Postprandial lipaemia

With the pattern of meal ingestion in Western societies, a greater part of the day is spent in the postprandial than fasting state. Kolovou et al.⁽ Reference Kolovou, Mikhailidis and Nordestgaard ^{14 )} defined postprandial lipaemia as a complex syndrome characterised by non-fasting hypertriacylglycerolaemia and its augmentation is associated with an increased risk of cardiovascular events. Following a fat-containing meal, there is a transient rise in circulating TAG-rich lipoproteins (TRL), such as chylomicrons (CM) and VLDL. After entering the circulation, the CM-TAG is hydrolysed into NEFA by lipoprotein lipase (LPL), forming cholesteryl ester-rich CM remnants, which are cleared by the liver via receptor-mediated uptake. VLDL follows a similar route of metabolism in the circulation as CM particles, although VLDL are hydrolysed at a slower rate as the larger CM are the preferential substrate for LPL. VLDL TAG depletion produces smaller VLDL (intermediate-density lipoprotein or VLDL remnants), a proportion of which are metabolised to form LDL before they are cleared via hepatic LDL receptors using apo B-100 as a ligand. During the postprandial period, there is an accumulation of TRL in the circulation due to competition between intestinal and hepatic TRL for the same lipolytic and receptor-mediated uptake⁽ Reference Bjorkegren, Packard and Hamsten ^{15 )}. A delayed clearance of TRL in the circulation enhances the accumulation of TRL particles carrying acceptor sites for the cholesteryl ester transfer protein, which transfers TAG from TRL (CM and VLDL) and exchanges it with cholesteryl esters from HDL and LDL. Remodelling of the lipid content of the LDL and HDL particles make them suitable substrates for LPL and hepatic lipase, leading to the formation of smaller and denser LDL (LDL₃) and HDL (HDL₃) particles⁽ Reference Jackson, Poppitt and Minihane ^{16 )}. HDL₃ is rapidly removed from the circulation, decreasing circulating HDL-cholesterol (HDL-C) concentrations, which is one proposed mechanism for the inverse association between exaggerated postprandial lipaemia and CVD risk⁽ Reference Chapman, Le Goff and Guerin ^{17 )}. Another possible mechanism is that LDL₃ has a lower binding affinity for the LDL receptor, reducing their rate of clearance from the circulation and enabling them to infiltrate the arterial wall⁽ Reference Jackson, Poppitt and Minihane ^{16 )}.

Since atherosclerosis is now also considered to be a postprandial phenomenon, three large prospective cohort studies aimed to determine the link between cardiovascular events and non-fasting TAG⁽ Reference Bansal, Buring and Rifai ^{18 –} Reference Lindman, Veierød and Tverdal ^{20 )}. In the Norwegian Counties Study, hazard ratios of 1·2 and 1·03 for deaths from CVD per 1 mmol/l increase in non-fasting TAG were reported in women and men, respectively, after 27 years of follow-up in a total of 86 261 participants⁽ Reference Lindman, Veierød and Tverdal ^{20 )}. Furthermore, the Copenhagen City Heart Study that followed 7581 women and 6391 men for 31 years showed that relative to women with non-fasting TAG of <1 mmol/l, hazard ratios for myocardial infarction ranged from 1·5 for women with TAG between 1·0 and 1·99 mmol/l rising to 4·2 for those with TAG ≥5 mmol/l⁽ Reference Langsted, Freiberg and Tybjaerg‐Hansen ^{19 )}. However, the corresponding hazard ratios for men were lower at 1·3 and 2·1, respectively. In the Women’s Health Study, fasting (n 20 118) and non-fasting (n 6391) TAG predicted cardiovascular events after 11·4 years of follow-up after adjusting for age, blood pressure, smoking status and hormone therapy. The authors also reported that the strongest association between cardiovascular events and non-fasting TAG occurred 2–4 h after the last meal, with the association declining as the fasting time increased⁽ Reference Bansal, Buring and Rifai ^{18 )}. These studies have demonstrated the greater importance of non-fasting than fasting TAG concentrations as a predictor of CVD risk in women compared with men.

