Patient case: 24-year-old female with familial hypercholesterolemia; genetic feature: PCSK9

Clinical trial: Effect of Rosuvastatin Therapy on HDL2 Level

Summary: In many large trials, reducing low density lipoprotein (LDL) levels with rosuvastatin decreased the incidence of major cardiovascular events，but little attention to the effects of rosuvastatin on HDL level，especially on HDL subtype.
  Epidemiological evidence strongly favors the notion that the risk of cardiovascular disease (CVD) is inversely related to the plasma high-density lipoprotein (HDL) cholesterol concentration.
  HDL can be subdivided into large-sized (HDL2a, HDL2b) and small-sized subclasses (preb1-HDL, HDL3c, HDL3b, HDL3a) and preb2-HDL. Some studies indicate that only large HDL2a and HDL2b particles make HDLs possess anti-atherogenic functions.
  The investigators assume that rosuvastatin could play the role of anti-atherosclerosis though the levels of HDL2a、HDL2b increased.

Detailed description: Elevated LDL-C and lowered HDL-C are important risk factors for cardiovascular disease. Raising HDL-C is an attractive approach for reducing the residual risk of cardiovascular events that persist in many patients receiving low-density LDL-C -lowering therapy with statins. From previous studies, it is concluded that compared to atorvastatin, rosuvastatin could significantly increase HDL-C levels from baseline. However, which benefits the elevated HDL-C will bring to these patients who receive statin lowing LDL-C therapy are still unknown. Despite strong evidence that HDL-C levels predict atherosclerotic events, attempts at using an HDL-based treatment strategy as a therapeutic target have not yet been successful at the present time. However, on the basis of an enormous amount of basic scientific and clinical investigation, the International Atherosclerosis Society and US National Lipid Association still believe that there are a considerable number of reasons supporting the need to continue to investigate the therapeutic effect of modulating HDL structure and function.
  It has long been known that a low level of HDL cholesterol is a powerful independent predictor of increased cardiovascular risk, even among patients with LDL cholesterol levels below 70 mg/dl. In fact, a 1 mg/dl (0.026 mM) increment in HDL-C levels was associated with a significant decrease in the risk of coronary heart disease (CAD) of 2% in men and 3% in women. HDL-C has been proposed to have several anti-atherosclerotic properties, including the ability to mediate reverse cholesterol transport (RCT), antioxidant capacity, anti-inflammatory properties, nitric oxide-promoting activity, and an ability to transport proteins with their own intrinsic biological activities. RCT describes the metabolism and an important antiatherogenic function of HDL, namely, the HDL-mediated efflux of cholesterol from cells of the arterial wall and its subsequent delivery to the liver and steroidogenic organs, thus preventing atherosclerosis. HDL particles are responsible for RCT, as critical acceptors of cholesterol from lipid-laden macrophages and thereby play an important role in the maintenance of net cholesterol balance in the arterial wall and in the reduction of pro-inflammatory responses by lipid-rich macrophages. The antiatherogenic properties of HDL have been primarily ascribed to RCT. Khera et al. recently reported that HDL efflux capacity was inversely and significantly correlated with carotid intima-media thickness (CIMT). A one-standard deviation increase in HDL efflux capacity predicted a 30% reduction in the odds for CAD. Although cholesterol efflux from macrophages represents only a small portion of total RCT, the cholesterol efflux from macrophage foam cells is probably the most relevant step with respect to preventing or reversing atherosclerosis. HDL can be separated into two major parts, i.e., pre β-(further distinguished into preβ1-, preβ2-,preβ3-HDL) and a-HDL(separated into 5 distinct subclasses HDL3c 3b 3a 2a 2b). It has been postulated that RCT indeed was the metabolic process that nascent preβ-HDL converted to mature a-HDL, following the route of preβ1-HDL→preβ2-HDL→preβ3-HDL→HDL3→HDL2[13].
