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(Hypertension. 2003;42:1117.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Association Between Blood Pressure and C-Reactive Protein Levels in Acute Ischemic Stroke

From the Neurological Section, SMDN–Center for Cardiovascular Medicine and Cerebrovascular Disease Prevention, Sulmona (L’Aquila), Italy

Correspondence to Dr Mario Di Napoli, MD, Neurological Section, SMDN–Center for Cardiovascular Medicine and Cerebrovascular Disease Prevention, Via Trento, 41, 67039, Sulmona (AQ), Italy. E-mail mariodinapoli{at}katamail.com

	Abstract

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Among patients with acute stroke, high blood pressure (BP) and higher levels of circulating C-reactive protein (CRP) at the entry are often associated with poor outcome, although the reason is unclear. If the link between BP and stroke outcome is indeed mediated by inflammatory response, one would expect to see positive associations between BP and CRP. In a prospective observational stroke data bank involving 535 first-ever ischemic stroke patients, we studied the association between BP and baseline concentrations of CRP within 24 hours after stroke onset. The association between BP components and the odds of having an elevated CRP level (1.5 mg/dL) was assessed by logistic regression analysis. An increase in systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), or pulse pressure (PP) was significantly associated with an increase in the odds of having an elevated CRP level, independent of other associated study factors. For each 10 mm Hg increase in SBP, DBP, MAP, or PP, the odds of having a high CRP level increased by 72% (P<0.0001), 10% (P<0.0001), 21% (P<0.0001), and 10% (P<0.0001), respectively. When the same model was rerun, adjusting for all considered BP components, only SBP significantly increased the odds of an elevated CRP level by 77% (P<0.0001). Increased SBP was significantly associated with elevated levels of circulating CRP in ischemic stroke patients. These findings support a possible role of acute hypertension after stroke as an inflammatory stimulus contributing to ischemic brain inflammation.

Key Words: blood pressure • C-reactive protein • ischemia • stroke • risk factors

	Introduction

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Hypertension is a well-known risk factor for ischemic stroke,¹ and the effect of blood pressure–lowering treatment in preventing first stroke² is well established, but the pathologic and molecular mechanisms by which elevated blood pressure (BP) leads to vascular disease are uncertain: hypertension may promote endothelial expression of cytokines^3,4 and stimulate inflammation.^5,6 These data are particularly intriguing given that inflammation plays a critical role in the pathogenesis of atherosclerosis.⁷

Prospective data demonstrate that inflammation, particularly C-reactive protein (CRP), appears to predict the risk of cardiovascular events among healthy subjects,^8,9 patients with high vascular risk,^10,11 those with stable and unstable angina,^12–14 and stroke patients.^15–17

Signs of an acute inflammatory response are also evident in acute ischemic stroke.^15–19 These acute-phase reactants, such as cytokines and CRP may reflect inflammation related to the pathobiology of ischemic stroke.^19,20 However, many patients (25%) had normal levels of inflammation markers after stroke, implying that ischemic lesion itself does not induce a full-blown acute-phase response.^15–17 The specific stimuli that promote inflammatory response in acute ischemic stroke have not been fully elucidated.

In addition, the BP response after an ischemic stroke is variable²¹: three quarters of patients with acute ischemic stroke have elevated BP at presentation, of which about half have a history of hypertension.²² BP declines spontaneously after stroke onset and returns to prestroke levels in two thirds of patients within the first days.²³ Most studies, although not all, have found that high BP in the acute phase of stroke is associated with a poor outcome.^24–26 An explanation for these findings has not been given. High BP might promote early recurrence, hemorrhagic transformation, or the formation of cerebral edema.²⁷ Both high and low BP were found to be independent prognostic factors for poor outcome, relationships that appear to be mediated in part by increased rates of early recurrence and death resulting from presumed cerebral edema in patients with high BP and increased coronary heart disease events in those with low BP.²⁸ At the same time, a stronger inflammatory response after stroke is associated with a severe neurological deficit and a poor outcome with a higher risk of new recurrent cardiovascular events.^16,17 If the link between BP and stroke outcome is indeed mediated by inflammatory response, one would expect to see positive associations between BP and markers of systemic inflammation, such as CRP. An exploratory analysis in the same stroke cohort has suggested that elevated levels of systolic or diastolic BP in the acute phase after an ischemic stroke are associated with elevated levels of CRP.²⁹ In the present study, we sought to determine whether BP levels might contribute to inflammatory response in acute ischemic stroke among ischemic stroke patients.