The impact of menopausal status on the variability of the postprandial lipaemic responses has been reported in a number of studies⁽ Reference van Beek, de Ruijter-Heijstek and Erkelens ^{21 –} Reference Jackson, Abraham and Smith ^{24 )} (online Supplementary Table S1). In general, premenopausal women have lower postprandial TAG responses than men⁽ Reference Cohn, McNamara and Cohn ^{25 –} Reference Tentor, Harada and Nakamura ^{28 )}, which is in contrast to the higher reported responses observed in postmenopausal women compared with men of a similar age⁽ Reference Burdge, Powell and Calder ^{29 )}. In response to a single oral vitamin A fat loading test, van Beek et al. ⁽ Reference van Beek, de Ruijter-Heijstek and Erkelens ^{21 )} investigated whether a natural menopause was associated with reduced protection from exaggerated postprandial lipaemia. Higher concentrations of postprandial plasma TAG and retinyl palmitate (an indirect marker of CM) were observed in postmenopausal compared with premenopausal women of similar age, BMI, daily energy and fat intake, APOE genotype, LPL activity, and HDL-C concentration, even after adjusting for the confounding effect of fasting TAG. Relative to premenopausal women, Masding et al. ⁽ Reference Masding, Stears and Burdge ^{23 )}, Schoppen et al. ⁽ Reference Schoppen, Perez-Granados and Navas-Carretero ^{22 )} and Jackson et al. ⁽ Reference Jackson, Abraham and Smith ^{24 )} also reported significantly higher postprandial TAG responses after single and sequential fat-rich test meals in healthy postmenopausal women. Although raised LDL-cholesterol (LDL-C) is an established risk factor for CVD, large prospective studies have shown non-fasting TAG to be a better predictor of CVD risk in women than fasting LDL-C⁽ Reference Bass, Newschaffer and Klag ^{30 –} Reference Nordestgaard, Benn and Schnohr ^{32 )}. Post hoc analysis of the Dietary Studies: Reading Unilever Postprandial Trials (DISRUPT) menopausal groups according to age also revealed a greater increase in non-fasting TAG than fasting LDL-C concentrations during the late premenopausal period, suggesting that age and the menopause have a differential impact on these two lipid CVD risk biomarkers⁽ Reference Jackson, Abraham and Smith ^{24 )}.

A major biochemical change that occurs in women after the menopause is a reduction in the secretion of endogenous oestrogen and progesterone⁽ Reference Burger, Dudley and Robertson ^{33 )}. These hormones not only play a major role in sexual physiology, but are also involved in various physiological processes associated with the vasculature and lipid metabolism. A reduction in oestrogen following the menopause is associated with a detrimental impact on lipoprotein metabolism, vascular reactivity and blood pressure (Fig. 1). For example, there is much evidence to suggest that oestrogen (endogenous and exogenous) lowers fasting plasma concentrations of total and LDL-C, lipoprotein(a) and apo B, whilst elevating HDL-C, apo AI and apo AII⁽ Reference Žegura and Gužič-Salobir ^{34 –} Reference Windler, Kovanen and Chao ^{36 )}. The effects of oestradiol (the predominant type of oestrogen) on lipid metabolism is reported to contribute 25 % of its protective effects on the fasting lipid profile⁽ Reference Gordon, Probstfield and Garrison ^{37 )}. One possible mechanism to explain this effect, that was identified in in vitro animal studies, was an increase in the number of high-affinity LDL-receptors on liver cell membranes that enhance LDL uptake by the liver⁽ Reference Windler, Kovanen and Chao ^{36 )}. Furthermore, the administration of even short-term (2–6 weeks) oestradiol therapy reduces the menopause-related rise in postprandial TAG in postmenopausal women⁽ Reference Bessesen, Cox‐York and Hernandez ^{38 ,} Reference Westerveld, Kock and Van Rijn ^{39 )}. These findings indicate that 17β-oestradiol may accelerate the postprandial clearance of TRL and have a beneficial effect on postprandial lipaemia.

