPADHA.

10
Results
  • At 6,12, and 24 months after randomization,
    respectively, 46 51 and 65 of pts assigned to
    fish-oil had ICD therapy for VT/VF compared with
    36 41 and 59 of pts assigned to placebo
    (p.19).

11
Comment
  • In the subset of 133 pts whose qualifying
    arrhythmia at the time of study entry was VT, pts
    assigned to fish-oil had a 61 66 and 79
    incidence of VT/VF treated by the ICD at 6, 12,
    and 24 months, respectively compared with 37,
    43, and 65 among those assigned to placebo
    (p.007).

12
At 6, 12, and 24 months, 46, 51, and 65 of
patients assigned to receive fish oil had had ICD
therapy for VT/VF, compared with 36, 41, and
59 for patients assigned to receive placebo (p
0.19). In the subset of 133 patients whose
qualifying arrhythmia was VT, 61, 66, and 79
of patients in the fish oil group had had VT/VF
at 6, 12, and 24 months, respectively, compared
with 37, 43, and 65 of patients in the placebo
group (p 0.007). In addition, the number of
days with episodes of ICD therapy for VT/VF was
significantly greater in the fish oil group than
in the placebo group (p lt 0.001).
Raitt et al. JAMA. 20052932884-2891.
13
Conclusions
  • Among patients with a recent episodes of
    sustained ventricular arrhythmia and an ICD, fish
    oil supplement does not reduce the risk of VT/VF
    and may be proarrhythmic in some patients.

14
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15
  • 8 European countries
  • N 546 (parallel group design)
  • 273 fish-oil.
  • 273 placebo.
  • 1 year follow up.
  • Intervention dose
  • 2 g fish-oil 961 mg EPADHA.

16
Results
  • Event-free survival did not substantially
    improved in the fish-oil group (sustained ICD
    intervention or death from any cause accure 30
    in the fish-oil group and 33 in the placebo
    (p0.33).
  • In total 75 pts (27) in the fish oil group and
    81 pts (30) in the placebo received appropriate
    ICD intervention for VT or VF (p0.46).

17
Comments
  • In 342 patients with prior MI there was a
    nonsignificant tendency for a beneficial effect
    of fish oil on event free survival.
  • In this study patients had experienced MI between
    2 weeks and 25 years before entry!

18
Survival free from VT/VF or death from any cause
at 12 months
p
Placebo
Polyunsaturated fatty acid
Analyzed group
0.24
67
70
All patients, 273 in both arms ()
0.086
63
71
342 patients with prior MI ()
"We have no indication that there is any subgroup
that would have a harmful effect from fish oil."

European Society of Cardiology Congress 2005.
19
Conclusions
  • No evidence of a strong protective effect of
    intake of omega-3 PUFA from Fish oil against
    ventricular arrhythmias in patients with ICDs has
    been found.
  • In contrast to others, this study did not find
    that fish-oil may have proarrhythmic properties.

20
Circulation. 20051122762-2768
21
  • USA.
  • N 400 (parallel design).
  • 200 fish-oil
  • 202 placebo.
  • 1 year follow up.
  • Intervention dose
  • 4 g fish oil 2.6 g EPADHA

22
Results
  • In the primary analysis, according to the
    intention- to- treat principle, there was a trend
    toward a longer time to first ICD event for VT/VF
    confirmed by electrograms or death from any
    cause among patients randomized to fish oil
    compared with those of placebo (p0.057).

23
Results
  • In the second on-treatment analysis limited only
    to subjects who were compliant for at least 11
    months, the relative risk was 0.62 (P0.034).
  • 142 subjects (35!!) discontinued their
    supplement before completing their year in the
    trial.)

24
Conclusions
  • Although significant was not achieved for the
    primary end point, this study provides evidence
    that for individuals at high risk of fatal
    ventricular arrhythmias, regular daily ingestion
    of fish oil fatty acids may significantly reduce
    potentially fatal ventricular arrhythmias.

25
Experts comments
  • fish oil supplementation in ICD patients
    continues to be an evolving area.
  • there are no definitive data at this point..
  • there are supporting data for both positions.

Dr. Douglas Zipes Indiana University School of
Medicine, Indianapolis. Heart wire Nov. 4, 2005.
26
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27
Effect of Supplemental intake of Omega-3
Polyunsaturated Fatty-Acids on the rate and
complexity of spontaneously occurring ventricular
and supraventricular arrhythmia in patients with
Implantable Cardioverter Defibrillator.
Prof. Uri Goldburt Prof. Michael Glikson Prof.
Ehud Schwamental Dr. David Luria Prof. Sami
Viskin Dalit Weisman R.D, Msc, PhD student
28
Study objectives
  • Primary Outcomes
  • To investigate the effects of oral
    supplementation of omega-3 PUFA on the occurrence
    of life threatening ventricular arrhythmias in
    post-MI ICD recipients.
  • Secondary outcomes
  • 1) All-cause mortality, cardiac mortality,
    recurrent and myocardial infarction.
  • 2) Atrial arrhythmia and non-sustained
    ventricular arrhythmia (non-sustained VT or
    ventricular premature complex (PVC)) as
    documented by ICD memory or 24 hour ECG (Holter)
    recording.
  • 3) Whether omega-3 PUFA supplementation exerts
    different effects according to ischemia severity
    assessed by stress perfusion nuclear imaging.
  • 4) The effect of omega-3 PUFA supplementation on
    C-reactive protein blood levels

