**2. Theoretical framework**

### **2.1 Cardiovascular risk – Generalities**

Cardiovascular diseases are an unavoidable topic when discussing health related issues, particularly in developed societies. Cardiovascular disease is the leading cause of mortality in these countries (World Health Organization, 2002), assuming a progressively more important role in developing countries and even in less developed countries. In the latter, we may consider the presence of a *double-frontier* of health risk. These countries show

Dyslipidemia and Cardiovascular Risk:

1988).

Judelson *et al*, 1999).

sudden death (Silva, 2000).

Lipid Ratios as Risk Factors for Cardiovascular Disease 281

Regarding arterial hypertension, it always presents itself as a major risk factor, given its very high incidence and prevalence. Despite all the research carried out and considering all the remarkable therapeutic advances, the control of blood pressure levels only provides a reduction of about 40% in mortality from cerebrovascular disease and a more modest 20%

Diabetes is another important risk factor, with the particularity of becaming the major epidemy of this century given its substantial and consistent epidemiological growth. The high cardiovascular risk that diabetes provides is well illustrated by the prognostic similarity between a diabetic patient without clinical manifestations of coronary heart disease and a patient with a history of acute coronary events (Hafnner, Lethe, Ronnema *et al*,

Obesity is undoubtedly a major risk factor for cardiovascular disease (Higgins, Kannel, Garrison *et al*, 1988), now becoming a public health problem, given the alarming increase of its prevalence in industrialized countries. The pathogenic mechanisms involved in this situation are complex and not just related to the metabolic overload involved, but also determined by its close associations with arterial hypertension, type 2 diabetes,

Smoking is consensually assumed as a relevant contributer to cardiovascular disease, both in the active as well as the passive form. Some studies indicate that smokers have a reduced life expectancy of about ten years (although this number is dose-dependent) and that this habit cancells the natural cardioprotection in women (Silva, 2000). In fact, the differences in cardiovascular risk amongst men and women are well known, largely documented by the classic time lag between genders, with a higher risk in males until the fifth decade of life, with a progressive increase in women of cardiovascular risk until the eighth decade of life, when the risk is similar in men and women. The explanation for this is closely linked to the production and subsequent estrogen deficiency (as a consequence of menopause) seen in different phases of a woman's life. But other factors must not be overlooked. For instance, If we consider only the lipid profile changes induced by menopause, on average a 10% increase in LDL-cholesterol, an 8% reduction in HDLcholesterol and an elevation in triglycerides are expected. Nonetheless, these changes can be normalized by hormonal replacement therapy (Stampfer, Colditz, Willet *et al*, 1991). Oral contraception, by contrast, tends to cause an adverse impact on lipid profile. At present, the worrying rate of young women with acute coronary events, a situation rarely seen before, has directed special attention to factors that could be blamed for this surprising finding. The association of hormonal contraception with smoking has emerged as very common in this population, likely to concur not only for atherogenic metabolic features but also for potentially thrombotic coagulation disorders (Mosca, Grundy,

The cardiovascular impact of alcohollic intake must also be considered. The cardiovascular impact of this behaviour is closely related to the amount of alcohol consumed. A moderate intake may confer some cardiovascular protection, particularly by raising HDL-cholesterol and reducing platelet aggregation, yet it may lead to a higher incidence of arterial hypertension and cerebrovascular disease. Patterns of high alcoholic consumption are an unusually hazardous behaviour, particularly for the heart, greatly increasing the risk of

reduction in mortality from coronary heart disease (Kaplan, 2002).

dyslipidemia, and inflammation (Higgins, Kannel, Garrison *et al*, 1988).

coexistence of important mortality indexes related to diseases whose prevalence is a demonstration to their stage of development (perinatal, nutritional and infectious health problems), with a more consistent presence of coronary disease, with increased percentage reaching 137% for males and 120% for females by the year 2010 (Yusuf, Reddy, Ounpuu *et al*, 2001).

In epidemiological terms, coronary heart disease and cerebrovascular disease represent the most significant expressions of cardiovascular disease, and were the main causes of mortality and morbidity worldwide, accounting for one third of total mortality in the year 2001 (American Heart Association, 2003). According to the World Health Organization, every year 16 million deaths occur from cardiovascular disease, and this number is expected to rise to 20 million in the first decade of the XXI century (World Health Organization, 2002). The singular importance of coronary heart disease is extraordinarily important and it is estimated that mortality by this disease had risen to 7.2 million individuals by the year 2001 (World Health Organization, 2002). However, in recent years, there has been a trend towards a decline in this disease in Western countries, with a concomitant increase in other lands, notably in Russia and Eastern European countries. In fact, in Western countries, the number of deaths from coronary per 100,000 inhabitants was 151 in 1972, dropping to 44 in 2004, in men aged 64 or less. Similar reductions were also observed in females (36 to 11 women per 100,000). Paradoxically, in Russia, there was a marked increase of this rate, from 169/100.000, in the year 1980, to 242/100.000 deaths, in the year 2005 (Allender, Scarborough, Black *et al*, 2008).

