Download Polyunsaturated Fatty Acids in Heart Failure

Journal of the American College of Cardiology
© 2011 by the American College of Cardiology Foundation
Published by Elsevier Inc.
EDITORIAL COMMENT
Polyunsaturated Fatty
Acids in Heart Failure
Should We Give More
and Give Earlier?*
W. H. Wilson Tang, MD, Michael A. Samara, MD
Cleveland, Ohio
There is an emerging paradox that confronts the care for
patients with heart failure. On the one hand is the wellchronicled, woeful underutilization of evidence-based,
guideline-supported therapies (1). On the other hand is the
growing recognition that a monolithic approach to this very
complex and heterogeneous disease is suboptimal. While we
strive to fulfill performance measures, we simultaneously
aspire to refine and individualize patient care and demand
“evidence” to target new treatments to the subset of patients
who will benefit most. It is with this background and with
a decade-long drought in new drug therapies for heart
See page 870
failure that the story of n-3 polyunsaturated fatty acids
(PUFAs) in heart failure prevention and treatment has
unfolded. Over the last 3 decades, an extensive body of
observational, experimental, and now randomized clinical
trial data has built upon the initial observations of Bang and
Dyeberg (2) to present a compelling storyline for the
benefits of n-3 PUFAs in cardiovascular disease, particularly eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA). Animal and human studies have provided
insights into the mechanisms by which these benefits may
be achieved, including improvements in blood pressure
and systemic vascular resistance, autonomic function,
cardiac relaxation and filling, ventricular remodeling,
arrhythmic risk, coagulation and thrombosis, and inflammation (Fig. 1) (3,4).
In 1999, the GISSI (Gruppo Italiano per lo Studio della
Sopravvivenza nell’Infarto Miocardico) Prevenzione trial
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the Department of Cardiovascular Medicine, Heart and Vascular Institute,
Cleveland Clinic, Cleveland, Ohio. Dr. Tang is supported by the National Institutes
of Health grant 1RO1 HL103931-01; is a consultant for Medtronic Inc. and St. Jude
Medical; and receives research support from Abbott Laboratories. Dr. Samara has
reported that he has no relationships to disclose.
Vol. 57, No. 7, 2011
ISSN 0735-1097/$36.00
doi:10.1016/j.jacc.2010.11.014
represented the culmination of an extensive body of literature showing a 10% to 20% reduction in fatal and nonfatal
cardiovascular end points in patients receiving moderate
doses of n-3 PUFAs. The trial demonstrated a 21% relative
risk reduction in death among patients taking 1 g of n-3
PUFAs (containing 850 to 882 mg of EPA/DHA ethyl
esters with a ratio of 1:1.2) after myocardial infarction. This
was achieved principally due to a reduction in sudden cardiac
death (5). Post hoc subgroup analysis revealed that this
reduction in sudden cardiac death was concentrated in patients
with systolic dysfunction (relative risk: of 0.42 [95% confidence
interval: 0.26 to 0.67]), and was in fact nonsignificant in
patients with left ventricular ejection fraction ⬎50% (6).
Beyond their use in the treatment of known cardiovascular disease, the last decade has seen a series of large
epidemiological studies providing evidence for the effectiveness of n-3 PUFAs in preventing the development of heart
failure. During 12 years of follow-up, the Cardiovascular
Health Study demonstrated that among 4,738 elderly subjects, consumption of baked/broiled fish or supplemental
n-3 PUFAs conferred a lower risk of incident heart failure
(7). This risk was inversely proportional to the quantity of
fish/supplement intake with a 32% relative risk reduction in
patients consuming the equivalent of ⱖ1 g/day of n-3
PUFA, and the trend across consumption categories
achieved statistical significance (7). In contrast, patients
consuming much lower quantities of fish (the equivalent of
28 to 313 mg/day of n-3 PUFAs) in the Rotterdam study
had no significant risk reduction (8). The large JACC
(Japan Collaborative Cohort) study reaffirmed the inverse
relationship between fish and supplemental n-3 PUFA
intake and heart failure–associated mortality, although the
trend only achieved statistical significance in patients taking
supplemental n-3 PUFA (9). These results were further
corroborated by data from the ARIC (Atherosclerosis Risk
in Community) study, which demonstrated that higher
plasma levels of DHA were associated with a lower risk for
developing heart failure in women (10).
