Is the fatty meal a trigger for acute coronary syndromes

Atherosclerosis 159 (2001) 9 – 15 www.elsevier.com/locate/atherosclerosis

Hypothesis

Is the fatty meal a trigger for acute coronary syndromes R.A. Anderson *, C.J.H. Jones, J. Goodfellow Department of Cardiology, Wales Heart Research Institute, Uni6ersity of Wales, Heath Park, Cardiff, Wales CF14 4XN, UK Received 4 June 2001; accepted 31 July 2001

Abstract This hypothesis paper aims to illustrate the role of fatty meal ingestion has on the vascular endothelium and coagulation system. In particular highlighting the potential risk of fatty meal ingestion both as a trigger to an adverse factor in patients with acute coronary syndromes. We propose that as a result of ingesting fatty meals as a part of daily living, there occurs a constellation of changes in the vasculature that results in both a hypercoagulable and a provasoconstrictor state. These acute changes in response to a fatty meal on endothelial function, prothrombosis, and platelet activation can potentially trigger, facilitate and propagate the forces that drive acute coronary syndromes. In type 2 diabetes, adverse postprandial phenomena are exaggerated and prolonged and may therefore be expected to contribute significantly to the excess risk of acute coronary syndromes and atherosclerotic development in these subjects. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Postprandial lipaemia; Acute coronary syndromes; Endothelium

1. Introduction Epidemiological studies have demonstrated a link between eating habits, health and disease. The modern lifestyle with a tendency for high fat diets combined with a reduction in physical activity is detrimental to health. The trend towards increasing urbanisation has been directly associated with an increase in dietary fat, and a shift from plant to animal proteins [1]. Thirty years ago, the seven countries study [2] demonstrated that a high saturated fat intake strongly predicted coronary heart disease mortality, a link reinforced by two more recent studies [3,4]. A chronic high saturated fat intake results in only modest increases in cholesterol, raising the possibility that other mechanisms may be involved in the pathological process. Furthermore, with the increasing prevalence of fatty meals linked with popular ‘fast foods’ the role of fatty meal ingestion on the atherogenic diathesis needs re-evaluating. * Corresponding author. Tel.: + 44-2920-74-4430; fax: +44-292074-3500. E-mail address: [email protected] (R.A. Anderson).

William Heberden [5] made the first observation of a post-prandial (PP) effect on the circulation of blood over 200 years ago. Its role in exacerbating anginal symptoms is well described [6] but its role in acute coronary syndromes (ACS) is unclear. Both occlusive and non-occlusive coronary thrombosis occur when an atherosclerotic plaque becomes vulnerable to rupture, an extrinsic stressor causes rupture and local increases in coagulability and vasoconstriction contribute to coronary artery luminal disruption and occlusion. We aim to illustrate the role that fatty meal ingestion can have on these processes, its PP effects on lipoprotein interactions with the vascular endothelium and coagulation system. Highlighting the potential risk the fatty meal poses, both as a trigger to and an adverse factor in patients with ACS.

2. Post-prandial lipoproteins Immediate transient perturbations in circulating lipoprotein particles are detectable after a fatty meal, a phase termed alimentary or post-prandial lipaemia

0021-9150/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 2 1 - 9 1 5 0 ( 0 1 ) 0 0 6 6 9 - 4

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ated TG responses to fat containing meals. Elevated plasma TG levels after an oral high fat load predict carotid artery intimal thickness [17], atherosclerosis and exercise-induced ischaemic electro cardiogram (ECG) changes [18–20]. Furthermore intervention trials have shown that reduction of TG-rich lipoprotein in plasma leads to a slower rate of progression of coronary atherosclerosis [21] and coronary events [22], data consistent with the involvement of TG metabolism in atherogenesis. This raises the possibility of an enhanced atherogenic risk attributable to repeated episodes of PPL and the subsequent exposure to circulating TGrich atherogenic lipoproteins. How may acute elevation of TG-rich lipoproteins exert a deleterious vascular effect after a fatty meal?

3. Factors influencing post-prandial lipaemia Fig. 1. Schematic diagram of lipoprotein interactions with LPL at the endothelial cell surface releasing FFA, (remnants) CMr/VLDLr and IDL.

