Modulatory Effect of Inflammation on Blood Pressure Reduction via Therapeutic Lifestyle Change

INTRODUCTION

Prospective studies1–6 have demonstrated that plasma levels of C-reactive protein (CRP) are a strong independent predictor of future vascular events among individuals with and without known cardiovascular disease, and elevated levels of CRP have been positively correlated with most cardiovascular risk factors. Inflammation has recently been hypothesized to play a contributory role in the development of hypertension, and elevated CRP levels have been associated with elevated blood pressure (BP) levels in cross-sectional studies.7,8 Higher CRP levels may increase BP by reducing nitric oxide production in endothelial cells, resulting in vasoconstriction and increased endothelin 1 production, as well as by upregulating angiotensin type 1 receptor expression.9–11 Recently, elevation of CRP levels has been shown to increase the risk for the future development of hypertension, suggesting that hypertension is in part a disorder of inflammation.12 We are not aware, however, of any studies investigating the role of inflammation in modulating efficacy of therapies designed to reduce BP.

Cardiac rehabilitation and exercise training (CRET) is a proven modality for reducing the overall burden of cardiovascular risk and has been shown to significantly improve major cardiac risk factors, including exercise capacity, percentage of body fat, BP, and lipids.13,14 Moreover, we have recently reported14,15 the effectiveness of CRET in reducing both the prevalence of metabolic syndrome and CRP, whose levels can be diminished by as much as 40% to 50%.

We sought to determine if inflammatory status can modulate BP changes, as well as other risk factors typically improved with therapeutic lifestyle change, by using CRET.

RESULTS

Baseline data for the 635 patients enrolled in the rehabilitation program are detailed in Table 1. In our rehabilitation cohort, 179 patients (28%) were women (33% were receiving hormone replacement therapy), and the mean age of our cohort was 65±11 years. The mean body mass index (BMI) of the cohort was 28.3±5 kg/m², and the mean percentage of body fat was 28.9±7.6%. Of note, 41% of subjects upon entry were classified as overweight (25 kg/m²≤BMI<30 kg/m²), and an additional 32% were classified as obese (BMI≥30 kg/m²). The median concentration of CRP at entry was 3.2 mg/L (range, 0.2 to 80.1 mg/L); mean concentration was 5.8±8.4 mg/L at baseline. A total of 394 patients (62%) were receiving statin therapy, and 388 patients (61%) were receiving antihypertensive therapy upon entry and during the 3-month rehabilitation program. At entry, CRP levels were weakly, but significantly, correlated to BMI (r = 0.09; P = 0.04), resting heart rate (r = 0.12, P = 0.02), systolic BP (r = −0.12, P = 0.005), diastolic BP (r = −0.13, P = 0.002), and mean arterial pressure (r = −0.14, P = 0.0006).

Patients were divided into 2 groups based on baseline median CRP concentrations. Baseline differences between groups with high (>3.2 mg/L) and low (≤3.2 mg/L) CRP levels are described in Table 2. Compared to patients with low CRP levels, patients with elevated CRP levels were more likely to be women (33% vs 21%, P = 0.002) and had higher triglyceride concentrations (165±96 vs 146±92 mg/dL, P = 0.07), higher BMI (28.8±5.2 vs 27.8±4.7 kg/m², P = 0.02), higher percentage of body fat (29.7±7.8 vs 28.1±7.6%, P = 0.01), higher resting heart rate (69±12 vs 65±13 bpm, P = 0.004), and lower peak VO₂ (15.5±4.3 vs 17.1±5.2 mL/kg/min, P<0.0001).

