401
edits
Atherosclerosis: Difference between revisions
→Lipid-Altering therapy
| Line 221: | Line 221: | ||
==== ''Lipid-Altering therapy'' ==== | ==== ''Lipid-Altering therapy'' ==== | ||
One of the most important strategies to reduce the complications of atherosclerosis is diet and exercise. In order to decrease cholesterol, Mediterranean diet is often recommended. Mediterranean diet consists of low animal fat, high olive oil, moderate energy consumption, nuts, vegetables, regular and moderate wine, lots of whole grains and beans. A meta-analysis of six randomized trials showed that Mediterranean diet led to greater reduction in total cholesterol than low fat diets among overweight/obese population. Mediterranean-styled diet in this context means replacement of saturated fats with polyunsaturated fats such as omega-3 fatty acid and α-linolenic acid. Polyunsaturated fats are potential anti-atherogenic due to | Controlling serum lipids is a key step to limit the consequences of atherosclerosis. Major clinical trials have shown that coronary events and mortality significantly decreased when total and LDL-cholesterol levels were reduced for the primary and secondary prevention of CAD events. | ||
One of the most important strategies to reduce the complications of atherosclerosis is diet and exercise. In order to decrease cholesterol, Mediterranean diet is often recommended. Mediterranean diet consists of low animal fat, high olive oil, moderate energy consumption, nuts, vegetables, regular and moderate wine, lots of whole grains and beans. A meta-analysis of six randomized trials showed that Mediterranean diet led to greater reduction in total cholesterol than low fat diets among overweight/obese population. Mediterranean-styled diet in this context means replacement of saturated fats with polyunsaturated fats such as omega-3 fatty acid and α-linolenic acid. Polyunsaturated fats are potential anti-atherogenic due to their inhibiting action on cytokine-induced expression of leukocyte adhesion molecules at endothelial cells. Exercise and loss of excessive weight also contributes to improve abnormal lipid levels by reducing triglycerides and increasing HDL. | |||
In primary prevention, pharmacologic agents are the second option when lifestyle modifications fail to achieve targeted lipid profile. There are several groups of lipid-altering medicines such as HMG-CoA reductase inhibitors (statins), niacin, fibric acid derivatives, cholesterol intestinal absorption inhibitors, and bile acid-binding agents. In the clinical setting, statins are widely used, being the most cost-effective LDL-lowering drugs. They reduce intracellular cholesterol concentration by inhibiting HMG-CoA reductase, which is an enzyme that synthesizes cholesterol. This results into increased LDL-receptor expression and therefore leads to higher clearance of LDL molecules from blood. They also affect the liver and thereby lower the rate of VLDL synthesis, which results into lower levels of serum triglyceride. Statins also raise HDL, but this mechanism is not fully understood yet.< | In primary prevention, pharmacologic agents are the second option when lifestyle modifications fail to achieve targeted lipid profile. There are several groups of lipid-altering medicines such as HMG-CoA reductase inhibitors (statins), niacin, fibric acid derivatives, cholesterol intestinal absorption inhibitors, and bile acid-binding agents. In the clinical setting, statins are widely used, being the most cost-effective LDL-lowering drugs. They reduce intracellular cholesterol concentration by inhibiting HMG-CoA reductase, which is an enzyme that synthesizes cholesterol. This results into increased LDL-receptor expression and therefore leads to higher clearance of LDL molecules from blood. They also affect the liver and thereby lower the rate of VLDL synthesis, which results into lower levels of serum triglyceride. Statins also raise HDL, but this mechanism is not fully understood yet. | ||
Large studies, which have evaluated the effects of statin therapy, showed that ischemic cardiac events, the occurrence of MI and mortality rates were significantly reduced by implementing statin therapy. This significant improvement did not only apply to people with known preexisting atherosclerotic disease, but also to people within lower ranges of LDL and without preexisting atherosclerotic disease. For example, West of Scotland Coronary Prevention Study (WOSCPS trial) evaluated the effect of pravastatin on rates of nonfatal MI or CHD death, nonfatal MI, all cardiovascular deaths and total mortality among patients with hypercholesterolemia without preexisting CVD for five years. Use of pravastatin resulted in 31% risk reduction (p<0.001) in nonfatal MI or CHD death, and a 32% risk reduction (p=0.033) in all cardiovascular deaths as compared to the control group. | |||