(PPL). It is that period during absorption, when capacity for triglyceride (TG) metabolism is exceeded and is characterised by increased plasma levels of TG and subsequent lipoprotein enrichment by TG. This results in TG-enriched very low density lipoprotein (VLDL), a propensity for small dense low density lipoprotein (LDL), and low high density lipoprotein (HDL) levels [7] (with a shift in atherogenicity). The magnitude and duration of the hypertriglycerideamic phase depends upon a number of factors, some of which are listed in the Table 1. During this phase the vascular endothelium is exposed to potentially harmful lipoproteins [8] (VLDL, IDL, LDL and chylomicron [CM] remnants), the socalled circulating atherogenic lipoproteins (see Fig. 1). The concentrations of these circulating atherogenic lipoproteins are higher in subjects with coronary artery disease (CAD) than normal healthy subjects [9] and predictors of recurrent events in patients with CAD [10]. The remnant levels of these lipoproteins have also been correlated with the severity of coronary atherosclerosis in cases of sudden death [11]. Elevated fasting remnant lipoprotein levels are associated with impaired coronary vasomotor function [12]. TG-rich lipoprotein remnant particles have been independently associated with the presence, severity and progression of atherosclerosis [13], and high fasting remnant lipoprotein levels predict future coronary events in subjects with CAD [14]. However, it seems that PP TG levels may provide an independent marker of risk for the development of atherosclerosis. Patients with CAD [9,15], and offspring of patients with premature CAD [16] exhibit exagger-

Insulin plays a pivotal role in PP lipid metabolism by modulating the activity of key lipolytic enzymes, lipoprotein lipase (LPL) and hepatic lipase. LPL is the key enzyme for hydrolysis of TG from dietary fat (CM and VLDL) to free fatty acids (FFA) and monoglycerides [23]. LPL is bound to the vascular endothelium and acts on CM and VLDL to deplete them of TG to form CM remnants and LDL, respectively (see Fig. 1). Therefore, LPL holds a key role in controlling lipoprotein/FFA interactions at the endothelial interface. FFA have also been implicated as a causal factor for injury to arterial wall cells and foam cell formation. Indeed elevated circulating FFA levels impair endothelium-dependent vasodilatation [24]. In excess, they can also impede endothelial cells to produce prostacyclin and cGMP, resulting in an increase in oxidative stress at the endothelial cell surface, impeding directly and indirectly platelet aggregation [25]. There is a tendency for increasing age to be accompanied by greater PP responses [26]. Women have lower TG and HDL responses to an oral fat load test when compared with men [27] although visceral adiposity is a major contributing factor in this gender difference as there is markedly greater PPL in obese subjects [28]. Exercise increases the rate of removal of circulating TG in training men compared with sedentary men [29]. Table 1 Factors influencing PP hypertriglyceridaemia Insulin LPL (hepatic or endothelium-bound) Age Sex Obesity Exercise Apolipoproteins LDL receptor protein and activity

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4. Post-prandial lipaemia and effects on vascular endothelium The vascular endothelium plays a key role in the local regulation of vascular tone by the release of vasodilator substances such as nitric oxide (NO) and prostacyclin, and vasoconstrictor substances such as thromboxane A2, endothelin and free radicals. NO is important to both basal and stimulated control of vascular tone. Impaired endothelium-dependent dilatation is a feature of atherosclerosis, which may be due to reduced production, and/or increased inactivation of NO (by reaction with oxygen free radicals or cyclooxygenase) major risk factors include elevated cholesterol, homocysteine, blood pressure and diabetes. Atherosclerotic risk might, therefore, be expected to be increased if fatty meals induce transient endothelial dysfunction, particularly if occurring two to three times a day on a repeated basis. Human vascular endothelial function evaluated by brachial artery flow-dependent dilatation is diminished after a fatty meal in healthy subjects, starting after 2 h with a nadir at 3 and 4 h. The change is independent of total or LDL-cholesterol levels [30]. The phenomenon does not occur with low fat meals, implying a causal role for TG and TG-rich lipoproteins. This appears consistent with in vitro and in vivo studies, which show that remnant lipoprotein particles are associated with impaired endothelium-dependent coronary vasodilatation [31,32]. Furthermore, evidence shows that remnant lipoproteins induce proatherothrombogenic changes in endothelial cells via increases in adhesion molecule and tissue factor expression partly via a redox sensitive mechanism (and therefore blunted by HDL-C) [33]. Normal individuals with high fat intakes and disease states with abnormal fat handling (PPL) would, therefore, be expected to have either/both repetitive and prolonged endothelial dysfunction, giving a cyclical stimulus to atherothrombosis. PP endothelial dysfunction may be limited by interventions modifying the production or inactivation of NO. Angiotensin converting enzyme (ACE) inhibition by quinapril prevents PP endothelial dysfunction in healthy individuals. Angiotensin II receptor antagonists provide lesser benefit, the difference supporting a protective role for bradykinin-induced nitric oxide (NO) synthesis by endothelial cells following ACE inhibition [34]. Endothelial dysfunction associated with PPL is also prevented by prior folate supplementation, an intervention that can increase NO production by increasing the availability of tetrahydrobiopterin, an essential co-factor for NO synthase activity. It may also improve endothelial redox status and in general folic acid possesses direct scavenging effects in vitro [35]. Recent evidence has suggested that PP elevations of asymmet-