The onset of cardiovascular disease is consistently related to the presence of a group of cardiovascular risk factors, whose manipulation can be crucial to its prevention (see Table 1).


Table 1. Conventional cardiovascular risk factors.

Concerning reversible risk factors in which intervention could be decisive, we should highlight the relative importance of smoking, arterial hypertension and hypercholesterolaemia. Although the global fight against all reversible risk factors constitute a therapeutic imperative, the elimination of hypercholesterolemia would result in the single most important benefit against the incidence of coronary heart disease as well as other atherosclerotic vascular problems (Wilson, D'Augustine, Levy *et al*, 1998).

coexistence of important mortality indexes related to diseases whose prevalence is a demonstration to their stage of development (perinatal, nutritional and infectious health problems), with a more consistent presence of coronary disease, with increased percentage reaching 137% for males and 120% for females by the year 2010 (Yusuf, Reddy, Ounpuu *et* 

In epidemiological terms, coronary heart disease and cerebrovascular disease represent the most significant expressions of cardiovascular disease, and were the main causes of mortality and morbidity worldwide, accounting for one third of total mortality in the year 2001 (American Heart Association, 2003). According to the World Health Organization, every year 16 million deaths occur from cardiovascular disease, and this number is expected to rise to 20 million in the first decade of the XXI century (World Health Organization, 2002). The singular importance of coronary heart disease is extraordinarily important and it is estimated that mortality by this disease had risen to 7.2 million individuals by the year 2001 (World Health Organization, 2002). However, in recent years, there has been a trend towards a decline in this disease in Western countries, with a concomitant increase in other lands, notably in Russia and Eastern European countries. In fact, in Western countries, the number of deaths from coronary per 100,000 inhabitants was 151 in 1972, dropping to 44 in 2004, in men aged 64 or less. Similar reductions were also observed in females (36 to 11 women per 100,000). Paradoxically, in Russia, there was a marked increase of this rate, from 169/100.000, in the year 1980, to 242/100.000 deaths, in the year 2005 (Allender,

The onset of cardiovascular disease is consistently related to the presence of a group of cardiovascular risk factors, whose manipulation can be crucial to its prevention (see Table 1).

Concerning reversible risk factors in which intervention could be decisive, we should highlight the relative importance of smoking, arterial hypertension and hypercholesterolaemia. Although the global fight against all reversible risk factors constitute a therapeutic imperative, the elimination of hypercholesterolemia would result in the single most important benefit against the incidence of coronary heart disease as well as other

*al*, 2001).

Scarborough, Black *et al*, 2008).

**Reversible**  Smoking

 Obesity Sedentarism Alcohol Stress **Irreversible**  Family history Male gender

Age

Table 1. Conventional cardiovascular risk factors.

 Diabetes Menopause

 Arterial hypertension Hyperlipidemia

**Partially Reversible** 

atherosclerotic vascular problems (Wilson, D'Augustine, Levy *et al*, 1998).

Regarding arterial hypertension, it always presents itself as a major risk factor, given its very high incidence and prevalence. Despite all the research carried out and considering all the remarkable therapeutic advances, the control of blood pressure levels only provides a reduction of about 40% in mortality from cerebrovascular disease and a more modest 20% reduction in mortality from coronary heart disease (Kaplan, 2002).

Diabetes is another important risk factor, with the particularity of becaming the major epidemy of this century given its substantial and consistent epidemiological growth. The high cardiovascular risk that diabetes provides is well illustrated by the prognostic similarity between a diabetic patient without clinical manifestations of coronary heart disease and a patient with a history of acute coronary events (Hafnner, Lethe, Ronnema *et al*, 1988).

Obesity is undoubtedly a major risk factor for cardiovascular disease (Higgins, Kannel, Garrison *et al*, 1988), now becoming a public health problem, given the alarming increase of its prevalence in industrialized countries. The pathogenic mechanisms involved in this situation are complex and not just related to the metabolic overload involved, but also determined by its close associations with arterial hypertension, type 2 diabetes, dyslipidemia, and inflammation (Higgins, Kannel, Garrison *et al*, 1988).