Cumulatively, these findings contributed to the hypothesis that n-3 PUFA supplementation in relatively high doses
would result in reductions in heart failure–associated morbidity and mortality in patients with established heart failure
of any etiology, and that these effects would be largely driven
by reductions in nonfatal arrhythmic complications and
sudden cardiac death as in GISSI-Prevenzione. To investigate this hypothesis, the GISSI-HF trial enrolled nearly
7,000 patients with New York Heart Association (NYHA)
functional class II to IV heart failure and randomized them
to 1 g/day of n-3 PUFA versus placebo on top of optimal
medical care. Over the 3.9-year median follow-up, n-3
PUFA use resulted in a modest 9% relative risk reduction in
all-cause mortality and an 8% reduction in the composite of
mortality and cardiovascular hospitalization (11). Surprisingly, these benefits were conferred without a reduction in
sudden cardiac death, hospitalizations for heart failure, or
JACC Vol. 57, No. 7, 2011
February 15, 2011:880–3
Figure 1
Tang and Samara
n-3 PUFA in Heart Failure
881
Beneficial Effects of n-3 PUFAs in Heart Failure
AA ⫽ arachadonic acid; COX ⫽ cyclooxygenase; DHA ⫽ docosahexaenoic acid; EPA ⫽ eicosapentaenoic acid; ET ⫽ endothelin; ICAM ⫽ intracellular adhesion molecule;
IL ⫽ interleukin; NF-KB ⫽ nuclear factor kappa B; NO ⫽ nitric oxide; PAF ⫽ platelet activating factor; PPAR␥ ⫽ peroxisome proliferator-activated receptor gamma; SBP ⫽
systolic blood pressure; SVR ⫽ systemic vascular resistance; TNF ⫽ tumor necrosis factor; TxA2 ⫽ thromboxane A2; VCAM ⫽ vascular cell adhesion molecule; PUFA ⫽
polyunsaturated fatty acids.
arrhythmia. An echocardiographic substudy also found
small but significant improvement in left ventricular ejection
fraction with n-3 PUFA but not with rosuvastatin (12).
Although providing the strongest evidence to date for the
role for n-3 PUFA in established heart failure, GISSI-HF
managed to generate as many questions as it answered. How
were these benefits achieved? Why was the risk reduction so
small compared with that anticipated by prior data? Which
patients with heart failure benefit most? Was the n-3 PUFA
dose insufficient? The desire to answer these questions and
the lack of a second large confirmatory trial have clearly
contributed to the ambivalence towards adopting n-3
PUFA use in the broader heart failure population and
incorporating the recommendation into current guidelines.
In this issue of the Journal, Nodari et al. (13) report
results from a mechanistic study of 133 subjects examining
the effect of n-3 PUFA therapy on conventional measures of
systolic and diastolic dysfunction, ventricular remodeling,
and functional impairment. Although not a prespecified end
point with relatively small event rates, the marked reduction
in cardiovascular and heart failure hospitalizations in the
current study stand in stark contrast to the modest reduction
present in GISSI-HF. Although patients in both studies
were generally on optimal medical therapy, several contrasts
between this study and GISSI-HF are illustrative. First, this
study was confined to patients with angiographically proven
nonischemic cardiomyopathy as compared with patients in
GISSI-HF who may have had heart failure from any
etiology. Furthermore, in contrast to GISSI-HF, this study
focused on a patient population with less advanced heart
failure, having a mean left ventricular ejection fraction of
37% (vs. 33% in GISSI-HF), NYHA functional class I to II
symptoms (vs. approximately 40% of patients with NYHA
functional class III or IV symptoms in GISSI-HF), and no
deaths during the 12 months of follow-up. Pre-defined
subgroup analysis from GISSI-HF suggested a stronger
trend favoring n-3 PUFA use in patients with NYHA
functional class II symptoms as compared with those with
NYHA functional class III to IV symptoms (hazard ratio:
0.93, 95% confidence interval: 0.86 to 1.01) (11). Analogously in the current study, multivariate analysis demonstrated that a shorter duration of heart failure predicted
subsequent improvements in left ventricular ejection fraction. Finally, one-half of the patients enrolled in GISSI-HF
experienced a heart failure hospitalization within the previous year, alluding to their overall poorer prognosis (14).
