**2.6 Apolipoproteins & atherogenic lipoprotein phenotype**

There are limited prospective studies about the relationship between apolipoproteins (apo A-I and apo B) and the CVD risk. The QCS10 was studied 2155 men aged between 45-76 years and reported a direct correlation between apo B levels and prevalence of ischemic heart disease over the future 5 years, [ relative risk (RR) 1.4; 95 percent CI, 1.2 to 1.7] (Lamarche et al., 1996), independent of other risk factors of CVD. For apo A–I, a negative correlation (RR = 0.85; 95 percent CI, 0.7 to 1.0) was reported.

Since the measurement of apo B and apo A–I is an indicator of total atherogenic (lDL, VLDL, and LDL) and antiatherogenic particles (HDL), some studies (Lamarche et al., 1996; Meisinger et al., 2005; Yusuf et al., 2004; Walldius et al., 2001, 2005) proposed that measurements of apo B and apo A are more important predictors of the CVD than above measurements. The AMORIS11 study evaluated this relationship in 175,553 subjects with 65 months follow up (Walldius et al., 2001). In the multivariate analysis the apo B concentration was significantly higher than LDL levels and served as a better predictor of CVD than LDL.

The results regarding the role of apolipoproteins in prediction of CVD risk are conflicting. Two studies; Women's Health Study and the Framingham Study obtained a similar predictive value for apo B/A–I ratio versus total cholesterol/ HDL ratio (Ridker et al., 2005; Ingelsson & Schaefer, 2007). However, in contrast to Health Professionals Follow-up Study (Pischon et al., 2005; Sniderman, 2005) and AMORIS study, apo A–I and apo B did not have any predictive value for CHD risk in ARIC12 study (Sharrett et al., 2001). The explanation for these disparate results is not clear. However, it seems apolipoproteins have a potential role in CHD risk stratification. Standardization of laboratory methods and measurements to the same reference system, and establishing threshold and target values for diagnosis could help recognize the full potential of apolipoproteins (Srinivasan & Berenson, 2001; Denke, 2005).

Apo E is important in plasma lipid metabolism and Apo E gene affects plasma levels of LDL. Three major apo E isoforms are E2, E3, and E4, which are encoded by three common alleles at the APO E locus. The less common and the most common isoforms in society are E2 and E3, respectively. E4 allele is associated with higher plasma total cholesterol and LDL cholesterol levels and with risk of heart attack. In contrast, subjects with E2 allele have lower risk of heart attack compared to people with E4 isoform (Song et al., 2004).

Some clinical researches have focused on the relationship between small dense LDL particles and risk of CVD. This status, also called atherogenic lipoprotein phenotype, is usually associated with increased triglyceride, VLDL and LDL levels (Krauss, 1994). The Physician's Health Study showed that small dense LDL particles can increase three times the risk of CVD more than LDL cholesterol (Zambon et al., 1996). In QCS study, during 5 year follow up, 114 cases from a total of 2103 were diagnosed with heart disease. In this study, in multivariate analysis small dense LDL was more important predictor of CVD [odds ratio (OR) = 3.7; 95 percent CI, 1.4 to 9.7) than LDL (OR = 1.8; 95 percent CI, 1.2 to 2.9) (Lamarche et al., 1997). The Familial atherosclerosis Treatment Study (FATS) found that LDL subclasses were the most important predictor of coronary progression (Zambon et al., 1999). In the Pravastatin Limitation of Atherosclerosis in the Coronaries (PLAC–I) study showed that

<sup>10</sup> Quebec Cardiovascular Study

<sup>11</sup> Apolipoprotein-related MOrtality RISk

<sup>12</sup> Atherosclerosis risk in Communities

There are limited prospective studies about the relationship between apolipoproteins (apo A-I and apo B) and the CVD risk. The QCS10 was studied 2155 men aged between 45-76 years and reported a direct correlation between apo B levels and prevalence of ischemic heart disease over the future 5 years, [ relative risk (RR) 1.4; 95 percent CI, 1.2 to 1.7] (Lamarche et al., 1996), independent of other risk factors of CVD. For apo A–I, a negative

