**4. Discussion and conclusions**

As previously mentioned, cardiovascular disease, as an expression of atherosclerotic processes, is the leading cause of death in industrialized countries. The key role played by cholesterol in essential pathophysiologic processes that lead to the occurrence of clinically significant cardiovascular events is well recognized. In contemporary clinical practice, this notion is well entrenched, and the individual cardiovascular risk definition incorporates, among other factors, the lipid profile, including the Total Cholesterol, LDL Cholesterol, HDL Cholesterol and triglycerides. A practical evidence of the aforementioned is the fact that the major cardiovascular risk tables currently available (e.g. the Framingham score or the EuroSCORE), incorporate lipid parameters in the definition of thresholds of risk. On the other hand, therapeutic decisions and monitoring have been largely centered on the conventional lipid profile. Even the international recommendations (such as those issued by the National Cholesterol Education Program - NCEP, 2001) recommend target levels of LDL and HDL -cholesterol to determine cardiovascular risk and evaluate the effectiveness of lipid-lowering therapies. However, some studies have indicated important limitations of these parameters in the prediction of cardiovascular risk, particularly in patients with intermediate cardiovascular risk (Gotto, Whitney, Stein *et al*, 2000).

However, more recent evidence has suggested other lipidic components to optimize the definition of cardiovascular risk in clinical practice. In fact, several studies have expressed the superiority of the levels of apolipoprotein (apo) B, apo A-1 and its ratio, both in predicting cardiovascular events and in the evaluation of treatment efficacy (Packard & Marcovina, 2006; Yusuf , Hawken, Ounpuu, *et al*, 2004; Meisinger, Loewel, Mraz *et al*, 2005; Barter, Ballantyne, Carmena *et al*, 2006; Kim, Chang, Choi *et al*, 2005). In fact, considering that each lipidic particle contains one molecule of the atherogenic apo B, then its levels are a direct measure of the number of potentially atherogenic particles in the different

Fig. 4. Adjusted Hazard Ratios for major acute cardiovascular events amongst those in the extreme quintiles of each considered lipidic parameter. The hazard ratios are multi-adjusted

As previously mentioned, cardiovascular disease, as an expression of atherosclerotic processes, is the leading cause of death in industrialized countries. The key role played by cholesterol in essential pathophysiologic processes that lead to the occurrence of clinically significant cardiovascular events is well recognized. In contemporary clinical practice, this notion is well entrenched, and the individual cardiovascular risk definition incorporates, among other factors, the lipid profile, including the Total Cholesterol, LDL Cholesterol, HDL Cholesterol and triglycerides. A practical evidence of the aforementioned is the fact that the major cardiovascular risk tables currently available (e.g. the Framingham score or the EuroSCORE), incorporate lipid parameters in the definition of thresholds of risk. On the other hand, therapeutic decisions and monitoring have been largely centered on the conventional lipid profile. Even the international recommendations (such as those issued by the National Cholesterol Education Program - NCEP, 2001) recommend target levels of LDL and HDL -cholesterol to determine cardiovascular risk and evaluate the effectiveness of lipid-lowering therapies. However, some studies have indicated important limitations of these parameters in the prediction of cardiovascular risk, particularly in patients with

However, more recent evidence has suggested other lipidic components to optimize the definition of cardiovascular risk in clinical practice. In fact, several studies have expressed the superiority of the levels of apolipoprotein (apo) B, apo A-1 and its ratio, both in predicting cardiovascular events and in the evaluation of treatment efficacy (Packard & Marcovina, 2006; Yusuf , Hawken, Ounpuu, *et al*, 2004; Meisinger, Loewel, Mraz *et al*, 2005; Barter, Ballantyne, Carmena *et al*, 2006; Kim, Chang, Choi *et al*, 2005). In fact, considering that each lipidic particle contains one molecule of the atherogenic apo B, then its levels are a direct measure of the number of potentially atherogenic particles in the different

to conventional Framingham cardiovascular risk factors.

