Francesco Fici

Comparative effects of nebivolol and metoprolol on oxidative stress, insulin resistance, plasma adiponectin and soluble P-selectin levels in hypertensive patients

Objectives To determine the effects of nebivolol on oxidative stress, insulin resistance, adiponectin and plasma soluble P-selectin levels in hypertensive patients in comparison with metoprolol. Material and methods Eighty newly diagnosed hypertensive patients in grade 1 hypertension according to the European Society of Hypertension and European Society of Cardiology guidelines were enrolled in this prospective, blinded, randomized study. Seventy-two patients completed the study. After baseline assessment, each patient was randomly allocated to a 5 mg daily dose of nebivolol (n = 37, 20 male) or a 100 mg daily dose of metoprolol (n = 35, 18 male) and treated for 6 months. Blood pressure, heart rate, oxidative stress (malonyldialdehyde), homeostasis model assessment: insulin resistance, adiponectin and plasma soluble P-selectin levels were measured before and after treatment. Results At the end of treatment, nebivolol and metoprolol significantly decreased blood pressure and heart rate, with a more pronounced bradycardic effect of metoprolol. Nebivolol, but not metoprolol, significantly lowered oxidative stress (P = 0.03), the insulin resistance index (P = 0.003) and plasma soluble P-selectin levels (P = 0.008), and increased adiponectin levels (P = 0.04). Conclusion Nebivolol, in contrast to metoprolol, improved oxidative stress, insulin sensitivity, decreased plasma soluble P-selectin and increased adiponectin levels in hypertensive patients. These beneficial effects of nebivolol may contribute to a reduction in cardiovascular risk in hypertensive patients.

Comparative effects of nebivolol and metoprolol on red cell distribution width and neutrophil/lymphocyte ratio in patients with newly diagnosed essential hypertension.

Abstract: High level of circulating red cell distribution width (RDW) and neutrophil/lymphocyte (N/L) ratio may reflect ongoing vascular inflammation and play an important role in pathophysiology of hypertension. We evaluate the effects of nebivolol and metoprolol on the RDW and N/L in new essential hypertensive patients. After baseline assessment, 72 patients were randomly allocated to 5 mg/d of nebivolol (n = 37, 20 men) or 100 mg/d of metoprolol (n = 35, 18 men) and treated for 6 months. Blood pressure (BP), heart rate (HR), RDW, and N/L were measured before and after treatment. BP significantly decreased with both drugs (P < 0.001). Analog reduction was observed for resting HRs (P < 0.001), but metoprolol caused greater HR fall as compared with nebivolol (P < 0.001). After 6 months of treatment, nebivolol significantly lowered not only RDW but also the total white blood cell and N/L (P < 0.001, P = 0.023, P = 0.017, respectively). No changes were observed in metoprolol group. Percent decrease in RDW was found to be significantly higher in nebivolol than in the metoprolol group (P = 0.001) and remained also after correction for confounders (P = 0.012). Nebivolol improved RDW and N/L to a greater extent than metoprolol in patients with hypertension. These favorable effects may participate, together with the BP reduction, at the favorable properties of the drug in hypertension.

Efficacy and tolerability of nebivolol compared with other antihypertensive drugs: a meta-analysis.