Since the measurement of apo B and apo A–I is an indicator of total atherogenic (lDL, VLDL, and LDL) and antiatherogenic particles (HDL), some studies (Lamarche et al., 1996; Meisinger et al., 2005; Yusuf et al., 2004; Walldius et al., 2001, 2005) proposed that measurements of apo B and apo A are more important predictors of the CVD than above measurements. The AMORIS11 study evaluated this relationship in 175,553 subjects with 65 months follow up (Walldius et al., 2001). In the multivariate analysis the apo B concentration was significantly higher than LDL levels and served as a better predictor of CVD than LDL. The results regarding the role of apolipoproteins in prediction of CVD risk are conflicting. Two studies; Women's Health Study and the Framingham Study obtained a similar predictive value for apo B/A–I ratio versus total cholesterol/ HDL ratio (Ridker et al., 2005; Ingelsson & Schaefer, 2007). However, in contrast to Health Professionals Follow-up Study (Pischon et al., 2005; Sniderman, 2005) and AMORIS study, apo A–I and apo B did not have any predictive value for CHD risk in ARIC12 study (Sharrett et al., 2001). The explanation for these disparate results is not clear. However, it seems apolipoproteins have a potential role in CHD risk stratification. Standardization of laboratory methods and measurements to the same reference system, and establishing threshold and target values for diagnosis could help recognize the full potential of apolipoproteins (Srinivasan & Berenson, 2001; Denke,

Apo E is important in plasma lipid metabolism and Apo E gene affects plasma levels of LDL. Three major apo E isoforms are E2, E3, and E4, which are encoded by three common alleles at the APO E locus. The less common and the most common isoforms in society are E2 and E3, respectively. E4 allele is associated with higher plasma total cholesterol and LDL cholesterol levels and with risk of heart attack. In contrast, subjects with E2 allele have lower

Some clinical researches have focused on the relationship between small dense LDL particles and risk of CVD. This status, also called atherogenic lipoprotein phenotype, is usually associated with increased triglyceride, VLDL and LDL levels (Krauss, 1994). The Physician's Health Study showed that small dense LDL particles can increase three times the risk of CVD more than LDL cholesterol (Zambon et al., 1996). In QCS study, during 5 year follow up, 114 cases from a total of 2103 were diagnosed with heart disease. In this study, in multivariate analysis small dense LDL was more important predictor of CVD [odds ratio (OR) = 3.7; 95 percent CI, 1.4 to 9.7) than LDL (OR = 1.8; 95 percent CI, 1.2 to 2.9) (Lamarche et al., 1997). The Familial atherosclerosis Treatment Study (FATS) found that LDL subclasses were the most important predictor of coronary progression (Zambon et al., 1999). In the Pravastatin Limitation of Atherosclerosis in the Coronaries (PLAC–I) study showed that

risk of heart attack compared to people with E4 isoform (Song et al., 2004).

**2.6 Apolipoproteins & atherogenic lipoprotein phenotype** 

correlation (RR = 0.85; 95 percent CI, 0.7 to 1.0) was reported.

2005).

<sup>10</sup> Quebec Cardiovascular Study

<sup>11</sup> Apolipoprotein-related MOrtality RISk <sup>12</sup> Atherosclerosis risk in Communities

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) (Otvos et al., 2002).

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 al., 2002).

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

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 was no longer associated with CHD.

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 type 2 diabetics and the elderly subjects.

#### **3. Summary**

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 percent CI.

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

<sup>14</sup> Cardiovascular health Study

<sup>15</sup> Nuclear Magnetic Resonance

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

Dyslipidemia and Cardiovascular Disease 315

Abbott RD, Wilson PWF, Kannel WB, Castelli WP (1988). High density lipoprotein

Abbott RD, Yano K, Hakim AA (1998). Changes in total and high - density lipoprotein

Alwan A (2008). 2008–2013 action plan for the global strategy for the prevention and control

Ballantyne CM, Grundy SM, Oberman A, et al (2000). Hyperlipidemia: diagnostic and

Bansal S, Buring JE, Rifai N, et al (2007). Fasting compared with nonfasting triglycerides and

Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, et al (2007). HDL

Bennet A, Di Angelantonio E, Erqou S, et al (2008). Lipoprotein (a) levels and risk of future coronary heart disease: large-scale prospective data. *Arch Intern Med*; 168:598– 608. Blake GJ, Otvos JD, Rifai N, Ridker PM (2002). Low–density lipoprotein particle

as predictors of cardiovascular disease in women. *Circulation*; 106: 1930–7. Blood cholesterol levels by sex, adults aged 35–64, latest available data MONICA project

Bostom AG, Gagnon DR, Cupples LA, et al (1994). A prospective investigation of elevated