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ric dimethylarginine (ADMA) may also play a role in the PP deterioration of endothelial dysfunction in T2DM blunting NO production at an endothelial level [36]. There is increasing evidence that PPL leads to oxidative stress, a condition in which NO inactivation may be increased. During oxidative stress, the superoxide anion can rapidly bind NO, attenuating flow-dependent dilatation either directly or via the toxic cellular consequences of the resultant peroxynitrite. Thus increased NO activity might explain the partial prevention of PPL related endothelial dysfunction by the antioxidant vitamins E and C [30]. Red wine also decreases fatty meal-induced changes in lipid hydroperoxides through its antioxidant (polyphenol) effect and might be expected to improve endothelial function although so far evidence is conflicting, possibly due to differences in fat content in the meals [37,38]. Williams et al. showed that cooked rather than uncooked fats cause PP endothelial dysfunction and postulated that ingested products of lipid peroxidation induce endothelial dysfunction [39]. We have shown that PPL in healthy individual results in endothelial dysfunction with significant elevations in both lipid derived free radicals and products of lipid peroxidation in the plasma [40]. An observation that is related to the TG enrichment of VLDL and is inversely related to protective HDL levels. This environment of increased oxidative stress may play a role in endothelial cell surface disruption, as shown in vitro recently [41], and result in increased platelet/endothelial cell adhesion in the PP phase. Not all meals lead to endothelial dysfunction. Although most studies PP phenomena utilise a standard butter fat meal, Vogel et al. [42] have investigated the impact of different meal types on endothelial function. Olive oil based meals have similar effects to butter fat products inducing PP endothelial dysfunction. Canola oil enriched with a-linolenic acid (v-3), a component of the diet in the Lyon heart study [43] did not cause PP endothelial dysfunction significantly. Fish oils eaten in the form of salmon resulted in a lesser absolute rise in plasma TG and also did not result in PP endothelial dysfunction [44]. These findings may help to explain the low incidence of CAD in Eskimos whose high fat intake is mainly based on fish oil, and may offer a theoretical basis for at least in part some of the benefit seen in the Lyon heart study [43].

5. Post-prandial endothelium and type 2 diabetes (T2DM) Patients with T2DM exhibit exaggerated and prolonged PPL and also premature atherosclerosis [45]. Fatty meal-induced decreases in endothelial function and increases in oxidative stress are greater in T2DM

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than in healthy controls [40]. Oxidative stress may be accentuated by low levels of HDL since HDL normally shuttles lipid hydroperoxides to the liver for inactivation [46] and may be expected to reduce levels of lipid-derived free radicals that remain in the vicinity of vascular endothelium. Diabetic patients also exhibit fasting increased TG enrichment of VLDL and LDL particles, the abnormality most closely associated with PPL-related endothelial dysfunction. It appears, therefore, that patients with T2DM, who are generally predisposed to abnormal fat handling, demonstrate a constellation of PP adverse events, superimposed on a background of increased FFA fluxes, decreased antioxidant capacity and endothelial dysfunction in the fasting state. It, therefore, seems highly likely that excessive PPL contributes to the risk of macro-vascular disease in T2DM. Modification of TG metabolism may protect endothelial function. In diabetic patients, PPL is attenuated by a fibric acid derivative therapy (ciprofibrate) which upregulates LPL activity and thus decreases circulating VLDL and TG while increasing HDL-C. Ciprofibrate improves both fasting and PP endothelial function in subjects with T2DM, with favourable blunting of PP induced oxidative stress [47]. These findings imply that fibrates could impact substantially on coronary events in T2DM. Prospective studies are awaited but trial data show that non-diabetic CAD mortality is decreased in subjects with low HDL-cholesterol taking fibrate therapy [48]. In a subgroup analysis of the diabetics in this study there was a 25% reduction in the risk of vascular events.