Smoking is consensually assumed as a relevant contributer to cardiovascular disease, both in the active as well as the passive form. Some studies indicate that smokers have a reduced life expectancy of about ten years (although this number is dose-dependent) and that this habit cancells the natural cardioprotection in women (Silva, 2000). In fact, the differences in cardiovascular risk amongst men and women are well known, largely documented by the classic time lag between genders, with a higher risk in males until the fifth decade of life, with a progressive increase in women of cardiovascular risk until the eighth decade of life, when the risk is similar in men and women. The explanation for this is closely linked to the production and subsequent estrogen deficiency (as a consequence of menopause) seen in different phases of a woman's life. But other factors must not be overlooked. For instance, If we consider only the lipid profile changes induced by menopause, on average a 10% increase in LDL-cholesterol, an 8% reduction in HDLcholesterol and an elevation in triglycerides are expected. Nonetheless, these changes can be normalized by hormonal replacement therapy (Stampfer, Colditz, Willet *et al*, 1991). Oral contraception, by contrast, tends to cause an adverse impact on lipid profile. At present, the worrying rate of young women with acute coronary events, a situation rarely seen before, has directed special attention to factors that could be blamed for this surprising finding. The association of hormonal contraception with smoking has emerged as very common in this population, likely to concur not only for atherogenic metabolic features but also for potentially thrombotic coagulation disorders (Mosca, Grundy, Judelson *et al*, 1999).

The cardiovascular impact of alcohollic intake must also be considered. The cardiovascular impact of this behaviour is closely related to the amount of alcohol consumed. A moderate intake may confer some cardiovascular protection, particularly by raising HDL-cholesterol and reducing platelet aggregation, yet it may lead to a higher incidence of arterial hypertension and cerebrovascular disease. Patterns of high alcoholic consumption are an unusually hazardous behaviour, particularly for the heart, greatly increasing the risk of sudden death (Silva, 2000).

Dyslipidemia and Cardiovascular Risk:

mmol/L) in women (UK HDL-C Consensus Group, 2004).

International Lipid Information Bureau, 2003).

**Lipidic** 

 Lipoproteic remnants Lipoprotein (a) Small and dense LDL HDL subspecies apolipoprotein B Apolipoprotein A-1 **Inflammatory** 

 High-sensitivity CRP Homocysteine Interleukin-6

 Selectin-CD40 **Metabolic** 

(insulin resistance)

Cell adhesion molecule-1

Postprandial hyperinsulinemia

Table 2. Emerging cardiovascular risk factors.

Lipid Ratios as Risk Factors for Cardiovascular Disease 283

heterogeneity of triglyceride-rich lipoproteins (Quilomicra and VLDL) and its inseparable association with other risk factors. However, several studies have demonstrated a clear correlation between their levels and the occurrence of coronary heart disease, indicating that the presence of high levels of Triglycerides leads to a 13% increase in the risk of cardiovascular disease in men and 37% in women (Castelli, 1986; Criqui, Heiss, Cohn *et al*, 1993; Hokanson & Austin, 1996; Assman, Schulte & von Eckardstein, 1996). With regard to HDL-cholesterol, its inverse relationship with the risk of coronary heart disease is well accepted. In fact, this risk is 2 to 3% lower for each 1mg/dl elevation of HDL-Cholesterol (Gordon, Probstfiel, Garrison *et al*, 1989). The protective properties of this fraction derive not only from its involvement in reverse cholesterol transport, but are also a consequence of its anti-inflammatory capacity and protection against LDL-cholesterol oxidation (Ansell, Navab, Watson *et al*, 2004). On the other hand, it is recognized that individuals with very low levels of HDL-cholesterol have a higher cardiovascular risk. This population is often characterized for having concomitant hypertriglyceridemia, obesity, a sedentary lifestyle, active tobacco intoxication and decreased glucose tolerance (World Health Organization, 1999). In fact, an increased occurrence of cardiovascular events is expected for levels of HDL-cholesterol below 40 mg/dl (1.0 mmol/L) in men and less than 46 mg/dl (1.2

Recent evidence further stresses the importance of determining the non-HDL-cholesterol, defined by the concentration of LDL-cholesterol + VLDL-cholesterol. This parameter can better translate the risk of cardiovascular mortality than LDL-cholesterol, as it expresses

