Rodrigo Cardoso Santos

Hypoadiponectinemia and aldosterone excess are associated with lack of blood pressure control in subjects with resistant hypertension

Obesity, arterial stiffness and high aldosterone levels can interact to cause resistant hypertension (RHTN). Lower adiponectin (APN) levels may be significantly associated with hypertension. However, the importance of hypoadiponectinemia as a complicating factor in the lack of blood pressure (BP) control in individuals with RHTN has not been demonstrated. Ninety-six RHTN patients were classified into uncontrolled (UCRHTN, n=44) and controlled (CRHTN, n=52) subgroups. Their APN and aldosterone levels, office and ambulatory BP (ABPM) measurements, endothelium-dependent brachial artery responses (flow-mediated dilation (FMD)), left ventricular mass index (LVMI) and pulse wave velocity (PWV) were evaluated. The UCRHTN subgroup had increased aldosterone levels, as well as higher LVMI and PWV. In addition, lower APN levels and impaired FMD response were found in this subgroup. The brachial and ABPM pulse pressures were inversely associated with the APN levels (r=−0.45, P=0.002; r=−0.33, P=0.03, respectively), as were the aldosterone levels and the PWV (r=−0.38, P=0.01; r=−0.36, P=0.02, respectively) in UCRHTN patients. The PWV was only significantly influenced by the APN level in the UCRHTN subgroup in the multivariate regression analysis. None of the correlations mentioned above were observed in the CRHTN subgroup. Hypoadiponectinemia and high aldosterone levels may therefore be implicated in resistance to antihypertensive therapy related to arterial stiffness.

Infliximab prevents increased systolic blood pressure and upregulates the AKT/eNOS pathway in the aorta of spontaneously hypertensive rats

High systolic blood pressure caused by endothelial dysfunction is a comorbidity of metabolic syndrome that is mediated by local inflammatory signals. Insulin-induced vasorelaxation due to endothelial nitric oxide synthase (eNOS) activation is highly dependent on the activation of the upstream insulin-stimulated serine/threonine kinase (AKT) and is severely impaired in obese, hypertensive rodents and humans. Neutralisation of circulating tumor necrosis factor-α (TNFα) with infliximab improves glucose homeostasis, but the consequences of this pharmacological strategy on systolic blood pressure and eNOS activation are unknown. To address this issue, we assessed the temporal changes in the systolic pressure of spontaneously hypertensive rats (SHR) treated with infliximab. We also assessed the activation of critical proteins that mediate insulin activity and TNFα-mediated insulin resistance in the aorta and cardiac left ventricle. Our data demonstrate that infliximab prevents the upregulation of both systolic pressure and left ventricle hypertrophy in SHR. These effects paralleled an increase in AKT/eNOS phosphorylation and a reduction in the phosphorylation of inhibitor of nuclear factor-κB (Iκβ) and c-Jun N-terminal kinase (JNK) in the aorta. Overall, our study revealed the cardiovascular benefits of infliximab in SHR. In addition, the present findings further suggested that the reduction of systolic pressure and left ventricle hypertrophy by infliximab are secondary effects to the reduction of endothelial inflammation and the recovery of AKT/eNOS pathway activation.

Infliximab reduces cardiac output in rheumatoid arthritis patients without heart failure

OBJECTIVE Human anti-tumor necrosis factor (TNF-α) monoclonal antibody (infliximab) is used to treat autoimmune diseases such as rheumatoid arthritis (RA). Although the risk of worsening heart failure has been described in patients under chronic treatment, the acute cardiovascular effects of this drug are unknown in RA patients without heart failure. METHODS 14 RA patients with normal echocardiography and no history of heart failure were evaluated during the 2-hour infliximab (3-5 mg/kg) infusion period, using a noninvasive hemodynamic beat-to-beat system (Portapres). Stroke volume (SV); systolic, diastolic and mean blood pressures (SBP, DBP and MBP, respectively); cardiac output (CO); heart rate (HR); and total peripheral vascular resistance (PVR) were recorded. All patients also received saline infusion instead of infliximab as a control. Significant differences in hemodynamic parameters were determined using Tuckeys test. All values were expressed as mean ± standard deviation (SD). RESULTS Fourteen RA patients (6M/8F) with mean age of 47.2 ± 8.8 years were evaluated. A significant decrease was found in cardiac output and stroke volume (7.04 ± 2.3 to 6.12 ± 2.1 l/min and 91 ± 29.0 to 83 ± 28.8 mL/beat, respectively) after infliximab infusion. Although not statistically significant, a progressive increase was detected in SBP, DBP and total PVR during infusion. Saline infusion did not cause significant hemodynamic changes in the same group of RA patients. No adverse effects were observed during the infusion period. CONCLUSION Acute infliximab administration decreased cardiac output due to low stroke volume in RA patients without heart disease. The results also demonstrated that, in spite of its negative inotropic effect, infliximab enhanced BP, probably by increasing PVR.