Bostom AG, Cupples LA, Jenner JL, et al (1996). Elevated plasma lipoprotein (a) and

Butler WJ, Ostrander LDJ, Carman WJ (1985). Mortality from coronary heart disease in the

Carlson LA, Böttiger LE, Ahfeldt PE (1979). Risk factors for myocardial infarction in the

Caroll MD, Lacher DA, Sorlie PD, Cleeman JI, Gordon DJ, Wolz M, et al. (2005).Trends in serum lipids and lipoproteins of adults, 1960–2002. *JAMA*; 294:1773– 81. Castelli WP (1983). Cardiovascular disease and multifactorial risk: Challenge of the 1980s.

Cobbaert C, Jukema JW, Zwinderman AH, et al (1997). Modulation of lipoprotein(a)

triglycerides and cholesterol. *Acta Med Scand*;206(5):351–60.

cholesterol, very low levels of LDL cholesterol, and cardiovascular events. *N Engl J* 

concentration and size as determined by nuclear magnetic resonancespectroscopy

LP (a) detected by electrophoresis and cardiovascular disease in women: the

coronary heart disease in men aged 55 years and younger: a prospective study.

Tecumseh Study: long–term effect of diabetes mellitus, glucose tolerance and other

Stockholm prospective study. A 14–year follow-up focussing on the role of plasma

atherogenicity by high density lipoprotein cholesterol levels in middle-aged men with symptomatic coronary artery disease and normal to moderately elevated serum cholesterol. Regression Growth Evaluation Statin Study (REGRESS) Study

of noncommunicable diseases. *Report World Health Organization*.

therapeutic perspectives. *J Clin Endocrinol Metab*; 85:2089–112.

risk of cardiovascular events in women. *JAMA*; 298:309–16.

population, 4th August 2008, Available from:

Framingham Heart Study. *Circulation*; 90: 1688–95.

http://www.ktl.fi/publications/monica.

risk factors. *Am J Epidemiol*; 121: 541–7.

cholesterol, total cholesterol screening, and myocardial infarction: the Framingham

holesterol over 10– and 20–year periods (the Honolulu Heart program). *Am J* 

**4. References** 

Study. *Arteriosclerosis*; 8: 207–11.

*Cardiol*; 82: 172–8.

*Med*; 357: 1301–10.

*JAMA*; 276: 544–48.

*Am Heart J*; 106: 1191–200.

Group. *J Am Coll Cardiol;* 30:1491–9.

Legend: LDL: Low Density Lipoprotein; Apo A-I: Apolipoprotein A-I; HDL: High Density Lipoprotein; Apo B100: Apolipoprotein B100; CRP: C - reactive protein.

Fig. 3. Adjusted Hazard ratios for future cardiovascular events.

Today, interventional studies have investigated the effects of augmentation of HDL levels. The clinical trials which deal with this matter will be discussed in a separate part. In assessment of dyslipidemia two points should be stipulated:


#### **4. References**

314 Dyslipidemia - From Prevention to Treatment

Legend: LDL: Low Density Lipoprotein; Apo A-I: Apolipoprotein A-I; HDL: High Density Lipoprotein;

Today, interventional studies have investigated the effects of augmentation of HDL levels. The clinical trials which deal with this matter will be discussed in a separate part.

1. Decline of coronary events could be possible by modifying the serum lipid levels in order to prevent or delay the reduction of vessel diameter, and also to stabilize atheroma plaques. Small plaques are mostly filled with lipid and are prone to disposable rupture, thrombosis, acute, serious and ultimately fatal atherosclerosis. Reduction of LDL leads to removal of fatty deposits from the inside of the atheroma plaque and makes them more stable. In addition, lowering the lipids levels can return the normal activity of vessel wall endothelium and its ability to produce nitric oxide,

2. During lipid-lowering drug therapy the cost-effectiveness of the treatment should be considered. This depends on the price of drugs as well as patient's risk. For example, at least cost-effectiveness includes patients with intermediate elevation of serum cholesterol, who, without any other risk factors, are under- lipid lowering agent therapy. In 4S study which was performed in patients with high risk of CVD, cost per year of life gain, was depended on age, sex and baseline levels of lipid. The range of this cost was varied from 3,800 \$ U.S. for men aged 70 years and the mean serum cholesterol 309 mg/dl, to 27,400 \$ U.S. for women aged 35 years and the average serum cholesterol 213 mg/dl (Johannessonet al., 1997). In other studies these figures were different from 19,000 \$ U.S. to 56,000 \$ U.S. which depends on drug dose and formulation used. Also, these costs were three folds, two folds and 1.3 folds more in women at age 40, 60 and 70 years, respectively, when compared with the men at age 40 years (Martens & Guibert,

Apo B100: Apolipoprotein B100; CRP: C - reactive protein.