In recent years, a large number of risk factors for vascular disease have emerged from the international literature (see Table 2), demonstrating the relevance of more complex lipid disorders for the pathophysiology of atherosclerosis. Other emerging risk factors are related to inflammatory markers, as well as by the presence of metabolic changes, subtle changes in coagulation, hormonal disturbances and psychological or behavioral disorders (ILIB

> **Coagulation**  Fibrinogen

Factor VII

 Alcoholism Depression Social Isolation

**Hormonal** 

Von Willebrand Factor

**Psychological / Behavioral** 

 Loss and social support Low socioeconomic status

Plasminogen activator inhibitor (PAI-1)

Loss of estrogen production (menopause)

more accurately the lipoprotein atherogenicity (Cui, Blumenthal, Flaws *et al*, 2001).

### **2.2 Cardiovascular risk – Dislipidemia**

Lipids are a very heterogeneous group of compounds, and their influence on metabolism goes far beyond the misdeeds attributed to him. Lipids constitute an important source of energy storage, represented by triglycerides, and assume a great importance in the constitution of the brain (17% of its dry weight), the formation of hormones, lipoproteins, bile acids, vitamins, and in the structure of cell membranes. Cholesterol and Triglycerides are transported between various components of the organism by specific proteins called apoproteins. These constitute the protein fraction of lipoproteins whose lipid component includes phospholipids, cholesterol and Triglycerides. Lipoproteins are usually divided into six classes according to their composition, size, density and function: Quilomicra, VLDL (very low density lipoproteins), IDL (intermediate density lipoprotein), LDL (low density lipoprotein), HDL (high density lipoprotein) and Lipoprotein (a). The interaction of lipoproteins with a high number of enzymes, transport proteins and receptors, constitutes a complex metabolism where equilibrium is determined by intrinsic and extrinsic factors, and its unbalance leads to the pathophysiological cascade of atherosclerosis, with its well known clinical consequences (Silva, 2000). In very one-dimensional terms, fat from the diet is transported to the intestinal wall and integrated into large lipoprotein particles rich in triglycerides - the Quilomicra - which, when secreted by the lymphatic system eventually reach the bloodstream. The liver, in its turn, synthesizes other lipoproteins with high content of triglycerides, the VLDL. The extracellular lipoprotein-lipase degrades triglycerides of Quilomicra and VLDL into free fatty acids, which are deposited in tissues. Lipoproteins, by reducing their concentration in triglycerides, are converted into IDL, which are usually hydrolyzed by the hepatic lipase, and are than converted into LDL, which bind to specific liver or peripheral receptors. Meanwhile, in another cycle - the reverse transport of cholesterol - HDL particles pick up cholesterol deposited in the arterial wall and provide transportation to the liver, where it is subsequently excreted in the bile (Eckardstein, Hersberger & Roher, 2005).

The disorder of lipid metabolism is a key player for the occurrence of cardiovascular disease and particularly heart disease. For many years, cholesterol has been directly related to cardiovascular prognosis. This relationship is very consistent, as an increase of 2 to 3% in the incidence of coronary heart disease is expected for every 1% increase in total cholesterol (Carlson, Bottiger & Ahfeldt, 1979). A review of internationally published studies showed, however, that this association may be even stronger. Thus, a 10% increase in total cholesterol relates to a 38% increase in the risk of coronary-related mortality (Law, Wald & Thompson, 1994). More recently, several clinical studies on the primary and secondary prevention of coronary heart disease emphasized the importance of the LDL fraction (ILIB International Lipid Information Bureau, 2003) allowing the potential for the discrimination of cardiovascular risk. In fact, the risk of each patient may best be defined by the magnitude of the LDL-cholesterol rather than its total cholesterol, which is why international standards for the treatment of dyslipidemia have been oriented to listing the risk thresholds and treatment goals depending on the plasma levels of this lipoprotein. In practical terms, the determination of LDL-cholesterol may be derived by the Friedewald formula, where LDL Cholesterol = Total Cholesterol - HDL Cholesterol - VLDL cholesterol, VLDL cholesterol are derived from triglycerides/5.