	Methods

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Study Design and Participants
The current study is based on data from the prospective hospital-based Villa Pini Stroke Data Bank.^15,16 The original inclusion criteria were a diagnosis of first-ever ischemic stroke within 24 hours before enrollment.¹⁵ We restricted our study to the 535 patients included between March 1998 and March 2000, who were free of diseases that might substantially affect their levels of CRP (recent clinical infection, concurrent major renal hepatic or cancerous disease, recent surgery or major trauma, acute osteoarthritis, or inflammatory disease), and who had complete data on BP, CRP levels, and covariates. Additional information on the design of the Villa Pini Stroke Data Bank has been published elsewhere.^15,16

Blood Pressure
BP was measured at the entry by a trained nurse. Two measurements were taken on each arm. The lowest measurements on each arm were averaged to obtain the systolic (SBP) and diastolic BP (DBP) values that were recorded. The first and fifth Kortokoff sounds were recorded and used to determine SBP and DBP, respectively. Mean arterial pressure (MAP) was calculated as (SBP+2DBP)/3. Pulse pressure (PP) was calculated as SBP-DBP.

C-Reactive Protein Assay
Blood samples were taken at admission, within 24 hours after qualifying stroke, and at discharge. Levels of CRP were determined with a commercially available, high-sensitivity, immunonephelometric, latex-enhanced assay (Dade Behring).^15–17

Other Study Variables
Other factors included in this study were age, gender, body mass index, cerebrovascular risk factors (cigarette smoking status, alcohol abuse, hypercholesterolemia, hypertriglyceridemia, diabetes mellitus), cardiovascular comorbidity (arrhythmias and impulse conduction disorders, valvulopathies, left ventricular hypertrophy, coronary heart disease, symptomatic internal carotid stenosis, peripheral arterial disease), stroke subtypes (atherothrombotic, cardioembolic, small-vessel occlusive (lacunar), or undetermined cause), neuroradiological findings (leukoaraiosis, single/multiple infarcts, large/small infarcts, brain edema, hemorrhagic transformation). The Canadian Neurological Stroke Scale (CNSS) assessed initial stroke severity. All definitions are previously given^15–16 and definitions of stroke subtypes and neuroradiological findings are summarized in the Appendix of an online supplement (available at http://www.hypertensionaha.org). Information on current use of antihypertensive medications was also obtained.

Statistical Analysis
Differences in proportions were evaluated by ² analysis, unpaired t test for continuous normally distributed variables, and Mann-Whitney U test for nonnormally distributed variables. A Pearson correlation analysis was performed to assess any relationship between log-normalized levels of CRP and blood pressure at the entry. Analyses were designed to assess the association of BP components (SBP, DBP, MAP, and PP) with CRP levels after adjusting for the other study variables. In our analyses, the BP components and other study factors were independent variables, and CRP was the dependent variable. We analyzed CRP as a dichotomous outcome (CRP <1.5 mg/dL or CRP 1.5 mg/dL) in logistic regression models. We chose a cutoff point of 1.5 mg/dL because it has provided better sensitivity and specificity for adverse outcome, based on the receiver operator curves in a previous analysis in this stroke cohort.¹⁶ Individual BP component models assessed the effect of a single BP component (SBP, DBP, MAP, or PP) on CRP, without adjustment for other BP components. Dual BP component models assessed the effects of MAP and PP on CRP after adjustment for one of the other BP components (SBP and DBP). A final model assessed the effects of all BP components (SBP, DBP, MAP, and PP) on CRP level. Extended method and details on statistical plan can be found in an online supplement available at http://www.hypertensionaha.org.