Following CRET, both the groups with high and those with low CRP levels exhibited statistically significant improvements in percentage of body fat (−3% and −4%, respectively), HDL cholesterol levels (+7% and +7%, respectively), triglyceride levels (−12% and −8%, respectively), peak Vo₂ (+11% and +9%, respectively), and resting heart rate (−6% and −6%, respectively) (Tables 3 and 4). Systolic, diastolic, and mean arterial pressure statistically improved (each by −4%) in patients with low CRP levels but did not change in patients with high CRP levels. In a multiple regression model incorporating 9 independent baseline variables (age, gender, BMI, percentage of body fat, peak VO₂, HDL cholesterol, LDL cholesterol, triglycerides, and CRP), only age, CRP levels, and BMI were significant independent predictors of reduction in mean arterial pressure (Table 5).

DISCUSSION

The major finding of this study is that, in contrast to patients with coronary artery disease who have low levels of CRP, patients with high baseline CRP levels do not demonstrate BP reduction after therapeutic lifestyle change via CRET.

Inflammatory processes are now recognized as playing a fundamental role in atherogenesis.5,23 Prospective studies1–6 have demonstrated that plasma levels of CRP are a strong independent predictor of risk of future vascular events among individuals with and without known cardiovascular disease, and elevated levels of CRP have been positively correlated with most cardiovascular risk factors. Hypertension remains a central risk factor for cardiovascular events, and inflammation has recently been hypothesized to play a contributory role in the development of hypertension; moreover, increased CRP levels have been associated with elevated BP levels in cross-sectional studies.7,8 Higher CRP levels may increase BP by reducing nitric oxide production in endothelial cells, resulting in vasoconstriction and increased endothelin 1 production, as well as by upregulating angiotensin type 1 receptor expression.9–11 Recently, elevation of CRP levels has been shown to increase the risk for the development of hypertension, suggesting that hypertension is in part a disorder of inflammation.12

Moreover, elevated BP may promote vascular inflammation by alterations of pulsatile blood flow. Cyclic strain has been shown to increase soluble intercellular adhesion molecule-1 and vascular cellular adhesion molecule-1 expression by endothelial cells24 and to upregulate endothelial cell secretion of monocyte chemoattractant protein-1,25–27 all of which lead to increased monocyte adhesion to the endothelium.28 Levels of CRP have been shown to correlate with mononuclear cell oxidative stress.29 These changes, taken together, suggest that hypertension may provide multiple pathways for proinflammatory stimuli at the vessel wall.

Therapeutic lifestyle change by incorporating dietary changes, exercise training, and weight reduction has been shown to be effective in reducing BP, particularly systolic BP.13,19,30–32 These lifestyle changes are routinely incorporated in CRET and favorable changes in lipids, BP, weight, and exercise capacity are commonly observed.13,14 We previously reported the effectiveness of these therapies in reducing CRP,15 suggesting that inflammation can be effectively treated nonpharmacologically. The observation that inflammation can influence efficacy of these therapies has heretofore not been reported.

In our cohort of patients with coronary artery disease, those with higher CRP values were preponderantly women, had high obesity indices, and had a reduced aerobic capacity. Although there were differences in resting pulse rate, there were no differences in BP values between groups with high and low CRP levels. Those patients with elevated CRP concentrations had numerous cardiac benefits after rehabilitation, including improvements in HDL cholesterol, triglyceride, and CRP levels and in exercise capacity, resting pulse, and percentage of body fat. The observation of a lack of reduction in BP despite these positive effects will require further study.

There are several limitations to this study. First, this is a single-center, retrospective analysis of patients enrolled in CRET, and several confounding factors may contribute to the observations reported. Second, BP was determined by a single resting measurement, not as an average of several measurements over time. Finally, although therapeutic lifestyle changes such as CRET produce BP reductions in both hypertensive and normotensive patients, we did not stratify patients on the basis of BP status. Despite this, a multivariate analysis controlling for many confounding factors revealed that CRP status plays a significant role in effecting change in BP.

In conclusion, we have observed that inflammatory status may play a role in effecting BP reduction after therapeutic lifestyle change. Further research is needed to evaluate this effect prospectively in patients receiving pharmacologic and nonpharmacological therapy for hypertension.