The white coat effect is not associated with additional increase of target organ damage in true resistant hypertension

BACKGROUND AND OBJECTIVE White coat effect (WCE) (i.e., the difference between office blood pressure [OBP] and awake ambulatory blood pressure monitoring [ABPM]) may be present in hypertensive individuals. The relationship between occurrence of WCE and target organ damage (TOD) has not yet been assessed in true resistant hypertension (RHTN). PATIENTS AND METHODS RHTN patients were divided into two groups: RHTN with WCE (WCE, n=66) and RHTN without WCE (non-WCE, n=61). All patients were submitted to OBP measurement, ABPM, echocardiography and renal function evaluation in three visits. RESULTS No differences were observed between the WCE and non-WCE groups regarding age, body mass index or gender. OBP were 169.8±15.8/95.1±14.0 (WCE) and 161.9±9.0/90.1±10.4mmHg (non-WCE), ABPM=143.0±12.8/86.1±9.9 (WCE) and 146.1±13.6/85.1±14.9mmHg (non-WCE). No statistical differences were observed between WCE and non-WCE subgroups with respect to left ventricular mass index (LVMI) (WCE=131±4.7; non-WCE=125±2.9g/m(2)), creatinine clearance (WCE=78±4.7; non-WCE=80±3.6ml/min/m(2)) and microalbuminuria (MA) (WCE=44±8.4; non-WCE=49±6.8mg/g Cr). CONCLUSIONS This finding may suggest that WCE is not associated with additional increase of TOD in true RHTN subjects.

301 ADIPONECTIN AND ALDOSTERONE LEVELS IS ASSOCIATED WITH ARTERIAL STIFFNESS IN RESISTANT HYPERTENSION

Objective: Obesity, arterial stiffness, cardiac hypertrophy, high aldosterone and endothelial dysfunction may interact to cause resistant hypertension (RHTN). Lower adiponectin (APN) and aldosterone excess may be significantly associated with hypertension. However, the importance of hypoadiponectinemia as a complicating factor for the lack of blood pressure (BP) control in RHTN has not been demonstrated. Methods: Ninety-six RHTN patients were divided into uncontrolled (UCRHTN, n=44) and controlled (CRHTN, n=52) subgroups. APN and aldosterone, office BP and ambulatory BP measurement (ABPM), endothelium-dependent brachial artery responses [flow-mediated dilation (FMD)], left ventricular mass index (LVMI) and pulse wave velocity (PWV) were evaluated. Results: UCRHTN had increased aldosterone (12.6 ± 1.4 vs. 8.9 ± 0.8 ng/dL, p=0.02) as well as LVMI (142.2 ± 6.0 vs. 122.9 ± 4.3 g/m2, p=0.02) and PWV (12.0 ± 0.3 vs. 9.2 ± 0.2 m/s, p<0.0001). However, lower APN (6.9 ± 0.7 vs. 9.5 ± 0.8 &mgr;g/mL, p=0.01) and impaired FMD response (6.6 ± 0.3 vs. 7.5 ± 0.3%, p=0.001) were found in this same subgroup. Brachial and ABPM pulse pressures were inversely associated with APN (r = - 0.45, p=0.002; r= - 0.33, p=0.03, respectively) as well as aldosterone and PWV (r = - 0.38, p=0.01; r = - 0.36, p=0.02, respectively) in UCRHTN. PWV was only significantly influenced by APN levels in UCRHTN (&bgr;= - 0.16, SE= 0.05, p=0.01). APN did not correlate with the same parameters in CRHTN. Conclusion: Hypoadiponectinemia and high aldosterone may be implicated in antihypertensive therapy resistance in respect to arterial rigidity.

