Peripheral Vessels Unit, 1st Department of Cardiology Athens Medical School Hippokration Hospital, Athens, Greece D Terentes-Printzios, C Vlachopoulos, G Vyssoulis, N Ioakeimidis, P Xaplanteris, K Aznaouridis, E Christoforatou, A Samentzas, A Siama, C Stefanadis
No conflict of interest.
Methods Results Background Clinical perspectives Conclusions
Background
Hypertension-related subclinical alterations in several organs indicate progression in the CVD continuum which markedly increases the risk beyond that caused by the simple presence of risk factors
Left ventricular hypertrophy (i.e. U/S, ECG) Carotid IMT Microalbuminuria Arterial stiffness (i.e. PWV, AIx) Renal function tests (i.e. creatinine, egfr) Ankle-brachial index Waeber B, de la Sierra A, Ruilope LM J Hypertens 2009
Following on the ferment in the basic science laboratory regarding inflammation in atherosclerosis, we have now entered an era of translation of inflammation biology to the clinic.
Emerging Risk Factors Collaboration. Lancet 2010 CRP concentration has continuous associations with the risk of CHD, ischaemic stroke and vascular mortality
Kvakan H, et al., Trends Cardiovasc Med 2009 Inflammation ìs a central feature in the pathogenesis of atherosclerosis and also in hypertensioninduced target organ damage
Acute inflammationinduced vascular impairment is associated with an increase of level of inflammatory mediators Vlachopoulos C, et al. Circulation 2005
Most studies suggest that inflammatory markers are associated with hypertension-induced target organ damage. Carotid IMT Hashimoto H, et al., Circulation 2001 Yasmin Zoccali Tsioufis Winbeck et C, al., et K, JASN al., ATVB et AJC al., 2006 2004 Cerebrovasc 2005 Dis 2002 Okura Leibowitz Vlachopoulos Van et der al.,clin D, Meer et et al., Exp IM, al., Blood Circulation et Nephrol al., Press Stroke 2010 2005 2002 Kullo Mehta Santos Hashimoto et S, al., S, et et AJH al. al., H, Hypertension 2005 et Vasc al., Med Stroke 2004 2007 2004 Pietri Salles Makita et G, al., et S, J al., et al., Hypertension Stroke 2006 20052007 Nakhai-Pour Rosello-Lleti Corrado E, et E, et al., et al., al., J Arch Hum AJH Med Hypert 2009 Res 2007 2006 Schnabel Lorenz et MW, al., et Hypertension al., Stroke 2007 2008 Schumacher Rizzo M, et et al., al., Intern Hypertension Med J 2009 2009 Vlachopoulos et al., AJH 2010 Amer M, et al., JASH 2011 Aortic stiffness and wave reflection Renal function ABI LV mass
Navarro-Gonzalez J, et al., J Hypertens 2008 Inflammation may participate in the development of early TOD in essential hypertension and also is related to the extent of TOD Ratto E, et al., JASH 2007
To investigate whether the prevalence and extent of subclinical TOD among never-treated hypertensives is related to subclinical inflammation
Methods
The study participants were 1225 patients with never treated essential hypertension recruited from the Hypertension and Peripheral Vessels Units of our Department with no established CVD. Hypertension was diagnosed according to ESC/ESH 2007 guidelines.
1225 consecutive never-treated hypertensives according to ESC/ESH 2007 criteria Ankle-brachial index Aortic stiffness and wave reflections Echocardiography Blood samples for hscrp, creatinine and other biochemical parameters Investigation of whether the prevalence and extent of subclinical TOD among never-treated hypertensives is related to subclinical inflammation
Left ventricular mass was calculated using the Devereux formula LVMI was calculated using the formula LVM/BSA Left ventricular hypertrophy (LVH) was defined as a LVMI 125 g/m 2 in men and 110 g/m 2 in women
Carotid-femoral PWV was calculated with a validated noninvasive device (Complior, Artech Medical). ` Augmentation index (AIx) was estimated by pulse wave analysis with the Sphygmocor device (Sphygmocor, AtCor Medical, Sydney, Australia). Ankle-brachial index (ABI) was calculated by dividing the highest ankle systolic blood pressure by the highest brachial systolic blood pressure.
An increase in aortic PWV by 1 m/s corresponded to a risk increase of 15% in total CV events, CV mortality, and all-cause mortality Vlachopoulos C and Aznaouridis K, et al., JACC 2010
Augmentation index predicts clinical events independently of peripheral pressures Vlachopoulos C and Aznaouridis K, et al., ΕHJ 2010
High-sensitivity C-reactive protein (hscrp) was measured by immunonephelometry (Dade Behring, Marburg, Germany) Creatinine and biochemical variables such as triglycerides, total cholesterol, HDL, LDL and plasma glucose levels were measured using standard techniques egfr was estimated using the MDRD formula
Stepwise multivariable linear regression analysis was applied to evaluate the association between each marker of subclinical TOD as dependent variable and hscrp as independent variable, after adjustment for potential confounders (age, gender, mean blood pressure, smoking habits, body-mass index, blood glucose and lowdensity lipoprotein). Receiver operating characteristic (ROC) curves were generated to evaluate the ability of hscrp to discriminate subjects with and without TOD in separate and as a total.
