Current Vascular Pharmacology - Volume 9, Issue 3, 2011

An Expert Panel group of scientists and clinicians met to consider several aspects related to non-fasting and postprandial triglycerides (TGs) and their role as risk factors for cardiovascular disease (CVD). In this context, we review recent epidemiological studies relevant to elevated non-fasting TGs as a risk factor for CVD and provide a suggested classification of non-fasting TG concentration. Secondly, we sought to describe methodologies to evaluate postprandial TG using a fat tolerance test (FTT) in the clinic. Thirdly, we discuss the role of non-fasting lipids in the treatment of postprandial hyperlipemia. Finally, we provide a series of clinical recommendations relating to non-fasting TGs based on the consensus of the Expert Panel: 1). Elevated non-fasting TGs are a risk factor for CVD. 2). The desirable non-fasting TG concentration is <2 mmol/l (<180 mg/dl). 3). For standardized postprandial testing, a single FTT meal should be given after an 8 h fast and should consist of 75 g of fat, 25 g of carbohydrates and 10 g of protein. 4). A single TG measurement 4 h after a FTT meal provides a good evaluation of the postprandial TG response. 5). Preferably, subjects with non-fasting TG levels of 1-2 mmol/l (89-180 mg/dl) should be tested with a FTT. 6). TG concentration ≤ 2.5 mmol/l (220 mg/dl) at any time after a FTT meal should be considered as a desirable postprandial TG response. 7). A higher and undesirable postprandial TG response could be treated by aggressive lifestyle modification (including nutritional supplementation) and/or TG lowering drugs like statins, fibrates and nicotinic acid.

Background/Aim: Triglycerides (TGs) are measured in studies evaluating changes in non-fasting lipid profiles after a fat tolerance test (FTT); however, the optimal timing for TG measurements after the oral fat load is unclear. The aim of this study was to evaluate how non-fasting TG levels vary after an oral FTT in healthy subjects. Methods: This meta-analysis included 113 studies with >5 participants of Caucasian race that were indexed in PubMed from its inception through March 2010, using the search term “postprandial lipemia”. We only included studies that provided mean values and standard deviation (SD) (or standard error of the mean) for TG measurements at baseline (=fasting) and for at least one other time-point. Exclusion criteria included uncommon sampling time-points after the FTT, baseline TGs≥2.0 mmol/L (≥177mg/dl), and a body mass index ≥30kg/m2. Results: All studies combined, weighted mean±SD TG values in mmol/L were 1.25±0.32 fasting, 1.82±0.40 at 2 h, 2.31±0.62 at 4 h, 1.87±0.63 at 6 h, and 1.69±0.80 at 8 h. After stratifying studies based on fat quantity in the test meal (<40,≥40-<50, ≥50-<60, ≥60-<70, ≥70-<80, ≥80-<90, ≥90-<100, ≥100- <110, ≥110-120, ≥120 g), the highest standardized mean difference in TG levels from fasting levels was found in those having an oral fat load of ≥70 g and <80 g, and at 4 h (difference=1.74 mmol/L; p<0.001). Conclusion: The 4 h time-point after an oral fat load during a FTT was the most representative measurement of TGs. The highest standardized mean difference of TGs was found after a meal containing 70-79g of fat. The relevance of these two key parameters determined in healthy subjects should be considered for further developments of an oral FFT for clinical purposes.

Non-fasting triglycerides are measured at any time within up to 8 h (14 h) after any normal meal, while postprandial triglycerides are measured at a fixed time point within up to 8 h (14 h) of a standardised fat tolerance test. The simplest possible way of evaluating remnant cholesterol is non-fasting/postprandial total cholesterol minus low-density lipoprotein (LDL) cholesterol minus high-density lipoprotein (HDL) cholesterol. Elevated levels of non-fasting/ postprandial triglycerides directly correlate with elevated remnant cholesterol. In the general population, 38% of men have non-fasting/postprandial triglycerides > 2mmol/L (>176 mg/dL) while 45% of men have non-fasting/postprandial triglyceride levels of 1-2 mmol/L (89-176 mg/dL); corresponding fractions in women are 20% and 47%. Also, 31% of men have remnant cholesterol levels > 1mmol/L (>39 mg/dL) while 46% of men have remnant cholesterol levels of 0.5-1 mmol/L (19-39 mg/dL); corresponding fractions in women are 15% and 43%. Non-fasting triglycerides ≥5 mmol/L vs. <1 mmol/L marked a 17 and 5 fold increased risk of myocardial infarction, a 5 and 3 fold increased risk of ischemic stroke, and a 4 and 2 fold increased risk of early death in women and men in the general population. As all cells can degrade triglycerides it is biologically unlikely that it is the triglyceride molecules themselves that cause atherosclerosis and cardiovascular disease. However, elevated remnant cholesterol may lead to cholesterol entrapment in the arterial intima and consequently to accelerated atherosclerosis and cardiovascular disease.

