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1Lipides Membranaires et Fonctions Cardiovasculaires, Institut National de la Recherche Agronomique-UR1154, Faculté de Pharmacie, Université Paris-Sud, 92290 Châtenay-Malabry;2Laboratory of Experimental Cardiovascular Pathophysiology and Pharmacology, Faculté de Médecine, 21033 Dijon, France; and 3Department VFHF, F. Hoffmann-La Roche, 4070 Basel, Switzerland
Submitted 25 July 2002 ; accepted in final form 26 December 2002
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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hypertension; nutrition; prevention; telemetry; heart
Fish oils are rich in the long-chain n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). DHA and EPA have antiatherogenic actions, are beneficial in experimental myocardial infarctions, prevent arrhythmias (3, 31), and have a positive effect on mortality in human coronary heart disease (13). Dietary fish oil has also been shown to prevent hypertension (17). In previous studies, our laboratory reported that dietary purified n-3 PUFA can help to prevent the rise of blood pressure in a psychosocial stress model in rats (42) and in the Goldblatt 2K, 1C hypertension model (41). However, it remains to be clarified which one of the n-3 PUFAs (EPA or DHA) is more potent in the prevention of cardiovascular diseases. EPA has been thought to produce its beneficial cardiovascular effects through a stimulation of prostaglandin action (which influences vasodilatation and platelet aggregation), whereas DHA may be cardioprotective via its antiarrhythmic capacity (43). This study was designed to investigate, by continuous clinical evaluation in rats, the separate actions of EPA and DHA in the lowering of blood pressure and the prevention of cardiac dysfunction in a HI rat model.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Pathophysiological model. Male Wistar rats were obtained from IFFA CREDO (a Charles River company providing laboratory animals; Les Oncins, France) at 8 wk of age and divided into six groups. One-half of the rats, designated the control group, were fed a balanced semipurified gel diet containing cornstarch + sucrose as the carbohydrate sources.
The second half of the animals, designated the HI group, was fed a 62% fructose diet. Each group was further divided into three subgroups: one group receiving a normal fat diet (NFD group), another group receiving the same fat diet supplemented with EPA (EPA group), and the last group receiving the same fat diet supplemented with DHA (DHA group).
Diets. The rats were fed ad libitum a semipurified gel diet (39) in accordance with the recommendations of the American Institute of Nutrition (1993) and the Nutrient Requirements of Laboratory Animals (1995). The meal was prepared to form a jellied mass, cut into cubes for feeding, stored at –20°C, and distributed daily to maintain moisture content. The base fabricated diet was composed of soy protein isolate (140 g/kg, ICN 905456), L-cystine (1.8 g/kg), gelatin (50 g/kg), lipids (80 g/kg), a salt mixture (40 g/kg, ICN 960401), a vitamin mixture (10 g/kg, ICN 960402), choline bitartrate (2 g/kg), cellulose (50 g/kg), and either starch (526.2 g/kg) + sucrose (100 g/kg) for the control groups or fructose (626.2 g/kg) for the HI groups. In the NFD groups, the lipid part (80 g/kg) was composed of 40 g/kg cocoa butter (CACAO BARRY) and 40 g/kg sunflower seed oil (Fruidor). In the n-3 PUFA-supplemented groups (DHA and EPA groups), the lipid part (80 g/kg) was composed of 40 g/kg cocoa butter, 30.4 g/kg sunflower seed oil, and 9.6 g/kg either DHA or EPA, respectively, supplied as purified ethyl esters (Hoffmann-LaRoche; Basel, France). The fatty acid composition of the diets (Table 1) shows the characteristic trends of the three diets, poor in n-3 PUFAs (NFD diet), rich in EPA (EPA diet), or rich in DHA (DHA diet), with roughly similar contents in saturated fatty acid (SFA; 30%), monounsaturated fatty acid (MUFA; 30%), and PUFA (40%).
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Measurement of blood pressure and ECG. Blood pressure was measured
using either the tail-cuff technique or telemetry. The tail-cuff technique was
used each week in the three control groups (n = 6) and three HI
groups (n = 6). Each rat was trained to the tail-cuff technique 2
days before each measurement. The measurements were achieved with a
Physiograph Desk Model and an Electro-Sphygmomanometer (Roucaire; Paris,
France). Five separate measurements were made on conscious rats in a
restraining box heated at 40°C, with the cuff and the pulse-wave
transducer set around the tail 
15 min before measurements.
