Thiago Quinaglia

High-circulating leptin levels are associated with increased blood pressure in uncontrolled resistant hypertension

Leptin and aldosterone have been associated with the pathophysiological mechanisms of hypertension. However, despite studies showing the association of leptin with intima-media thickness, arterial distensibility and sympathetic nerve activation, the relationship between leptin and blood pressure (BP) in resistant hypertension (RHTN) is unknown. We aimed to assess the correlation of plasma leptin and aldosterone levels with BP in uncontrolled controlled RHTN (UCRHTN) and CRHTN patients. Plasma leptin and aldosterone levels, office BP, ambulatory BP monitoring and heart rate were measured in 41 UCRHTN, 39 CRHTN and 31 well-controlled HTN patients. No differences were observed between the three groups regarding gender, body mass index and age. The UCRHTN group had increased leptin when compared with CRHTN and well-controlled HTN patients (38.2±21.4, 19.6±8.7 and 20.94±13.9 ng ml−1, respectively; P<0.05). Aldosterone levels values were also statistically different when comparing RHTN, CRHTN and well-controlled HTN patients (9.6±3.8, 8.1±5.0 and 8.0±4.7 ng dl−1, respectively; P<0.05). As expected, UCRHTN patients had higher heart rate values compared with CRHTN and well-controlled HTN patients (86.2±7.2, 83.5±6.7 and 83.4±8.5, respectively; P<0.05). Plasma leptin positively correlated with systolic (SBP) and diastolic BP (DBP), and aldosterone (r=0.43, 0.35 and 0.47, respectively; all P<0.05) in UCRHTN, but neither in the CRHTN nor in the HTN group. Simple linear regression showed that SBP, DBP and aldosterone may be predicted by leptin (r2=0.16, 0.15 and 0.19, respectively; all P<0.05) only in the UCRHTN subgroup. In conclusion, UCRHTN patients have higher circulating leptin levels associated with increased plasma aldosterone and BP levels when compared with CRHTN and HTN subjects.

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.

Acute effects of pharmacotherapies in blood pressure in normotensive moderate smokers

Abstract This study was designed to evaluate the changes in arterial blood pressure (BP) and heart rate (HR) in moderate smokers during smoking abstinence after 7 days of treatment with bupropion alone, transdermal nicotine or bupropion combined with transdermal nicotine. Twenty-four healthy moderate smokers (12 female/12 male; 40±7 years) were evaluated randomly on five occasions and their systolic, diastolic, mean arterial blood pressure (MAP) and HR were measured by a Finapres device for 10 h, immediately after smoking interruption. All of the 24 smokers participated on five protocols during 7 days: control group (C) – no drugs; placebo group (PL); bupropion group (BUP) 150–300 mg; transdermal nicotine group (TN) – 21 mg; and BUP+TN-nicotine patch. Concomitantly, the subjects were evaluated by ABPM (ambulatory BP monitoring). All of BP parameters monitored shown significant statistical differences in the BUP, TN and BUP+TN groups compared with the controls (p<0.05), when measured by Finapres. The HR remained unaltered in all of the groups. No significant differences were seen in the BP or HR during the 24-h ABPM. These findings indicate that in moderate smokers, bupropion, transdermal nicotine or bupropion associated with transdermal nicotine caused an elevation in the BP after acute smoking interruption.

Acute Sildenafil Use Reduces 24‐Hour Blood Pressure Levels in Patients With Resistant Hypertension: A Placebo‐Controlled, Crossover Trial

The authors previously demonstrated that acute administration of sildenafil—a phosphodiesterase 5 (PDE5) inhibitor—improves hemodynamic parameters in patients with resistant hypertensive (RH), but its effect on ambulatory blood pressure monitoring (ABPM) is unknown. This interventional, nonrandomized, single‐blinded, placebo‐controlled, crossover trial included 26 patients with RH. A dose of sildenafil (187.5mg) was given, and after a washout period of 14 days the patients received a single oral dose of placebo and the protocol was repeated. The patients underwent 24‐hour ABPM recordings the day before and immediately after the protocols. The reduction of systolic (−8.8±1.4 vs 1.3±1.2 mm Hg, P=.02), diastolic (−5.3±3.3 vs 1.8±1.1 mm Hg, P=.03), and mean (−7.9±3.6 vs 0.8±0.9 mm Hg, P=.01) 24‐hour BP were found after the use of sildenafil compared with placebo. Improvement in daytime BP levels was also observed (systolic −6.0±4.7 vs 4.4±1.5 mm Hg [P=.02] and mean −4.8±3.9 vs 3.5±1.4 mm Hg [P=.02] for sildenafil vs placebo, respectively). Considering its antihypertensive effect, sildenafil may represent a therapeutic option for RH treatment.