	Results

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Between March 1998 and March 2000, 881 potential first-ever ischemic stroke patients were registered, and 535 (60.7%) were subsequently found to be eligible because they fulfilled the inclusion criteria for the present study (Figure). The exclusion criteria were mainly related to conditions associated with increased levels of inflammation markers or a not-confirmed diagnosis of first-ever ischemic stroke. The mean (mean±SD) age of cohort was relatively old (72.7±9.1 years), and 309 (57.8%) subjects were women. The median time from the onset of symptoms to BP measurement and blood sample collection was 12 hours and 15 hours to CT scan execution. At the entry, the average SBP, DBP, MAP, and PP of the stroke cohort were 160±16 mm Hg, 94±13 mm Hg, 116±13 mm Hg, and 66±9 mm Hg, respectively. BP decreased on average by 11±25 mm Hg in systolic, 14±14 mm Hg in diastolic, and 12±13 mm Hg in mean during in-hospital stay; PP increased on average by 2±27 mm Hg.

View larger version (24K): [in this window] [in a new window]   Study flow diagram. Diagnosis of exclusion is also indicated. Concomitant disease includes major renal (n=13), hepatic (n=13), and hematological disease (n=8). Ninety-two patients with recent clinical infection had also a relevant comorbidity that was capable of increasing acute-phase reactants.

Approximately 47% (n=250) of the cohort had a CRP level of 1.5 mg/dL or higher, within 24 hours after stroke. This percentage was reduced at 34% (n=182) at discharge (12±5 days). Log-normalized concentration of CRP within 24 hours after stroke was significantly correlated, but modestly, with SBP (r=0.46; P<0.0001), DBP (r=0.46; P<0.0001), and MAP (r=0.40; P<0.0001) at the entry. PP was only poorly correlated (r=0.16; P<0.0001). While PAD (r=0.49; P<0.0001) and MAP (r=0.46; P<0.0001) at discharge remained modestly and significantly correlated with CRP levels at the entry, SBP was weakly (r=0.24; P<0.0001), and PP was not more (r=0.07; P=0.350). Patients without a history of arterial hypertension had significantly higher levels (median, 25th to 75th percentiles) of CRP at the entry than patients with a documented history (2.0 [1.0 to 5.4] versus 1.0 [0.6 to 3.2] mg/dL; P<0.0001).

Table 1 shows the distribution of SBP, DBP, PP, and other study measures according to CRP level. Those with a high CRP level had higher mean SBP, DBP, MAP, and PP values. Additionally, stroke patients with a high CRP level were older male smokers with a higher prevalence of cardiovascular comorbidities and a more severe neurological deficit resulting from a larger embolic infarct frequently complicated by brain swelling and hemorrhagic transformation. Furthermore, they were less likely to be taking lipid lowering and antihypertensive medications, such as calcium channel blockers and angiotensin-converting-enzyme inhibitors (ACE-I), than were those with a low CRP level.