1994; Thorvik et al., 1996).

Fig. 3. Adjusted Hazard ratios for future cardiovascular events.

In assessment of dyslipidemia two points should be stipulated:

the main mediator of coronary vasodilation (Krauss, 1994).


Dyslipidemia and Cardiovascular Disease 317

Harper CR, Jacobson TA (1999). New perspectives on the management of low levels of high–density lipoprotein cholesterol. *Arch Intern Med;* 159(10):1049–57. Heiss G, Tamir I, Davis CEo (1980). Lipoprotein –Cholesterol distributions in selected North

Hokanson IE, Austin MA (1996). Plasma triglyceride level is a risk factor in cardiovascular

Kagan A, Harris BR, Winkelstein W Jr (1974). Epidemiologic studies of coronary disease and

physical, dietary and biochemical characteristics. *J Chronic Dis*; 27: 345–64. Kannel WB, Castelli WP, Gordon T, McNamara PM (1971). Serum cholesterol, lipoproteins,

Kannel WB, Castelli WP, Gordon T (1979). Cholesterol in the prediction of atherosclerotic

Kannel WB (1983). High–density lipoproteins: epidemiologic profile and risks of coronary

Krauss RM (1994). Heterogeneity of plasma low–density lipoproteins and atherosclerosis

Kuller L, Arnold A, Tracy R, et al (2002). Nuclear magnetic resonance spectroscopy of

Kushi LH, Lew RA, Stare FJ (1985). Diet and 20–year mortality from coronary heart disease.

Labarthe DR (2011). Coronary heart disease, In: *Epidemiology and prevention of cardiovascular* 

Lamarche B, Moorjani S, Lupien PJ, et al (1996). Apolipoprotein AI and B levels and the risk

The Ireland –Boston Diet–Heart Study. *N Engl J Med*; 312: 811–8.

lipoproteins and risk of coronary heart disease in the cardiovascular health study.

*disease: a global challenge*, Labarthe DR, pp. 59-87, Jones and Bartlett, ISBN-13: 978–0–

of ischemic heart disease during a five year follow up of men in the Quebec

Keys A (1970). Coronary heart disease in seven countries. *Circulation*; 41 (suppl 1): 1–199. Keys A, Menotti A, Aravanis C, Blackburn H, Djordevic BS, Buzina R, et al. (1984). The seven countries study: 2289 deaths in 15 years. *Prev Med*; 13: 141–54. Kinosian B, Glick H, Garland G (1994). Cholesterol and coronary heart disease: predicting

of population - based prospective studies. *J Cardiovasc Risk*; 3: 213–9. Ingelsson E, Schaefer EJ, Contois JH, et al (2007). Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. *JAMA*; 298: 776–85. Johannesson M, Jonsson B, Kjekshns J (1997). Cost–effectiveness of Simvastatin treatment to

High blood cholesterol and other lipids–statistics, 8 June 2011, Available from:

*Circulation*; 61: 302–15.

www.americanheart.org

332–6.

1–12.

90: 85–91.

artery disease. *Am J Cardiol*; 52:9B–l2B.

risk. *Curr Opin Lipidol;* 5: 339–49.

7637–4689–6, Canada.

*Arterioscler Thromb Vasc Biol;* 22:1175–80.

Cardiovascular Study. *Circulation*; 94: 273–278.

risk s by levels and ratios. *Ann Intern Med*; 121: 641–7.

