Hypercholesterolemia And Cardio Vascular Diseases

Tuesday, 16 February 2010 00:00

Is the effective management of hypercholestelomia still an open question?

Several key factors contribute to CVD, including age, high blood pressure (BP), smoking, high cholesterol levels, high body mass index (BMI), obesity, and diabetes. The median age in most member states of the EU is now over 30 years (Italy is the highest with 41.6 years). By 2020, 20% of people in Europe will be over 60 years and more than 5% will be over the age of 80 years. Obesity and diabetes are estimated to be 30 million in 2020, with obesity and overweight, in particular, affecting 30 to 80% of adults in countries comprising WHO Europe.
The fall in mortality in several countries was mainly due to a net reduction in population risk factors (−58%) and improved efficacy and uptake of treatments (−42% reduction). The improvements in certain major risk factors (e.g., smoking, serum total cholesterol, and BP), was, however, offset by adverse trends for some other risk factors, including a worsening of obesity, diabetes mellitus, and physical activity.
Among the mentioned risk factors correlated to Cardio Vascular Disease - CVD, Hypercholesterolemia represents, from one side, the single biggest risk for MI and, on other side, the more modifiable one. Further it combines its effect with ageing, overweight, insulin resistance, diabetes, hypertension, and smoking. The consequent multiple risk approach is becoming the way to reduce the global risk of cardiovascular diseases and of the correlated renal damage (Lancet 2007; 370:591-603). Hypercholesterolemia is a proven risk factor for CHD and plays a key role in the development and progression of atherosclerosis (a chronic inflammatory disease) JAMA 1990; 264 (23): 3047-3052; Ann Epidemiol 1992; 2 (1-2): 23-28; Am J Cardiol 1980; 46 (4): 649-654; JAMA 1986; 256 (20): 2823-2828).
It is well known that contemporary, highly effective treatment regimens do not prevent many (residual) cardiovascular events, particularly in high risk individuals (Circulation 2006; 113:2936-42). The success of the LDL-C lowering medical approach requires that more attention be focused on decreasing the residual cardiovascular risk that still remains at levels of 60-70% and requires greater knowledge of the residual combined risk factors (J Clin Lipidology 2007; 1:306-7). The diabetic patient with hyperlipedemia combined with insulin-resistance represents a population where a more aggressive approach is required to reduce disability and mortality in such very high risk patients. (see also http://www.lorenzinifoundation.org/MRM/slides/)
Therapeutic interventions to lower LDL-C levels show a clear reduction in the progression of atherosclerosis, and this translates into a decline in the incidence of major coronary and vascular events. Regression analysis showed a linear relationship between LDL-C level achieved (or the percent reduction in LDL-C) and the change in percent diameter stenosis or change in minimum luminal diameter (MLD). The updated guidelines propose an LDL-C level of less than 100 mg/dL (ca 2.6 mmol/L), less than 70 mg/dL (ca 1.8 mmol/L) as an optional therapeutic goal for persons at very high risk of developing CVD. Plasma LDL-C levels are un-physiologically high in the Western world. LDL-C less than 100 mg/dL (ca 2.6 mmol/L) is safe and is associated with a low rate of CV events in the population. Reduction of un-physiologically high LDL-C levels is also safe and reduces events, although adherence and persistence with statins therapy is poor and remains to be addressed in order to spend health care funds effectively.


February 16, 2010

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Insight to Different Approach for Cardiovascular Risk Prevention Dr. Pradeep Dabla 2010-03-12 21:57:07 Evolving knowledge that a significant number of cardiovascular events occur in subjects with normal levels of both LDL-cholesterol and HDL-cholesterol has stressed a search for additional biomarkers with better predictive value. It is well accepted that HDL-cholesterol levels are inversely related to the risk of clinical events due to atherosclerosis. Many literatures reveal the importance of HDL-cholesterol levels in predicting coronary events such as Framingham study, Air Force–Texas Coronary Atherosclerosis Prevention Study. (1,2) Most HDL particles contain both apoA-I and apoA-II. The HDL particles contain apoA-I and have preβHDL mobility, are considered to be the most active in removing cholesterol from cells. HDL inhibits the LDL oxidation and prevents atherosclerosis by different mechanisms. HDL abolishes the synthesis and secretion of monocyte chemoattractant protein (MCP)-1 by the cells, which evokes a potent inflammatory response of the type seen in atherosclerosis (3). Also, it causes decrease in activity of two HDL-associated enzymes, paraoxonase-1 (PON1) and platelet-activating factor acetylhydrolase (PAF-AH) which prevents ability of normal HDL to inhibit proinflammatory LDL-derived oxidized lipids (4). Hedrick et al. (5) showed that glycation of HDL by incubation under hyperglycemic conditions caused the HDL to lose its ability to inhibit monocyte adhesion to human aortic endothelial cells exposed to oxidized LDL. Examination of therapeutic potential and various properties of HDL is an emerging area of research, important for improving the detection of people at risk for atherosclerotic events and for targeting novel therapies. The HDL level can be increased by treatment with fibrates or peroxisome proliferative activating receptor agonists, and infusion of apoA-IMilano for acute treatment (6). On the other hand search for apoA-I mimetic peptides has shown promising results with 4F (7). References: 1. Castelli WP et al. (1986) Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham study. JAMA 256:2835-2838. 2. Downs JR et al. (1998) Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 279:1615-1622. 3. Navab M, Imes SS, Hama SY, Hough GP, Ross LA, Bork RW, Valente AJ, Berliner JA, Drinkwater DC, Laks H. Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein. J Clin Invest 1991; 88:2039–2046. 4. Watson AD, Leitinger N, Navab M, Faull KF, Ho rkko S, Witztum JL, Palinski W, Schwenke D, Salomon RG, Sha W, Subbanagounder G, Fogelman AM, Berliner JA. Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/endothelial interactions and evidence for their presence in vivo. J Biol Chem 1997;272:13597–13607. 5. Hedrick CC, Thorpe SR, Fu MX, Harper CM, Yoo J, Kim SM, Wong H, Peters AL. Glycation impairs high-density lipoprotein function. Diabetologia 2000;43:312–320. 6. 6. Alexander ET, Tanaka M, Kono M, Saito H, Rader DJ, Phillips MC. Structural and functional consequences of the Milano mutation (R173C) in human apolipoprotein A-I. J Lipid Res 2009;50:1409–1419. 7. Navab M, Anantharamaiah GM, Hama S, Garber DW, Chaddha M, Hough G, Lallone R, Fogelman AM. Oral administration of an Apo A-I mimetic peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation 2002;105:290– 292.

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