The primary finding of this study is that two high-fat diets administered to animals with advanced hypertensive heart disease elicited opposite effects on HF mortality despite having similar effects on cardiac morphology and function. Our data corroborate previous evidence that high-fat diets attenuate hypertension-induced cardiac hypertrophy and systolic dysfunction,9,10
but demonstrate that the fatty acid composition of a high-fat is a critical determinant of its effect on HF mortality. The mechanisms by which the Lard and HLSO diets elicited such diametrically opposed opposite effects on survival are not entirely clear from this study, but our data demonstrate that they are independent of changes in systolic blood pressure and are closely associated with changes in the content and composition of myocardial cardiolipin.
Okere et al
demonstrated that administration of high-fat diet (60% of kcal consisting primarily of stearate, 18:0) attenuates the cardiac hypertrophy, remodeling and contractile dysfunction associated with high-salt feeding in Dahl salt-sensitive rats without any reduction in systolic blood pressure. We observed nearly identical effects with the Lard and HLSO diets in aged SHHF rats in present study, indicating that high-fat diets of different fatty acid compositions appear have similar effects on cardiac morphology and function in the presence of chronic hypertension independent of any modulation of cardiac afterload. The mechanisms by which high-fat diets elicit these effects were not examined in the present study, but previous studies indicate that a suppression of insulin-mediated hypertrophic signaling and/or activation of peroxisome proliferator-activated receptor-α (PPARα) may be involved (recently reviewed by Sharma et al
The primary aim of this study was to determine the effect of a LA-enriched diet on L4
CL deficiency and mortality associated with terminal HF, based on evidence that cardiac L4
CL deficiency is sufficient to cause lethal cardiomyopathy in humans16
, and is associated with common forms of HF in humans17,18
and animal models.17,19,20
Dietary LA supplementation has been previously shown to reverse experimentally induced L4
but the present study is the first to demonstrate that a LA-enriched diet effectively preserves L4
CL during the pathogenesis of hypertensive HF. The mechanism by which the HLSO and Lard diets altered L4
CL levels was not directly examined in this study, but biosynthesis of L4
CL is achieved by at least two CL remodeling pathways that require LA as a substrate (esterified to CoA29
or to glycerol in diacyl phospholipids such as phosphtidylcholine30
). The extent to which dysfunction of CL remodeling pathways is responsible for L4
CL deficiency in the failing heart is presently unknown, but the >50% increase in myocardial LA content induced by the HLSO diet suggests that L4
CL levels may have been restored simply by mass action, overwhelming any deficiencies in CL remodeling capacity. However, at this point we cannot exclude the possibility that the HLSO and Lard diets directly modulated CL biosynthesis and/or degradation pathways. It has been previously demonstrated that palmitate (elevated in hearts from rats fed the Lard diet herein) decreases CL content in cardiomyocytes by interfering with biosynthesis of CL when doubly esterified to phosphatidylglyercol.31
In the present study, the Lard diet significantly decreased myocardial LA content compared to CON in the present study, despite having a greater LA content than the CON diet, suggesting that it may have altered CL synthesis, remodeling, and/or degradation processes. How LA and other dietary fatty acids directly modulate CL biosynthesis and remodeling requires further investigation.
The significant correlation of survival with myocardial L4
CL and CL contents suggests that the diets may have affected mortality by modulating the content and/or composition of CL. Several proteins and processes involved in mitochondrial energy metabolism are known to require CL for optimal function,12
and impaired mitochondrial function likely contributes to the progression of HF.32–36
Furthermore, reductions in CL content can trigger apoptotic signaling in cardiomyocytes,37
which may also accelerate HF progression.38
Therefore, it is plausible that increasing myocardial levels of CL in its optimal L4
configuration may delay terminal HF by attenuating mitochondrial dysfunction and apoptosis during the advancing stages of the disease. Now that the survival benefit and CL restorative effects of the HLSO diet have been established, future investigations will focus on elucidating the cellular manifestations of this intervention during the various stages of hypertensive heart disease and HF.