  The effect of HDL-C on plaque formation is complex, since HDL particles are highly heterogeneous, and exist as a spectrum of small, intermediate and large particles that differ in lipid and protein content. So the increase in plasma HDL-C does not necessarily reflect an increase in reverse cholesterol transport (RCT). Former studies from cholesteryl ester transfer protein(CETP) modulators and inhibitors such as dalcetrapib have limited efficacy to be still on the way may attributed to their concentration only on raising total HDL-C level and undesirable side effects. Results obtained in some studies, have shown that HDL quality (HDL subpopulations), rather than quantity (total HDL concentration), should be the target of future pharmacological therapies. A number of investigations have reported that, with the increase of plasma LDL-C or the decrease of plasma HDL-C concentrations or elevated TC(total cholesterol), or in some CAD patients with hyperlipidemia, or patients of CAD with diabetes, there was a general shift toward smaller-sized HDL (HDL3), which, in turn, indicates that reverse cholesterol transport might be weakened and HDL maturation might be abnormal. Significantly lower larger-sized HDL-HDL2 in CAD patients with hyperlipidemia compared with control patients, and this inverse relationship between HDL-C, HDL2, and CAD is particularly strong in men with type 2 diabetes mellitus. In type 2 diabetes patients, the difference between HDL2 in the myocardial infarction (MI) and non-MI group persists after adjustment for physical activity, alcohol intake, obesity, duration of diabetes, and glycemic control. Moreover, HDL2 deficiency has also been demonstrated to be a primary alteration in myocardial infarction patients even without other significant risk factors. The tendency that small-sized HDL3b, and HDL3a levels were significantly higher, and the large-sized HDL2a and HDL2b levels were significantly lower were also detected in ACS(acute coronary syndrome) patients. From articles on Chinese patients with elevate TC or LDL-C/HDL-C ratio, there was also a general shift toward smaller-sized HDL particles, which implied that the maturation process of HDL was blocked. Overall, accumulate evidences have demonstrated that in patients with CAD/CAD comorbid with diabetes/elevated TC levels, HDL maturation was hampered in the stage of the transformation of small-sized HDL3 to larger sized HDL2. HDL2 levels have inverse associations with the risk of acute myocardial infarction and thus to be protective factors in ischemic heart disease. It has also demonstrated that patients with high HDL2 level were better protected from atherosclerosis.
  It has been demonstrate that atorvastatin 20 mg/d treatment for 8 weeks could result in a favorable modification of HDL subfraction phenotype. Treated with atorvastatin 20mg/d significantly increased the cholesterol concentration of large HDL particles and decreased the cholesterol concentration of small HDL particles although without changes of serum HDL-C level in patients with atherosclerosis. However, there are still lack of evidence on the effect of rosuvastatin treatment for HDL maturation(for the step of transformation of HDL3 to HDL2)and RCT process in CAD and Chinese patients. It has been demonstrated that Low HDL cholesterol is frequently associated with low HDL2b and high HDL cholesterol frequently associated with high HDL2b. As the investigators discussed above, compared to atorvastatin, rosuvastatin could significantly decrease LDL-C level and increase HDL-C level from baseline. So besides the basic effect of lowing LDL-C, it has a strong possibility that rosuvastatin therapy on CAD patients with hyperlipidemia could reverse the aberrant HDL maturation process via elevating lager HDL2 level, and then restore the RCT process to the normal to prevent atherosclerosis.

Eligibility: Inclusion Criteria:
  1. Patients with CAD undergoing quantitative coronary angiography ;
  2. Patients with hyperlipidemia: TG(Triglyceride)>1.6mmol/L and/or TC(total cholesterol)>4.6mmol/L, and they didn't take antilipemic agents or steroid hormone at least three months before this trial.
  3. Patients between the ages of 30 and 75 years, the functions of liver or kidney are not severe.
  Exclusion Criteria:
  1. Thyroid dysfunction, Liver or Biliary Tract Diseases, Acute Myocardial Infarction during the last half year, Renal Insufficiency or Kidney Failure and Cerebrovascular Trauma;
  2. Drug induce Hyperlipidemia, Familial Hypercholesterolemia;
  3. Having a major trauma , operation with intestines and stomach recently or the disease affecting drug absorbed;
  4. Having Anaphylactic Reaction, Mental Disorders and Drinking history.
  5. Taking statin, Nicotinic Acids and other drugs which can influence the level of HDL.

Relevance to patient case: not relevant