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© 2007 American Society for Nutrition J. Nutr. 137:2377-2383, November 2007

Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

(n-3) Long Chain PUFA Dose-Dependently Increase Oxygen Utilization Efficiency and Inhibit Arrhythmias after Saturated Fat Feeding in Rats1

Salvatore Pepe2,* and Peter L. McLennan3

2 Department of Surgery, Monash University, and Department of Cardiothoracic Surgery, Alfred Hospital, Melbourne, Australia; and 3 Division of Medical Sciences, Graduate School of Medicine, University of Wollongong, Australia

* To whom correspondence should be addressed. Email: salvatore.pepe{at}med.monash.edu.au.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Methods
 Results
 Discussion
 LITERATURE CITED
 
Fish oil (FO) modifies cardiac membrane phospholipid fatty acid composition to confer increased efficiency of oxygen utilization and antiarrhythmic effects. We tested the capacity of low-dose increments of FO, rich in (n-3) PUFA, to reverse the detrimental pro-arrhythmic and inefficient oxygen usage effects of dietary saturated fat (SAT) [including high ratio of (n-6) PUFA:(n-3) PUFA] during ischemia and reperfusion. Wistar rats were fed an SAT-enriched diet (15.3% fat, including 12% SAT, added by weight) for 6 wk and were then divided into 4 groups (n = 10/group) fed that diet or a 12% fat diet containing 3, 6, or 12% FO in place of SAT for 6 wk. Paced (300/min), erythrocyte-perfused isolated working hearts were subjected to low coronary flow ischemia (15 min) and were then reperfused. At normoxic baseline, external work capacity increased marginally at 6 and 12% FO; however, marked dose-related reductions in oxygen consumption were evident due to FO-dependent reduction in oxygen-energy utilization efficiency and associated reductions in coronary flow and oxygen extraction. Postischemic recovery resulted in lower oxygen consumption, greater oxygen-energy utilization efficiency, reduced coronary release of creatine kinase, and reduced incidence of arrhythmias in all FO groups compared with the SAT group. FO at a dose as low as 3% of total fat dietary supplement effectively reversed the high oxygen requirements and pro-arrhythmic effects of a SAT-rich diet even with continued consumption of SAT (9%) in this ex vivo animal model.


   Introduction
TOP
 ABSTRACT
 Introduction
Methods
 Results
 Discussion
 LITERATURE CITED
 
Considerable research has focused on the clinical actions of (n-3) PUFA to lower plasma triglyceride levels, lower systemic blood pressure, and regulate the function of platelets, monocytes, macrophages, arterial, and endothelial cells to reduce the incidence of atherosclerosis and thrombosis (1–4). However, many of the specific effects of (n-3) PUFA on cardiovascular risk factors are modest and can only be achieved with high dietary intake. One important exception is a direct effect of (n-3) PUFA on cardiac function, in particular the prevention of fatal cardiac arrhythmia (5–7). Whereas animal studies have clearly established the antiarrhythmic properties of fish oil (FO)4 (8–16), we recently further demonstrated that (n-3) PUFA, through their incorporation into myocardial membranes, reduce cardiac oxygen consumption per unit work, thereby increasing the efficiency of cardiac metabolism and delivering an increased coronary vasodilator reserve (17). Notably, the hearts isolated from rats fed (n-3) PUFA were afforded protection against ischemia-reperfusion injury, permitting enhanced postischemic recovery of ventricular contractility and cardiac output while limiting postischemic increases in oxygen demand (17). A further consequence was the sustained integrity of mitochondrial calcium homeostasis and NADH supply for cardiac ATP synthesis during oxidative phosphorylation (18). Cellular calcium handling is further implicated in prevention of both postmyocardial infarction sudden death (19) and cardiac arrhythmia in isolated heart (16) after prolonged FO feeding in rats and involves altered protein kinase activity and reduced sarcoplasmic reticulum ryanodine receptor activation (17,19). These cardiac cell-signaling and substrate-altering effects are important elements that may underlie the clinical cardiovascular protective effects of dietary FO.

Although these studies clearly show that a diet rich in FO can produce a different physiological and metabolic profile in the isolated working heart compared with that achieved with a saturated fat (SAT)-rich diet, the doses [30–40% of dietary fat by weight as long chain (n-3) PUFA] far exceed human intakes. It has not been determined whether similar effects can be achieved with smaller proportions of FO fatty acids. Moreover, most studies begin FO feeding at or shortly after weaning and the reversibility of the lifetime habits (and associated detrimental effects of dietary SAT) has not been considered. Therefore, the aim of the current study was to test the capacity of low doses of (n-3) PUFA-rich FO [low ratio of (n-6) PUFA:(n-3) PUFA] to reverse the detrimental pro-arrhythmic and metabolic effects of dietary SAT [high ratio of (n-6) PUFA:(n-3) PUFA] in isolated working hearts from rats. In doing so, we also employed dietary crossover replacement with a shorter feeding period of 6 rather than 16 wk.