American populations: the Lipid Research Clinics Program Prevalence Study.

disease independent of high density lipoprotein cholesterol level: a meta – analysis

lower cholesterol levels in patients with coronary heart disease. *N Engl J Med*; 336:

stroke in Japanese men living in Japan, Hawaii and California: demographic,

and the risk of coronary heart disease: the Framingham Study. *Ann Intern Med*; 74:

disease: new perspective based on the Framingham Heart Study. *Ann Intern Med*;


Critchley J, Liu J, Zhao D (2004). Explaining the increase in coronary heart disease mortality

Dawber TR, Meadors GF, Moore FE Jr (1951). Epidemiological approaches to heart disease:

Denke MA (2005). Weighing in before the fight: low–density lipoprotein cholesterol and

Dobsn A, Filipiak B, Kuulasmaa K (1996). Relations of changes in coronary disease rates and

Dyer AR, Stamler J, Paul O (1981). Serum cholesterol and risk of death from cancer and other causes in three Chicago epidemiological studies. *J Chronic Dis*; 39: 249–60. E'g'gen DA, Strong JP, McGill HCJ (1964). Calcification in the abdominal aorta: relationship

El Harchaoui K, van der Steeg WA, Stroes ES, et al (2007). Value of low–density lipoprotein

Emerging Risk Factors Collaboration, Erqou S, Kaptoge S, et al (2009). Lipoprotein(a)

Fager G, Wiklund O, Olofsson SO, Wilhelmsen L, Bondjers G (1981). Multivariate analysis

Ford ES, Li C, Zhao G, Pearson WS, Mokdad AH (2009). Hypertriglyceridemia and its pharmacologic treatment among US adults. *Arch Intern Med*; 169: 572–8. Genest JJ Jr, Martin-Munley SS, McNamara JR, Ordovas JM, Jenner J, Myers RH, et al. (1992).

Glueck CJ, Gartside P, Fallat RW, et al (1976). Longevity syndromes: familial hypobeta and

Glueck CJ, Stein EA (1979). Treatment and management of hyperlipoproteinemia in

Goldstein JL, Hazzard WR, Schrott HG, Bierman EL, Motulsky AG (1973). Hyperlipidemia

Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, et al. (1989).

Gorelick PB, Schneck M, Berglund LF, Feinberg W, Goldstone J (1997). Status of lipids as a

Haim M, Benderly M, Brunner D, et al (1999). Elevated serum triglyceride levels and long-

familial hyperalphalipoproteinemia. *J Lab Clin Med*; 88: 941–75.

Coronary Heart Disease, New York: Raven Press; pp. 285–307.

to race, sex, and coronary atherosclerosis. *Arch Pathol*; 78: 575– 83.

non–high–density lipoprotein cholesterol versus apolipoprotein B as the best predictor for coronary heart disease and the best measure of therapy. *Circulation*;

changes in risk factor levels: methodological issues and a practical example. *Am J* 

particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC–Norfolk Prospective Population Study. *J Am* 

concentration and the risk of coronary heart disease, stroke, and nonvascular

of apolipoproteins and risk factors in relation to acute myocardial infarction.

Familial lipoprotein disorders in patients with premature coronary artery disease.

childhood. In: Levy R, Rifkind B, Dennis B, Ernst N. Nutrition, Lipids, and

in coronary heart disease I. Lipid levels in 500 survivors of myocardial infarction. *J* 

High-density lipoprotein cholesterol and cardiovascular disease. Four prospective

term mortality in patients with coronary heart disease: the Bezafibrate Infarction

in Beijing between 1984 and 1999. *Circulation*; 110: 1236–44.

the Framingham Study. *Am J Public Health*; 41: 279–86.

112: 3368–70.

*Epidemiol*; 143: 1025–34.

*Coll Cardiol*; 49:547–53.

*Arteriosclerosis*; 1: 273–7.

*Circulation*; 85: 2025–33.

*Clin Invest*; 52:1533–43.

American studies. *Circulation*; 79: 8–15.

risk factor for stroke. *Neuroepidemiology*; 16: 107–15.

Prevention (BIP) Registry. *Circulation*; 100: 475–82.

mortality. JAMA; 302:412– 23.


Dyslipidemia and Cardiovascular Disease 319

Rifkind BM, Segal P (1983). Lipid Research Clinics Program reference values for Hyperlipidemia

Roncaglioni MC, Santoro L, D'Avanzo B, Negri E, Nobili A, Ledda A, et al. (1992). Role of

Rosengren A, Wilhelmsen L, Eriksson E (1990). Lipoprotein (a) and coronary heart disease

Rosenson RS (2005). Low HDL–C: a secondary target of dyslipidaemia therapy. *Am J Med*;

Sacks FM, Tonkin AM, Craven T, Pfeffer MA, Shepherd J, Keech A, et al (2002). Coronary

Schaefer EI, Lamon - Fava S, Ianner I (1994). Lipoprotein (a) levels and risk of coronary heart

