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Hypertension is a major risk factor for coronary heart disease.¹ Understanding the mechanisms related to the development of hypertension may result in potential targets for nonpharmacologic and pharmacologic interventions and may potentially reduce the risk of cardiovascular deaths. Numerous epidemiologic studies have shown an association between inflammation, measured by C-reactive protein (CRP) concentration, and prevalent hypertension.^2-4 Further evidence has supported a role for inflammation in the development of hypertension in middle-aged adults.^5,6 We evaluated whether CRP levels predicted future risk of hypertension in a young adult cohort, which would potentially allow for earlier and more aggressive prevention and treatment of hypertension.

Subjects and methods
The Coronary Artery Risk Development in Young Adults (CARDIA) study was started in 1985-1986 to identify the elements associated with coronary risk factor development in young adults. C-reactive protein (CRP) concentrations of 3919 white and African-American men and women aged 25-to-37 years who were enrolled in the CARDIA study were measured. Incident hypertension was defined as a self-reported physician diagnosis of hypertension, current use of antihypertensive medication among individuals who did not have hypertension 8 years earlier, or a blood pressure of ≥ 140/90 mm Hg. The relationship between CRP concentration and incident hypertension was assessed by logistic regression modeling. We used generalized linear modeling to determine whether CRP levels predicted a change in systolic or diastolic blood pressure over a period of 8 years.

Results
In univariable models, CRP concentrations > 3 mg/L were associated with a 79% greater risk of incident hypertension compared with CRP concentrations < 1 mg/L (odds ratio [OR] = 1.79; 95% confidence interval [CI], 1.40-2.28). This risk was attenuated and no longer statistically significant, however, after adjusting for body mass index (BMI; OR = 1.14; 95% CI, 0.86-1.53) or BMI and other potential confounders (OR = 1.13; 95% CI, 0.83-1.52). When assessing the risk of incident hypertension by quartiles of CRP, comparing the highest quartile (> 3.19 mg/L) with the referent (< 0.48 mg/L), the risk of developing hypertension was increased 2-fold (OR = 2.25; 95% CI, 1.66-3.06; P = .001). After adjusting for BMI, however, CRP did not predict incident hypertension (OR = 1.35; 95% CI, 0.95-1.92; P = .20). CRP concentration also did not correlate with change in systolic or diastolic blood pressure after adjusting for BMI (P = .10 and P = .70, respectively). These findings were similar for men and women (Table) and within race-specific groups.

Discussion
Numerous studies have shown an independent association between elevated concentrations of CRP and prevalent^2-4 or incident hypertension^5-6 in middle-aged adult populations. In the current study of a younger cohort, when the prevalence of hypertension and other risk factors is low, we determined whether CRP predicted the development of hypertension. In the CARDIA study, an association between CRP concentration and incident hypertension was attenuated and no longer statistically significant after adjustment for BMI. These results were true for both men and women and for African-American and white participants.

Although an apparent CRP-hypertension relationship may be confounded by obesity, it is also possible that a complex relationship exists between inflammation and obesity, leading to the development of hypertension. The latter possibility is supported by a link between the renin-angiotensin system and adiposity,⁷ and obesity-related hypertension via insulin-mediated sympathetic stimulation,⁸ both of which have an inflammatory component.^9,10 Delineating differences in this relationship as individuals age could also play an important role in understanding an obesity-inflammation mechanism related to hypertension.

Conclusions
In a young cohort, CRP does not independently predict risk for incident hypertension after accounting for BMI. Additional research is required in the area of inflammation and hypertension, with a special focus on the effect of obesity and age-related changes on this process. In addition, it is also important to investigate other potential unmeasured variables, such as environmental factors (eg, air pollution), which may have an inflammatory component and may partially account for a CRP-hypertension relationship.

References
1. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004; 364(9438): 937-952.

2. Lakoski SG, Cushman M, Palmas W, et al. The relationship between blood pressure and C-reactive protein in the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Coll Cardiol. 2005; 46(10):1869-1874.

3. Blake GJ, Rifai N, Buring JE, et al. Blood pressure, C-reactive protein, and risk of future cardiovascular events. Circulation. 2003; 108(24): 2993-2999.

4. Bautista LE, Atwood JE, O'Malley PG, et al. Association between C-reactive protein and hypertension in healthy middle-aged men and women. Coron Artery Dis. 2004; 15(6):331-336.

5. Sesso HD, Buring JE, Rifai N, et al. C-reactive protein and the risk of developing hypertension. JAMA. 2003; 290(22): 2945-2951.

6. Niskanen L, Laaksonen DE, Nyyssonen K, et al. Inflammation, abdominal obesity, and smoking as predictors of hypertension. Hypertension. 2004; 44(6):859-865.

7. Engeli S, Negrel R, Sharma AM. Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Hypertension. 2000; 35(6): 1270-1277.

8. Landsberg L. Insulin-mediated sympathetic stimulation: role in the pathogenesis of obesity-related hypertension (or, how insulin affects blood pressure, and why).  J Hypertens. 2001; 19(3 pt 2): 523-528.

9. Kranzhofer R, Schmidt J, Pfeiffer CAH, et al. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1999; 19(7):1623-1629.

10. Kern PA, Ranganathan S, Li C, et al. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001; 280(5):E745-E751.

A more detailed discussion of this topic can be found in Lakoski SG, Herrington DM, Siscovick DM, et al. C-reactive protein concentration and incident hypertension in young adults. Arch Intern Med. 2006;166(3): 345-349.