29
Inclusion criteria
  • 1. Patients with old myocardial infarction who
    have a dual chamber ICD that was implanted gt1
    months ago.
  • 2. Patients should be on no antiarrhythmic agents
    or on stable antiarrhythmic medications for one
    month (except class I drugs, which are
    contraindicated).
  • 3. Agree to give written informed consent.

30
Exclusion criteria
  • 1) Less than 18 years of age.
  • 2) ICD implantation as a bridge to heart
    transplantation.
  • 3) Patients taking class I antiarrhythmic
    medication.
  • 4) A projected lifespan less than one year.
  • 5) Participation in another trial (during or
    within 30 days before the study).
  • 6) Use of supplemental n-3 fatty acids during the
    last 3 months.
  • 7) Women who are pregnant and of childbearing
    potential who do not use adequate contraception.
  • 8) Patients known to have a history of recent
    drug or alcohol abuse.
  • 9) History or current intestinal or hepatic
    disease.

31
Omega-3 Fatty Acids Intervention
  • ???? ?? ????? 1529 ?"? ??????
  • EPA 400 ?"?
  • DHA 200 ?"?
  • ?????? ???? ????? ???? ?????-3 - 30 ?"?
  • ?????-9 - 40 oleic acid) - ?"?(
  • ?????? 2- E?"?
  • ????? ?????? ?????? ???
  • ?????? (??"?) - 10
  • ??????? 0
  • ??????? 0
  • ?????? (???) 1
  • ????? ???? ?????? 6 ??????? ???? (???? - 9.174
    ???) ???????
  • 3.6 ??? ?? EPADHA
  • 60 ???????

21 Ratio
??? ????? ?????? ????
32
Three considerations let to this decision
  • First, the negligible amount of dietary omega-3
    PUFA intake which characterize the Israeli
    population
  • The safety profile of omega-3 PUFA
    supplementation, up to 3 gram per day.
  • The recent clinical experience with 3.4 gram
    omega-3 PUFA, delivered I.V. without reported
    hazards.

33
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34
Three considerations let to this decision
  • The safety profile of omega-3 PUFA
    supplementation, up to 3 gram per day.
  • The recent clinical experience with 3.4 gram
    omega-3 PUFA, delivered I.V. without reported
    hazards.

35
Kris-Etherton PM et al. Circulation
20021062747-2757.
36
Three considerations let to this decision
  • The recent clinical experience with 3.4 gram
    omega-3 PUFA, delivered I.V. without reported
    hazards.

37
We did electrophysiological testing in ten
patients with implanted cardioverter
defibrillators who were at high risk of sudden
cardiac death. To assess their immediate effects
on the induction of sustained ventricular
tachycardia, n-3 fatty acids were infused (3.8g).
Such tachycardia was not induced in five of seven
patients. Our findings show that infusion of n-3
polyunsaturated fatty acids does not induce
arrhythmia, but did result in a reduction of
sustained ventricular tachycardia in some
patients. Lancet 2004 363 144142
38
????? ?????? ????? ?"? ??? ?????? EF
??????????? ?????? ICD
  • ????? 1 EF ???? ?? ???? ?-35 ?? Spontaneous
    VT.
  • ????? 2 EF ???? ?- 35 ?? Spontaneous VT .
  • ????? 3 EF ???? ?? ???? ?- 35 ?? ??? ?????????
    (VF, SCD, Inducible VT, Primary prevention
    MADIT II).
  • ????? 4 EF ???? ?- 35 ?? ??? ????????? (VF,
    SCD, Inducible VT, Primary prevention MADIT II).