Sharrett AR, Ballantyne CM, Coady SA, et al (2001). Coronary heart disease prediction from

Sniderman AD (2005). Apolipoprotein B versus non–high–density lipoprotein cholesterol:

Song Y, Stampfer MJ, Liu S (2004). Meta–analysis: apolipoprotein E genotypes and the risk

Sprecher DL, Pearce GL, Cosgrove DM, et al (2000). Relation of serum triglyceride levels to

Srinivasan SR, Berenson GS (2001). Apolipoproteins B and A–I as predictors of risk of

Stamler, J, Wentworth, D, Neaton, JD (1986). Is relationship between serum cholesterol and

Stein IH, Rosenson RS (1997). Lipoprotein LP (a) excess and coronary heart disease. *Arch* 

Steyrer E, Durovic S, Frank S, et al (1994). The role of lecithin: cholesterol acyltransferase for

Thom TJ, Kannel WB, Silbershats S (1998). Incidence, prevalence and mortality of

for coronary heart disease. *Ann Intern Med*; 141 (2): 137–47.

The WHO MONICA Project: Risk factors (1989). *Int J Epidemiol*; 339: 861–7.

Rosenson RS. Screening guidelines for dyslipidemia, May 2011, Available from:

family history in patients with myocardial infarction. An Italian case- control study.

risk: a prospective case - control study in a general population sample of middle –

Heart disease in patients with low LDL–cholesterol: benefit of pravastatin in diabetics and enhanced role for HDL– cholesterol and triglycerides as risk factors.

disease in men: the Lipid Research Clinics Primary Prevention Trial. J*AMA*; 271:

lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A–I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC)

Relation of serum triglyceride levels to survival after coronary artery bypass

risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial

lipoprotein (a) assembly. Structural integrity of low density lipoproteins is a prerequisite for Lp(a) formation in human plasma. *J Clin Invest*; 94: 2330– 40.

cardiovascular diseases in the United States. In: Hurst's the Heart, 9th ed, Alexander R W, Schlant RC, Fuster V, Roberts R (Eds), McGraw Hill, New York,

and hypolipidemia. *JAMA*; 250: 1869–72.

aged men. *BMJ*; 301: 1248–51.

*Circulation*; 105: 1424–8.

Study. *Circulation*; 104: 1108–13.

grafting. *Am J Cardiol*; 86:285–8.

(MRFIT). *JAMA*; 256:2823–8.

*Intern Med*: 157: 1170–6.

P.3.

and the winner is... *Circulation*; 112: 3366–7.

Coronary artery disease. *Lancet*; 358:2012–3.

118: 1067–77.

www.uptodate.com

999–1003.

GISSI–EFRIM investigators. *Circulation*; 85: 2065–72.


Lamarche B, Tchernof A, Mooljani S, et al (1997). Small, dense low–density lipoprotein

Law MR, Wald NJ, Thompson SG (1994). By how much and how quickly does reduction in

Loscalzo J, Weinfeld M, Fless GM, Scanu AM (1990). Lipoprotein(a), fibrin binding, and

Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Manttar M, Heinonen OP, et al (1992).

Martens LL, Guibert R (1994). Cost–effectiveness analysis of Lipid – modifying therapy in

Meisinger C, Loewel H, Mraz W, Koenig W (2005). Prognostic value of apolipoprotein B and

Murray CJ, Lopez AD (1997). Mortality by cause for eight regions of the world: Global

Murray CJ, Lopez AD (1997). Alternative projections of mortality and disability by cause

Nieto FJ, Alonso J, Chambliss LE (1995). Population awareness and control of hypertension

Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A (2007). Nonfasting triglycerides

Otvos JD, Shalaurova I, Freedman DS, Rosenson RS (2002). Effects of pravastatin treatment

Palabrica TM, Liu AC, Aronovitz MJ, Furie B, Lawn RM, Furie BC (1995). Antifibrinolytic

Pischon T, Girman CJ, Sacks FM, et al (2005). Non–high–density lipoprotein cholesterol and

Rabbani N, Godfrey L, Xue M, Shaheen F, Geoffrion M, Milne R, et al (2011). Glycation of

increased risk of cardiovascular disease in diabetes. *Diabetes*; 60 (7): 1973–80. Ridker PM, Rifai N, Cook NR, Bradwin G, Buring JE (2005). Non–HDL cholesterol,

risk factors for cardiovascular disease in women. *JAMA*; 294:326– 33.