Background and objectiveLowering BP to normal levels without quality of life deterioration is the most important means of reducing cardiovascular risk. Recent studies have challenged the position of β-adrenoceptor antagonists (β-blockers) as first-line antihypertensive drugs. Nebivolol is a third-generation, highly selective β1-blocker that causes vasodilation through nitric oxide (NO) release. This meta-analysis investigates the efficacy and tolerability of nebivolol compared with other antihypertensive drugs and placebo in patients with hypertension.MethodsTwelve randomized controlled studies were included in which nebivolol 5 mg once daily was compared with the recommended clinical doses of other antihypertensive drugs (n = 9), placebo (n = 2), and both (n = 1). The clinical studies were selected after a MEDLINE search up to 2007 using the key words ‘nebivolol’ and ‘hypertension.’ResultsAntihypertensive response rates (the percentage of patients achieving target BP levels or a defined DBP reduction) were higher with nebivolol than with ACE inhibitors (odds ratio [OR] 1.92; p = 0.001) and all antihypertensive drugs combined (OR 1.41; p = 0.001) and similar to β-blockers, calcium channel antagonists (CCAs) and the angiotensin receptor antagonist (ARA) losartan. Moreover, a higher percentage of patients receiving nebivolol achieved target BP levels compared with patients treated with losartan (OR 1.98; p = 0.004), CCAs (OR 1.44; p = 0.024), and all antihypertensive drugs combined (OR 1.35; p = 0.012). The percentage of patients experiencing adverse events did not differ between nebivolol and placebo; adverse event rates were significantly lower with nebivolol than losartan (OR 0.52; p = 0.016), other β-blockers (OR 0.56; p = 0.007), nifedipine (OR 0.49; p < 0.001), and all antihypertensive drugs combined (OR 0.59; p < 0.001).ConclusionResults of previous pharmacokinetic studies suggest that nebivolol 5 mg may not conform completely to the definition of a classic β-blocker demonstrating additional antihypertensive effect due to endothelial NO release-mediated vasodilation. This meta-analysis showed that nebivolol 5 mg achieved similar or better rates of treatment response and BP normalization than other drug classes and other antihypertensive drugs combined, with similar tolerability to placebo and significantly better tolerability than losartan, CCAs, other β-blockers, and all antihypertensive drugs combined. Although not definitive, this meta-analysis suggests that nebivolol 5 mg is likely to have advantages over existing antihypertensives and may have a role in the first-line treatment of hypertension.

Vascular inflammation and aortic stiffness relate to early left ventricular diastolic dysfunction in prehypertension

Abstract Prehypertension is characterized by an increased cardiovascular risk and by an increased prevalence of target organ damage compared with the pure normotensive state. The present study was designed to assess in prehypertensive subjects the possible relationships between early left ventricular dysfunction, vascular inflammation and aortic stiffness. The study population consisted of 31 untreated prehypertensive subjects (age: 34 ± 6 years, mean ± SD) and 31 age-matched pure normotensive controls. Left ventricular function was assessed by echocardiography, aortic distensibility parameters were derived from aortic diameters measured by ultrasonography, and high-sensitivity C-reactive protein was assessed by latex-enhanced reagent. Prehypertensive subjects displayed a significantly lower E/A ratio and a significantly greater deceleration time and isovolumetric relaxation time compared with normotensive controls. They also displayed aortic systolic diameter, diastolic diameter and mean aortic stiffness index beta significantly increased while systo-diastolic diameter change, mean aortic distensibility and aortic strain were significantly reduced compared with controls. Values of inflammatory markers were increased. At multiple regression analysis, E/A ratio was significantly related to high-sensitivity C-reactive protein and aortic stiffness index beta, after correction for age, left ventricular mass index and mean blood pressure (β coefficient = −0.49, overall r2 = 0.24, p = 0.01 and β coefficient =−0.46, overall r2 = 0.21, p = 0.02, respectively). Thus, in prehypertension, left ventricular dysfunction is significantly related to vascular inflammation and aortic stiffness, suggesting that early cardiac and vascular alterations may have an increased inflammatory process as a common pathophysiological link.

P-wave dispersion and its relationship to aortic elasticity in young prehypertensive patients.

BACKGROUND Prolonged P-wave duration (P(dur)) and increased P-wave dispersion (PWD) are independent predictors of atrial fibrillation (AF) in patients with hypertension. This study was designed to evaluate the possible relationship between aortic elasticity and PWD in young prehypertensive patients. METHODS Twenty-five newly diagnosed prehypertensive patients (18 men, mean age = 34 +/- 6 years) and 25 healthy control subjects (16 men, mean age = 33 +/- 6 years) were enrolled in the study. The P(dur) measurements were calculated using a 12-lead surface electrocardiogram (ECG). Aortic elasticity parameters were derived from aortic diameters measured by echocardiography, and simultaneous blood pressure (BP) measurements by sphygmomanometry. RESULTS The baseline characteristics of patients with prehypertension were homogeneous with those of the controls. PWD and P(maximum) values were found to be higher in patients with prehypertension as compared to those of the controls (PWD; 65 ms vs. 35 ms, P < 0.001; P(maximum); 110 ms vs. 80 ms, P < 0.001). However, P(minimum) values were not significantly different between the two groups (40 ms vs. 45 ms, P = 0.358). Also, a moderate positive correlation was found between stiffness index (SI) and PWD (r = 0.500, P = 0.011), and a moderate negative correlation between aortic elasticity parameters (aortic distensibility and strain indexes) and PWD (for aortic distensibility, r = -0.498, P = 0.011; for strain index, r = -0.578, P = 0.002), in patients with prehypertension. CONCLUSIONS Young patients with prehypertension have increased PWD and arterial stiffness. These parameters are correlated and may pose additional risk factors for future cardiovascular events.

