Pulse Pressure and Inflammatory Process in Atherosclerosis

Jerome L. Abramsona Viola Vaccarinoa,h aDepartment ofEpidemiology, Rollins School ofPublic Health, and bDepartment ofMedicine, Division of Cardiology, Emory University School of Medicine, Emory University, Atlanta, Ga., USA


Recent studies have reported positive associations between pulse pressure (PP) and markers of inflammation. These studies are intriguing because they suggest that elevations in PP could induce an inflammatory state and thereby increase the risk of inflammation-related diseases such as atherosclerotic cardiovascular disease. In the present chapter, we review potential mechanisms by which an elevated PP could increase inflammation. We also review human-based studies that have investigated the association between PP and inflammatory biomarkers such as C-reactive protein. The majority of studies support a positive association between PP and inflammatory markers. However, it remains unclear whether the association is truly causal and whether it has relevance in terms of predicting cardiovascular diseases.

Copyright © 2007 S. Karger AG, Basel

Pulse pressure (PP) is defined as the difference between systolic blood pressure (SBP) and diastolic blood pressure (DBP). A number of factors, most notably large artery stiffness [1], can lead to a high PP (i.e. a large or 'wide' difference between SBP and DBP). Recent studies have demonstrated that higher PP values are associated with higher levels of inflammatory markers [2-10]. These studies are of great interest, because they suggest that elevations in PP may induce inflammation, which would help to explain why an elevated PP

has been associated with a higher risk of inflammation-dependent atherosclerotic cardiovascular diseases (CVD) [11, 12]. Although the studies of PP and inflammation are intriguing, many issues surrounding the PP/inflammation association remain to be investigated and clarified.

In the present chapter, we will attempt to review current knowledge about the relationship between PP and inflammation. First, we will highlight patho-physiological mechanisms by which an elevated PP might induce inflammations. Second, evidence linking PP to inflammation in humans will be reviewed. Third, a critical assessment of the existing studies of PP and inflammation will be presented.

Pathophysiological Mechanisms Linking PP to Inflammation

In assessing whether a wide PP may lead to higher inflammation, it is important to consider whether there are plausible biological mechanisms by which PP could promote inflammation. Several experimental studies have suggested that such mechanisms may exist. In general, these mechanisms fall under two categories: (1) cyclic strain and (2) non-steady shear stress.

Elevated Cyclic Strain and Inflammation

Higher levels of PP presumably lead to greater degrees of cyclic strain, the repetitive mechanical deformation that is experienced by the arterial wall as it expands and contracts during each cardiac cycle. PP-induced cyclic strain could be a mechanism by which higher PP increases inflammation, because evidence indicates that endothelial cells can detect cyclic strain signals and transmit these signals into pro-inflammatory biochemical responses. For example, studies indicate that cyclic strain is associated with endothelial cell production of superoxide and other reactive oxygen species (ROS) [13,14] that can act as important signaling molecules in inflammation. In addition, cyclic strain induces higher levels of pro-inflammatory factors such as chemokines and adhesion cell molecules. With respect to chemokines, investigators have demonstrated that in endothelial cells, cyclic strain leads to substantial increases in the gene expression of the pro-inflammatory chemokine monocyte chemotactic protein-1 (MCP-1) [14-16]. Similarly, it has been shown that cyclic strain increases endothelial cell gene expression of the pro-inflammatory adhesion molecules intracellular adhesion molecule-1 (ICAM-1) [17, 18], vascular cell adhesion molecule-1 (VCAM-1) [18], and E-selectin [18]. Furthermore, by inducing expression of these pro-inflammatory molecules, cyclic strain leads to greater adhesion of monocytes to endothelial cells [17, 18], an important part of the inflammatory process. In addition to ROS, chemokines, and adhesion molecules, cyclic strain has also been associated with other factors that appear to be closely linked to inflammatory processes, such as matrix me-talloproteinases. For example, production of MMP-2 in endothelial cells exposed to cyclic strain is as much as 4 times greater than MMP-2 production in control cells [19]. Overall, the evidence above tends to suggest that cyclic strain induces endothelial cell responses that could foster inflammation, indicating that cyclic strain may represent a potential biological mechanism by which PP could promote inflammation.