That being said, almost 1 out of 5 subjects in this study still
experienced a heart failure hospitalization within a year.
Cumulatively, the previously demonstrated marked benefits
observed in the primary prevention of heart failure and the
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Tang and Samara
n-3 PUFA in Heart Failure
contrasting results of these 2 trials suggest the possibility
that n-3 PUFAs are most effective when introduced early in
the course of cardiomyopathy, when they may potentially
exert their effects on viable myocardium. This type of
divergent effect across the spectrum of heart failure has been
proposed for other drugs such as statins (15), and should
n-3 PUFA therapy be considered, they should be given
prior to advanced stages of heart failure.
Another significant difference is the fact that subjects in
the current study were given higher doses of n-3 PUFAs
(⬃5 g of EHA/DPA daily for a month and ⬃2 g for the
remainder of the study) than those given in GISSI-HF
(⬃1 g of EHA/DPA). On the basis of the lack of any
subject withdrawal and the high level of compliance as
assessed by pill counting, this formulation of n-3 PUFA
appears well tolerated. Answering the question of whether
or not higher or “pulse” doses of n-3 PUFAs can achieve
more favorable clinical and echocardiographic outcomes
reaffirms the importance of phase II, dose-ranging studies in
heart failure clinical trial programs. This is a critical question to address, since prescription-strength, high-dose n-3
PUFA regimens differ significantly, from the lower and
inconsistent dosages found in over-the-counter supplements
(some have 300 mg or less EHA/DPA per pill). In other
words, simply telling patients to take “fish oil” supplements
without understanding the adequacy of dosing is unlikely to
yield the same benefits as promised in the current study.
One final provocative finding in the current study is the
marked reduction in inflammatory cytokines achieved with
the study regimen and the fact that multivariate analysis
established higher baseline values of tumor necrosis factor
(TNF)-alpha as a predictor of improvement in left ventricular ejection fraction. This finding is consistent with the
post hoc analysis of data from GISSI-HF, which has
demonstrated that circulating levels of the TNF receptor
osteoprotegerin were strongly associated with the incidence
of death and the composite end point of death and heart
failure hospitalization (16). Whether exerting this immunemodulating effect earlier in the course of disease (as previously demonstrated in animal studies) impacts disease progression remains to be seen. Regardless, these data may
suggest a potential role for the use of “inflammatory
biomarkers” in selecting patients for n-3 PUFA therapy and
for serving as potential biomarkers to gauge drug response.
That being said, reliable inflammatory biomarkers are few
and far between in the clinical setting (in fact, none of the
cytokines measured are available for routine testing), and high
cytokine levels are often generated in those with more advanced disease states. Defining this window of opportunity for
n-3 PUFA therapy to exert its maximal effect on the natural
history of heart failure is worthy of further investigation.
We continue to strive for the best supportive evidence for
our treatment approaches. However in the era of personalized medicine, traditional large-scale clinical trials that have
revolutionized heart failure care are unlikely to be the lone
means to this end. With their concomitant need for large
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sample sizes and high-risk patients to achieve adequate
event rates, these trial designs may be particularly inept at
informing the management of specific groups of less advanced patients. This study succeeds in demonstrating how
a modest treatment effect observed in a broad, unselected
heart failure population can be magnified when applied to a
smaller but enriched population of heart failure patients.
With the fortunate hindsight of GISSI-HF, Nodari et al.
(13) present a compelling test case for the dilemma facing
clinicians and guideline committees alike. Would the benefits be more apparent if n-3 PUFA supplementation was
given at higher doses and at earlier disease stages than that
in GISSI-HF? Without a new clinical trial in sight, we are
now challenged to ask ourselves whether we can be convinced to prescribe an otherwise safe and well-tolerated (but
not inexpensive) drug to a broad heart failure population
without the traditional strength of endorsement that largescale pivotal studies provide, or whether future clinical
effectiveness studies are needed to justify such indications.