Accumulating evidence suggests that elevated plasma triglycerides concentrations, in both the fasting and the postprandial states, may pose a significant independent risk for cardiovascular disease (CVD). Both fasting and postprandial lipoprotein concentrations vary substantially among individuals, and this interindividual variability is driven by a combination of non-genetic and genetic factors. Regarding the genetic component, the efforts to elucidate the variability in postprandial response have resulted in the identification of associations with multiple lipid candidate genes. However, most reported associations are based on very simple models including one single-nucleotide polymorphism (SNP) or haplotype at a time and small sample sizes. Progress in this promising area of research requires more comprehensive experimental models, including larger sample sizes that will allow investigating gene-gene interactions. Reviews of the literature in the area of ApoA5, GCKR, and PLIN genes and postprandial lipemia are used to demonstrate the complexities of genotype-phenotype associations. Knowledge of how these and other genes influence postprandial response should increase the understanding of personalised nutrition.

At the present time, there is no widely agreed definition of postprandial lipaemia (PPL). This lack of a shared definition limits the identification and treatment of patients with exaggerated PPL as well as the evaluation of potential therapeutic agents. PPL is a complex syndrome characterized by non-fasting hypertriglyceridaemia that is associated with an increased risk of vascular events. This review considers the definition of PPL and the methodology for assessing this process.

Postprandial lipemia (PPL) refers to a dynamic sequence of plasma lipid/lipoprotein changes induced by ingestion of food. PPL results from absorption of digested dietary lipids which form chylomicrons (CM) and increased hepatic production of VLDL, stimulated by increased delivery of fats to the liver. In general, PPL occurs over 4-6 h in normal individuals, depending on the amount and type of fats consumed. The complexity of PPL changes is compounded by ingestion of food before the previous meal is fully processed. PPL testing is done to determine the impact of (a) exogenous factors such as the amount and type of food consumed, and (b) endogenous factors such as the metabolic/genetic status of the subjects, on PPL. To study PPL appropriately, different methods are used to suit the study goal. This paper provides an overview of the methodological aspects of PPL testing. It deals with markers of postprandial lipoproteins, testing conditions and protocols and interpretation of postprandial data. The influence of the meal itself will not be discussed as it is the subject of another paper in this series.

Numerous factors including diet, lifestyle conditions, genetic background and physio-pathological conditions modulate the amplitude and time-courses of postprandial changes in humans. This review focuses on dietary factors affecting postprandial lipemia and lipoproteins metabolism in humans. The known effects of amount or type of fat, carbohydrate, protein and fiber are summarized. Changing the habitual dietary pattern can also alter the postprandial response. This review highlights that postprandial metabolism is a key link between dietary pattern and cardiovascular health or risk.

Recent studies have demonstrated the value of non-fasting serum triglycerides (TG) as risk markers for cardiovascular and cerebrovascular disease. This underscores the importance of knowing the postprandial lipid/lipoprotein responses to different foods. A systematic approach is needed to make use of postprandial lipid data as a practical nutritional tool, similar to the well known glycemic index (GI), which is a measure of the effect of carbohydrates on blood glucose levels. Using GI as a model, we propose that a similar and parallel nutritional tool called Lipemic Index (LI) be developed to facilitate the planning of a healthy diet. LI could also serve as a tool in human nutrition research. LI would refer to the postprandial increase of serum TG after a test meal with a specific food relative to a reference meal. The reference meal could take the form of a fat load that has a fixed amount (e.g. 50-70 g) of a mixture of saturated, polyunsaturated and monounsaturated fats in known proportions. It is possible that a test meal may have a greater degree of postprandial lipemia (PPL) than the reference meal and, unlike GI, the LI may exceed 100%. We recommend total plasma TG as the blood parameter to follow after consumption of the fat load. The TG incremental area under the curve (iAUC) will be calculated from the curve drawn from hourly measurements of plasma TG up to 6 hours using the trapezoid rule. The LI of the test meal (%) will equal the iAUC of the test meal divided by the iAUC of the reference meal x 100. Consideration will be given to the impact of background diet, other nutrients in the test meal and gender differences on LI testing. The establishment of LI into practice will be complicated and challenging. However, it is important for work to begin on establishing a practical and quantifiable index of PPL, in order to benefit clinical management of patients as well as research.

Atherosclerosis is a result of a lifelong process that has its origins in childhood. Data in adults suggest that impaired postprandial lipoprotein metabolism may contribute to, or be a marker of, the development and progression of atherosclerosis. After an 8-year follow up period, the Bogalusa Heart Study showed that children with low high density lipoprotein cholesterol, high triglyceride levels and high body mass index had a notably increased occurrence of dyslipidemia as adults. A significantly greater postprandial response of triglycerides in children with elevated fasting triglyceride levels was reported. It is well known that dietary fat is associated with higher plasma triglyceride levels. It is not clear if postprandial lipemia should be evaluated in children and adolescents. However, in special situations this may help determine the underlying lipid disorder. This review discusses the current status in this field.