Flow-mediated dilation: An evolving method

Endothelial dysfunction embodies roles of precursor and perpetuator of systemic atherosclerotic disease. Identifying and quantifying its impact would therefore provide insight on the genesis of atherosclerosis initiation and progression. However, endothelial dysfunction comprises a broad spectrum of impaired functionsdranging from vascular tone regulation to plaque stabilizing propertiesdand available clinical methods effectively estimate only singular aspects of the underlying condition. Functionally, vasomotor regulation reflects endothelial function and its regulation occurs at the macrovascular [1] and microvascular [2] levels. Substantial evidence indicates that impairment in vasomotor function signalizes subsequent atherosclerotic disease [3e5] and recurrence of cardiovascular events [6,7]. However, this discriminator is not an effective surrogate indicator in all populations [2,8]. Some studies suggest that microvascular dysfunction predicts risk more reliably in healthier and younger populations as opposed to patients with established systemic, macrovascular atherosclerosis [9]. Flow mediated dilation methods (FMD) provide a surrogate endpoint to evaluate the potential dilatatory response of a conduit (macrovascular) artery stimulated by reactive hyperemia. This observed response generally mimics the increase in myocardial blood flow to accommodate local metabolic demands, known as coronary flow reserve [10,11]. Arterial flow and vessel wall shear stress variables (stimulus for FMD) are not traditionally assessed;

Short-term effects of extended-release niacin with and without the addition of laropiprant on endothelial function in individuals with low HDL-C: a randomized, controlled crossover trial.

BACKGROUND Reduced plasma concentration of high-density lipoprotein cholesterol (HDL-C) is associated with vulnerability to oxidative stress and propensity to endothelial dysfunction. Niacin directly activates both GPR-109A in leukocytes and the heme oxygenase-1 pathway, promoting strong anti-inflammatory and antioxidative effects, as well as induces immediate production of prostaglandin D2, leading to endothelial vasodilation. OBJECTIVE This study investigated the short-term effects of extended-release niacin (ERN) administered with or without the prostaglandin D2 receptor antagonist laropiprant on endothelial function in patients with low HDL-C. METHODS Asymptomatic men and women aged between 20 and 60 years who had plasma HDL-C levels <40 mg/dL were treated with ERN monotherapy 1 g/d or ERN/laropiprant 1 g/20 mg (ERN/LRP) in a crossover study design. The sequence of treatments was decided by simple randomization. Plasma samples and flow-mediated dilation (FMD) of the brachial artery were obtained at baseline, day 7 of treatment period 1, day 7 of washout, and day 7 of treatment period 2. RESULTS Eighteen patients were enrolled (mean [SD] age, 42 [17] years; 11 men). Triglyceride levels decreased by 4% and 3%, and HDL size decreased by 5.8% and 6.2%, with ERN and ERN/LRP, respectively (both, P < 0.05). There were no changes in HDL-C levels or in cholesteryl esterase transfer protein activity with either treatment. The median increases in FMD were 4.5% and 4.1% with ERN and ERN/LRP, which receded after washout. On intergroup analysis, there were no differences with respect to variation in plasma HDL-C, triglycerides, C-reactive protein, direct bilirubin, or FMD. CONCLUSIONS In these patients, the addition of laropiprant did not influence the effects of niacin on endothelial function. Based on these findings, short-term niacin treatment might improve endothelial function in patients with low HDL-C levels. ClinicalTrials.gov identifier: NCT01942291.

[PP.23.07] ACUTE SILDENAFIL USE LOWER 24H BLOOD PRESSURE LEVELS IN RESISTANT HYPERTENSION A RANDOMIZED, PLACEBO CONTROLLED, CROSS-OVER TRIAL

Objective: The present study sought to evaluate whether acute administration of sildenafil compared with placebo improves ambulatory BP levels in RHTN subjects. Design and method: This interventional, single-blinded, placebo-controlled, one-way crossover trial included 26 patients with true RHTN. Increasing oral doses of sildenafil were given at 30 minute-interval (37.5 mg, 50 mg and 100 mg) in a single day. After a washout period of 14 days, patients received consecutive oral doses of placebo and the protocol was repeated. Before and after each protocol day (sildenafil and placebo), patients underwent 24-hour ABPM evaluation. Results: The reduction of systolic (−8.8 ± 1.4 vs. 1.3 ± 1.2mmHg), diastolic (−5.3 ± 3.3 vs. 1.8 ± 1.1mmHg) and mean (−7.9 ± 3.6 vs. 0.8 ± 0.9mmHg) 24-hour BP were higher after sildenafil compared with placebo. The main differences were observed on daytime BP levels (systolic; −6 ± 4.7 vs. 4.4 ± 1.5 mmHg; and mean: −4.8 ± 3.9 vs. 3.5 ± 1.4 mmHg; sildenafil vs. placebo, respectively). Conclusions: Our study suggests that an acute high-dose load of sildenafil improves ABPM parameters in resistant hypertensive patients. Considering its antihypertensive effect, sildenafil may represent a therapeutic option for the treatment of RHTN.

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.