For many years it was difficult to classify unequivocally Triglycerides as an independent risk factor for the occurrence of coronary heart disease, a situation presumably related to the wide fluctuations observed in their concentrations throughout the day, with the

Lipids are a very heterogeneous group of compounds, and their influence on metabolism goes far beyond the misdeeds attributed to him. Lipids constitute an important source of energy storage, represented by triglycerides, and assume a great importance in the constitution of the brain (17% of its dry weight), the formation of hormones, lipoproteins, bile acids, vitamins, and in the structure of cell membranes. Cholesterol and Triglycerides are transported between various components of the organism by specific proteins called apoproteins. These constitute the protein fraction of lipoproteins whose lipid component includes phospholipids, cholesterol and Triglycerides. Lipoproteins are usually divided into six classes according to their composition, size, density and function: Quilomicra, VLDL (very low density lipoproteins), IDL (intermediate density lipoprotein), LDL (low density lipoprotein), HDL (high density lipoprotein) and Lipoprotein (a). The interaction of lipoproteins with a high number of enzymes, transport proteins and receptors, constitutes a complex metabolism where equilibrium is determined by intrinsic and extrinsic factors, and its unbalance leads to the pathophysiological cascade of atherosclerosis, with its well known clinical consequences (Silva, 2000). In very one-dimensional terms, fat from the diet is transported to the intestinal wall and integrated into large lipoprotein particles rich in triglycerides - the Quilomicra - which, when secreted by the lymphatic system eventually reach the bloodstream. The liver, in its turn, synthesizes other lipoproteins with high content of triglycerides, the VLDL. The extracellular lipoprotein-lipase degrades triglycerides of Quilomicra and VLDL into free fatty acids, which are deposited in tissues. Lipoproteins, by reducing their concentration in triglycerides, are converted into IDL, which are usually hydrolyzed by the hepatic lipase, and are than converted into LDL, which bind to specific liver or peripheral receptors. Meanwhile, in another cycle - the reverse transport of cholesterol - HDL particles pick up cholesterol deposited in the arterial wall and provide transportation to the liver, where it is subsequently excreted in the bile (Eckardstein,

The disorder of lipid metabolism is a key player for the occurrence of cardiovascular disease and particularly heart disease. For many years, cholesterol has been directly related to cardiovascular prognosis. This relationship is very consistent, as an increase of 2 to 3% in the incidence of coronary heart disease is expected for every 1% increase in total cholesterol (Carlson, Bottiger & Ahfeldt, 1979). A review of internationally published studies showed, however, that this association may be even stronger. Thus, a 10% increase in total cholesterol relates to a 38% increase in the risk of coronary-related mortality (Law, Wald & Thompson, 1994). More recently, several clinical studies on the primary and secondary prevention of coronary heart disease emphasized the importance of the LDL fraction (ILIB International Lipid Information Bureau, 2003) allowing the potential for the discrimination of cardiovascular risk. In fact, the risk of each patient may best be defined by the magnitude of the LDL-cholesterol rather than its total cholesterol, which is why international standards for the treatment of dyslipidemia have been oriented to listing the risk thresholds and treatment goals depending on the plasma levels of this lipoprotein. In practical terms, the determination of LDL-cholesterol may be derived by the Friedewald formula, where LDL Cholesterol = Total Cholesterol - HDL Cholesterol - VLDL cholesterol, VLDL cholesterol are

For many years it was difficult to classify unequivocally Triglycerides as an independent risk factor for the occurrence of coronary heart disease, a situation presumably related to the wide fluctuations observed in their concentrations throughout the day, with the

**2.2 Cardiovascular risk – Dislipidemia** 

Hersberger & Roher, 2005).

derived from triglycerides/5.

heterogeneity of triglyceride-rich lipoproteins (Quilomicra and VLDL) and its inseparable association with other risk factors. However, several studies have demonstrated a clear correlation between their levels and the occurrence of coronary heart disease, indicating that the presence of high levels of Triglycerides leads to a 13% increase in the risk of cardiovascular disease in men and 37% in women (Castelli, 1986; Criqui, Heiss, Cohn *et al*, 1993; Hokanson & Austin, 1996; Assman, Schulte & von Eckardstein, 1996). With regard to HDL-cholesterol, its inverse relationship with the risk of coronary heart disease is well accepted. In fact, this risk is 2 to 3% lower for each 1mg/dl elevation of HDL-Cholesterol (Gordon, Probstfiel, Garrison *et al*, 1989). The protective properties of this fraction derive not only from its involvement in reverse cholesterol transport, but are also a consequence of its anti-inflammatory capacity and protection against LDL-cholesterol oxidation (Ansell, Navab, Watson *et al*, 2004). On the other hand, it is recognized that individuals with very low levels of HDL-cholesterol have a higher cardiovascular risk. This population is often characterized for having concomitant hypertriglyceridemia, obesity, a sedentary lifestyle, active tobacco intoxication and decreased glucose tolerance (World Health Organization, 1999). In fact, an increased occurrence of cardiovascular events is expected for levels of HDL-cholesterol below 40 mg/dl (1.0 mmol/L) in men and less than 46 mg/dl (1.2 mmol/L) in women (UK HDL-C Consensus Group, 2004).