The story for n-3 PUFAs in heart failure is still being
written, but it is not too early to begin to heed its lessons.
Among these is the importance of opening the door for
future trials in metabolic interventions to patients who are
not too late in the course of their disease to benefit from
what are otherwise “preventive” therapies.
Reprint requests and correspondence: Dr. W. H. Wilson Tang,
Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue,
Desk J3-4, Cleveland, Ohio 44195. E-mail: [email protected].
REFERENCES
1. Fonarow GC, Yancy CW, Albert NM, et al. Heart failure care in the
outpatient cardiology practice setting: findings from IMPROVE HF.
Circ Heart Fail 2008;1:98 –106.
2. Bang HO, Dyerberg J. Plasma lipids and lipoproteins in Greenlandic
west coast Eskimos. Acta Med Scand 1972;192:85–94.
3. Lavie CJ, Milani RV, Mehra MR, Ventura HO. Omega-3 polyunsaturated fatty acids and cardiovascular diseases. J Am Coll Cardiol
2009;54:585–94.
4. Witte KK, Clark AL. Marine polyunsaturated fatty acids in heart
failure: are the theoretical benefits matched by the clinical data? Pol
Arch Med Wewn 2009;119:162–9.
5. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids
and vitamin E after myocardial infarction: results of the GISSIPrevenzione trial. Lancet 1999;354:447–55.
6. Macchia A, Levantesi G, Franzosi MG, et al., GISSI-Prevenzione
Investigators. Left ventricular systolic dysfunction, total mortality, and
sudden death in patients with myocardial infarction treated with n-3
polyunsaturated fatty acids. Eur J Heart Fail 2005;7:904 –9.
7. Mozaffarian D, Bryson CL, Lemaitre RN, Siscovick DS. Fish intake
and risk of incident heart failure. J Am Coll Cardiol 2005;45:2015–21.
8. Dijkstra SC, Brouwer IA, van Rooij FJ, et al. Intake of very long chain
n-3 fatty acids from fish and the incidence of heart failure: the
Rotterdam Study. Eur J Heart Fail 2009;11:922– 8.
9. Yamagishi K, Iso H, Date C, et al. Fish, omega-3 polyunsaturated
fatty acids, and mortality from cardiovascular diseases in a nationwide
community-based cohort of Japanese men and women the JACC
(Japan Collaborative Cohort Study for Evaluation of Cancer Risk)
study. J Am Coll Cardiol 2008;52:988 –96.
JACC Vol. 57, No. 7, 2011
February 15, 2011:880–3
10. Yamagishi K, Nettleton JA, Folsom AR, et al. Plasma fatty acid
composition and incident heart failure in middle-aged adults: the
Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J
2008;156:965–74.
11. The GISSI-HF investigators. Effect of n-3 polyunsaturated fatty acids in
patients with chronic heart failure (the GISSI-HF trial): a randomized,
double-blind, placebo-controlled trial. Lancet 2008;372:1223–30.
12. Ghio S, Scelsi L, Latini R, et al. for the GISSI-HF investigators.
Effects of n-3 polyunsaturated fatty acids and of rosuvastatin on left
ventricular function in chronic heart failure: a substudy of GISSI-HF
trial. Eur J Heart Fail 2010;12:1345–53.
13. Nodari S, Triggiani M, Campia U, et al. Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional capacity in
Tang and Samara
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883
patients with dilated cardiomyopathy. J Am Coll Cardiol 2011;57:
870 –9.
14. Ahmed A, Allman RM, Fonarow GC, et al. Incident heart failure
hospitalization and subsequent mortality in chronic heart failure: a
propensity-matched study. J Card Fail 2008;14:211– 8.
15. Tang WH, Francis GS. Statin treatment for patients with heart
failure. Nat Rev Cardiol 2010;7:249 –55.
16. Røysland R, Masson S, Omland T, et al. Prognostic value of
osteoprotegerin in chronic heart failure: the GISSI-HF trial. Am
Heart J 2010;160:286 –93.
Key Words: functional capacity y heart failure y n-3 PUFAs y
nonischemic cardiomyopathy y NYHA functional class.