The telemetric transmitter (TL11M2-C50-PXT, DSI; St. Paul, MN) was
surgically implanted in the abdominal cavity of the HI rats (n = 6).
Blood pressure measurements were made using a floating catheter (0.7 mm
internal diameter and packed at the tip with gel to prevent thrombus
formation), which was inserted 10 mm retrograde directly in the abdominal
aorta and which was maintained by a drop of surgical glue (not by a ligature)
to allow for regular blood flow. A pair of subcutaneous electrodes were
inserted and fixed beneath the skin at the basis of the right forelimb and the
left hindlimb to record the electrocardiogram (ECG) in a derivation similar to
lead II in humans. Blood pressure, ECG, and total rat motion were received
individually through specific Physiotel receivers (RLA1020, DSI) located under
each cage and continuously recorded on a 2100 Mo FAST SCSI hard disk before
analysis by the specific Dataquest IV program (DSI). Blood pressure and heart
rate were monitored for 5 wk in unrestrained conditions at 10-min intervals
continuously for 3 days each week, starting 1 wk after surgery. The digital
signals of blood pressure were sampled for 10 s every 10 min. This monitoring
resulted in >2,500 measurements per parameter for each rat. The first
treatment was carried out to separate the night recordings (corresponding to
the rat activity period) from the day recordings (corresponding to the rat
resting period). The stressful (2 h) periods of transition between night/day
and day/night were removed. The pathological evolution of blood pressure was
expressed as the individual linear regression over 5 wk. The heart rate was
studied as the difference between the last week and the initial data. To study
the ECG, we selected the period of least activity (identified as a zero
activity), which was always at the same time during the day and night. The
same person analyzed all ECG records. Because the length of the QT interval is
rate dependent, the QT analysis was realized on the transformed parameter
QTc according to the following formula of Bazett:
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Biochemical investigations. At the end of the experiment, the rats were killed by bleeding under anesthesia (50 mg/kg pentobarbital). The blood was collected for serum biochemistries after an 8-h fast. Triglycerides (TG) and cholesterol were determined by spectrophotometry according to the procedures described in kits (Sigma Diagnostics Triglycerides-Int and Sigma Diagnostics Cholesterol, Sigma, respectively). Insulinemia was determined by radioimmunology using the kit Insulin-CT 100 In Vitro test, whereas glycemia was just measured using an automat One Touch.
The heart, adrenals, and kidneys were withdrawn and rinsed with saline. The organs were weighed and stored at –20°C in CHCl3-MeOH (2:1) to determine their fatty acids profile or frozen at –80°C for the assessment of catecholamine content. The catecholamines were extracted from heart and adrenals in a solution containing EDTA (1 g/l), 70% HClO4 (35 ml/l), and dihydroxybenzylamine (0.5 mg/l for hearts and 10 mg/l for adrenals as the internal standard) and analyzed as previously described (10). After centrifugation (20 min, 1,300 g, 4°C), the supernatants were collected on activated alumina in Tris-EDTA-glutathione buffer (pH 8.6), and the catecholamines were eluted with perchloric acid and analyzed by HPLC coupled to electrochemical detection (42). The lipids were extracted from the heart and kidneys in 2:1 chloroform-methanol (12). Phospholipids (PL) were separated from nonphosphorous lipids (NL) on silica acid cartridges (22), and the fatty acids were trans-methylated with BF3-methanol (34). Methyl esters were analyzed by gas chromatography on an Econo-Cap EC-WAX capillary column (0.32 x 30 m, Alltech Associates) coupled to a flame ionization detector using C17:0 as the internal standard.