6. Post-prandial hypercoagulability Vascular endothelial cells influence platelet function and thrombosis as well as smooth muscle tone, processes that may all be disturbed during PPL. PPL is associated with transient activation of factors VII and XII [49]. Activated factor VII is a potent procoagulant, initiating the thrombotic response to atheromatous plaque rupture after its formation by complexing with exposed tissue factor to activate the coagulation cascade [50]. This finding perhaps supports the positive association between activated factor VII and the risk of fatal CAD [51]. Increased PP factor VII activation may thus raise the likelihood that plaque rupture leads to occlusive coronary thrombosis. In adults taking a diet rich in long-chain saturated fatty acids [52], activated factor VII increases after a meal containing more than 90 g fat [53]. Factor VII activation correlates quantitatively with the degree of PP triglyceridaemia and seems to be related to FFA production during lipolysis of TG-rich lipoproteins by LPL on the endothelial cell surface [54]. It appears that

large PP TG-rich lipoproteins are required in vivo [55] and that long-chain saturated fatty acids provide the surface that activates the coagulation system at the endothelial bound LPL/lipoprotein interface [56]. However, the PP rise in activated factor VII can be attenuated. There is limited evidence that acutely, a meal containing n-3 polyunsaturated fatty acids does not increase activated factor VII [57] or induce endothelial dysfunction [44], suggesting that the two outcomes may be linked.

7. Fibrinolytic resistance Not only does PPL induce a prothrombotic tendency but a fatty meal can also decrease the fibrinolytic capacity in the blood. Tissue-type plasminogen activator (t-PA) is the principal fibrinolytic mechanism that operates in the coronary vascular bed [58]. Therefore, any increase in the natural inhibitor of this plasminogen activator inhibitor-1 (PAI-1), will intimately influence coronary thrombosis in vivo, the importance of the fibrinolytic system being highlighted recently with PAI-1 and tPA levels correlating with risk of reinfarction in both men and women [59]. Increased plasma TG levels chronically are associated with increased PAI-1 activity due to activation of the promotor gene by VLDL [60]. This undermines the principal fibrinolytic protection in the coronary vasculature in chronic conditions e.g. T2DM. There is also evidence that PAI-1 activity and PAI-1 antigen is increased acutely after a fat load by 76 and 64%, respectively. This infers relative fibrinolytic resistance in the aftermath of a fatty meal [61]. Two and 4 h after a fatty meal in CAD patients there is also a significant rise in plasma fibrinogen again reinforcing the procoagulant milieu [62].

8. Platelet activation There is evidence of altered platelet function after fatty meal ingestion. The membrane expression of platelet P-selectin is enhanced PP [63]. This suggests that platelets are sensitised to thrombin and collagen after a meal [64], a finding of potential importance to thrombus formation after plaque rupture. Platelet P-selectin actually increases platelet/leucocyte adhesion. Indeed in ACS, increased P-selectin actually facilitates microembolisation distally in the coronary artery, as this process is thrombin and collagen dependent [65]. It also stabilises glycoprotein IIb/IIIa-fibrinogen interactions allowing the formation of large stable platelet aggregates [66]. It may even predict unsuccessful thrombolysis in patients with acute myocardial infarction [67].

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Increased platelet sensitivity is detectable 3 h after a fatty acid meal and follows a similar time course to endothelial dysfunction. These platelet changes in the PP state may be of importance if placed in the context of ACS. Therefore, if plaque rupture occurs in the context of a PP phase there may be expected to be a milieu of endothelial dysfunction, vasospasm with resulting low flow, low fibrinolytic activity, a procoagulant state, high levels of fibrinogen and reactive platelets, processes that clearly promote thrombus formation and subsequent stabilisation in the coronary arteries.

9. Summary Several potentially atherogenic changes occur in healthy individuals after a fatty meal. Endothelial function is transiently disturbed, probably via increased oxidative stress which attenuates bioavailable NO resulting in provasoconstrictor forces. This phenomenon can be blunted by manipulation of NO activity by antioxidants, ACE inhibitors and folate supplements. A number of physiological processes can lead to plaque rupture and progression to coronary artery occlusion. We propose that as a result of ingesting fatty meals as a part of daily living, there occurs a constellation of changes in the vasculature that results in both a hypercoagulable and a provasoconstrictor state. These acute changes in endothelial function, prothrombosis, and platelet activation in response to a fatty meal, can potentially trigger, facilitate and propagate the forces that drive ACS. In T2DM, adverse PP phenomena are exaggerated and prolonged and may, therefore, be expected to contribute significantly to the excess risk of ACS and atherosclerotic development in these subjects.

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