Revascularization procedures used for the treatment of cardiovascular disease can be associated with restenosis, although drug-coated stents have greatly reduced this complication. Both type 2 diabetes (T2DM) and metabolic syndrome (MetS) are associated with a high risk for atherosclerosis and restenosis. Insulin resistance, defined as the inability of insulin to exert its metabolic actions, characterizes both T2DM and MetS. Recent data suggest that insulin resistance is directly implicated in atherosclerosis/restenosis, because of the unresponsiveness to the vasculoprotective action of insulin, including its phosphoinositide 3-kinase (PI3K)-Akt-endothelial nitric oxide synthase mediated enhancement of endothelial function. However, insulin also has ‘atherogenic’ actions, including enhancement of vascular smooth muscle cell (VSMC) proliferation, which are mitogen-activated protein kinase-mediated. These ‘atherogenic’ actions are less affected by insulin resistance, which mainly involves the PI3K pathway. The role of insulin in the atherosclerotic disease process is still highly controversial, where some investigators view insulin as a growth factor with pro-atherogenic effects while some others believe insulin resistance to be pro-atherogenic rather than insulin itself. We attempt to produce a balanced review with a focus on the effect of insulin in vivo, in animal models of atherosclerosis and restenosis.

Hypoxia-inducible factor-1 (HIF-1) is a nuclear transcription factor that is upregulated in hypoxia and coordinates the adaptive response to hypoxia by driving the expression of over 100 genes. In facilitating tissues to adapt to hypoxia, HIF-1 may have a role in reducing the cellular damage induced by ischaemia, such as that seen in peripheral arterial disease (PAD), or following acute ischaemic insults such as stroke and myocardial infarction. This therefore raises the possibility of HIF-1 modulation in such contexts to reduce the consequences of ischaemic injury. HIF1 has further been implicated in the pathogenesis of atherosclerosis, abdominal aortic aneurysm (AAA) formation, pulmonary hypertension and systemic hypertension associated with obstructive sleep apnoea. Through a better understanding of the role of HIF-1 in these disease processes, novel treatments which target HIF-1 pathway may be considered. This review summarises the role of HIF-1 in arterial disease, specifically its role in atherosclerosis, ischaemic heart disease, in-stent restenosis following coronary revascularisation, stroke, PAD, AAA formation, pulmonary artery hypertension and systemic hypertension. The potential for exploiting the HIF-1 signalling pathway in developing therapeutics for these conditions is discussed, including progress made so far, with attention given to studies looking into the use of prolyl-hydroxylase inhibitors.

Atrial fibrillation (AF) is the most common clinically relevant cardiac arrhythmia. Prevalence and incidence rates are rising with the advancing population age. A severe complication of untreated AF is thrombus formation in the left atrial appendage with consecutive peripheral thromboembolism. Thus, AF is a major contributor to thromboembolic events, especially in the elderly. Depending on the CHADS2 score for thromboembolic events that takes into account congestive heart failure, hypertension, age, diabetes mellitus and stroke as risk factors, oral anticoagulation therapy with vitamin K antagonists is currently the treatment of choice for the prevention of thromboembolism. However, due to drawbacks of current anticoagulation therapy new substances for oral therapy are currently evaluated in various clinical studies. This article provides an up to date overview of orally active compounds for the future treatment of AF. Emphasis lies on comparison of direct thrombin inhibitors with factor Xa inhibitors that are currently investigated in clinical phase III studies for the treatment of non-valvular AF. The direct thrombin inhibitor dabigatran will be compared with factor Xa inhibitors like rivaroxaban and apixaban. Other promising agents currently investigated in phase II trials such as direct factor Xa inhibitors DU-176b (edoxaban) and YM150, will also be discussed.

Vascular endothelial growth factor (VEGF) is an endogenous polypeptide that modulates angiogenesis in normal physiological conditions as well as in cancer. During angiogenesis, VEGF interacts with several other angiogenic factors, playing an important role in cell proliferation, differentiation, migration, cell survival, nitric oxide (NO) production, release of other growth factors and sympathetic innervation. Based on these mechanisms of action, several anti-VEGF drugs have been developed for cancer treatment. This review discusses the physiology and interactions of VEGF, its mechanisms of action and role in modulating vascular homeostasis. It also discusses the adverse cardiovascular effects of recently developed anti-VEGF drugs for the treatment of various types of cancer. A critical appraisal of the human studies on these drugs is provided. Furthermore, putative mechanisms for the onset of hypertension, the most common adverse cardiovascular effect, are discussed.