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Omega-3 PUFA and Cardiac Arrhythmias
Dalit Weisman R.D, Msc, PhD student
Electrophysiology Unit
Heart Institute
Sheba Medical Center
WILLIAM S. HARRIS, PhD. CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 3 MARCH 2004
Breaking News on Food & Beverage Development - Europe
27/11/2007-
The inventor of omega-3
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
science explosion has been followed by consumer and product blast-off. Different ratios for
EPA (C20:5 n-3) to DHA (C22:6 n-3) are being marketed, or DHA alone, or products containing
alpha-linolenic acid (ALA, C18:3 n-3), a shorter long-chain omega-3 from plants.
The
It's all a bit confusing…
If we want the benefits of omega-3, we have to eat them
as long chain," he said, referring to EPA and DHA.
"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 3:2 EPA:DHA."
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.
Mozaffariam D et al. JAMA. 2006;296:1885-99.
Circulation. 2007:116:e320-e335.
• 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. 2007:116:e320-e335.
• 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 EPA+DHA.
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).
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).
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 < 0.001).
Raitt et al. JAMA. 2005;293:2884-2891.
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.
• 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 EPA+DHA.
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 (p=0.33).
• 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 (p=0.46).
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!
Survival free from VT/VF or death from any cause at 12 months
Analyzed group
Polyunsaturated fatty acid
Placebo
p
All patients, 273 in both arms (%)
70
67
0.24
342 patients with prior MI (%)
71
63
0.086
"We have no indication that there is any subgroup that
would have a harmful effect from fish oil."
European Society of Cardiology Congress 2005.
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.
Circulation. 2005;112:2762-2768
• USA.
• N= 400 (parallel design).
– 200 – fish-oil
– 202 placebo.
• 1 year follow up.
• Intervention dose:
– 4 g fish oil = 2.6 g EPA+DHA
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 (p=0.057).
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 (P=0.034).
• 142 subjects (35%!!) discontinued their
supplement before completing their year in the
trial.)
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.
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.
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
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
Inclusion criteria
• 1. Patients with old myocardial infarction who
have a dual chamber ICD that was implanted >1
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.
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.
‫‪Omega-3 Fatty Acids Intervention‬‬
‫•‬
‫•‬
‫•‬
‫•‬
‫•‬
‫– משקל כל כמוסה ‪ 1529‬מ"ג ובתוכה‪:‬‬
‫‪EPA – 400‬מ"ג‬
‫‪2:1 Ratio‬‬
‫‪DHA – 200‬מ"ג‬
‫חומצות שומן אחרות מסוג אומגה‪ 30 - 3-‬מ"ג‬
‫אומגה‪ oleic acid) - 40 - 9-‬מ"ג(‬
‫ויטמין ‪ E-2‬מ"ג‬
‫– סימון תזונתי לכמוסה אחת‪:‬‬
‫אנרגיה (קק"ל) ‪10 -‬‬
‫חלבונים – ‪0‬‬
‫פחמימות – ‪0‬‬
‫שומנים (גרם) – ‪1‬‬
‫•‬
‫•‬
‫•‬
‫•‬
‫למה בחרנו במינון הזה?‬
‫•‬
‫•‬
‫– במחקר נוטל המשתתף ‪ 6‬קפסולות ביום (משקל ‪ 9.174 -‬גרם) שמספקות‪:‬‬
‫‪3.6‬גרם של ‪EPA+DHA‬‬
‫‪60‬קלוריות‬
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.
Reference
Sample
Size (N)
NHANES [48].
Fish consumption (grams/day)
EPA + DHA
consumption
(grams/day)
78 – 102 (mean range)
0.04 – 0.1
Israel Center for
Disease Control [47].
3242
27.04
0.17
Israel Center for
Disease Control [47].
605 (fish
eaters only)
144.9
0.75
Daniel Abraham
Nutrition Center, BenGurion University
(personal
communication).
1124
10
Data not available
Daniel Abraham
Nutrition Center, BenGurion University
(personal
communication).
158 (fish
eaters only)
91
Data not available
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 omega3 PUFA, delivered I.V. without reported hazards.
Kris-Etherton PM et al. Circulation 2002;106:2747-2757.
Three considerations let to this decision
• The recent clinical experience with 3.4 gram omega3 PUFA, delivered I.V. without reported hazards.
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: 1441–42
‫ריבוד קבוצות המחקר ע"פ שני גורמים ‪– EF‬‬
‫והאינדיקציה להשתלת‪ICD‬‬
‫•‬
‫•‬
‫•‬
‫•‬
‫קבוצה ‪ – EF 1‬פחות או שווה ל‪ 35%-‬עם‬
‫‪Spontaneous VT.‬‬
‫קבוצה ‪ – EF 2‬גדול מ‪ 35% -‬עם ‪Spontaneous‬‬
‫‪VT .‬‬
‫קבוצה ‪ – EF 3‬פחות או שווה ל‪ 35% -‬עם שאר‬
‫האריתמיות ‪(VF, SCD, Inducible VT, Primary‬‬
‫‪prevention – MADIT II).‬‬
‫קבוצה ‪ – EF 4‬גדול מ‪ 35% -‬עם שאר‬
‫האריתמיות ‪(VF, SCD, Inducible VT, Primary‬‬
‫‪prevention – MADIT II).‬‬
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
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.
Conclusions—
”Although any of the tissues examined could
serve as a surrogate for cardiac omega-3 FA
content, RBC EPA+DHA was highly
correlated with cardiac EPA+DHA; 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 EPA+DHA (also called the
Omega-3 Index) may be the preferred
surrogate for cardiac omega-3 FA status”.
We also chose to obtain subcutaneous adiposetissue 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.
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
Subcutaneous Fat Biopsy
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 8:499-511 (1960).
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: 925S–932S, 2003.
Visit 2 - Baseline
Visit 1 – Screening
Inclusion/ Exclusion
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
The S. Daniel Abraham International Center for Health and Nutrition
Ben-Gurion University
Validated Israeli Food Frequency Questionnaire
(FFQ)
• 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.
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
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