**2.3 Cardiovascular risk – Atherogenesis**

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 physiology of this system.

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

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.

Dyslipidemia and Cardiovascular Risk:

Lipid Ratios as Risk Factors for Cardiovascular Disease 287

Collaborative Group, 2002) showed that a reduction of 30% compared to the more restrictive goal (LDL cholesterol <100 mg/dl) was related to an additional 30% reduction in the relative risk of coronary heart disease. The PROVE IT study (Cannon, Braunwald, McCabe *et al*, 2004), enrolled patients who had had acute coronary events and showed that larger reductions of LDL-cholesterol, to levels lower than 100 mg/dl, could significantly provide

According to these results one has to consider more challenging treatment goals. The aim is to reach values of LDL-cholesterol <70mg/dl in patients with very high cardiovascular risk, such as those combining several primary risk factors (with primary relevance for diabetics), in patients with primary risk factors that are poorly controlled (with special care to the ones that maintain smoking habits), in patients with multiple risk factors of the so-called metabolic syndrome (triglycerides ≥ 200 mg/dl, non-HDL-cholesterol> 130 mg/dl, HDL-

The establishment of a therapeutic basis grounded in the control of cardiovascular risk factors has demonstrated its strong validity, and is further reinforced for its effectiveness in terms of cost-benefit. Improved control of risk factors almost certainly contributed to the 50% reduction in cardiovascular mortality observed in the United States of America between 1980 and 1990, with 43% attributable to the verified pharmacological advances (Hunink, Glodman, Tosteson *et al*, 1997). In the Netherlands, similar results were observed, and primary prevention was responsible for a 40% decline in mortality from coronary heart disease between 1978 and 1985 (Grobee & Bots, 1996). The adoption of dietary measures in Finland, relying on an increase in the consumption of fruits and vegetables and a reduction of saturated fats intake, has resulted in a 65% reduction in mortality from coronary heart

Despite the promising results indicated by these data, only 35% of Americans with a formal indication for dietary or pharmacological therapy, according to the recommendations of the NCEP (2001), are complying with it (Hoerger, Bala, Bray *et al*, 1988). In Canada, a study carried out between 1988 and 1993, including patients at high cardiovascular risk admitted to hospitals, showed very low percentages in relation to lipid dosing prescription (28%) and early dietary (22%) or pharmacological (8%) therapy (The Clinical Quality Improvement

In Europe, results have fallen below expectations. An important follow-up study - EUROASPIRE - between 1995 and 1996, envolving nine European countries, showed that 86% of the enrolled patients had hypercholesterolaemia. Nevertheless, only 32% were on medication, and among those treated only 21% had achieved the target lipid levels

In Asia and the Pacific, the outlook is not encouraging either. In patients hospitalized for acute coronary events, quite small rates of lipid profile dosing (1 to 58%) were observed, as well as for the prescription of diet (1 to 32%) or pharmacological (6 to 60%) therapy to patients with high Cholesterol levels (Asian-Pacific CHD Risk Factor Collaborative Group,

The control of risk factors in clinical practice is thus a vaguely realized desideratum. The EUROASPIRE study has clarified some trends from 1995 to 2000. If the positive results have raised expectations, with an improvement seen in the control of hypercholesterolemia and hypertension, they are still accompanied by other rather disappointing indicators, such as those of smoking habits, obesity and diabetes, whose prevalence has been steadily increasing (EUROASPIRE Study Group, 1997; EUROASPIRE I and Group II, 2001). In the

aditional benefit in terms of future cardiovascular mortality and morbidity.

cholesterol<40 mg/dl) and in patients with history of acute coronary events.

disease in a time horizon of 20 years (Pekka, Pirjo & Ulla, 2002).

(EUROASPIRE Study Group, 1997; EUROASPIRE I and II Group, 2001).

Network (CQIN) Investigators, 1995).

1998).

Thus, the atherosclerotic process brings with it a wide array of metabolic, inflammatory and coagulation phenomena, decisively contributing to its clinical expression. Herein lies the justification of the diverse therapeutic targets that aimed for in these patients.

The importance of hypercholesterolemia as a key-player in this cascade of events is unquestioned and widely demonstrated in the published literature. A perfect expression of the interaction between research and practice is surely the publication of recommendations and guidelines that assist clinicians in the rationalization of therapeutic means available. These emerge as regular updates of successive collections of published scientific data, outlined in an admirably succinct way so they can be strategically combined and applied to the most varied health systems worldwide. Regarding the core topic of this paper, we have to address the most relevant recommendations published by the European Society of Cardiology and the National Cholesterol Education Program (NCEP). These recomendations were prepared according to an individual-risk perspective, and the therapeutic goals are defined according to the expected individual risk at long-term. Table 3 sumarizes the NCEP guidelines, revealing a clear therapeutic aggressiveness increase based on individual risk, as well as the adoption of progressively reduced target LDL-cholesterol values.


Table 3. Hypercholesterolemia treatment algorithm of the second Report of the Third National Cholesterol Education Program – NCEP (2001).