Recent evidence further stresses the importance of determining the non-HDL-cholesterol, defined by the concentration of LDL-cholesterol + VLDL-cholesterol. This parameter can better translate the risk of cardiovascular mortality than LDL-cholesterol, as it expresses more accurately the lipoprotein atherogenicity (Cui, Blumenthal, Flaws *et al*, 2001).

In recent years, a large number of risk factors for vascular disease have emerged from the international literature (see Table 2), demonstrating the relevance of more complex lipid disorders for the pathophysiology of atherosclerosis. Other emerging risk factors are related to inflammatory markers, as well as by the presence of metabolic changes, subtle changes in coagulation, hormonal disturbances and psychological or behavioral disorders (ILIB International Lipid Information Bureau, 2003).


Table 2. Emerging cardiovascular risk factors.

Dyslipidemia and Cardiovascular Risk:

**2.3 Cardiovascular risk – Atherogenesis** 

physiology of this system.

Lipid Ratios as Risk Factors for Cardiovascular Disease 285

Another point that reinforces the superiority of the lipid ratios in the stratification of cardiovascular risk arises from the effect of dietary cholesterol on plasma lipid levels. Several studies have demonstrated that these ratios are not affected by dietary cholesterol (Greene, Zerner, Wood *et al*, 2005; Herron, Vega-Lopez, Earl *et al*, 2002). On the contrary, some studies have shown that dietary cholesterol interferes with LDL-cholesterol and HDLcholesterol, with little variation in the ratio (McNamara, 2000). On average, the predicted change in the LDL-Cholesterol/HDL-Cholesterol ratio per 100 milligrams/day increase in

To understand the sequence of events that occur at the vascular level, resulting in devastating clinical manifestations that are all too familiar, we must look a little closer at the

One of the most important organs we have without doubt is the vascular endothelium. The endothelium is the inner portion of our vessels, which can be compared to a thin membrane that carpets the blood vessels, and its integrity is fundamental for the maintenance of several potentially unstable equilibria. In this sense, a huge amount of vascular wall or circulating factors are present in close relation to the endothelium, endlessly alternating between defense and aggression, aggression, with Nitric Oxide as the key protector. As the most egregious examples of interaction near the endothelium vicinity, we have the following associations: vasodilation/vasoconstriction; anti-trombotic/pro-trombotic; anti-inflamatory/pro-inflamatory, among others. The relative hegemony of each of these interacting factors will determine the final maintenance of endothelial integrity or, conversely, its dysfunction and destruction (Houston, 2002). Endothelial dysfunction is thus the initial phase of a cascade of events that flow until the onset of clinically overt disease. In a very simplified overview, once the endothelial barrier is compromised, an association of events takes place, mainly with a lipid flooding process of the vascular wall, with the mobilization of inflammatory cells, the expression of chemotactic factors, growth and proliferation of smooth muscle and connective tissue, among others. The histologic consequence of these processes ranges from an initial lipid streak that evolves for an atherosclerotic plaque that may progress to

Curiously, most clinical cases are not determined directly by the extreme portion of the atherosclerotic continuum. In other words, cardiovascular events do not usually stem from progressive and insidious arterial occlusion, with consequent ischemia of downstream areas. Of course, cardiovascular events tend to be characterized by their acute nature, that is, by their sudden and unpredictable occurrence. As such, the implicit pathophysiology should express facts that support real-life events. In fact, one of the most important factors in the emergence of cardiovascular events is related to the so-called "atherosclerotic plaque stability". Thus, plaques with a small lipid core, with small inflammation infiltrate, and fitted with a thick, tough outer layer will be less susceptible to disruption by various harmful factors, such as blood pressure, sympathetic activity and other vasoconstrictor stimuli. In contrast, plaques with a rich lipid core, inflammatory activity and a significant weak fibrous cap will present a higher risk of fracture and exposure of their internal contents (Ridolfi & Hutchins, 1977). This in turn will lead to the activation of several factors that promote clotting and platelet aggregation *in-sito* (Falk, 1991), which may also lead to a sudden reduction of the vascular lumen, or even its complete occlusion by thrombosis.

dietary cholesterol is quite small, around 0.01 (McNamara, 2000).

calcification, progressively reducing the vascular lumen (Silva, 2000).