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

**4. Discussion and conclusions** 

conventional lipid components (Walldius & Junger, 2006). In contrast, the concentration of apo A-1 translates the number of anti-atherogenic particles contained in the HDLcholesterol, thus enclosing the conceptual framework of apoB/apoA-1 ratio as a measure of the ratio of atherogenic particles versus anti-atherogenic particles transported in the blood. Despite the growing enthusiasm about the potential of these emerging parameters for their best performance in the definition of cardiovascular risk, there still remain some questions that limit their dissemination in clinical practice. The central question is very practical, and focuses on the cost-benefit relation associated with a change in the traditional clinical approach. In fact, it is not yet clear whether the superiority of these new lipid parameters over the more conventional ones for risk stratification is enough to justify the additional cost inherent to their laboratory determination (Pischon, Girman, Sacks *et al*, 2005). Furthermore, despite the current literature supporting apolipoproteins as better predictors of cardiovascular events, its use may not be the most practical operational perspective. Moreover, it is not yet clear whether the replacement of conventional parameters for emerging ones will translate into clear clinical benefit, or if, conversely, it will confuse the various protagonists over the clinical decision frame.

In contrast to this line of argument, several studies have also emerged affirming quite clearly the advantages of using lipid ratios, based on conventional parameters, such as those studied in this work. This is based on the fact that, on the one hand, they add cardiovascular risk discriminative capacity to the individual lipid parameters, and on the other, they are more favorable than the apolipoproteins considering cost and immediate operationalization (Gotto, Whitney & Stein, 2000). As mentioned earlier, several studies have shown fairly consistently that changes in these ratios are favorable indicators of cardiovascular disease risk, above the absolute levels of individual lipids (Natarajan, Glick, Criqui *et al*, 2003; Kannel, 2005). Accumulating evidence in this regard is quite broad, spreading over several clinical frameworks (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; Packard, Ford, Robertson *et al*, 2005). The results presented here clearly fall into this line, reinforcing the belief in the superiority of the lipid ratios, particularly the Total-Cholesterol/HDL-Cholesterol and the LDL-Cholesterol/HDL-Cholesterol ratios, over the classic lipid parameters, predicting peripheral arterial disease in hypertensive patients (in a high cardiovascular risk) and predicting future major cardiovascular events (including stroke and myocardial infarction) in a low-to-intermediate cardiovascular risk population. One of the curious aspects extracted from the second presented study was the existence of a linear relationship for the Total-Cholesterol/HDL-Cholesterol ratio with the risk of MACE, something not apparent in the LDL-Cholesterol/HDL-Cholesterol ratio. This same result was reproduced in the Quebec Cardiovascular Study, in which more than 2.000 middleaged men were followed for 5 years, monitoring the occurrence of major cardiovascular events (Lemieux, Lamarche, Couillard *et al*, 2001). The lipid parameters with better performance in predicting risk in this study were the Total-Cholesterol/HDL-Cholesterol ratio and the LDL-Cholesterol/HDL-Cholesterol ratio, although only the first stated ratio expressed a linear relationship with risk. One possible explenation for this result is metabolic in nature. In fact, it is well documented that patients with dyslipidemia showing high triglycerides and low HDL-cholesterol (generally patients with abdominal obesity and insulin resistance), often have marginal or even normal levels of LDL-Cholesterol (Lamarche, Després, Moorjani *et al*, 1996). Moreover, LDL-Cholesterol concentrations are often estimated indirectly from 3 measurements (Total-Cholesterol, Triglycerides and HDL-

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Cholesterol), which may include a variation that can reach 25% (Schectman & Sasse, 1993), with a potential and quite significant impact in the LDL-Cholesterol/HDL-Cholesterol ratio, eventually under-estimated. By contrast, the two components included in the Total-Cholesterol/HDL-Cholesterol ratio are measured directly. Supporting the superiority of these ratios over the isolated lipid parameters, is their unique ability to reflect the bidirectional cholesterol traffic (in and outward) through the arterial intima in a way that the individual LDL and HDL-Cholesterol levels cannot reach (Kannel, 2005). Consistent with this assumption, another recent cohort prospective study, involving over 15.000 women followed over a period of 10 years, demonstrated that the Total-Cholesterol/HDL-Cholesterol ratio alongside the non-HDL Cholesterol were predictors of future cardiovascular events, as good or better than apolipoprotein fractions (Ridker, Rifai, Cook *et al*, 2005).

Of course, there are still unresolved issues, such as the definition of a cut-off in these ratios from which lipid-lowering therapy should be considered. The current guidelines of the NCEP (2001) recommend a cut-off of 2.5 for the ratio LDL-cholesterol/HDL-cholesterol. However, recent studies suggest that the risk of cardiovascular events begins to have significant expression for values between 3.3-3.7 (Cullen, Assmann & Schulte, 1997), in line with the results we reported here.

Given all the data currently available, as long as the fundamental reservations to the routine use of apolipoproteins are not exceeded, the use of lipid ratios in clinical practice is strongly advised, both in risk stratification and therapeutic decision and in monitoring its effectiveness.