1990–2020: Global Burden of Disease Study. *Lancet*; 349: 1498–504.

results from the Quebec Study. *Circulation*; 95: 69–75.

plasminogen activation. *Arteriosclerosis;* 10:240– 5.

implications for treatment. *Circulation*: 85: 37–45.

Burden of Disease Study. *Lancet*; 349: 1269–76.

of coronary heart disease. *Clin Therapeut*; 16: 1052–62.

367–72.

965–70.

*Med*; 155: 677–84.

160:41–8.

112: 3375–83.

women. *JAMA*; 298:299–308.

particles as a predictor of the risk of ischemic heart disease in men: prospective

serum cholesterol concentration lower risk of ischemic heart disease? *BMJ*; 308:

Joint effects of serum triglyceride and LDL–cholesterol and HDL– cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study:

Canada: comparison of HMG–COA reductase inhibitors in the primary prevention

A–I in the prediction of myocardial infarction in middle-aged men and women: results from the MONICA/KORA Augsburg cohort study. *Eur Heart J*; 26:271–8. Miller NE, Thelle DS, Forde OH, Mjos OD (1977). The TromsØ heart study. High–density

Lipoprotein and coronary heart disease: a Prospective case–control study. *Lancet*; 1:

and hypercholesterolemia: the atherosclerosis in communities study. *Arch Intern* 

and risk of myocardial infarction, ischemic heart disease, and death in men and

on lipoprotein subclass profiles and particle size in the PLAC–I trial. *Atherosclerosis*;

activity of apolipoprotein(a) in vivo: human apolipoprotein(a) transgenic mice are resistant to tissue plasminogen activator-mediated thrombolysis. *Nat Med*; 1:256– 9.

apolipoprotein B in the prediction of coronary heart disease in men. *Circulation*;

LDL by methylglyoxal increases arterial atherogenicity. A possible contributor to

apolipoproteins A–I and B100, standard lipid measures, lipid ratios, and CRP as


**16** 

*Tunisia* 

**Cardiovascular Risk in Tunisian Patients** 

Asma Ezzaher1,2, Dhouha Haj Mouhamed1,2, Anwar Mechri2,

*²Research Laboratory "Vulnerability to Psychotic Disorders LR 05 ES 10",* 

Bipolar disorder (previously also labeled manic-depressive illness) is typically referred to as an episodic, yet lifelong and clinically severe affective (or mood) disorder, affecting approximately 3.5% of the population (Marmol, 2008; Simon, 2003; Wittchen et al., 2003; Woods, 2000). The term bipolar disorder, however, encompasses several phenotypes of mood disorders, i.e. mania, hypomania or cyclothymia that may present with a puzzling variety of other symptoms and disorders. According to the Fourth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (American Psychiatric Association, 2004), the diagnostic classificatory system used in most epidemiological studies, bipolar disorder is defined by a set of specific symptom criteria. Bipolar type I requires the presence or the history of at least one manic or mixed episode. Although, typically, patients with a manic episode also experience major depressive episodes, bipolar disorder can be diagnosed even if only one manic episode and no past major depressive episodes are present. Bipolar disorder type II differs from type I only by presence of hypomanic but no manic episodes. Hypomanic episodes differ from mania by a shorter duration (at least 4 days instead of 1 week), and less severe impairment (not severe enough to cause marked impairment in social or occupational functioning, psychiatric hospitalization, or psychotic features). The DSM-IV also includes "cyclothymia" as a bipolar spectrum disorder with hypomanic as well as depressive episodes that do not meet criteria for major depression (American Psychiatric

Bipolar disorder is a chronic disease that is associated with a potentially devastating impact on patients' wellbeing and social, occupational, and general functioning (Revicki et al., 2005). The disorder ranks as the sixth leading cause of disability in the world, with an economic burden that in the US alone that was estimated more than a decade ago at \$7 billion in direct medical costs and \$38 billion (1991 values) in indirect costs (Wyatt et al.,

A number of reviews and studies have shown that people with severe mental illness, including bipolar disorder, have an excess mortality, being two or three times as high as that

**1. Introduction** 

Association, 2004).

1991).

**with Bipolar I Disorder** 

and Mohamed Fadhel Najjar1 *1Laboratory of Biochemistry-Toxicology,* 

Fadoua Neffati1, Wahiba Douki1,2, Lotfi Gaha2

*Department of Psychiatry/Monastir University Hospital,* 