As we have seen, each stated factor conveys a certain risk to the affected population. However, in everyday clinical practice a large majority of patients have associations of these factors and, as such, have cardiovascular risks that express the magnitude of individual risk factors present in an exponential, rather than additive, trend (Yusuf, Giles, Croft *et al*, 1998; American Heart Association, 2002).

An alternative option, with very promising results in the context of cardiovascular risk stratification and assessment of the effectiveness of lipid-lowering interventions, is the use of lipid ratios, just as the LDL-Cholesterol/HDL-Cholesterol ratio and the Total-Cholesterol/HDL-Cholesterol ratio, which have the added advantage of being easy to use in clinical practice (Gotto, Whitney & Stein, 2000). Changes in these relations have in fact been shown to better indicate the reduction in cardiovascular risk compared with the absolute levels of conventionally used lipid measures (Natarajan, Glick, Criqui *et al*, 2003; Kannel, 2005). On the other hand, the estimated LDL-Cholesterol/HDL-Cholesterol ratio translates, albeit imperfectly, an approach to the relationship of plasma apolipoproteins (apo) A-1 and apo B (Walldius & Jungner, 2005), thus enriching the lipid characterization of each patient, with the possibility of a better discrimination of cardiovascular risk, particularly among groups at intermediate cardiovascular risk (Gotto, Whitney, Stein *et al*, 2000).

Several large studies have demonstrated that the LDL-Cholesterol/HDL-Cholesterol ratio is an excellent predictor of risk of coronary disease and an excellent way to monitor the impact of lipid-lowering therapies (Manninen, Tenkanen, Koskinen *et al*, 1992; Kannel, 2005; Cullen, Schulte, Assmann *et al*, 1997; Stampfer, Sacks, Salvini *et al*, 1991; Gaziano, Hennekens, O'Donnell *et al*, 1997). In the Helsinki Study, a clinical trial with a 5-year follow-up, involving more than 4000 middle-aged men with hyperlipidemia, the LDL-Cholesterol/HDL-Cholesterol ratio had a superior prognostic value compared with isolated values of LDL-Cholesterol and HDL-Cholesterol. The predictive ability of this ratio was particularly strong in patients with concomitant elevation of triglycerides. It was further shown that the LDL-Cholesterol/HDL-Cholesterol ratio together with the fasting triglyceride concentration, allowed the identification of a particular subgroup of patients that had a remarkable 70% reduction in the risk of coronary heart disease with gemfibrozil (lipid-lowering agent) therapy. In the PROSPER trial, a retrospective analysis of 6,000 patients, the LDL-Cholesterol/HDL-Cholesterol ratio was the stronger predictor of cardiovascular events in elderly patients (Packard, Ford, Robertson *et al*, 2005). From this study has emerged the recommendation of pharmacological intervention whenever the LDL-Cholesterol/HDL-Cholesterol ratio values exceed 3.3 units. Another study (PROCAM study) involving about 11,000 men aged between 36 and 65, followed over 4 to 14 years, has documented an extremely important and linear relationship between the LDL-Cholesterol/HDL-Cholesterol ratio and cardiovascular mortality (Cullen, Schulte, Assmann *et al*, 1997). In this study, cardiovascular mortality peaked for LDL-Cholesterol/HDL-Cholesterol values between 3.7 and 4.3 units. In line with these results is the Physician's Health Study, involving 15,000 men (40 to 84 years), where there was a 53% increase in the risk of an acute coronary event for each one-unit increase in the LDL-Cholesterol/HDL-Cholesterol ratio (Stampfer, Sacks, Salvini *et al*, 1991). In another mixed study, involving men and women under the age of 76, the LDL-Cholesterol/HDL-Cholesterol ratio showed a strong relationship with the risk of coronary events (Gaziano, Hennekens, O'Donnell *et al*, 1997), aspect reinforced in an analysis of patients from the Framingham Heart Study, where a clear superiority of LDL-Cholesterol/HDL-Cholesterol ratio in predicting cardiovascular events compared to the levels of isolated LDL-cholesterol and HDL-cholesterol was depicted (Kannel, 2005).