303 ASSOCIATION BETWEEN RESISTIN AND ARTERIAL STIFFNESS IN PATHOGENESIS OF RESISTANT HYPERTENSION

Background: Resistant Hypertension (RHTN) subjects are frequently overweight or obese, and have increased plasma aldosterone levels and arterial rigidity which are related to target organ damage. Hormones secreted by adipose tissue, such as resistin, may have effects regardless of obesity on blood pressure (BP) control. Resistin has significant associations with pulse wave velocity (PWV) in patients with abdominal adiposity. However, it is unknown whether this adipocitokine is associated with arterial stiffness in RHTN patients. Methods: Body mass index (BMI), office BP and ambulatory blood pressure monitoring (ABPM), aldosterone and resistin plasma concentration (ELISA), and PWV were evaluated in 94 RHTN subjects. Results: Pearsons correlation analysis indicated that, besides pulse pressure (60.3 ± 14.9 mmHg; r= 0.31; p< 0.001) and systolic BP (148.7 ± 17.8 mmHg; r= 0.33; p< 0.001), PWV is associated with aldosterone (121.5± 65.9 pg/mL; r= 0.34; p< 0.0008) and resistin levels (11.4 ± 5.8 ng/mL; r = 0.43; p<0.0001). Multivariate regression analysis revealed resistin and aldosterone plasma levels, but not BMI (30.9 ± 4.8 kg/m2; r= -0.05; p= 0.6; &bgr;= -0.003, p= 0.9), as independent predictors of PWV changes (&bgr;=0.12, p< 0.01; &bgr;= 0.01, p< 0.05; respectively) in RHTN patients. Conclusion: Resistin plasma levels are as important as aldosterone when associated with PWV in RHTN subjects, regardless of obesity. These results show that resistin is an independent predictor of arterial stiffness and may be partially responsible for arterial rigidity in RHTN patients.

ENDOTHELIAL DYSFUNCTION IN REFRACTORY HYPERTENSION: CORRELATION BETWEEN BLOOD PRESSURE LEVELS AND NOCTURNAL DIPPING BP IMPAIRMENT: PP.6.261

Introduction: There is marked association between hypertensive disease and the absence of the nocturnal blood pressure (BP) fall. There is also evidence of correlation between endothelial dysfunction and the non-dipping pattern which is associated with increased cardiovascular mortality. In this study we aimed to evaluate the influence of BP levels on endothelium dependent (Flow Mediated Dilation – FMD) and non-dependent (Nitroglycerin – NTG) vasodilation and on the presence of dipping profile (evaluated by ABPM) in resistant hypertensive patients controlled (CRH) or uncontrolled (UCRH). Methods: Refractory hypertensive (RH) patients (n = 76) were divided in 2 groups: CRH (n = 40; M14/ F26; 50,3 + 6,4 yrs) and UCRH (n = 36; M9/F27; 48 + 5,1 yrs). Normotensive individuals (NT, n = 29; M11/F17; 46,1 ± 10,2 yrs) constituted the third group. BP was measured by using ABPM in two occasions. FMD was performed and evaluated by non participating viewers. Statistics: Variables were compared by ANOVA test and Dunns test was used for multiple comparisons. Pearsons coefficient was used to correlate variable. Results: The UCRH group presented the highest BP levels of the three groups. The FMD tests unveiled that the UCRH patients had a greater impairment of the endothelial function (6,9 + 0,5%) in comparison to the CRH patients (7,5 + 0,5%) (p < 0,05) and that also occurred when comparing the latter group to control subjects (12,0 + 1,4%) (p < 0.001). A positive correlation (Pearson) between 24 hour BP and endothelial dysfunction in the UCRH (p < 0,001; R = 63%) and CRH (p < 0,0001; r = 71%) groups was also noted. In addition, the data revealed nocturnal BP decline in UCRH subjects was less evident than in CRH (10,8 + 4,9 vs. 22,4 + 7,2 mmHg). Conclusions: We concluded that there is a direct correlation between BP levels and endothelial dysfunction both greater in UCRH patients than in CRH patients. The vascular function impairment probably determines the attenuated dipping blood pressure pattern in the hypertensive groups, especially the former.