Table 2 presents the results of multivariable-adjusted logistic regression models assessing the association of single BP components with elevated CRP. Model 1 shows that, after adjustment for other study factors, an increase in SBP was significantly associated with an increase in the odds of having an elevated CRP level. For each 10 mm Hg increase in SBP, the odds of having an elevated CRP level increased by 72% (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.46 to 2.02; P<0.0001). Models 2, 3, and 4 show that, similarly to SBP, an increase in DBP, MAP, or PP was significantly associated with an increase in the odds of having an elevated CRP level, independent of other study factors. For each 10 mm Hg increase in DBP, MAP, and PP, the odds of having a high CRP level increased by 10% (OR, 1.10; 95% CI, 1.06 to 1.14; P<0.0001), 21% (OR, 1.21; 95% CI, 1.15 to 1.29; P<0.0001), and 10% (OR, 1.10; 95% CI, 1.06 to 1.14; P<0.0001), respectively. Next, we ran dual-component BP models that assessed the association between SBP and DBP with CRP after adjustment for MAP and PP and other study factors (Table 3). In model 1 the dual effects of SBP and MAP were considered. This model showed that MAP was no longer associated with elevated CRP, whereas a 10 mm Hg rise in SBP significantly increased the odds of an elevated CRP level by 79% (P<0.0001). In model 2, the dual effects of SBP and PP were considered. A 10 mm Hg increase in PP was not related to CRP levels, but each 10 mm Hg increase in SBP was associated with a significant 72% increase (P<0.0001) in the odds of an elevated CRP. In models 3 and 4, when we compared the dual effects of DBP with MAP and PP (Table 3), all components were significantly associated with CRP levels. We then added all BP components in the final model (Table 4); DBP, MAP, and PP were no longer associated with elevated CRP, whereas a 10 mm Hg rise in SBP significantly increased the odds of an elevated CRP level by 77% (OR, 1.77; 95% CI, 1.48 to 2.11; P<0.0001). To check whether our results were applicable, we repeated the analyses with different cut-points of CRP level (0.5 mg/dL, 1.0 mg/dL, and 2.0 mg/dL). We found that only a 10 mm Hg increase in SBP was associated with 14% (P<0.0001), 56% (P<0.0001), and 72% (P<0.0001) increases, respectively, in the odds of having an elevated CRP level in the model adjusted for all BP components. In contrast, DBP, MAP, and PP were not associated with CRP in this model. We then ran 2 subgroup analyses. First, we have previously reported that the use of an ACE-I is associated with reduced levels of CRP after stroke.³⁰ Therefore, we examined the association between SBP and CRP in the group taking an ACE-I. We found that in this group the association between SBP and CRP was reduced and not more significant (OR, 1.01; 95%CI, 0.96 to 1.05; P=0.8136). Second, it has been reported that the association of increasing SBP is stronger in older populations.²⁸ Therefore, we sought to determine whether the association between SBP and elevated CRP (1.50 mg/dL) differed according to age by constructing separate models among persons <70, 70 to 79, and 80 years of age. When controlling for all BP components and other study factors, there was some indication that the association between SBP and CRP was strongest among older persons; a 10 mm Hg increase in SBP among those <70, 70 to 79, and 80 years of age was associated with 0.6% (P=0.0017), 62% (P<0.0001), and 37% (P<0.0001) increases, respectively, in the odds of having an elevated CRP level.

	Discussion

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The primary finding of the present study was that an increase in BP levels was associated with increased odds of having an elevated CRP level (1.5 mg/dL) among first-ever ischemic stroke patients. This association was independent of a number of other factors, including demographic factors, cardiovascular risk factors, and neuroradiological findings. Only SPB showed a persistent, strong, significant association with CRP when DBP, MAP, and PP were also taken into account. The result persisted even when a different cut-off threshold of CRP (0.5 mg/dL, 1.0 mg/dL, and 2.0 mg/dL) was used. Previous studies have reported many independent factors related to BP in the acute phase of stroke and their relationship with prognosis,^23,28 but these studies did not consider whether BP was associated with levels of CRP, a new and up-and-coming prognostic factor of cardiovascular risk.^16,17 Our study addresses the possible relationship between BP levels and CRP in ischemic stroke. The present study is the first to show that an increasing SBP is associated with an elevated CRP level in the acute phase after stroke, independent of DBP, MAP, and PP. The present study also found some indication that the association between an increasing SBP and elevated CRP was stronger in older than in younger persons.

Increased BP may promote inflammation by modulation of the biomechanical stimuli³¹: cyclic strain has been shown to increase soluble intercellular adhesion molecule 1 (sICAM-1) expression and mRNA expression and secretion of monocyte chemotactic protein 1 (MCP-1).^32–35 Ischemia in vivo and in vitro have also been shown to upregulate the expression of Ig-families of adhesion molecules in cerebral endothelial cells and to facilitate leukocyte adhesion and transmigration into the brain.³⁶ These data suggest mechanisms by which the increase in pulsatile load and cyclic wall stress imposed by high SBP on the cerebral vasculature may facilitate and increase ischemic brain inflammation.

Stimulation of human vascular smooth muscle cells by angiotensin (Ang) II, a key regulator of BP, results in inflammatory activation with dose-dependent increases in expression and release of IL-6.^5,6 Furthermore, cerebral ischemia induces the expression of IL-6 in neurons and astrocytes, and ischemic brain tissues appear to be a major source of IL-6 in stroke.^18,19,37

BP may also have a proinflammatory effect on the arterial wall because of increased oxidative stress.³⁸ In addition to its effects on IL-6 expression,^5,6 Ang II also stimulates increased sICAM-1 expression and vascular infiltration by monocytes and macrophages, which is reversible by ACE-I and Ang type 1 receptor blockade.³⁹ It is possible that the lack of association between SBP and CRP levels in ACE-I–treated patients may in part be due to anti-inflammatory effects mediated by Ang II suppression.^5,30

However, it is important to note that we had no information on sICAM or reactive oxygen species or Ang II levels in the present investigation. Explaining our results in terms of these mechanisms is necessarily speculative, and other explanations are possible.

