In the present study, we show that treatment with krill oil prior to induction of MI attenuates ventricular dilatation and hypertrophy. These findings were further reflected by attenuated increase in lung weight, heart weight, and altered expression of various genes encoding peptides known as markers and mediators of myocardial remodeling. However, when treatment with krill oil was introduced 7 days after MI, increased ventricular dilatation was seen.
Since the beneficial effects of krill oil were dependent on initiation of treatment before induction of MI, our data indicate that krill oil may have a favorable influence on the initial remodeling process after MI. This hypothesis is supported by previous experimental studies demonstrating that n-3 PUFA given prior to aortic banding protects against ventricular remodeling and dysfunction in rats [8
]. In the GISSI-HF trial, significant reductions in overall mortality and hospital admissions in patients with chronic HF were seen in patients receiving n-3 PUFA in the form of ethyl esters [6
]. In a sub-study of GISSI-HF, the effects of n-3 PUFA on LV structure and function were investigated, and a small but significant effect on LV ejection fraction was observed [16
]. In addition, a small study in patients with non-ischemic cardiomyopathy demonstrated increased LV ejection fraction after 12 months of supplementation with 2 g of n-3 PUFA [17
]. However, no effects on LV structure were found, which support our hypothesis that krill oil may have beneficial effects on the initial cardiac remodeling process after MI rather than on the remodeling process in the more chronic phases after MI.
The rats pretreated with krill oil showed attenuated expression of several mRNA known to be involved in the cardiac remodeling process; tissue inhibitor of matrix metalloproteinase (TIMP), atrial natriuretic peptide (ANP), and IL-6. Several studies have shown that the balance of matrix metalloproteinase (MMP) and their endogenous inhibitors TIMP is an important regulator of ventricular dimensions as they regulate structure and function of the extracellular matrix (ECM) [18
]. Myocardial ANP levels have been observed to increase in response to hemodynamic overload [19
]. Also, elevated levels of inflammatory cytokines, like IL-6, have been observed in several studies on HF and cardiac remodeling [20
]. In consequence of the assumed involvement of TIMP, ANP, and IL-6 in the regulation of the ECM structure and function, lower expression of these mRNA levels in the myocardial tissue could potentially be related to the echocardiographic finding of less LV dilatation in the rats pretreated with krill oil.
The beneficial effect of pretreatment with krill oil on post-infarction cardiac remodeling may also be a result of a favorable effect on MI size. Previous experimental studies have observed that n-3 PUFA induces significant myocardial resistance to ischemia-reperfusion injury and thereby significant smaller myocardial infarct size in rodents [21
]. We therefore hypothesize that pretreatment with krill oil, in addition to possible effects on early cardiac remodeling, may also lead to smaller MI with less LV dilatation and hypertrophy. However, in the present study we have no data on MI size, and this hypothesis will have to be further explored in forthcoming studies.
The potential beneficial effects of krill oil on post-MI remodeling could have several explanations. First, as shown in our study, dietary supplement with n-3 PUFA leads to slightly reduced myocardial SFA levels. Substituting PUFA for SFA may be associated with lower risk of coronary heart disease and studies on isolated myocardial cells have shown that the SFA palmitic acid induces cardiomyocyte apoptosis under certain conditions [23
]. Second, krill oil supplementation induced an increase in myocardial levels of EPA and DHA, which have been shown to be incorporated into cell membranes in both healthy and failing hearts [14
]. This may lead to an increased production of anti-inflammatory or resolving mediators including resolvins of the E series. In contrast to n-3 PUFA, n-6 PUFA may lead to enhanced generation of inflammatory mediators including prostaglandin-E2 and lipoxins. As a consequence, a relative decrease in n-6 PUFA during krill oil supplementation may further enhance the anti-inflammatory properties of krill oil [8
]. Finally, incorporation of n-3 PUFA into mitochondrial membranes under conditions of myocardial stress has also been hypothesized to be beneficial as it may help maintain myocardial oxidative function [26
Even though this study was not designed as to compare the effects of fish oil to that of krill oil, other studies allows hypothesizing that the molecular form of the supplemented n-3 PUFA is of importance to their various effects [10
]. It was recently demonstrated that the incorporation of EPA and DHA into myocardial phospholipids was higher when delivered in the form of krill oil/n-3 phospholipids, compared to n-3 bound in the form of triglycerides (fish oil) [27
]. Two recent studies compared the absorption of DHA and EPA from triglycerides versus phospholipid n-3 PUFA sources and they showed that supplementation with krill oil gave a dose-equivalent higher plasma concentration of EPA and DHA in women and men compared to fish oil [28