Results
Unstandardized Standardized R 2 coefficient coefficient change P value Model (dependent variable: loglvmi) adjusted R 2 =0.29 Sex (male/female) 0.036 0.355 0.108 <0.001 logage (years) 0.125 0.268 0.103 <0.001 logmbp (mmhg) 0.182 0.190 0.049 <0.001 logcrp (mg/l) 0.018 0.130 0.023 <0.001 logglucose (mg/dl) 0.077 0.107 0.011 <0.001 Smoking (yes/no) 0.006 0.056 0.003 0.021
Unstandardized Standardized R 2 coefficient coefficient change P value Model (dependent variable: logpwv) adjusted R 2 =0.38 logage (years) 0.269 0.354 0.194 <0.001 logmbp (mmhg) 0.449 0.292 0.114 <0.001 logcrp (mg/l) 0.040 0.178 0.044 <0.001 logglucose (mg/dl) 0.196 0.167 0.027 <0.001 Smoking (yes/no) 0.011 0.065 0.004 0.004
Unstandardized Standardized R 2 coefficient coefficient change P value Model (dependent variable: AIx) adjusted R 2 =0.42 logage (years) 44.375 0.409 0.208 <0.001 Sex (male/female) -8.046-0.341 0.116 <0.001 logmbp (mmhg) 52.967 0.239 0.051 <0.001 Smoking (yes/no) 4.599 0.195 0.036 <0.001 logbmi (mg/dl) 20.569-0.119 0.013 <0.001 logcrp (mg/l) 0.093
Unstandardized Standardized R 2 coefficient coefficient change P value Model (dependent variable: logabi) adjusted R 2 =0.11 logage (years) 0.013 0.170 0.033 <0.001 logmbp (mmhg) -0.114-0.158 0.027 <0.001 logcrp (mg/l) -0.017-0.164 0.018 <0.001 logbmi (kg/m 2 ) 0.103 0.182 0.026 <0.001 Smoking (yes/no) -0.007-0.095 0.009 0.001 logglucose (mg/dl) -0.035-0.065 0.004 0.021
Unstandardized Standardized R 2 coefficient coefficient change P value Model (dependent variable: logcreatinine) adjusted R 2 =0.24 Sex (male/female) 0.085 0.454 0.203 <0.001 logcrp (mg/l) 0.031 0.122 0.025 <0.001 logglucose (mg/dl) 0.091 0.069 0.007 0.008 logage (years) 0.060 0.070 0.005 0.008 logmbp (mmhg) 0.091 0.052 0.003 0.041
Unstandardized Standardized R 2 coefficient coefficient change P value Model (dependent variable: logegfr) adjusted R 2 =0.17 logage (years) -0.272-0.278 0.123 <0.001 Sex (male/female) 0.032 0.155 0.020 <0.001 logcrp (mg/l) -0.035-0.127 0.021 <0.001 logglucose (mg/dl) -0.105-0.072 0.005 0.008 logmbp (mmhg) -0.105-0.054 0.003 0.041
Prediction of increased aortic stiffness AUC=0.73 (95% CI: 0.61-0.85, P<0.001) Prediction of LVH AUC=0.68 (95% CI: 0.65-0.71, p<0.001)
Prediction of increased plasma creatinine AUC=0.66 (95% CI: 0.61-0.71, p<0.001) Prediction of decreased ABI AUC=0.80 (95% CI: 0.70-0.90, p<0.001)
Prediction of decreased egfr AUC=0.69 (95% CI: 0.61-0.76, p<0.001)
hscrp (mg/l) 6 5 P < 0.001 5,68 4 3,35 3 2 1,13 1,67 1,89 1 0 No marker of TOD (n=637) One marker of TOD (n=471) Two markers of TOD (n=105) Three markers of TOD (n=11) Four markers of TOD (n=1)
AUC=0.85 (95% CI: 0.71-0.98, p<0.001) The sensitivity for prediction of more than 2 abnormal markers of TOD at a hscrp level of more than 2.45 mg/l was 83% (95% CI, 52% 97%) and the specificity was 84% (95% CI, 82% 86%)
Clinical perspectives
Conclusions
The present study demonstrates a progressive unfavourable effect of subclinical inflammation on subclinical target organ damage. Although this is a cross-sectional study and no etiological relationships can be established, it might be inferred that inflammation may begin to adversely alter the function of target organs early in the progress of hypertension, thus highlighting the importance of a close monitoring of patients regarding their CRP levels. However, the exact role of inflammation in the development of target organ damage in hypertension warrants further investigation.