Fig. 1 Consequences of the decline in oestrogen during the menopause on lipid metabolism, vascular function and blood pressure. Adapted from Davis et al. ⁽ Reference Davis, Lambrinoudaki and Lumsden ^{106 )}. ACE, angiotensin converting enzyme; AT-1; angiotensin 1 receptor; COX, cyclo-oxygenase; eNOS, endothelial NO synthase; HDL-C, HDL-cholesterol; iNOS, inducible NO synthase; LDL-C, LDL-cholesterol; ROS, reactive oxygen species.

Vascular function and blood pressure

Vascular function is a measure of cardiovascular health. The components of impaired vascular function, including hypertension⁽ Reference Huang, Wang and Cai ^{40 ,} Reference Ettehad, Emdin and Kiran ^{41 )}, arterial stiffness⁽ Reference Vlachopoulos, Aznaouridis and Stefanadis ^{42 )} and impaired endothelial dependent vasodilation (endothelial dysfunction)⁽ Reference Ras, Streppel and Draijer ^{43 ,} Reference Matsuzawa, Kwon and Lennon ^{44 )}, are all associated with cardiovascular mortality. In a healthy blood vessel, the endothelium, which is comprised of a monolayer of endothelial cells that lines the blood vessel walls, regulates vascular wall homeostasis by immediately responding to blood-borne and locally produced stimuli to regulate blood flow, blood pressure and vascular tone. It does so by maintaining a precise balance between the release of endothelium-derived vasodilators (such as NO) and vasoconstrictors (such as endothelin-I), which actively regulates vascular permeability to plasma constituents, platelets and leucocyte adhesion molecules⁽ Reference Yao, Ober and Krishnaswami ^{45 )} as well as aggregation and thrombosis⁽ Reference Cohen ^{46 )}. However, when the synthesis or bioavailability of NO is reduced, the resulting imbalance of these vasoactive substances disrupts vascular homeostasis. This ‘endothelial dysfunction’ is characterised by vasoconstriction, increased expression of adhesion molecules and pro-inflammatory cytokines, platelet activation and increased oxidative stress⁽ Reference Verma and Anderson ^{47 )}, and is becoming increasingly recognised as an important step for the initiation of coronary atherosclerosis⁽ Reference Widlansky, Gokce and Keaney ^{48 )} and increased CVD risk in postmenopausal women⁽ Reference Rossi, Nuzzo and Origliani ^{49 )}.

There are a number of non-invasive methods that are used to evaluate endothelial function⁽ Reference Fichtlscherer, Rosenberger and Walter ^{50 )}. Flow-mediated dilatation (FMD) is the ‘gold standard’ technique that uses ultrasound to assess endothelium-dependent vasodilation in the conduit arteries in the peripheral circulation and is used as a surrogate measure of NO production⁽ Reference Moens, Goovaerts and Claeys ^{51 )}. It is now recognised as a screening tool to assess future CVD risk⁽ Reference Ras, Streppel and Draijer ^{43 ,} Reference Rossi, Nuzzo and Origliani ^{49 ,} Reference Inaba, Chen and Bergmann ^{52 ,} Reference Schächinger, Britten and Zeiher ^{53 )}. Rossi et al. reported that postmenopausal women in the lowest tertile of percentage FMD response (reflective of impaired vascular reactivity) had the greatest relative risk of cardiovascular events. Furthermore, it has been shown that endothelial function is impaired across the stages of the menopause transition in healthy women with the highest percentage FMD response reported in premenopausal women, with a progressive decline in perimenopausal and postmenopausal women, respectively⁽ Reference Moreau, Hildreth and Meditz ^{54 )}. These findings suggest that the perimenopausal stage (the transition towards the menopause where oestrogen production starts to fall) is a crucial turning point in women where changes in CVD risk commence.