These recommendations also included some secondary therapeutic goals, including the attempt to reduce non-HDL cholesterol in patients with triglycerides above 200 mg/dl for values 30 mg/dL higher than the individual target for LDL-cholesterol. Another objective lies in promoting an increase in HDL-cholesterol. Although these objectives are based on a very interventionist philosophy, recent studies may impose additional requirements on these recommendations. In fact, the Heart Protection Study (Heart Protection Study

Thus, the atherosclerotic process brings with it a wide array of metabolic, inflammatory and coagulation phenomena, decisively contributing to its clinical expression. Herein lies the

The importance of hypercholesterolemia as a key-player in this cascade of events is unquestioned and widely demonstrated in the published literature. A perfect expression of the interaction between research and practice is surely the publication of recommendations and guidelines that assist clinicians in the rationalization of therapeutic means available. These emerge as regular updates of successive collections of published scientific data, outlined in an admirably succinct way so they can be strategically combined and applied to the most varied health systems worldwide. Regarding the core topic of this paper, we have to address the most relevant recommendations published by the European Society of Cardiology and the National Cholesterol Education Program (NCEP). These recomendations were prepared according to an individual-risk perspective, and the therapeutic goals are defined according to the expected individual risk at long-term. Table 3 sumarizes the NCEP guidelines, revealing a clear therapeutic aggressiveness increase based on individual risk, as well as the adoption of progressively reduced target LDL-cholesterol

**Target Therapeutic options** 

mg/dl Dietary intervention Drug treatment?

LDL≥130 mg/dl Dietary intervention Drug treatment

LDL 130-160 mg/dl Dietary intervention

Dietary intervention Drug treatment?

LDL≥130 mg/dl Dietary intervention Drug treatment

LDL≥160 mg/dl Dietary intervention Drug treatment

LDL≥190 mg/dl Dietary intervention Drug treatment

LDL<100 mg/dl LDL<100 mg/dl-129

LDL<160 mg/dl LDL 160-190 mg/dl

These recommendations also included some secondary therapeutic goals, including the attempt to reduce non-HDL cholesterol in patients with triglycerides above 200 mg/dl for values 30 mg/dL higher than the individual target for LDL-cholesterol. Another objective lies in promoting an increase in HDL-cholesterol. Although these objectives are based on a very interventionist philosophy, recent studies may impose additional requirements on these recommendations. In fact, the Heart Protection Study (Heart Protection Study

Table 3. Hypercholesterolemia treatment algorithm of the second Report of the Third

LDL<130 mg/dl

LDL<130 mg/dl

National Cholesterol Education Program – NCEP (2001).

justification of the diverse therapeutic targets that aimed for in these patients.

values.

**High risk**  10-year risk> 20% Established cardiovascular disease Equivalents of Cardiovascular Disease

**Intermediate risk**  ≥ 2 Risk Factors 10-year risk ≤ 20%

10-year risk ≤ 10%

**Low risk**  10-year risk ≤ 10% ≤ 1 risk factor

Collaborative Group, 2002) showed that a reduction of 30% compared to the more restrictive goal (LDL cholesterol <100 mg/dl) was related to an additional 30% reduction in the relative risk of coronary heart disease. The PROVE IT study (Cannon, Braunwald, McCabe *et al*, 2004), enrolled patients who had had acute coronary events and showed that larger reductions of LDL-cholesterol, to levels lower than 100 mg/dl, could significantly provide aditional benefit in terms of future cardiovascular mortality and morbidity.

According to these results one has to consider more challenging treatment goals. The aim is to reach values of LDL-cholesterol <70mg/dl in patients with very high cardiovascular risk, such as those combining several primary risk factors (with primary relevance for diabetics), in patients with primary risk factors that are poorly controlled (with special care to the ones that maintain smoking habits), in patients with multiple risk factors of the so-called metabolic syndrome (triglycerides ≥ 200 mg/dl, non-HDL-cholesterol> 130 mg/dl, HDLcholesterol<40 mg/dl) and in patients with history of acute coronary events.

The establishment of a therapeutic basis grounded in the control of cardiovascular risk factors has demonstrated its strong validity, and is further reinforced for its effectiveness in terms of cost-benefit. Improved control of risk factors almost certainly contributed to the 50% reduction in cardiovascular mortality observed in the United States of America between 1980 and 1990, with 43% attributable to the verified pharmacological advances (Hunink, Glodman, Tosteson *et al*, 1997). In the Netherlands, similar results were observed, and primary prevention was responsible for a 40% decline in mortality from coronary heart disease between 1978 and 1985 (Grobee & Bots, 1996). The adoption of dietary measures in Finland, relying on an increase in the consumption of fruits and vegetables and a reduction of saturated fats intake, has resulted in a 65% reduction in mortality from coronary heart disease in a time horizon of 20 years (Pekka, Pirjo & Ulla, 2002).

Despite the promising results indicated by these data, only 35% of Americans with a formal indication for dietary or pharmacological therapy, according to the recommendations of the NCEP (2001), are complying with it (Hoerger, Bala, Bray *et al*, 1988). In Canada, a study carried out between 1988 and 1993, including patients at high cardiovascular risk admitted to hospitals, showed very low percentages in relation to lipid dosing prescription (28%) and early dietary (22%) or pharmacological (8%) therapy (The Clinical Quality Improvement Network (CQIN) Investigators, 1995).