   Methods
TOP
 ABSTRACT
 Introduction
 Methods
Results
 Discussion
 LITERATURE CITED
 
    Animals, diets, and design. Male Wistar rats were fed a SAT-enriched diet for 6 wk. The animals were then randomly assigned to 1 of 4 groups (n = 10/group) in which they continued to eat a diet supplemented with 12% fat by weight consisting of either: 1) 12% SAT; 2) 3% FO 9% SAT; 3) 6% FO 6% SAT; or 4) 12% FO for a further 6 wk. The diets were prepared as previously reported (16) by adding fat to the dry mix components of unrefined commercial rat feed pellets (Milling Industries) containing as dry mixture 3.7% fat, 20% protein, 55% carbohydrate, 12% moisture, and 5% crude fiber. The residual fat in the dry mix was present in the crude carbohydrate (grains) and protein (soy, meat, and fish meal) sources. Fat was added at the rate of 12 g/100 g dry diet and the final fat concentration was 15.3 g/100 g (with an energy value of 18.5–19.3 kJ/g by combustion calorimetry). The individual diets were prepared by adding to the dry mix 12 g/100 g of sheep perirenal fat [0% FO (SAT)], 12 g/100 g purified FO (Shaklee eicosapentaenoic acid) (12% FO), or a blend of FO with sheep perirenal fat to a total of 12% fat addition (3 and 6% FO diets). The final formulated diets had fatty acid compositions expressed as a percentage of total dietary fatty acids (Table 1). The diets were designed for a dose increase in (n-3) PUFA and a proportional decrease in SFA with minimal differences in monounsaturated fatty acids and (n-6) PUFA. The FO also included 1 g/100 g of the antioxidant all-rac-{alpha}-tocopherol, 21 µg/g retinol palmitate, and 1 µg/g cholecalciferol. d-{alpha}-Tocopherol was added to the SAT and blended FO diets to the same level as the 12% FO diet. All diets contained 0.05 g/100 g butylated hydroxytoluene to prevent peroxidation of fats during storage. All diets were stored below 4°C following pelleting and drying and new diet was prepared every 14 d.


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  		TABLE 1 Fatty acid composition of rat diets

 
Rats were 6 mo old (~400 g body weight) at the time of isolated heart experiments. Body weights did not differ between the dietary groups. Rats were food deprived overnight prior to each experimental day and the experimenter was unaware of the dietary history of the rat under investigation. Animal care and experiments were conducted with the approval of the local animal ethics committee according to the guidelines of the National Health and Medical Research Council, Australia, Australian Code of Practice for the Care and Use of Animals for Scientific Purposes (20).

    Isolated working heart preparation and perfusion protocol. Rats were anaesthetized (pentobarbitone sodium 60 mg·kg–1) and killed by cervical dislocation. Isolated hearts were prepared for working heart perfusion at 37°C (maintained afterload ischemia configuration) with the erythrocyte buffer (washed porcine blood cells, hematocrit = 0.40), perfused and monitored as described in detail previously (17,21). Briefly, hearts were cannulated by the aorta for initial Langendorff-mode perfusion, the left atrium for working heart perfusion and the pulmonary artery for coronary venous collection. Erythrocyte-perfused working heart mode was commenced (coronary perfusion pressure, preload, and afterload set at 75, 10, and 75 mm Hg, respectively) with right atrial pacing (300 beats/min). After hearts had equilibrated and were stabilized, measures of cardiac output, aortic pressure, arterial and venous blood gas content, and pH were taken every 5 min for the entire perfusion. After equilibration, low-flow global ischemia was induced by reducing coronary perfusion pressure to 35 mm Hg (maintaining 75 mm Hg afterload) and maintained for 15 min followed by reperfusion at a coronary perfusion pressure of 75 mm Hg. Arterial and venous perfusate samples were measured under control conditions at the end of 15 min of ischemia and after 5 min of reperfusion. Oxygen tension and pH were analyzed in the arterial and coronary venous samples. Erythrocytes were separated by centrifugation (800 g) and the sample supernatant was frozen in liquid nitrogen and stored at –80°C until analysis.