First, we cannot exclude the possibility that the relationship between CRP and BP levels is only an epiphenomenon. The present study was based on observational data, and confounding from factors that were not controlled for and/or residual confounding from factors that we did control for, but that were imperfectly measured, may be an alternative explanation for our results. The presence of a selection bias is also plausible because this is not a randomized controlled trial; both CRP and SBP may be markers for something involved in the selection bias. One cannot definitively rule out chance as an explanation for the findings of this study; the large number of variables entered into the univariable analysis and a borderline modeling technique make it possible, suggesting that, without internal or external validation, our results should be considered as hypothesis generating.

Second, our analyses are based on single measurements of BP and inflammatory markers, which may not reflect these relationships over time, making it impossible to determine the temporal ordering of the association that we observed between SBP and CRP. Cross-sectional independent association of high BP and plasma levels of CRP have been reported.^40,41 Although the evidence noted above suggests that increases in SBP would enhance inflammation, the nature of our data could leave open different possibilities in the relationship between BP and the acute phase response after stroke. One important possibility is that inflammation, reflected by the levels of CRP, is not playing a role in the development of high BP even before the ischemic stroke occurs. However, in our cohort, an acute increase of BP more than a history of arterial hypertension was associated with higher levels of CRP after stroke. Probably the levels of BP after an ischemic stroke are one of the underlying processes related to inflammation that are relevant in the inflammatory response in ischemic stroke patients, more so than a history of arterial hypertension. Furthermore, the consistency of the association between SBP and CRP across different models and different definitions of CRP elevation indicates that our results may not simply be due to chance.

Several theories have been offered as to why an elevated BP may be a predictor of poor outcome after stroke. High BP might promote early recurrence, hemorrhagic transformation, or the formation of cerebral edema, thus increasing the risk of death or new cardiovascular events.^25–28 The present study suggests another explanation as to why SBP may be predictive of poor outcome. Our study shows that increasing levels of BP were associated with higher odds of having an elevated CRP level, a higher BP, more specifically SBP, thus facilitating or increasing an inflammatory response after stroke, which influences the prognosis of ischemic stroke patients as previously demonstrated.^16,17 However, low BP was also found to be an independent prognostic factor for poor outcome in patients with ischemic stroke, and this observation is apparently in contrast with the relationship between SBP and CRP that is suggested by our results.²⁸ The relationship between CRP and SBP is probably more complex than we realize. Given the observational nature of our study, our results should not be taken as evidence of a causal relationship and should be interpreted with caution. Patients with high CRP in acute brain ischemia might have a predisposition to the activation of inflammation in response to triggering stimuli in cardiovascular events. Acute brain ischemia increases BP, and ischemia may induce brain inflammation separately.

In conclusion, we found that increased SBP was significantly associated with elevated levels of circulating CRP in ischemic stroke patients. These findings support a possible role of acute hypertension after stroke as an inflammatory stimulus contributing to ischemic brain inflammation.

Perspectives
Future studies need to clarify whether or not an elevated BP leads to increased inflammatory response after stroke, whether this effect is more or less pronounced in certain subgroups such as the elderly, and whether the association between BP and inflammation helps to explain why SBP has been associated with outcome in stroke. Probably, the levels of BP after an ischemic stroke are one of underlying processes related to inflammation, and they are relevant in the inflammatory response after an ischemic stroke. From this point of view, because higher CRP levels are an independent prognostic factor after stroke¹⁶ and high BP is apparently associated with higher CRP levels, the current approach to the treatment of acute hypertension²⁷ after stroke probably should be revisited from different perspectives.

Received August 13, 2003; first decision September 8, 2003; accepted October 1, 2003.

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