In Europe, results have fallen below expectations. An important follow-up study - EUROASPIRE - between 1995 and 1996, envolving nine European countries, showed that 86% of the enrolled patients had hypercholesterolaemia. Nevertheless, only 32% were on medication, and among those treated only 21% had achieved the target lipid levels (EUROASPIRE Study Group, 1997; EUROASPIRE I and II Group, 2001).

In Asia and the Pacific, the outlook is not encouraging either. In patients hospitalized for acute coronary events, quite small rates of lipid profile dosing (1 to 58%) were observed, as well as for the prescription of diet (1 to 32%) or pharmacological (6 to 60%) therapy to patients with high Cholesterol levels (Asian-Pacific CHD Risk Factor Collaborative Group, 1998).

The control of risk factors in clinical practice is thus a vaguely realized desideratum. The EUROASPIRE study has clarified some trends from 1995 to 2000. If the positive results have raised expectations, with an improvement seen in the control of hypercholesterolemia and hypertension, they are still accompanied by other rather disappointing indicators, such as those of smoking habits, obesity and diabetes, whose prevalence has been steadily increasing (EUROASPIRE Study Group, 1997; EUROASPIRE I and Group II, 2001). In the

Dyslipidemia and Cardiovascular Risk:

 **Total**

**Tobacco Consumption,** 

absence of peripheral artery disease.

interval.

**3.2.2 Results** 

respectively).

**no:yes** 

Lipid Ratios as Risk Factors for Cardiovascular Disease 289

Groups were compared using the χ2 test for categorical variables and the Student's t test (2 groups) or ANOVA with the post-hoc Tukey test (3 groups) for quantitative variables. A value of P≤0.05 was taken as the criterion of statistical significance for a 95% confidence

The general characteristics of the studied population are summarized in Table 4. Mean age was 64.23±12.30, with a similar proportion of men versus women (49% and 51%,

**Age, years** 64.23±12.30 63.23±12.30 69.88±8.15 <0.01 **Sex, men:women** 49:51 48:52 52:48 0.462 **Body Mass Index, Kg/m2** 28.79±11.85 28.92±12.53 27.94±5.31 0.416 **CV events history, no:yes** 88:12 90:10 75:25 <0.01

**Dyslipidemia, no:yes** 40:60 42:58 26:74 <0.01 **Diabetes, no:yes** 66:34 68:32 54:46 <0.01 **SBP, mmHg** 150.14±20.69 148.97±19.60 157.81±25.59 <0.01 **DBP, mmHg** 86.28±10.91 86.59±10.63 84.20±12.43 0.025 **Heart Rate, bpm** 70.52±10.48 69.12±9.42 71.22±9.21 0.791 **Plasma Glucose, mg/dl** 112.42±39.65 111.35±39.10 119.61±42.60 0.035 **Plasma Creatinine, mg/dl** 0.88±0.22 0.87±0.21 0.96±0.26 <0.01 **eGFR, ml/min/1.73m2** 84.73±23.28 85.86±23.40 76.94±20.88 <0.01 **ABI** 1.09±0.14 1.12±0.12 0.8±0.10 <0.01 PAD – peripheral artery disease; CV – cardiovascular events; SBP – systolic blood pressure; DBP – diastolic blood pressure; eGFR – estimated Glomerular Filtration Rate; ABI – Ankle-Brachial Index Table 4. Characteristics of the study population, in general and stratified for the presence or

Mean body mass index was 28.79±11.85, indicating an overwheighted population. With regard to cardiovascular risk factors, all patients were hypertensive, 60% had dyslipidemia and 34% were diabetic; 11% were smokers and 12% had a personal history of cardiovascular events (mainly Stroke). About 37% were medicated for cardiovascular pathologies, with 13.6% of the patients undertaking statins. This factor was controlled in all the multivariable analysis. Peripheral artery disease (PAD) was encountered in 117 patients (12.7%). Patients with PAD were older, and had a worst metabolic and hemodynamic profile. The proportion of patients with a personal history of cardiovascular events was also greater in patients with PAD (25% versus 10%, p<0.01). The Ankle-Brachial Index (ABI) was also significantly lower

**No PAD Patients**  (n=803)

89:11 89:11 88:12 0.856

**PAD Patients**  (n=117)

*p-value*  **(PAD versus No PAD)** 

(n=920)

United States of America the results are also somewhat disappointing. In survivors of acute myocardial infarction or stroke, the control percentages for some primary risk factors are below expectations, particularly for smoking habits (18%), control of hypercholesterolemia (46%), diabetes (48%) and hypertension (53%) (Qureshi et al, 2001).

As in almost all chronic conditions, the real picture lags far behind the expectations and available resources. Regarding hypercholesterolemia, the current situation is even less understandable, given its clear and strong association with the prevailing causes of death and incapacity, and the public awareness of the problem and in consideration of the demonstrated effectiveness of the available lipid-lowering drugs, that may have a quite favorable impact upon the prognosis of patients.