39
Visit 1 Screening
Inclusion/ Exclusion
Visit 2 - Baseline
Inform Consent Blood Withdrawal Subcutaneous fat
biopsy SPECT 24 h Holter SF-36 Depression
Food Questionnaires ICD interrogation
programming Capsules distribution according to
Randomization
Telephone Contact
Visit 3 3 months
ICD interrogation Compliance assessment and
capsules supply to patients
Telephone Contact
Visit 4 6 months
ICD interrogation 24 h Holter Blood Withdrawal
Subcutaneous fat biopsy SF-36 Depression
Questionnaires Compliance assessment (capsules)
4 months washout period
40
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41
A case for the use of the Omega-3 Index as a risk
stratification tool for CHD death. Harris et al.
suggested that an Omega-3 Index level of 8 is
a reasonable preliminary target value for
reducing risk. The Omega-3 Index may represent a
novel, physiologically relevant, modifiable, and
independent marker of risk for death from CHD.
42
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43
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44
Conclusions Although any of the tissues
examined could serve as a surrogate for cardiac
omega-3 FA content, RBC EPADHA was highly
correlated with cardiac EPADHA the RBC omega-3
response to supplementation was similar to that
of the heart RBCs are easily collected and
analyzed and they have a less variable FA
composition than plasma. Therefore, RBC EPADHA
(also called the Omega-3 Index) may be the
preferred surrogate for cardiac omega-3 FA
status.
45
We also chose to obtain subcutaneous
adipose-tissue biopsies, a biomarker considered
the gold-standard for the objective assessment of
long-term habitual dietary intake of fish and
marine omega-3 PUFA (EPA and DHA). It can be
considered a helpful tool in interpreting
results.
46
Visit 1 Screening
Inclusion/ Exclusion
Visit 2 - Baseline
Inform Consent Blood Withdrawal Subcutaneous fat
biopsy SPECT 24 h Holter SF-36 Depression
Food Questionnaires ICD interrogation
programming Capsules distribution according to
Randomization
Telephone Contact
ICD interrogation Compliance assessment and
capsules supply to patients
Visit 3 3 months
Telephone Contact
Visit 4 6 months
ICD interrogation 24 h Holter Blood Withdrawal
Subcutaneous fat biopsy SF-36 Depression
Questionnaires Compliance assessment (capsules)
4 months washout period
47
Subcutaneous Fat Biopsy
48
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49
ADIPOSE TISSUE AS A MEDIUM FOR EPIDEMIOLOGIC
EXPOSURE ASSESSMENT
  • Experience in the use of adipose tissue sampling
    in epidemiologic studies in various countries has
    shown that it is simple to conduct, requires
    little training, carries little risk, and does
    not result in excessive participant refusal.
  • In contrast to more traditional methods of
    assessment of long term dietary intakes it holds
    the promise of being able to sample past dietary
    habits without bias.

Kohlmeier, Lenore, Kohlmeier, Martin,
Environmental Health Perspectives Supplements,
10780475, Apr95, Vol. 103, Issue Suppl. 3 Hirsch
J. Studies of adipose tissue in man a
microtechnic for sampling and analysis. Am J Clin
Nutr 8499-511 (1960).
50
Biomarkers of Fat and Fatty Acid Intake
The majority of fatty acids in human tissue are
nonessential and are both dietarily supplied and
endogenously produced. For those interested in
exogenous sources of fatty acids and
their relationships to chronic disease, one of
the strongest biomarkers of long-term intake
available is the relative distribution
of individual fatty acids in adipose tissue.
Adipose samples may be aspirated from one of
various sites (most commonly gluteal or
abdominal) and measured by gas chromatography
(GC) or HPLC. Quantities as small as 10 mg are
adequate for these analyses. The longest
abolished procedure for sampling adipose tissue
carries a low risk of infection.
Arab L. J. Nutr. 133 925S932S, 2003.
51
Visit 1 Screening
Inclusion/ Exclusion
Visit 2 - Baseline
Inform Consent Blood Withdrawal Subcutaneous fat
biopsy SPECT 24 h Holter SF-36 Depression
Food Questionnaires ICD interrogation
programming Capsules distribution according to
Randomization
Telephone Contact
Visit 3 3 months
ICD interrogation 24 h Holter Compliance
assessment and capsules supply to patients
Telephone Contact
Visit 4 6 months
ICD interrogation 24 h Holter Blood Withdrawal
Subcutaneous fat biopsy SF-36 Depression
Questionnaires Compliance assessment (capsules)
3 months washout period
52
Validated Israeli Food Frequency Questionnaire
(FFQ)
The S. Daniel Abraham International Center for
Health and NutritionBen-Gurion University
  • The final FFQ included 126 food items that
    contribute 80 to between people variation.
  • Quantification of food intake was done using
    usual serving sizes and different portion sizes
    of selected dishes.
  • Computerized Israeli nutrition data base.

53
The S. Daniel Abraham International Center for
Health and Nutrition Ben-Gurion University
Food pictures and models were donated from USDA,
EPIC, Epidemiology Department- Tel Hashomer, and
Al-Qutz University
54
Visit 5 9 months
Blood Withdrawal 24 h Holter SF-36 Depression
Questionnaires ICD interrogation Compliance
assessment (capsules) Capsules distribution
Visit 6 12 months
Telephone contact
ICD interrogation 24 h Holter Compliance
assessment and capsules supply to patient
Visit 7 15 months
Telephone contact
ICD interrogation 24 h Holter Blood Withdrawal
Subcutaneous fat biopsy SF-36 Depression
Questionnaires Compliance assessment (capsules)
End of trial
55
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