While the pathologic consequences of myocardial CL deficiency have been well-established, the HLSO and Lard diets may have modulated HF mortality by other mechanisms. In addition to being associated with a pro-atherogenic serum lipid profile39,40
, consumption of saturated and trans-fats present in the Lard diet may increase production of pro-inflammatory cytokines, such as tumor necrosis factor-α, in HF patients.41
Moreover, saturated fatty acids, particularly palmitate, are known to result in ceramide accumulation and apoptosis in cardiomyocytes42
, however this has been recently reported following a saturated fat-rich diet independent of any adverse effects on cardiac function.43
Consumption of polyunsaturated fatty acids is generally associated with reduced cardiovascular risk44
, but benefits have been ascribed primarily to the omega-3 PUFAs, principally, DHA (22:6n3) and EPA(20:5n3), due to their putative anti-arrhythmic, anti-hypertensive and anti-inflammatory effects45
. In fact, some groups recommend that omega-6 PUFA intake be limited relative to n-3 PUFAs 46
given evidence that LA may limit DHA and EPA synthesis from α-linolenic acid (18:3n3, ALA)47
, or promote increases in arachidonic acid (20:4n6) and its pro-inflammatory and pro-hypertensive metabolites. Interestingly, the HLSO diet in the present study improved survival despite decreasing myocardial ALA and DHA content, and had no effect on arachidonic acid content or excretion of its pro-hypertensive derivative TXA2
. Elucidating the effects of chronic HLSO intake on PUFA metabolism is beyond the scope of this study, but our data clearly demonstrate that a LA-enriched diet is beneficial in the setting of advanced hypertensive heart disease despite its suppressive effect on some omega-3 PUFAs. Finally, consumption of LA may also benefit the hypertrophied heart by activating PPARα, which may be downregulated in the hypertrophied and failing heart.23,48
However, whether reactivation of PPARα in the hypertrophied heart is beneficial49,50
to long-term prognosis is not entirely clear.
Limitations of the study
As stated above, the primary aim of this study was to determine the effect of the selected diets on the cardiac CL profile and mortality in the SHHF rat model. While this investigation has provided novel insight into the effects of dietary fatty acid composition on long-term prognosis in hypertensive heart disease, there are limitations associated with the survival study design that warrant further comment. In particular, preparation of high-quality mitochondria for functional assessments was not feasible in this study given the inconsistent and unpredictable timing of animal death or sacrifice. However, it is also plausible that any subcellular effects elicited by the diets that could have influenced mortality might have occurred early during the course of disease progression and would no longer be evident when animals progressed to terminal HF. Therefore, the extent to which the selected diets elicit such changes during the early and late stages of disease progression requires further study and is currently under investigation in our laboratories. Finally, the decision to sacrifice animals and determination of HF vs. non-HF mortality was based on a well-documented series of clinical HF symptoms, tissue morphology and echocardiography indices that coincide with classic histological (e.g., fibrosis) and biochemical markers (myosin heavy chain isozymes and atrial natriuretic peptide) of HF previously established in this model.24–26
However, no additional analyses were performed to further characterize the precise cause of death or extent of disease progression at the time of sacrifice.
While consumption of a low-fat diet is currently recommended for optimal cardiovascular health,6
recent studies indicate that a high-fat diet can attenuate the progressive cardiac hypertrophy and contractile dysfunction associated with chronic hypertension without altering systolic blood pressure.4,9,10
The present study corroborates these findings in an established model of senescent hypertensive heart disease, but demonstrates that a high-fat diet may increase or decrease HF mortality depending on its fatty acid composition. The pro-survival effect of the HLSO diet may result in part from a preservation of a favorable CL profile in the heart, but further studies are needed to elucidate the physiological consequences of this effect. Moreover, it will be important to examine the many other effects that LA and/or HLSO may have on cardiovascular parameters in patients with advanced cardiac disease before considering the clinical feasibility of this intervention. It is worth noting, however, that serum and dietary intake of LA has been previously associated with reduced cardiovascular disease incidence and mortality in humans.44,52
Therefore, determining how LA and other dietary fatty acids modulate cardiac health and disease clearly merits further investigation.