Statistical analysis. Morphological and biochemical data are expressed as means ± SE and analyzed by two-way ANOVA with one or two fixed factors among diet (NFD, EPA, or DHA), pathology (control vs. HI), and day vs. night variability. When significantly different, the means were further compared by one- or two-factor Neuman-Keuls test (7). For the telemetry-derived blood pressure measurements, a linear regression was carried out to determine the mean blood pressure progression per day (or per night) for each rat. A two-way multivariate ANOVA was then carried out on the 1,080 values per rat per parameter per period to take into account all the pressure parameters in each rat and to compare the individual blood pressure progression. The blood pressure data obtained by tail cuff were submitted to two-way ANOVA using diet and pathology as fixed factors. The heart rate was recorded by telemetry, and the data were subjected to linear regression of the evolution of cardiac frequency. Unfortunately, the individual variance due to environmental factors was so large that it masked any other changes that may have been induced by the pathology under investigation. This prevented the statistical analysis of these parameters. For this reason, all heart rate data were pooled to obtain an average value for the day and an average value for the night for each rat. Differences in these values among the groups were tested by ANOVA. The data collected for ECG were submitted to the same analysis.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Biochemical data. Table 3 summarizes the effect of fructose and/or PUFA supplementation on several biochemical parameters. Compared with the control rats, the non-insulin-dependent rats exhibited HI associated with normoglycemia. These parameters were not influenced by dietary PUFAs, as in control rats. The insulin resistance induced a significant increase in plasma TGs, but no alteration in total plasma cholesterol. In both HI and control rats, the n-3 PUFA intake had no effect on TGs. Conversely, both EPA and DHA significantly reduced plasma total cholesterol in HI and control rats.
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Neither the dietary PUFA intake nor the fructose-induced diabetes affected
epinephrine, norepinephrine, and dopamine content of the adrenal gland (data
not shown). In the heart, only norepinephrine could be detected. Epinephrine
and dopamine content were below the detection limits. The amount of cardiac
norepinephrine was significantly higher (20% increase in ng/g) in HI rats
irrespective of the diet. This increase could not only be attributed to
cardiac hypotrophy. In the control groups, the cardiac norepinephrine content
was slightly lower in EPA- and DHA-fed rats, although this did not achieve
statistical significance. This tendency for difference was not apparent in the
HI rats.
Fatty acid composition. The fatty acid composition of the total
lipid fraction of plasma is presented in
Table 4. The diet significantly
affected the plasma PUFAs mainly by increasing circulating EPA in the EPA-fed
rats and DHA in the DHA-fed rats. Interestingly, the development of insulin
resistance itself was associated with large alterations of the fatty acid
composition. This included a significant decrease in arachidonic acid, EPA,
and DHA, which resulted in a general decrease in circulating PUFA irrespective
of the diet (no significant cross-interaction for 
PUFAs, n-6
PUFAs, and n-3 PUFAs; Table
4). Interestingly, this decrease in PUFA content was balanced for
the most part by a significant increase in total MUFAs and a slight
modification in total SFAs.
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The fatty acid composition of the cardiac PL fraction was also determined (Table 5). SFAs and MUFAs were only weakly affected by n-3 PUFA supplementation. Conversely, the diet strongly altered the PUFA content in heart PLs. Dietary DHA strongly increased the myocardial DHA content. However, dietary EPA induced only a small increase in EPA (always low in cardiac membranes) and a greater increase in its elongated metabolite docosapentenoic acid (22:5 n-3). Dietary EPA failed to significantly increase the content of DHA in the heart. In both groups, the increase in n-3 PUFA was balanced by a significant decrease in arachidonic acid, which was significantly more pronounced in the DHA-fed groups. The development of insulin resistance did not noticeably alter the cardiac PL fatty acid composition except for the DHA content, which was, irrespective of the diet, slightly higher in the HI group than in the corresponding control. These results explain the significant effects of both the fructose diet and PUFA intake and the absence of cross-interaction between these two factors.