As we have seen, each stated factor conveys a certain risk to the affected population. However, in everyday clinical practice a large majority of patients have associations of these factors and, as such, have cardiovascular risks that express the magnitude of individual risk factors present in an exponential, rather than additive, trend (Yusuf, Giles, Croft *et al*, 1998;

An alternative option, with very promising results in the context of cardiovascular risk stratification and assessment of the effectiveness of lipid-lowering interventions, is the use of lipid ratios, just as the LDL-Cholesterol/HDL-Cholesterol ratio and the Total-Cholesterol/HDL-Cholesterol ratio, which have the added advantage of being easy to use in clinical practice (Gotto, Whitney & Stein, 2000). Changes in these relations have in fact been shown to better indicate the reduction in cardiovascular risk compared with the absolute levels of conventionally used lipid measures (Natarajan, Glick, Criqui *et al*, 2003; Kannel, 2005). On the other hand, the estimated LDL-Cholesterol/HDL-Cholesterol ratio translates, albeit imperfectly, an approach to the relationship of plasma apolipoproteins (apo) A-1 and apo B (Walldius & Jungner, 2005), thus enriching the lipid characterization of each patient, with the possibility of a better discrimination of cardiovascular risk, particularly among

Several large studies have demonstrated that the LDL-Cholesterol/HDL-Cholesterol ratio is an excellent predictor of risk of coronary disease and an excellent way to monitor the impact of lipid-lowering therapies (Manninen, Tenkanen, Koskinen *et al*, 1992; Kannel, 2005; Cullen, Schulte, Assmann *et al*, 1997; Stampfer, Sacks, Salvini *et al*, 1991; Gaziano, Hennekens, O'Donnell *et al*, 1997). In the Helsinki Study, a clinical trial with a 5-year follow-up, involving more than 4000 middle-aged men with hyperlipidemia, the LDL-Cholesterol/HDL-Cholesterol ratio had a superior prognostic value compared with isolated values of LDL-Cholesterol and HDL-Cholesterol. The predictive ability of this ratio was particularly strong in patients with concomitant elevation of triglycerides. It was further shown that the LDL-Cholesterol/HDL-Cholesterol ratio together with the fasting triglyceride concentration, allowed the identification of a particular subgroup of patients that had a remarkable 70% reduction in the risk of coronary heart disease with gemfibrozil (lipid-lowering agent) therapy. In the PROSPER trial, a retrospective analysis of 6,000 patients, the LDL-Cholesterol/HDL-Cholesterol ratio was the stronger predictor of cardiovascular events in elderly patients (Packard, Ford, Robertson *et al*, 2005). From this study has emerged the recommendation of pharmacological intervention whenever the LDL-Cholesterol/HDL-Cholesterol ratio values exceed 3.3 units. Another study (PROCAM study) involving about 11,000 men aged between 36 and 65, followed over 4 to 14 years, has documented an extremely important and linear relationship between the LDL-Cholesterol/HDL-Cholesterol ratio and cardiovascular mortality (Cullen, Schulte, Assmann *et al*, 1997). In this study, cardiovascular mortality peaked for LDL-Cholesterol/HDL-Cholesterol values between 3.7 and 4.3 units. In line with these results is the Physician's Health Study, involving 15,000 men (40 to 84 years), where there was a 53% increase in the risk of an acute coronary event for each one-unit increase in the LDL-Cholesterol/HDL-Cholesterol ratio (Stampfer, Sacks, Salvini *et al*, 1991). In another mixed study, involving men and women under the age of 76, the LDL-Cholesterol/HDL-Cholesterol ratio showed a strong relationship with the risk of coronary events (Gaziano, Hennekens, O'Donnell *et al*, 1997), aspect reinforced in an analysis of patients from the Framingham Heart Study, where a clear superiority of LDL-Cholesterol/HDL-Cholesterol ratio in predicting cardiovascular events compared to the levels of isolated LDL-cholesterol and HDL-cholesterol

groups at intermediate cardiovascular risk (Gotto, Whitney, Stein *et al*, 2000).

American Heart Association, 2002).

was depicted (Kannel, 2005).

Another point that reinforces the superiority of the lipid ratios in the stratification of cardiovascular risk arises from the effect of dietary cholesterol on plasma lipid levels. Several studies have demonstrated that these ratios are not affected by dietary cholesterol (Greene, Zerner, Wood *et al*, 2005; Herron, Vega-Lopez, Earl *et al*, 2002). On the contrary, some studies have shown that dietary cholesterol interferes with LDL-cholesterol and HDLcholesterol, with little variation in the ratio (McNamara, 2000). On average, the predicted change in the LDL-Cholesterol/HDL-Cholesterol ratio per 100 milligrams/day increase in dietary cholesterol is quite small, around 0.01 (McNamara, 2000).