    Cardiac arrhythmia. Arrhythmias were assessed during the first 5 min of reperfusion from a continuous recording of the whole heart electrocardiogram as previously reported (16). Arrhythmias were recorded as: 1) number of ventricular premature beats (VPB) defined as discrete QRS complexes that were premature in relation to the P wave; 2) the incidence and duration of ventricular tachycardia (VT) defined as 4 or more consecutive VPB of similar morphology; and 3) the incidence and duration of ventricular fibrillation (VF), defined as an electrocardiogram signal from which QRS deflections are no longer distinguishable and no sinus rhythm can be accurately measured (distinct from the flat signal of asystole in which no sinus rhythm is evident).

    Analysis of coronary venous effluent. Arterial and venous samples were also assayed for creatine kinase (CK), lactic acid, and K+ concentrations as previously described (17,21). CK was quantified according to the rate of change of absorbance per minute. Whole heart release of CK was adjusted according to coronary flow rate and expressed in U·min–1·g dry ventricle–1. Lactic acid wash-out was adjusted according to coronary flow rate and expressed in µmol·min–1·g dry ventricle–1. For determination of K+ ion concentration, all samples were assayed by flame photometry and results were expressed in micromoles per liter.

    Data handling and statistical analysis. Myocardial left ventricular external work, the pressure-time integral, incidence of reperfusion arrhythmias, perfusate oxygen content, oxygen extraction, myocardial oxygen consumption, and percentage oxygen-energy utilization efficiency were calculated as previously described (17,21). Results were expressed as means ± SD. For each parameter, the effects of ischemia/reperfusion and dietary treatment were tested by 2-way repeated measures ANOVA with individual between-dose comparisons by Scheffé's post hoc F-test. The percentage of isolated hearts acutely exhibiting spontaneous, sustained VT or VF was scored during the first 5 min of reperfusion and group contrasts were tested by Fisher's exact test. Values were considered significantly different at P < 0.05.


   Results
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 ABSTRACT
 Introduction
 Methods
 Results
Discussion
 LITERATURE CITED
 
    Baseline normoxic perfusion. Small increases in external work were evident in hearts of rats fed the 6 and 12% FO diets compared with those fed SAT (P < 0.01) (Fig. 1A). This was accompanied by a marked reduction in oxygen consumption at the lowest supplemental intake of 3% FO (P < 0.0001) compared with SAT and small further reductions in myocardial oxygen consumption (P < 0.01) as the FO dose increased (Fig. 1B). The SAT hearts exhibited higher coronary flow than hearts of rats fed all doses of FO (Fig. 2A; P < 0.0001) and oxygen extraction was significantly lower in 6 and 12% FO hearts than in SAT hearts during baseline normoxic perfusion (Fig. 2B). Efficiency of use of oxygen to produce external work increased with each dose of FO (Fig. 1C; P < 0.001).


Figure 1
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  		FIGURE 1  External work (A), myocardial oxygen consumption (B), and cardiac oxygen-energy utilization efficiency (C) during normoxic baseline function of the erythrocyte-perfused, isolated working hearts of rats that consumed the SAT- or FO-supplemented diets for 6 wk. Values are means ± SD, n = 10. Bars without a common letter differ, P < 0.05.

 

Figure 2
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  		FIGURE 2  Effects of low-flow ischemia (15 min) and reperfusion on coronary flow (A), myocardial oxygen extraction (B), and myocardial oxygen consumption (C) in isolated working hearts of rats that consumed the SAT- or FO-supplemented diets for 6 wk. Values are means ± SD, n = 10. Means at a time without a common letter differ, P < 0.05. *Different from the previous time point, P < 0.05.

 
    Ischemia and reperfusion. As coronary perfusion pressure was uniformly set to 35 mm Hg to induce low-flow ischemia (21) in all groups, coronary flow rates were markedly reduced, leaving no significant differences between dietary groups during ischemia (Fig. 2A; P = 0.9). During low-flow ischemia, the percent oxygen extraction rose in all dietary groups (P < 0.0001), reaching >80% extraction in SAT hearts (Fig. 2B). The percent oxygen extraction during ischemia decreased with FO supplementation and was lower with each dose increase (P < 0.01). During reperfusion, the percent oxygen extraction was reduced slightly from ischemic levels in all dietary groups (P < 0.05). The postischemic percent oxygen extraction was lower in the 6 and 12% FO hearts than in SAT hearts (P < 0.01).