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Blood pressure. Blood pressure was followed continuously by
telemetry over a 5-wk period in the three groups of HI rats. The increase in
blood pressure increase, as recorded with this nonstress technique, was
moderate in this model (10 mmHg over 5 wk) compared with the usual
tail-cuff technique. A multivariate ANOVA was carried out to take into account
the linear regression of all of the blood pressure parameters in each rat to
evaluate the progression of blood pressure in each separate rat. The mean of
the data obtained from all of the rats is shown in
Fig. 1 for each group. This
model of HI is characterized by an increase in blood pressure of
0.15–0.20 mmHg/day in each rat. The increase was similar during the day
(resting period) and the night (activity period). The dietary n-3 PUFA
supplementation slowed the development of hypertension. The effect of EPA and
DHA appeared to be more pronounced on diastolic pressure than on systolic
pressure, although the statistical approach did not allow for a
differentiation of these two parameters. The lack of significant
cross-interaction between the two factors indicates that the effect of EPA and
DHA on hypertension development was similar during day and night. This
beneficial effect of dietary PUFAs on hypertension development was confirmed
at week 5 by using a tail-cuff sphygmomanometer
(Fig. 2). The values determined
for blood pressure were obtained only during the day and were much more
elevated than the values recorded by telemetry due to the stress associated
with the tail-cuff technique. In all of the dietary groups, the control rats
displayed a constant and low blood pressure of 116.3 ± 3.33 mmHg
in the same conditions. At the same time, the blood pressure was significantly
higher in the HI groups. However, this increase in blood pressure was
significantly attenuated in the EPA and DHA groups (132.5 ± 1.12 and
133.3 ± 1.67 mmHg, respectively) compared with the NFD group (142.5
± 1.12 mmHg).
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Heart rate. The heart rate was recorded throughout the study in the HI rats, and the individual linear regression of cardiac frequency in separate rats over time was determined. All of the rats displayed a very similar heart rate at the beginning of the study. The development of insulin resistance was associated with a slight increase in heart rate after 5 wk into the study. This was affected during daytime as well as nighttime (Fig. 3). The increase in heart rate was observed in the NFD-fed rats and the EPA-supplemented rats. However, no increase in heart rate could be observed in the DHA-supplemented rats. In this group of HI rats, the heart rate remained constant between weeks 0 and 5 during the activity period. A slight decrease could even be observed during the resting period. A moderate but significant decrease in overall activity in HI rats was detected (data not shown), which could account for the slight decrease in heart rate.
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ECG. The ECG was continuously recorded in the HI rats during the whole experiment. The difference in heart rate between day and night was shown on the ECG by a shortened R-R interval during the active night period compared with the resting day period. The data collected from the ECG were analyzed by ANOVA, which confirmed that the heart rate was significantly lower in the DHA group than in the NFD and EPA groups in both the day and night periods (data not shown). None of the treatments applied in this study influenced the PR interval significantly (data not shown). However, because the length of the QT interval is rate dependent and our results indicated an effect of diet on heart rate, QT intervals were monitored. QT analyses were made on the QTc because it takes into account the rate variations. The QTc was longer during the night than during the day (Fig. 4). There was a significant difference in the linear regression values for separate rats (P < 0.01) between the DHA group and the NFD and EPA groups, but there were no significant cross-interactions between diet and time (data not shown). However, after 5 wk of dietary supplementation, the QTc segment was significantly shorter in the DHA rats than in the two other groups during both day and night (Fig. 4).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Insulin resistance has been shown to be accompanied by an increase in plasma TGs (19). This was also observed in our study. Surprisingly, we did not observe any significant decrease in plasma TGs in the rats fed n-3 PUFAs, contrary to data reported in human clinical studies (4, 44, 47). In humans, this effect is usually attributed to EPA (13, 49), and, in this study, plasma TGs were lower in the EPA group, although this difference was not significant. Our study may not have been long enough to allow the observation of a significant TG decrease. However, species specificity cannot be ruled out. The decrease in cholesterol levels due to n-3 PUFAs that is observed in rats (as in this study) has not been duplicated in humans (13). The recommendation of fish oil for the diabetic population is, therefore, more often based on their effect on TGs than on a supposed effect on glucose metabolism (43).
Chronic feeding with diets high in fat or glucose was shown to increase blood pressure and enhance sympathetic activity in rats (23). This activation of sympathetic activity has been demonstrated during a HI, euglycemic clamp (33). In rats fed 66% fructose, clonidine prevented hypertension but not the insulin resistance associated with fructose feeding. Reaven et al. (40) have suggested that the HI in this model may stimulate sympathetic nervous system activity that contributes to the hypertension but not to insulin resistance. Thus HI may enhance both blood pressure and sympathetic activity in the rat. Our results demonstrated an increased cardiac norepinephrine content in HI rats compared with controls, a result that may reflect the sympathetic hyperactivity associated with this model. Clearly, insulin is an important signal connecting dietary intake to sympathetic nervous system (25).
