**2.4 Non-HDL cholesterol**

Non–HDL cholesterol is defined as the difference between total and HDL cholesterols. Thus it includes LDL, Lp (a), IDL and VLDL (Ballantyne et al., 2000). In both LRCP study and the Women's Health Study non-HDL cholesterol has been suggested as a better tool for risk assessment of CVD than LDL levels (Cobbaert et al., 1997; Ridker et al., 2005). In the LRCP study in which the patients were followed for an average of 19 years, a 30 mg/dl difference in non–HDL and LDL concentrations, produced 19 and 15 percent, increase in mortality risk of CVD among men, respectively, and 11 and 8 percent, among women, respectively, (Cobbaert et al., 1997).

### **2.5 Lipoprotein (a)**

Lipoprotein (a), also called Lp (a), is established as an independent risk factor for CVD. Lp (a) is a modified form of LDL with a structure similar to plasminogen (Steyrer et al., 1994) that could interfere with fibrinolysis by competing with plasminogen for binding to cells (Loscalzo et al., 1990; Palabrica et al., 1995). Lp (a) also binds to macrophages to promote foam cell formation and deposition of cholesterol in atherosclerotic plaques (Zioncheck et al., 1991). Thus, Lp (a) accelerates atherosclerosis process by impairing fibrinolysis and increasing LDL oxidation (Stein & Rosenson, 1997). Evidences of association between Lp (a) excess [Lp (a) levels above the 95th percentile] and CVD mostly come from 2 large metaanalyses that found positive continuous correlation between Lp (a) and risk of CVD events (Bennet et al., 2008; Emerging et al., 2009). The 24 cohort studies in the meta-analysis (Bennet et al., 2008) found a risk ratio of 1.13 (95 percent CI, 1.09 to 1.18) between the top and third bottom baseline Lp (a) levels after adjustment for multiple traditional cardiovascular risk factors. Lp (a) excess concentration is usually detected in patients with premature CHD. In one study 18.6 percent of patients with premature CHD had excess levels of Lp (a), while 12.7 percent of them had no dyslipidemia (Genest et al., 1992).

LP (a) increases the risk of cerebrovascular disease, peripheral vascular disease, myocardial infarction (MI), re–stenosis after angioplasty, and failure after CABG (Rosengren et al., 1990; Schaefer et al., 1994). 12 years and more follow–up of patients in the Framingham Heart study showed that Lp (a) can increase the risk of premature coronary heart disease by two-times (Bostom et al., 1996), and augment the risk of MI, intermittent claudication, cerebrovascular disease, and coronary artery stenosis. In the 4S9 study an association between increased Lp (a) levels and overall mortality rate was also observed (Bostom et al., 1994).

<sup>9</sup> Scandinavian Simvastatin Survival Study

Dyslipidemia and Cardiovascular Disease 313

small LDL particle size (≤ 20.5 nm) could increase rate of coronary progression with OR= 5.0 and 95 percent CI, 1 to 9. High numbers of small LDL particles (>30 mg/dl) was the most important lipoprotein predictor in multivariate analysis (OR = 9.1; 95 percent CI, 2.1 to 39)

In the FATS13 study 95 percent variance in regression of atherosclerosis in coronary arteries were related to changes in lipid profile. Adding the LDL density to the equation showed that almost 45 percent of the variance was related to changes in LDL density (Lamarche et al., 1997). In contrast, the CHS14 reported that LDL particle concentration and not LDL size acted as a significant predictor of MI and angina in women, in which by every 100 nmol/l increase in LDL particle number, the OR of MI and angina increased by 11 percent (Kuller et

In Women's Health Study which assessed LDL particle size and concentration by NMR15 , the LDL particle concentration was a strong predictor of CVD after adjustment for

EPIC16- Norfolk prospective Population Study examined NMR-measured LDL particle size and concentration (EI Harchaoui et al., 2007) and found that LDL particle concentration did not increase the prediction of CHD. After LDL particle concentration adjustment, LDL size

Recently, some scientists from the University of Warwick in UK discovered a modified form of LDL, MGmin-LDL, also called super-sticky LDL, or very-bad LDL, that promotes CVD (Rabbani et al., 2011). High levels of this lipid are more common in diabetics and elderly patients. Diabetic subjects present almost four times more serum levels of MGmin-LDL than normal subjects. This may explain the high frequency of CVD in diabetics and elderly patients. Rabbani et al (Rabbani et al., 2011) found that secondary to hyperglycemia, LDL is glycated with methylglyoxal (MG) and makes a type of LDL with smaller, stickier and more atherogenic LDL than normal LDL. The MGmin-LDL can help to build fatty plaques. When these plaques grow, the wall of arteries become narrower and the blood flow reduces. Plaque rapture, an event that would eventually happen, triggers the blood clot cascades that could cause a heart attack or stroke. In elderly, the activity of the enzyme for detoxification of MGmin-LDL is reduced. They (Rabbani et al., 2011) also showed that metformin can block the glycation processes which might explain the cardioprotective effects of this drug. This discovery could lead to invention of new treatments for CVD prevention especially in

The relationships described above can be summarized in the figure-3 (Ridker et al., 2005). This figure shows the adjusted Hazard ratios of future cardiovascular events among patients who are in the extreme quintiles of each measured marker. Black bars present 95

(Otvos et al., 2002).

traditional risk factors (Blake et al., 2002).

was no longer associated with CHD.

type 2 diabetics and the elderly subjects.

<sup>13</sup> Familial Atherosclerosis Regression Study

<sup>16</sup> European Prospective Investigation into Cancer and Nutrition

<sup>14</sup> Cardiovascular health Study <sup>15</sup> Nuclear Magnetic Resonance

**3. Summary** 

percent CI.

al., 2002).