Majmudar et al. ⁽ Reference Majmudar, Robson and Ford ^{55 )} revealed that menopausal status is associated with reduced NO activity, which is restored with oestrogen replacement therapy and may be an important mechanism facilitating the detrimental effect of the menopause on CVD risk and mortality. Another study that acutely administered oestrogen (17β-oestradiol) to postmenopausal women demonstrated protective effects on forearm microvascular responses to the endothelium-dependent vasodilator acetylcholine via improvements in NO activity⁽ Reference Gilligan, Badar and Panza ^{56 )}. Impaired blood flow in the microcirculation has been proposed to be an indicator of initial endothelial damage in individuals at risk of CVD⁽ Reference Brodsky, Gealekman and Chen ^{57 )}. Furthermore, it has been repeatedly shown that 17β-oestradiol stimulates the production of vasodilatory prostaglandins, such as prostacyclin (PGI₂)⁽ Reference Ospina, Duckles and Krause ^{58 ,} Reference Ospina, Krause and Duckles ^{59 )}. These vascular effects are believed to be partly responsible for the long-term benefit of oestrogen therapy on cardiovascular risk in postmenopausal women. However, findings from the Women’s Health Initiative study have questioned the benefits of oestrogen therapy. After a short (6·8 years) or longer-term (18 years) follow-up relative to a placebo, oestrogen therapy did not protect against myocardial infarction or coronary death, although the findings did show a lower CHD risk among the younger postmenopausal women (50–59 years)⁽ Reference Manson, Aragaki and Rossouw ^{60 ,} Reference Hsia, Langer and Manson ^{61 )}. More recently, a systematic review involving 43 637 women reported the number of cardiovascular events to increase following the long-term (>1 year) use of oestrogen therapy⁽ Reference Marjoribanks, Farquhar and Roberts ^{62 )}, whereas a meta-analysis of peri- and post-menopausal women (n 40 048; aged 53–79 years) showed a risk reduction for fractures and diabetes but no significant impact on risk of CHD when oestrogen therapy was compared with a placebo⁽ Reference Gartlehner, Patel and Feltner ^{63 )}. In contrast, there is much evidence to suggest that oestrogens (endogenous and exogenous) have several cardioprotective effects (Fig. 1)⁽ Reference Vehkavaara, Silveira and Hakala-Ala-Pietilä ^{35 ,} Reference Žegura, Gužic-Salobir and Šebeštjen ^{64 ,} Reference Knopp, Zhu and Bonet ^{65 )}. These include reductions in plasma markers of endothelial activation (E-selectin), fibrinogen, plasminogen activator inhibitor type 1 and tissue plasminogen activator antigen⁽ Reference Vehkavaara, Silveira and Hakala-Ala-Pietilä ^{35 ,} Reference Vigen, Hodis and Chandler ^{66 )}. However, increases in plasma markers of inflammation (C-reactive protein) and hypercoagulability have also been reported⁽ Reference Vehkavaara, Silveira and Hakala-Ala-Pietilä ^{35 ,} Reference Žegura, Gužic-Salobir and Šebeštjen ^{64 )}.

Hypertension (high blood pressure) is one of the main age-related disorders in postmenopausal women⁽ Reference Wassertheil-Smoller, Anderson and Psaty ^{67 ,} Reference Nash, Magder and Lustberg ^{68 )}, which has been identified as a leading risk factor for myocardial infarction and stroke in women⁽ Reference Abramson and Melvin ^{69 )}. The renin–angiotensin system (RAS) is a hormonal cascade that plays a key role in the regulation of fluid and electrolyte balance and arterial blood pressure. Upon activation of the RAS cascade, angiotensin II is produced in the liver by angiotensin-converting enzyme (ACE) following conversion of angiotensin I to angiotensin II⁽ Reference Donoghue, Hsieh and Baronas ^{70 )}. Angiotensin II is a potent vasoconstrictor which degrades bradykinin (a vasodilator) causing arterioles to constrict, resulting in increased blood pressure⁽ Reference Leung ^{71 )}. It is well documented in the literature that oestrogen acts on RAS at different points of the cascade, including the inhibition of ACE activity. In vitro and in vivo animal studies have also demonstrated the potential effects of oestrogen on the endothelial-dependent vasodilator response to acetylcholine in coronary and uterine arteries⁽ Reference Bell ^{72 –} Reference Williams, Adams and Herrington ^{74 )}. Loss of oestrogen-dependent cardiovascular protection induces endothelial dysfunction, and may also be involved in the activation of the RAS cascade. Evidence from both clinical and animal studies has shown an inverse association between oestrogen and the activation of RAS⁽ Reference Hinojosa-Laborde, Craig and Zheng ^{75 –} Reference Schunkert, Danser and Hense ^{78 )}. This has been proposed to occur due to oestrogen-induced down-regulation of angiotensin receptor I expression leading to an augmented level of angiotensin II⁽ Reference Nickenig, Bäumer and Grohè ^{76 )}. This is a major component of the RAS system and has several harmful effects on the vascular wall including vasoconstriction, vascular smooth muscle cell proliferation, reactive oxygen species generation and endothelial cell apoptosis⁽ Reference Ginnan, Guikema and Halligan ^{79 –} Reference Wassmann, Wassmann and Nickenig ^{81 )}. Oestrogen deficiency has also been reported to lead to an up-regulation of ACE activity causing an accumulation of angiotensin II⁽ Reference Fischer, Baessler and Schunkert ^{82 )}.