In fructose-fed rats, we observed a significant decrease in PUFA content,
balanced by a MUFA and SFA increase. This decrease in PUFAs involved all of
the functionally important C20 and C22 fatty acids, including arachidonic
acid, EPA, and DHA. Dietary supplementation with EPA or DHA improved the n-3
PUFA status even in the fructose-fed rats, but worsened the arachidonic acid
status associated with insulin resistance. These observations are in agreement
with data reported in diabetic patients
(2). Cardiac membranes are very
sensitive to dietary-induced modifications of fatty acid composition
(3). In this study, like in
another (3), the dietary DHA
intake induced a large increase in DHA incorporation in cardiac PLs in the
control rats, balanced by a large arachidonic acid decrease. Conversely,
although dietary EPA supplementation resulted in a slight increase in EPA and
DPA in cardiac PLs and a slight reduction in arachidonic acid, it failed to
significantly increase the cardiac DHA content. The effects of EPA and DHA
dietary intake in HI rats were roughly similar to those of control rats, with
a large improvement of DHA status by DHA intake but not by EPA intake. In the
same model, both EPA and DHA were reported to increase 20:5 n-3, 22:5 n-3, and
22:6 n-3 and to decrease 20:4 n-6 in membranes
(43). However, although
cardiac membranes do accumulate both 20:4 n-6 and DHA, they incorporate very
little of the EPA compared with other tissues (platelets, the liver, and
kidneys) (30,
35). Moreover, dietary DHA
(but not EPA) also slightly increased the cardiac linoleic acid content. DHA
has been thought to stimulate the conversion of 18:2 n-6 into 20:4 n-6 by
decreasing 
6-desaturase activity
(21), which may explain the
increased 18:2 n-6 and decreased 20:4 n-6 in the HI rats fed a DHA diet
(38).
Although strongly affected by dietary PUFAs, insulin resistance did not
significantly influence the cardiac membrane profile. This is unlike other
organs such as the liver, kidneys, and adrenal glands (data not shown). Unlike
Type 1 diabetic rats induced by streptozotocin treatment (insulin-dependent
diabetes) (18,
24), HI rats in this study did
not display increased 18:2 n-6 in cardiac membranes. This suggests that the
decreased 6-desaturase activity observed in insulin-dependent rats did
not occur in insulin-resistant rats, or, alternatively, it may occur later.
However, because HI does affect the PUFA status of cardiac membranes in this
study, it should be noticed that supplementation with purified n-3 PUFA
maintained the n-3 PUFA status in HI rats. This is in accordance with the
specific requirement of the Type 1 diabetic heart for DHA
(32). Our results suggest,
therefore, that, although some fundamental differences do exist, Type 1
diabetes and insulin resistance may have some similarities in affecting n-3
PUFA incorporation into cardiac membrane. Insulin resistance is an additional
risk factor for the n-3 cardiac status, inducing a deficit in n-3 PUFA or a
high n-6-to-n-3 ratio
(45).
Fructose-induced hypertension in rats is a common model that has been used to investigate the relationship among HI, insulin resistance, and increased blood pressure. The results presented here show a 25-mmHg increase of blood pressure as measured by tail cuff in the HI rats compared with control rats 5 wk after the beginning of the dietary intervention. This response is similar to that reported in similar experimental conditions using indirect measurements of blood pressure (48). The use of telemetry, which allows for a constant monitoring of the cardiovascular hemodynamic variables (blood pressure and heart rate) without manipulation of the rats, offers a higher sensitivity and accuracy for detecting blood pressure changes. The blood pressure values recorded by telemetry were significantly lower than those recorded by tail cuff. However, irrespective of the method for measuring blood pressure, the HI rats fed either EPA or DHA exhibited a lower blood pressure than did the HI rats fed a nonsupplemented fat diet. This effect of n-3 PUFAs was observed as the blood pressure rose over time, as the calculated mean gain per 24 h, or after 5 wk. Interestingly, the prevention of the rise in blood pressure by n-3 PUFAs appears to be more pronounced for diastolic pressure than for systolic pressure. However, this is not statistically significant perhaps because of the large variability (means ± SE). The rat blood pressure is higher during the night, the period of activity, than during the day, when the rat is mainly sleeping. In the collected data, these two periods were examined separately and were always significantly different. However, neither the fructose diet nor the preventive effect by n-3 PUFAs could affect the differences between day and night. Moreover, all the dietary effects observed on blood pressure were similar between the EPA and DHA groups. These results clearly show that the effect of n-3 PUFAs in preventing the rise in blood pressure cannot be specifically attributed to either EPA or DHA but appears to be an effect of either PUFA.