Cardiac output (Fig. 3A), external work (Fig. 3B), and oxygen-energy utilization efficiency (Fig. 3C) declined to very low levels in all groups during low-flow ischemia and recovery was depressed comparably in all dietary groups relative to preischemia. Recovery of cardiac output, external work, and efficiency of oxygen use were greater in the 12% FO hearts than the SAT hearts (P < 0.01). There was a dose-related increase in postischemic efficiency; hearts at all FO doses were more efficient than the SAT hearts (P < 0.01) and hearts at each successive dose level were more efficient than the previous dose (P < 0.01).


Figure 3
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  		FIGURE 3  Effects of low-flow ischemia (15 min) and reperfusion on cardiac output (A), myocardial external work (B), and cardiac oxygen-energy utilization efficiency (C) in isolated working hearts of rats that consumed the SAT- or FO-supplemented diets for 6 wk. Values are means ± SD, n = 10. Means at a time without a common letter differ, P < 0.05. *Different from the previous time point, P < 0.05.

 
Venous [H+] (Fig. 4A) and [K+] (Fig. 4B) increased during ischemia in all hearts (P < 0.0001). The pH fell to a lower level and [K+] increased to a higher level in the SAT hearts (P < 0.001) than in the FO-supplemented hearts, which were not significantly different from each other. Postischemic washout of lactate (Fig. 4C) and CK (Fig. 4D) occurred in all dietary groups compared with control perfusion (P < 0.001); however, in the SAT group, there was greater postischemic release of both lactate (P < 0.0001) and CK (P < 0.001) than in hearts of any FO-supplemented groups.


Figure 4
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  		FIGURE 4  Effects of low-flow ischemia (15 min) and reperfusion on coronary venous effluent: pH (A), [K+] concentration (B), cardiac lactate production (C), and cardiac CK release (D) in isolated working hearts of rats that consumed the SAT- or FO-supplemented diets for 6 wk. Values are means ± SD, n = 10. Means at a time without a common letter differ, P < 0.05. *Different from the previous time point, P < 0.05.

 
Arrhythmias, assessed as the number of VPB that occurred in the first 5 min of reperfusion, were fewer in hearts from rats fed any dose of FO compared with the SAT hearts (P < 0.05) (Table 2). Sustained VF (>30 s) was not evident in any group; however, transitory VF that spontaneously reverted within 5–10 s occurred in every SAT heart, but not in any of the FO groups (P < 0.0001) (Table 2). The incidence of VT was lower in all FO groups compared with the SAT group (P < 0.025) (Table 2).


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  		TABLE 2 Reperfusion arrhythmia incidence in hearts of rats fed SAT- or FO-supplemented diets for 6 wk1

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Methods
 Results
 Discussion
LITERATURE CITED
 
In this study, we have demonstrated that dietary (n-3) PUFA FO (as little as 3% of total fat intake) could significantly reduce myocardial oxygen consumption while maintaining integrity of contractile function, and it did so in rats prefed with a SAT-supplemented diet previously shown to increase oxygen consumption (17). During control working heart perfusion, cardiac output, contractility, external work, and the energy efficiency of hearts from rats supplemented with 12% FO was greater than in SAT hearts. In addition, coronary flow, percent oxygen extraction and myocardial oxygen consumption were significantly lower in 12% FO than in SAT hearts. These results confirm the earlier report following a 16-wk feeding (17,21) and complement and extend our previous findings from the open chest rat-coronary artery ligation model (13) to the erythrocyte–perfused, isolated working heart low-flow ischemia model, thus permitting insight into the effect of dietary crossover on ventricular performance and metabolism. Notably, this was a relatively short feeding period of 6 wk with younger rats compared with a 9-mo feeding of FO following crossover from the initial feeding with SAT-supplemented diet (9,13).

Cardiac function was marginally augmented in a dose-related manner with the increased proportion of FO in the diet. However, although increased cardiac work is usually associated with increased oxygen consumption, the myocardial oxygen consumption during all periods of perfusion was markedly reduced by every dietary FO dose.

