Atherosclerosis and Remnant Lipoproteinemia

RLP-C and Cardiovascular Risk Prediction

High concentrations of RLP-C in the fasting state were associated with the presence of CAD in dyslipidemia. Kugiyama et al. reported that higher levels of remnant lipoproteins in fasting serum predicted future coronary events in patients with CAD independent of other risk factors. RLP-C and RLP-TG levels were elevated in subjects with not only type 2 diabetes mellitus but also in those with impaired glucose tolerance (IGT), suggesting that patients with IGT have a higher risk for atherosclerosis [5].

Patients at increased risk of CAD frequently exhibit an atherogenic lipoprotein phenotype characterized by elevated plasma levels of both triglyceride- rich lipoproteins, and small, dense LDL and low concentrations of HDL cholesterol [7, 8, 9]. Improvement in the predictability of CAD on inclusion of VLDL and IDL cholesterol in the form of non-HDL calculation emphasizes the proatherogenic nature of TRL and their remnant particles. The atherogenic lipoprotein phenotype has been defined by Austin, et al_._ [10] as the presence of a predominance of small, dense LDL particles, elevated plasma triglyceride levels, and low plasma HDL cholesterol levels in the lipoprotein profile, which is associated with an approximately three-fold increased risk of atherosclerotic disease [9]. The atherogenic lipoprotein phenotype is strongly linked to obesity, insulin resistance, FCH, hypertension, and abnormalities in postprandial lipid metabolism [9]. In the Framingham study, women with diagnosed cardiovascular disease displayed plasma RLP-C and RLP- TG levels that were 16% and 27% higher than in women without cardiovascular disease [9]. Remnant lipoprotein (RLP) not only increases in abnormality of lipoprotein metabolism, it is also associated with the progression of atherosclerosis, and CAD [3]. Takamitsu Nakamura, et al concluded that elevated RLP-C level was a significant and independent risk factor for impaired FMD and angiographically proven CAD [11]. Treatment with bezafibrate or atorvastatin for four weeks significantly reduced RLP-C levels, with a concomitant improvement in FMD. Therefore, elevated levels of RLP-C are risk factors and predictor for CAD and endothelial vasomotor dysfunction in metabolic syndrome. From this point of view, measurement of RLP- C is useful for assessment of CAD risk, and therapeutic effects in metabolic syndrome [12]. It is important to measure RLP-C level for the assessment of CAD risk in diabetic patients. It is shown in previous literature that high RLP-C level > 0.12 mmol/L (7.02 mg/dL) is a significant risk factor for presence of CAD in T2DM [3, 13]. A non-fasting remnant cholesterol increase of 1 mmol/L (39 mg/dL) is associated with a 2.8-fold causal risk for ischemic heart disease, independent of reduced HDL cholesterol. This implies that elevated cholesterol content of TRLs causes ischemic heart disease [14].

Multivariate logistic regression analysis showed that high RLP-C levels (> 4.7 mg/dL) were a significant risk factor for the presence of CAD, independent of traditional risk factors. Kaplan-Meier analysis demonstrated that higher RLP-C levels in patients with CAD resulted in a significantly higher probability for the development of coronary events. Multivariate Cox hazards analysis showed that high RLP-C levels in patients with CAD were a significant predictor of future coronary events, independent of other risk factors [15]. In another study with a three years follow-up period, the incidence of cardiovascular events in the high RLP-C group (RLP-C > 5.1 mg/dL) was higher than that in the low RLP-C group (RLP-C ≤ 3.3 mg/dL).

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Diabetes & Cardiovascular Disease

People with diabetes have a nearly 40% incidence of cardiovascular disease including CHD, stroke, peripheral vascular disease, and other vascular disease. Prospective longitudinal studies such as Framingham, MRFIT, the Physicians Health Study, and the Nurses' Health Study demonstrated that there was a greater risk of cardiovascular disease for a given blood pressure or cholesterol level in diabetics. The incidence of cardiovascular disease in people with greater than five years of diabetes and in the 55 to 65-years-old age range, was equivalent to cardiovascular risk in persons with previous myocardial infarction. Routine clinical parameters HbA1c, and non-HDL cholesterol predicted CVD in diabetes [16]. When compared to non-diabetic subjects, diabetic patients are at a three (men) to six fold (women) increased risk of suffering a myocardial infarction. Their prognosis is worse and CHD is the main cause of death in this population. Since diabetic subjects without known coronary artery disease have an infraction incidence and a cardiovascular mortality similar to those of non-diabetic subjects with a previous myocardial infarction, all patients with diabetes are considered to be on secondary prevention [17]. Myocardial ischemia due to coronary atherosclerosis commonly occurs without symptoms in patients with diabetes. As a result, multivessel atherosclerosis often is present before ischemic symptoms occur and before treatment is instituted. A delayed recognition of various forms of CHD undoubtedly worsens the prognosis for survival for many diabetic patients [18]. The increase in large VLDL particles is a specific features of dyslipidaemia in insulin resistance and type 2 diabetes which initiates a sequence of events that generates atherogenic remnants. Both LDL and HDL particles show variable compositional changes that are reflected in their functions [19]. Notably apo CIII levels are increased in subjects with T2DM. Together, TRL remnants, small dense LDL and small dense HDL comprise the atherogenic lipid profile, which is also characterized by an increase in apolipoprotein B concentration due to an increased number of apolipoprotein B-containing particles [20]. Importantly, TRLs, including chylomicron VLDL and their remnants, carry a single apolipoprotein B molecule, also like LDL particles. Therefore, the malignant nature of diabetic dyslipidemia is not always revealed by the lipid measures used in clinical practice, as LDL-C may remain within the normal range. It may be better revealed by non-HDL-C. Elevation of TGs or low HDL-C is seen in about half of subjects with T2DM. The abnormal features of the lipid profile precede the onset of T2DM by several years and are common in subjects with central obesity, metabolic syndrome, and T2DM [21, 22].