The chronic increase of insulin is known to induce an increase in heart
rate (33), which was also
observed in the present study. This increase occurred in the HI rats fed both
the NFD and the EPA-supplemented diet, with a larger amplitude during the
activity period than during the resting period. On the contrary, the heart
rate remained unchanged in the DHA group during the activity period, and we
even observed a slight decrease during the resting period. The rise in heart
rate during acute and chronic HI is often associated with an increase in
cardiac output (15,
27). Supraphysiological levels
of insulin increase cardiac contractility, as reflected by increased left
ventricular dP/dt
(15). Unlike the blood
pressure results, the effect of n-3 PUFA on heart rate was observed in the
DHA-fed rats but not in the EPA-fed rats. This specific effect of DHA can be
attributed to the presence of this fatty acid in cardiac membranes. With the
use of isolated cardiac myocytes, it was shown that the presence of DHA but
not EPA in the PLs decreases 
-agonist-induced cAMP production
(14). Moreover, in
postischemic conditions, high membrane DHA levels strongly decrease the
biochemical response to catecholamines
(8), an effect that mimics the
effects obtained with -blockers. The involvement of DHA in the
regulation of the -adrenergic transduction mechanism may explain its
effect on heart rate control in HI rats in vivo. In a previous study
(42), involving a psychosocial
stress in rats, our laboratory reported a reduction of cardiac contractility
in DHA-fed rats that could also be related to adrenergic regulation. The
continuous analysis of ECG in HI rats revealed a significant increase of R-R
interval length in DHA-fed rats, which confirmed the decreased heart rate. A
similar result was reported in sucrose-fed diabetic rats
(16). Another result of the
present study is the DHA-induced reduction of QT interval in HI rats. Again,
this effect was observed with DHA but not with EPA. The diabetic heart is
known to present a delayed afterdepolarization characterized by a longer QT
interval. This early dysfunction is viewed as representative of the gradual
change in the diabetic heart, i.e., cardiomyopathy with fibrosis and left
ventricular hypertrophy (36).
These characteristics are thought to be as an important component to explain
the high risk of ventricular arrhythmias and sudden death observed in diabetic
patients (6). The circadian
variations of the QT interval and its heart rate dependency have been
investigated, and it was shown recently that the daytime rate dependence of
the QT interval is decreased with -blocker therapy. This result suggests
the influence of the sympathetic nervous system on the rate dependence of
ventricular repolarization
(11). Again, the relationship
of DHA with the regulation of cardiac adrenergic system may account for the
effect of DHA on the QT interval observed here in vivo in HI rats. Moreover,
the QT interval is representative of the transmembrane ion channel activity
that is dependent, in part, on modifications of cardiac plasma membrane
composition. Previous results have shown that the incorporation of DHA into
the plasma membrane can modulate Ca2+ channels
(9) and Na+ channels
(26) to prevent arrhythmias
(29).
In conclusion, the present study demonstrated that dietary EPA and DHA
intake could not improve insulin resistance induced by high-fructose intake in
rats. However, the circulatory (or vascular) and cardiac consequences of
insulin resistance could be partly prevented by the fat intake. Both EPA and
DHA were efficient in vivo in delaying and decreasing the rise in blood
pressure, suggesting a positive effect in the prevention of hypertension
associated with HI. Moreover, DHA, which readily incorporates in cardiac
membranes, was able to prevent the increase in heart rate and QT interval
length also associated with insulin resistance. The mechanism of this effect
may be related to the regulation of cardiac adrenergic function by membrane
DHA. Although this -blocker-like activity was often suggested from in
vitro studies, the present results provide indirect in vivo arguments. The
results of this study demonstrate that purified n-3 PUFAs mimic the
cardiovascular actions of fish oils and imply that DHA may be the principal
active component conferring cardiovascular protection.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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