Because the total dietary fat supplementation was maintained at 12% in all diets, each increase in dietary (n-3) fatty acids was achieved by a concomitant reduction in SFA. Thus, it may be speculated that the cardiac effects observed with increased dietary FO could be attributable simply to a reduced proportion of dietary SAT. Indeed, it is well established that SAT-rich dietary supplementation in animals is pro-arrhythmic (11,12,14,16). Sargent and Riemersma (22) observed in Langendorff-mode perfused, isolated hearts from a rat strain having high arrhythmia incidence that VF was inversely related to linoleic acid and positively related to the SFA stearate and palmitate in adipose tissue. They proposed that the effects of PUFA in general on the incidence of sudden cardiac death may be due to reduced SAT intake. It has also been observed that the Greenland Eskimo diet associated with reduced risk of mortality from ischemic heart disease contains fewer SFA than the European diet (23) as well as fewer total PUFA (24). However, Hornstra and Kester (25) reported that in a rat model of arterial thrombosis, the antithrombotic effects of (n-3) PUFA of marine origin were greater against the pro-thrombotic effect of SFA than were those of (n-3) and (n-6) PUFA of terrestrial origin despite equivalent reductions in SAT intake. These authors proposed that the benefits of dietary marine PUFA could, however, be increased by concomitant reduction in the intake of dietary SAT. However, in cardiac actions, the antiarrhythmic effects of (n-3) PUFA can be clearly demonstrated even when diets are carefully balanced for total SAT and PUFA content (9,15). Furthermore, although there is a clear inverse relationship between the dietary PUFA:SFA ratio and arrhythmia vulnerability, collective analysis of a large array of studies reveals a separate independent and greater antiarrhythmic effect of (n-3) PUFA (26).

Recent systematic review and meta-analysis has further demonstrated that long chain (FO-derived) (n-3) PUFA are antiarrhythmic relative to n-6 PUFA. In contrast, the terrestrial 18C (n-3) PUFA, {alpha}-linolenic acid, was found to have no additional antiarrhythmic properties compared with (n-6) PUFA (27). Thus, the evidence is ever increasing that cardiac effects of FO feeding are due to the long-chain (n-3) PUFA content of the diet and their incorporation into membrane lipids.

In this study, we observed a significant reduction in extracellular [K+] during ischemia, a marked reduction in extracellular lactate in all perfusion phases, and a significant reduction in control and reperfusion CK release with as little as 3% FO. Indeed, with these and other variables, many marked effects were observed with 3% FO, whereas further increments of percent FO produced only marginally greater benefit. It is therefore likely that the cardiac mechanical and metabolic alterations resulting from the replacement of the SAT diet with FO is more related to the presence of dietary (n-3) PUFA of marine origin rather than the simple reduction of SFA.

We recently demonstrated that intakes of (n-3) PUFA from as little as 1.25% dietary fat as FO led to marked incorporation of (n-3) PUFA into rat myocardial membrane phospholipids (28). The efficacy of lower-level FO supplementation to alter cardiac mechanical function and metabolism following a diet rich in SAT as seen in this study indicates the physiological benefits of dietary change, even after only 6 wk. These results suggest that the effects of high dose (n-3) PUFA supplementation on heart function (17) can be attained with low doses even with continued SAT consumption, much as has been observed in human epidemiological studies (6,29–32). Furthermore, changing the properties of the myocardium to reduce oxygen demand, increase vasodilator reserve, and reduce vulnerability to myocardial ischemia offers a biologically plausible explanation for the report that fish consumption is associated with reduced incidence of age-associated heart failure (31) and may afford benefit in heart failure patients (33). The establishment of effects of lower intakes gives greater confidence that the animal studies and human outcomes can converge.

The recent controversy over the clinical efficacy of (n-3) PUFA catalyzed by a systematic review (34) and contrasting outcomes in clinical studies (35–40) reinforces the notion that clinical study design and heterogeneity in patient background (including lifestyle, disease etiology, progression, and treatment history) are major limitations that mask or confound the effects of compounds that are not pharmacological agents but may still evoke distinct molecular and physiological changes. In comparison, the simplified animal model employed in this study permits low levels of dietary (n-3) PUFA to reduce, and perhaps even reverse, the high oxygen demand and pro-arrhythmic vulnerability effects of an SAT diet. The experimental model we have presently used is devoid of disease, employing ischemia reperfusion of essentially healthy hearts and thus interpretation of our current data should cautiously note this. It is not surprising then that there is disparity of effect between preventative and therapeutic clinical study designs. To date the strongest evidence in support of the beneficial properties of FO is derived from numerous experimental animal-based studies (8–18,41). Thus, we await future human trials that overcome the key limitations of past clinical studies, as has been recently proposed and debated in detail (40–43), and directly examine the effects of (n-3) PUFA on cardiac oxygen use and arrhythmogenesis in homogenous patient groups with well-defined disease.


   FOOTNOTES
 
1 Author disclosures: S. Pepe and P. L. McLennan, no conflicts of interest. Back

4 Abbreviations used: CK, creatine kinase; FO, fish oil; SAT, saturated fat; VF, ventricular fibrillation; VPB, ventricular premature beat; VT, ventricular tachycardia. Back

Manuscript received 4 June 2007. Initial review completed 10 July 2007. Revision accepted 14 August 2007.


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 ABSTRACT
 Introduction
 Methods
 Results
 Discussion
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