Patients With Hypertension and the Cardiometabolic Syndrome: The Potential Impact of Inflammatory Biomarkers

E.M. is a 54‐year‐old African American woman who presents to her physician for an annual examination. She has been reading extensively concerning the prevention of heart disease and wants to keep her risk as low as possible. E.M. has a personal history of hypertension and has been taking antihypertensive medications since the age of 46. Physical examination reveals an obese woman with a body mass index of 31.4 kg/m², waist circumference of 36 inches, and blood pressure (BP) of 146/92 mm Hg. The remainder of the physical examination is unremarkable. Laboratory evaluation shows a fasting glucose of 106 mg/dL, high‐density lipoprotein cholesterol level of 52 mg/dL, low‐density lipoprotein level of 136 mg/dL, and triglycerides 122 mg/dL. She asks you if she should have a C‐reactive protein (hs‐CRP) level checked with her other annual laboratory values. Based on her elevated BP, fasting glucose, and lipid profile, what do you advise her about her risk and how do you manage her risk factor profile?

African Americans have a higher prevalence of coronary heart disease and a higher coronary heart disease mortality rate than white Americans. ¹ Much of this excess morbidity and mortality is due to the burden of hypertension‐related target organ damage along with the increased prevalence of multiple risk factors for coronary heart disease, including higher levels of obesity, especially in women; insulin resistance; and sedentary lifestyle. ² However, compared with other groups, most of the data have shown that African Americans may have similar or even better lipid profiles than whites, including lower total cholesterol, lower low‐density lipoprotein, and higher high‐density lipoprotein levels. ¹ , ² The combination of better lipid profiles despite worse insulin resistance, higher BP, and more prevalent obesity has led to data showing an unexpectedly overall low prevalence of the metabolic syndrome in population‐based epidemiologic studies. Newer data suggest that targeting emerging cardiovascular disease (CVD) risk factors in addition to traditional CVD risk factors may improve outcomes. These considerations are particularly relevant because a large body of data has suggested that African Americans tend to have higher levels of hs‐CRP and other inflammatory biomarkers. Developing approaches to assess cardiac risk include using biomarkers in addition to traditional CVD risk factors to help target more intense therapeutic goals for patients previously considered to be at low to intermediate risk for future CVD events.

hs‐CRP is the most extensively studied of the inflammatory biomarkers, with higher levels of hs‐CRP being associated with increased risk of CVD. In previous analyses, race and sex have both been shown to be independent predictors of elevated hs‐CRP, with African American race and female sex associated with higher levels. Accordingly, African American women tend to have the highest levels of hs‐CRP, even after controlling for other risk factors that influence CVD risk, such as body mass index, smoking status, and history of hypertension, diabetes, or high cholesterol. ³ , ⁴ In addition, the degree of elevation of hs‐CRP appears to be linearly related to the number of components of the metabolic syndrome. Investigators from the Women’s Health Study followed 14,719 women for 8 years to detect incident cardiovascular events. ⁵ At baseline, median hs‐CRP levels for those with 0, 1, 2, 3, 4, or 5 characteristics of the metabolic syndrome were 0.68, 1.09, 1.93, 3.01, 3.88, and 5.75 mg/L, respectively. Among those with the metabolic syndrome at baseline, age‐adjusted rates of future cardiovascular events were 3.4 per 1000 person‐years of exposure for those with baseline hs‐CRP levels <3.0 mg/L, compared with 5.9 per 1000 person‐years of exposure for those with baseline hs‐CRP levels >3.0 mg/L. Additive effects for hs‐CRP were seen for those with 4 or 5 components of the metabolic syndrome, leading the authors to conclude that hs‐CRP adds clinically important prognostic information to the established definitions of the metabolic syndrome.

The African American Rosuvastatin Investigation of Efficacy and Safety (ARIES) trial compared rosuvastatin and atorvastatin during 6 weeks of treatment in 774 hypercholesterolemic African American adults. ⁶ This open‐label trial randomized patients to 10 or 20 mg of rosuvastatin or 10 or 20 mg of atorvastatin. At week 6, significantly greater reductions in low‐density lipoprotein cholesterol, total cholesterol, non–high‐density lipoprotein cholesterol, and apolipoprotein B concentrations, as well as lipoprotein and apolipoprotein ratios, were seen with rosuvastatin vs milligram‐equivalent doses of atorvastatin, and greater than two thirds of the patients had an elevated baseline hs‐CRP level (>2.0 mg/dL). At 6 weeks, the median hs‐CRP levels were statistically significantly reduced from baseline with rosuvastatin 10 and 20 mg and atorvastatin 20 mg in patients with a baseline hs‐CRP level >2.0 mg/L. Although this study was not designed to compare the effects of rosuvastatin and atorvastatin in reducing hs‐CRP from baseline, there was a trend toward decreasing hs‐CRP levels with an increasing dose of either statin.

Recent data from Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) shows us that even patients with elevated hs‐CRP, but without overt hyperlipidemia, may benefit from statin therapy. ⁷ This trial followed 17,802 healthy men and women who had low‐density lipoprotein cholesterol levels <130 mg/dL, with hs‐CRP levels >2.0 mg/L. The patients were randomized to rosuvastatin 20 mg daily or placebo and followed for the primary end point of incident cardiovascular events, defined as nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, an arterial revascularization procedure, or confirmed death from cardiovascular causes. The trial was stopped early by the data safety monitoring board after only 1.9 years of median follow‐up. There was a significant reduction in the primary end point among participants assigned to receive rosuvastatin (142 primary events, vs 251 in the placebo group; hazard ratio, 0.56). Notably, data from JUPITER confirm robust reductions in cardiovascular events with statin therapy in women as well as black and Hispanic populations, who represented 38.2% and 25.2% of the total study population, respectively.