Impact of meal fat composition on postprandial lipaemia and vascular function

The chronic effects of substitution of SFA with PUFA on fasting lipid levels have been extensively studied⁽ Reference Mozaffarian, Micha and Wallace ^{83 )}, however, the acute effects are less well known. One systematic review and meta-analysis of randomised controlled trials (RCT) compared the effects of oral fat tolerance tests with differing fatty acid compositions on postprandial TAG responses in men and women⁽ Reference Monfort-Pires, Delgado-Lista and Gomez-Delgado ^{84 )}. Relative to a single SFA-rich meal challenge, a PUFA-rich meal significantly reduced the postprandial lipaemic response over 8 h, whereas a trend for a reduced response was identified following a MUFA-rich meal. However, differences were not evident at 4 h, suggesting that a longer follow-up time after the test meal (i.e. 8 h) is preferable to observe the acute effects of meal fat composition on postprandial lipaemia. Of the eighteen studies included in the review by Monfort-Pires et al.⁽ Reference Monfort-Pires, Delgado-Lista and Gomez-Delgado ^{84 )}, none included postmenopausal women, which reflects the paucity of postprandial data in this population subgroup.

With regards to vascular function, West⁽ Reference West ^{85 )} suggested that consumption of a single high-fat meal (50–105 g of fat) can impair postprandial FMD by 45 to 80 %, which appears to occur within 2 to 5 h after a high-fat meal⁽ Reference Ong, Dean and Hayward ^{86 –} Reference Vogel, Corretti and Plotnick ^{89 )}. Prolonged postprandial lipaemia is known to induce endothelial dysfunction by promoting the formation of free radicals by accelerating the rate of β-oxidation of NEFA (for example, superoxide radicals). Increased production of reactive oxygen species or free radicals reduces the amount of bioactive NO by chemical inactivation to form toxic peroxynitrite⁽ Reference Pacher, Beckman and Liaudet ^{90 )}. In addition, it has been shown that persisting oxidative stress will render endothelial NO synthase dysfunctional, markedly reducing NO production⁽ Reference Förstermann ^{91 )}. Furthermore, high concentrations of TRL during the postprandial state enhance inflammation by inducing the secretion of pro-inflammatory cytokines⁽ Reference Margioris ^{92 )} and expression of soluble cell adhesion molecules⁽ Reference Rubin, Claas and Pfeuffer ^{93 )}.

Reviews by Hall⁽ Reference Hall ^{94 )} and Vafeiadou et al. ⁽ Reference Vafeiadou, Weech and Sharma ^{95 )} stated that the acute effects of dietary fats on vascular function are less researched. The authors concluded that high-fat meals have a detrimental effect on postprandial vascular function and that there is limited and inconclusive evidence for the comparative effects of test meals rich in MUFA or n-6 PUFA with SFA. Of note, the data derived from these reviews were mainly from studies where the effects of a single high-fat meal on postprandial vascular function in different subject groups were determined; however, none of the studies identified included postmenopausal women only.