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proteins at baseline. However, they did find that higher levels of inflammation-sensitive proteins at baseline were predictive of greater increases in PP during follow-up. This association was observed after adjustment for numerous con-founders such as age, diabetes, baseline blood pressure, plasma lipids, smoking and physical activity. However, the magnitude of the association was not large.

Critical Assessment of the Studies of PP and Inflammation in Humans

Based on the evidence from the studies discussed above, it is tempting to conclude that higher PP is associated with, and may in fact provoke, an inflammatory response. However, before reaching such a conclusion, it is important to critically assess the strengths and weaknesses of the evidence from these studies. On the whole, these studies do have a number of strengths, which tend to bolster one's confidence in the belief in the existence of a real, positive association between PP and inflammation. First, as noted earlier, there are plausible biological mechanisms, such as cyclic strain and non-steady shear, by which a high PP could theoretically promote inflammation. Second, studies have been fairly consistent in reporting positive associations between PP and inflammation in humans. Some studies have reported no association in certain subgroups (e.g. women) [8], have reported that it is only central (and not peripheral) PP that is associated with inflammation [7], or have reported only weak associations after adjustment for confounders [5]. Nevertheless, the vast majority of studies which have examined the association between PP and inflammation have reported a positive association between these two factors. Third, the positive association between PP and inflammation has been observed in a wide variety of populations, including a nationally representative sample of healthy US adults [2], older British women [5], hypertensive persons in a clinical trial [24], and other populations [3, 9]. This fact indicates that the positive association between PP and inflammation may be a general one, and not simply an association that is confined to a selected population. Fourth, PP has been associated with a variety of inflammatory markers, including CRP [2, 3, 5, 7-10, 24], IL-6 [4], ICAM-1 [4], and other markers [6]. Again, this suggests that the positive association between PP and inflammation is valid, being not simply confined to one particular inflammatory marker.

In addition to the strengths just listed, however, the studies of PP and inflammation have a number of weaknesses which raise questions about the nature of the PP/inflammation association. One major limitation is that the studies in humans have primarily been based on observational data [2-8, 10]. As such, these studies have been unable to conclusively prove that PP and inflam mation are positively associated, independent of potentially confounding factors. The threat of confounding has been partially addressed through statistical adjustment for potential confounders such as age, sex, race, SBP, lipids, BMI, smoking, physical activity, and socio-economic status. That these studies have observed positive associations between PP and inflammation after adjustment for such confounders helps bolster the notion that the PP/inflamma-tion association is a true, independent association. At the same time, however, these observational studies can never really prove that their results were free of residual confounding or unknown confounders. For example, the study of older British women noted above observed a marked attenuation of the PP/in-flammation association after adjustment for potential confounders, raising concern that the small association which remained after adjustment may have simply been due to residual confounding [5]. Of all of the potential confounding factors, perhaps the most problematic is SBP. The correlation between SBP and PP tends to be very strong, and is often as high as 0.80. Due to this high correlation, it is often unclear whether the association between PP and inflammation is really independent of SBP. Regression models which simultaneously include continuous SBP and continuous DBP as predictors of inflammation, can help establish whether it is PP, and not SBP, which is related to inflammation. In such models, if continuous SBP predicts increases in inflammation while DBP predicts decreases in inflammation, it would suggest that it is an increasing difference between SBP and DBP (i.e. an increasing PP), and not simply increasing SBP, which is predictive of increased inflammation. Although some studies have, in effect, adopted this approach [2], others have not [4] and have left open questions about whether their findings of a positive association between PP and inflammation is truly independent of SBP.

A second limitation of studies of PP and inflammation is that almost all of these studies have been cross-sectional in nature (i.e. PP and inflammation were essentially measured at the same time) [2-5, 7-10]. This precludes an understanding of the temporal ordering of the association. In this chapter, we have argued that PP may induce an inflammatory response. However, it is certainly possible that the association is one in which inflammation leads to a higher PP. Indeed, a study of PP and inflammation which was prospective in nature showed that inflammation was predictive of an increase in PP over time [6]. In addition, in a treatment trial of hypertensive patients, a reduction in PP with anti-hypertensive treatment was associated with a decrease in CRP, a relationship not seen with SBP or DBP [24], Furthermore, several studies seem to show that inflammation is associated with arterial stiffness [7, 10, 25-28], perhaps because inflammation promotes atherosclerosis which then results in stiffening of the arteries. If so, one would expect to see an association between PP and inflammation, not because PP leads to inflammation, but because in flammation leads to arterial stiffness, which then leads to a higher PP. Some studies have argued against this latter possibility, by showing that PP and inflammation are associated, even after accounting for arterial stiffness [3]. Nevertheless, the cross-sectional nature of many studies of PP and inflammation have overall failed to clarify the temporal ordering of the PP/inflammation association, and more data are needed to clarify this issue.

A third limitation is that few studies have assessed the impact of genetic background on the association between PP and inflammation. Data indicate that genetic factors play a role in influencing PP [29]. Genetic factors also influence levels of inflammatory markers such as CRP [30, 31]. Thus, it would seem natural to believe that the association between PP and inflammation may be modified by inherited factors, but few studies have addressed this issue.

A fourth limitation is that the clinical importance of the association between PP and inflammation has not been adequately addressed by existing studies. Although the relationship between PP and inflammation is of scientific interest in the study of the pathophysiology of CVD, an understanding of its clinical significance is also important. Such understanding would require that studies not only analyze the association between PP and inflammation, but assess how this association affects the risk of adverse cardiovascular events. Unfortunately, such analyses have not been conducted.

Summary and Future Research

Overall, the relationship between PP and inflammation remains an intriguing and important area of research. Plausible biological mechanisms exist which suggest that PP may induce inflammation. Additionally, many cross-sectional, observational studies suggest that PP and inflammation are associated with one another in humans. However, due to methodological limitations of existing studies, it remains unclear whether PP and inflammation are truly causally related. Since PP and inflammation have been both associated with CVD risk, any relation between the two factors would also, presumably, have an impact on CVD risk. As such, it would be of considerable importance to conduct further research that would attempt to more definitively establish whether there is a causal relationship between PP and inflammation and, if so, what the precise character of the relationship is. Future studies could focus on establishing more conclusively the independence of the association between PP an inflammation, defining the temporal ordering of this association, and examining the role of genetic factors in the association. Hopefully such studies will improve our understanding of how PP and inflammation are related and, ultimately, how they interact to affect CVD risk.

References

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Jerome L. Abramson, PhD

Department of Medicine, Division of Cardiology

Emory University School of Medicine

1365-A Clifton Road, Room 1509, Atlanta, GA 30322 (USA)

Tel. +1 404 778 5542, Fax +1 404 778 5541, E-Mail [email protected]

Section III - Arterial Stiffness, Atherosclerosis and Cardiovascular Risk Factors

Safar ME, Frohlich ED (eds): Atherosclerosis, Large Arteries and Cardiovascular Risk. Adv Cardiol. Basel, Karger, 2007, vol 44, pp 234-244

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