Other inflammatory biomarkers have been shown to be associated with increased CVD risk and vary by self‐reported race/ethnicity. African Americans have been reported to have higher levels of fibrinogen, ⁸ lipoprotein (a), tumor necrosis factor α and interleukin 6 compared with Caucasians, although some of this difference may be related to differential allele expression of regulatory regions of the genes that express these cytokines. Currently, prospective data examining the relationship between levels of these biomarkers and cardiovascular outcomes are lacking, and so the influence of these markers in clinical practice remains to be seen.

In addition to the effects of statins on hs‐CRP, current evidence suggests that statins may have mild beneficial effects on BP itself. A number of mechanisms have been suggested through which statins may improve BP, including inhibition of vascular smooth muscle cell migration and proliferation, improvement in both small and large artery compliance, and improvements in endothelial dysfunction by modulating levels of nitric oxide bioavailability and reactive oxygen species. ⁹ Small clinical trials examining the impact of statins on BP control have had conflicting results. The largest analysis looking to investigate the effects of statins on BP was a cross‐sectional study of 2584 hypertensive adults with no known CVD from the National Health and Nutrition Examination Survey 1999–2002. ¹⁰ Logistic regression models were used to determine an association between statin use and BP control, and hs‐CRP was added to the model to determine its effect on the association. Compared with persons not on statin therapy, significantly more statin users had their BP under control (52.2% vs 38.0%). After adjustment for demographic factors, body mass index, diabetes, smoking, exercise, low‐salt diet, and antihypertensive medications, the likelihood of having BP under control remained more likely among statin users (odds ratio, 1.46; 95% confidence interval, 1.05–2.05). The association between statin use and lower BP was unchanged with the addition of hs‐CRP to the model.

Although hs‐CRP and other inflammatory biomarkers have established independent prognostic information on CVD risk, investigators continue to examine the effect of treating traditional CVD risk factors on levels of inflammation. Lipid‐lowering agents, such as statins, fenofibrate, niacin, and ezetimibe, have been shown to lower hs‐CRP levels. ¹¹ However, multiple antihypertensive medications have also been shown to decrease hs‐CRP levels, including β‐blockers, ACE inhibitors, and angiotensin receptor blockers. ¹¹ King and colleagues treated 75 patients with uncontrolled hypertension using extended‐release metoprolol succinate and followed them for a 3‐month period. ¹² In the 61 hypertensive patients who completed the study, hs‐CRP decreased from 6.2±7.5 mg/L at baseline to 5.4±7.0 mg/L (P=.03) at 1 month, and the 13 patients who received 200 mg of extended‐release metoprolol had a 32% decline in hs‐CRP from 7.0±9.0 mg/L to 4.8±6.6 mg/L (−2.2 mg/L) (P= .005) over the 3‐month period.

Additionally, the Valsartan‐Managing Blood Pressure Aggressively and Evaluating Reductions in hs‐CRP (Val‐MARC) trial was prospectively designed to compare the efficacy of valsartan vs valsartan plus hydrochlorothiazide (HCTZ) as initial therapy for hypertensive patients and determine whether any treatment effects on hs‐CRP were dependent or independent of BP reduction. ¹³ A total of 1668 patients were treated with 160 mg of valsartan or 160/12.5 mg of valsartan/HCTZ once daily for 2 weeks with forced titration to 320 mg of valsartan or 320/12.5 mg of valsartan/HCTZ for an additional 4 weeks. After 6 weeks, systolic BP (−25 vs −18 mm Hg; P<.001) and diastolic BP (−14 vs −9 mm Hg; P<.001) were reduced to a greater degree among patients assigned to valsartan/HCTZ than to valsartan alone. However, the median change in hs‐CRP was −0.12 mg/L among patients assigned to valsartan compared with +0.05 mg/L among those assigned to valsartan/HCTZ, a 13.3% difference (P<.001). No relationship was observed between hs‐CRP reduction and BP; thus, valsartan reduced hs‐CRP levels independent of degree of BP reduction. Also, telmisartan ¹⁴ and irbesartan ¹⁵ have been shown to reduce hs‐CRP levels in patients with type 2 diabetes and coronary artery disease, respectively.

Although the routine measurement of inflammatory biomarkers in clinical practice is not yet the standard of care, current guidelines ¹⁶ do suggest a measurement in asymptomatic individuals who have an intermediate level of risk, if the results of the hs‐CRP level might change the decision to initiate drug therapy. Evidence shows that certain populations who might not be considered for pharmacologic therapy on the basis of standard guidelines might become eligible on the basis of their inflammatory biomarker levels alone. This applies to women in particular and ethnic minorities who tend to have higher levels of hs‐CRP and other inflammatory biomarkers in large epidemiology studies. For our patient E.M., emphasizing therapeutic lifestyle interventions in addition to intensive management of her BP, lipids, and glucose might simultaneously improve levels of inflammation and further reduce her future risk of a CVD event.