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C. N. Manjunath
Department of cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, India
Jayesh R. Rawal
1U. N. Mehta Institute of Cardiology and Research Center, B. J. Medical College and Civil Hospital, Ahmedabad, India
Department of cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, India
1U. N. Mehta Institute of Cardiology and Research Center, B. J. Medical College and Civil Hospital, Ahmedabad, India
Corresponding Author: Dr. Madhu K, Cardiovascular Division, Medical Affairs, Astra Zeneca, Bangalore, India. E-mail: moc.acenezartsa
This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Bạn đang xem: Dyslipidemia là gì
Atherogenic dyslipidemia (AD) refers to elevated levels of triglycerides (TG) and small-dense low-density lipoprotein and low levels of high-density lipoprotein cholesterol (HDL-C). In addition, elevated levels of large TG rich very low-density lipoproteins, apolipoprotein B and oxidised low-density lipoprotein (LDL), and reduced levels of small high-density lipoproteins plays a critical role in AD. All three elements of AD per se have been recognised as independent risk factor for cardiovascular disease. LDL-C/HDL-C ratio has shown excellent risk prediction of coronary heart disease than either of the two risk markers. Asian Indians have a higher prevalence of AD than western population due to higher physical inactivity, low exercise and diet deficient in polyunsaturated fatty acids (PUFA). The AD can be well managed by therapeutic lifestyle changes with increased physical activities, regular exercise, and diets low in carbohydrates and high in PUFA such as omega-3-fatty acids, as the primary intervention. This can be supplemented drug therapies such as statin monotherapy or combination therapy with niacin/fibrates. Rosuvastatin is the only statin, presently available, to effectively treat AD in diabetes and MS patients.
Keywords: Atherogenic dyslipidaemia, cardiovascular disease, small-dense low-density lipoprotein statins
INTRODUCTION
In 1990, Austin and colleagues first explained Atherogenic Dyslipidemia (AD) as a clinical condition characterized by elevated levels of serum triglyceride (TG) levels and small-dense low-density lipoprotein (sdLDL) particles with low levels of high-density lipoprotein cholesterol (HDL-C), highlighting its atherogenic lipoprotein phenotype. Additionally, elevated levels of large TG rich very low-density lipoproteins (VLDL) and apolipoprotein B (Apo B) and reduced levels of small high-density lipoproteins plays critical role in AD. It is often observed in patients with metabolic syndrome (MS), obesity, insulin resistance and type 2 diabetes mellitus; hence also referred as either diabetic dyslipidemia or dyslipidemia of metabolic syndrome and is considered as an important CVD (Cardiovascular disease) risk factor in these patients.
The present review strives to underscore the role of AD in enhancing the risk of CVD. It also deals with the management of oxidized LDL integral to optimum CVD pharmacotherapy.
PATHOPHYSIOLOGY OF ATHEROGENIC DYSLIPIDAEMIA
In AD, there is impaired insulin signalling which increases lipolysis i.e. conversion of TG into free fatty acids (FFA) in adipocytes. These FFA are transported to liver and muscles via blood. Majority of FFA are re-esterified to TG which together with posttranslational stabilization of ApoB enhances the assembly and secretion of VLDL particles. The VLDL production is further augmented by elevated plasma glucose concentrations. Two types of VLDL are synthesized by liver- VLDL-1, the large TG-rich VLDL, and VLDL-2, the smaller TG-poor VLDL. Predominantly, overproduction of VLDL-1 in the liver is seen in patients with AD, insulin resistance and type 2 diabetes; determining atherogenicity of plasma lipoproteins.
Increased secretion of VLDL-1 led to increase in sdLDL production and decrease in HDL; substantially influencing the development of atherosclerosis.
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VLDL-1 production involves 3 steps: 1) Lipidation of Apo B100 in hepatocytes by utilising microsomal enzyme transfer protein in the endoplasmic reticulum, leading to production of nascent pre-VLDL particle; 2) lipidation of nascent pre-VLDL particle produce VLDL-2; and 3) lipidation of VLDL-2 produce VLDL-1. The synthesis of sdLDL from TG-rich VLDL-1 is a 2 step process: 1) Transfer of TG from VLDL1 to LDL by cholesteryl ester transfer protein (CETP) and 2) Conversion of TG rich LDL to sdLDL by hepatic lipase (HL). Though all LDLs are reported as atherogenic but sdLDLs are more atherogenic and serves as a better predictor of cardiovascular risk than LDL-C. They have an increased ability to penetrate arterial intima, susceptibility to retention in the extracellular matrix by binding to arterial proteoglycans, and have decreased antioxidant capacity. Increase in sdLDL generation has been noted when TG levels are >1.5 mmol/L. Since these particles have lower affinity to LDL-receptors on hepatocytes, there is decrease uptake and clearance of sdLDL, leading to their increased presence in the systemic circulation. Based on the size of LDL-C particles in the blood, there are 2 types of LDL patterns- A and B. LDL A has a particle size >25.5 nm while LDL B has particle size ≤25.5nm. Each VLDL, IDL, and LDL particle contains 1 Apo B100.
The LDL-C reflects the amount of cholesterol carried by an LDL particle. There are significant inter-individual variation in cholesterol content of LDL particles and varies as high as two times between individuals and change with lipid altering treatments. Therefore, total LDL particle (LDL-P) or Apo B is considered as an effective method to quantify LDL. In many patients, the levels of LDL-C and LDL-P were observed similar but in many others, due to variability in the cholesterol content of LDL particles both LDL-C and LDL-P levels were found discordant. Discordance was also reported in terms of LDL-C and LDL-P in patients receiving statin therapy as stains considerably lowers LDL-C than LDL-P. In AD, patients were reported to have a greater increase in LDL-P concentration at a given level of HDL-C.
Besides sdLDL, oxidized LDL also plays a significant role in AD. Oxidized LDL is generated via LDL or sdLDL. In vitro oxidation of LDL by metal ions occurs in three phases: 1) Initial lag phase- consumption of endogenous antioxidant; 2) propagation phase- rapid oxidation of unsaturated fatty acids to lipid hydroperoxides; and 3) decomposition phase-formation of reactive aldehydes. These aldehydes react with lysine residues in apoB-100 resulting in oxidized LDL. Circulating oxidized LDL does not originate from extensive metal ion-induced oxidation in the blood but from mild oxidation in the arterial wall by cell-associated LOX and/or myeloperoxidase. The amount of polyunsaturated fatty acids and antioxidant varies significantly within individuals, resulting in a great variation in susceptibility to LDL oxidation. The oxidized-LDL further interacts with scavenger receptors present on endothelial cells, macrophages, and smooth muscle cells causing endothelial dysfunction resulting in a huge build up of cholesterol within the blood vessel leading to atherosclerosis. Other functions of oxidized-LDL are inhibition of endothelial nitric-oxide synthase (eNOS) expression, adhesion molecule induction, facilitation of monocyte adhesion and infiltration, smooth muscle cell migration and proliferation, including the release of cytokine and growth factor from endothelial and smooth muscle cells.
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Besides production of sdLDL, CETP and HL acts on VLDL1 to produce small HDL. This small HDL has a high clearance from the circulation leading to decrease in the plasma level of HDL-C and apolipoprotein A-I. Hence, the metabolic disturbance that began with increased production of VLDL-TG ended in atherogenic reduction of HDL, intravascular remodelling, and reduced reverse cholesterol transport from peripheral tissues, hepatocytes and macrophages to liver, further aggravating atherosclerosis
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