Non-Steady Shear and Inflammation

In addition to cyclic strain, arteries experience a number of other mechanical forces which may be implicated in inflammation. For example, as blood flows through arteries, it creates a frictional force which acts parallel to the lining (endothelium) of the artery. This frictional force is known as shear stress. Although the relationship between PP and shear stress is not entirely clear, it has been suggested that a large PP would result in non-steady shear stress forces. This non-steady shear may actually result in oscillatory (i.e. reversing, or 'back-and-forth') shear stress forces, especially at arterial branch points where blood flow is already non-steady due to the geometry of the branch points [20]. As with cyclic strain, PP-induced non-steady or oscillatory shear may represent a mechanism by which elevated PP could lead to inflammation, because endothelial cells can detect shear stress forces and translate them into inflammatory biochemical responses. For example, Chappel et al. [21] compared the effect of steady and oscillatory shear on the upregulation of pro-inflammatory adhesion molecules in human umbilical vein endothelial cells. They found that, compared to steady shear, oscillatory shear was associated with a much greater (at least 7.5-fold) upregulation of ICAM-1, VCAM-1, and E-selectin. Moreover, they found that this oscillatory shear-induced upregulation of adhesion molecules was associated with a 10-fold increase in the level of monocyte binding. Hsiai et al. [22] examined the effect of oscillatory flow on bovine aortic endothelial cells. They found that oscillatory flow led to significant increases in ICAM-1 and MCP-1 expression, with a concomitant increase in the number of monocytes binding to the endothelial cells. Other investigators have also reported positive associations between oscillatory shear and monocyte adhesion to endothelial cells, and have suggested that such positive association may be mediated by ROS [23]. Overall, this evidence supports the notion that a high PP, by fostering non-steady or oscillatory shear, may promote inflammation.

Studies of PP and Inflammation in Humans

From the preceding discussion, it is apparent that there are plausible mechanisms by which a high PP, in and of itself, could lead to increased inflammation. In recent years, a number of studies have in fact attempted to address whether a high PP is indeed associated with inflammation in humans. In particular, studies have examined whether PP is associated with markers of inflammation that have been linked to an increased risk of CVD in humans, such as C-reactive protein (CRP) and interleukin-6 (IL-6).

Studies of PP and CRP

CRP is the inflammatory biomarker which has shown the most consistent association with increased CVD risk. For this reason, many of the studies looking at PP and inflammation have chosen to look at CRP as the primary marker of inflammation. In general, results from studies of PP and CRP have reported significant, positive associations between PP and CRP. In a study of over 9,000 apparently healthy US adults who participated in the Third National Health and Nutrition Examination Survey (NHANES), we examined the association between peripheral PP (measured at the brachial artery with a standard blood pressure cuff) and CRP levels [2]. We found that a 10 mm Hg increase in PP was associated with a statistically significant 13% increase in the odds of having an elevated CRP (>0.66 mg/dl). This association was observed after adjustment for numerous potential confounding factors, including age, sex, education, lipid levels, body mass index (BMI), smoking status, alcohol consumption, and physical activity. Furthermore, the association between PP and elevated CRP was stronger than the association between SBP and elevated CRP (table 1). In multivariable models including PP and SBP or PP and DBP simultaneously, PP (i.e. increasing SBP at any level of DBP and decreasing DBP at any level of SBP) proved to be the strongest predictor of elevated CRP. Amar et al. [3] also reported a positive, cross-sectional association between peripheral PP and CRP. In particular, they found that a high peripheral PP was associated with elevated CRP (>3.7 mg/l) after adjustment for age, sex, BMI, lipids, glucose, and antihypertensive drugs. Several other studies have also reported significant, positive associations between peripheral PP and CRP [5, 8, 9], though in some studies, the association became fairly weak after adjustment for potential confounding factors. For example, in a study of over 2,000 older British women, investigators found only a small positive association between peripheral PP and CRP after adjustment for age, BMI, smoking and indicators of socio-economic status [5].

Although studies reporting a positive association between peripheral/bra-chial PP and CRP are of interest, it has been noted that peripheral PP is often

Table 1. Logistic regression models assessing the association between single blood pressure components and the odds of having an elevated CRP level [from 2]


Odds ratio (95% CI)

p value

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