Inhibiting HMG-CoA reductase results | Inhibiting HMG-CoA reductase results in several mechanisms that explain the beneficial effect of using statins. One beneficial mechanism is via lowering LDL and raising HDL. This results into less lipid content in atherosclerotic plaques and improve their biologic activity. Furthermore, the anti-thrombotic and anti-inflammatory profile is enhanced by other mechanisms such as increased NO synthesis and fibrinolytic activity, inhibition of smooth muscle proliferation and monocyte recruitment, and reduced production of matrix-degrading enzymes by macrophages. Several studies suggest that other mechanisms also contribute to the anti-inflammatory profile. For example, statins reduce endothelial expression of leukocyte adhesion molecules and macrophage tissue factor production by inhibiting the macrophage cytokines or by activating PPAR-α. Another anti-inflammatory action of statins, supported by clinical trials is reducing the serum level of C-reactive protein, which is a marker of inflammation. <br /> | ||
Although statin therapy can reduce the risk of atherosclerotic cardiovascular disease by about one third, there is still a need for additional risk-reducing therapies. Thus, a new idea was developed to raise HDL cholesterol as a treatment for atherosclerosis. With the finding of the high-HDL phenotype of a human genetic deficiency of cholesteryl ester transfer protein (CETP), a new class of drugs was developed, which inhibits CETP. CETP functions as a mediator for transfer of cholesteryl ester from HDL to VLDL/LDL, which is then cleared by LDL receptors in liver. Thus when CETP is inhibited, this transfer process is inhibited and the direct hepatic HDL clearance pathway takes over. This leads to less fractional clearance of HDL from plasma, which is beneficial for atherosclerosis. Although the absolute clearance rate of HDL remains the same, the key step for atherosclerosis, which is the removal of cholesterol from macrophage foam cells in artery wall by HDL, is reduced. <br /> | Although statin therapy can reduce the risk of atherosclerotic cardiovascular disease by about one third, there is still a need for additional risk-reducing therapies. Thus, a new idea was developed to raise HDL cholesterol as a treatment for atherosclerosis. With the finding of the high-HDL phenotype of a human genetic deficiency of cholesteryl ester transfer protein (CETP), a new class of drugs was developed, which inhibits CETP. CETP functions as a mediator for transfer of cholesteryl ester from HDL to VLDL/LDL, which is then cleared by LDL receptors in liver. Thus when CETP is inhibited, this transfer process is inhibited and the direct hepatic HDL clearance pathway takes over. This leads to less fractional clearance of HDL from plasma, which is beneficial for atherosclerosis. Although the absolute clearance rate of HDL remains the same, the key step for atherosclerosis, which is the removal of cholesterol from macrophage foam cells in artery wall by HDL, is reduced. <br /> | ||
The most recently investigated CETP inhibitors are torcetrapib, anacetrapib, and dalcetrapib. In the Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) trial, involving 15,000 patients at high risk for coronary heart disease, torcetrapib was clinically investigated. Unfortunately this trial was prematurely stopped due to the finding of an increase in cardiovascular events associated with | The most recently investigated CETP inhibitors are torcetrapib, anacetrapib, and dalcetrapib. In the Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) trial, involving 15,000 patients at high risk for coronary heart disease, torcetrapib was clinically investigated. Unfortunately this trial was prematurely stopped due to the finding of an increase in cardiovascular events associated with an undiscovered off-target effect. Anacetrapib and dalcetrapib are still under active clinical investigation, since they lack the off-target effects of torcetrapib. | ||
==== ''Tobacco smoking'' ==== | ==== ''Tobacco smoking'' ==== | ||