Relationship between increased systemic inflammation and impaired aortic elasticity in young patients with prehypertension.

AimThis study was designed to evaluate the possible relationship between vascular inflammatory status [namely, high-sensitivity C-reactive protein (hs-CRP) and white blood cell (WBC)] and aortic elasticity parameters in patients with prehypertension. Materials and methodsThe study population consisted of 25 newly diagnosed prehypertensive individuals (18 men, mean age=34±6 years) and 25 healthy controls (16 men, mean age=33±6 years) eligible for this study. Aortic elasticity parameters were calculated from aortic diameters measured by echocardiography and blood pressures, simultaneously measured by sphygmomanometry. hs-CRP measurements were taken with latex-enhanced reagent using a Behring BN ProSpec analyzer. ResultsBaseline characteristics of patients with prehypertension and controls were homogeneous. Inflammatory markers were significantly higher in patients with prehypertension compared with those of controls [for WBC (×109/l): 11.46±0.77 (11.50) vs. 8.94±0.91 (9.20), P<0.001; for hs-CRP (&mgr;g/dl): 137.84±50.71 (130.00) vs. 78.30±35.20 (65.27), P<0.001]. There was a strong positive correlation between the mean aortic stiffness index and markers of inflammation (for WBC, r=0.857, P<0.001; for hs-CRP, r=0.858, P<0.001), whereas strong negative correlations were observed between aortic elasticity parameters and markers of inflammation (for aortic distensibility of WBC and hs-CRP, r=−0.862, P<0.001; r=−0.869, P<0.001, respectively, and for aortic strain of WBC and hs-CRP, r=−0.890, P<0.001; r=−0.906, P<0.001, respectively). ConclusionYoung prehypertensives have increased markers of inflammation, namely, hs-CRP and WBC, compared with controls. More importantly, impaired arterial stiffness is significantly associated with the markers of inflammation in patients with prehypertension.

Can a novel scoring system derived from hemodynamic and anthropometric variables predict sympathetic drive in young patients

AimSympathetic overdrive is generally the main pathophysiological abnormality in cardiovascular disease. However, its grading is not easy in clinical practice because of its complex interactions and differences in phenotypical expression. We proposed an easy, feasible, and global scaling system for sympathetic activity level. ‘Sympathetic activity index’ (SAI) is based on scores of heart rate, BMI, and blood pressure categories, which are the major representatives of sympathetic activity. Materials and methodsRespectively, 1, 2, and 3 points were determined for heart rate below 69, 70–89, and above 90 bpm; −1, 1, and 2 points for BMI less than 20, 20–24.9, and at least 25 kg/m2; and 1, 2, and 3 points for normal, prehypertension, and hypertension categories. Demographic and echocardiographic parameters, and left ventricular (LV) mass and mass indexes (LVMIBSA and LVMIHeight) of 545 young males were compared among groups with SAI 1–8. ResultsWe observed that LVM, LVMIBSA, and LVMIHeight, left atrial diameter were significantly increased in association with SAI (P<0.001). SAI was correlated with LVM (R=0.314, P<0.001), LVMIBSA (R=193, P<0.001), and LVMIHeight (R=0.316, P<0.001). SAI of at least 5.5 could determine the left ventricular hypertrophy with a sensitivity and a specificity of 57 and 70%, respectively (AUC=682, 95% confidence interval 0.610–0.753, P<0.001). ConclusionIntegration of clinical, anthropometric, and hemodynamic variables in a novel index such as SAI may provide an objective and noninvasive means of grading actual sympathetic drive. SAI may be used to follow-up sympathetic activity and to predict clinical events in the management of young patients with cardiovascular and metabolic abnormalities.

The Effect of Nebivolol on Endothelial Function in Newly Diagnosed Hypertensive Patients with and without Diastolic Dysfunction

AbstractObjective: Hypertension is associated with endothelial dysfunction and reduced nitric oxide (NO) activity. Recent observations have shown a significant correlation between endothelial and diastolic dysfunction in cardiovascular disease. The aim of this study was to assess the effect of nebivolol, a β-blocker with NO-mediated vasodilatation properties, on endothelial function in newly diagnosed, previously untreated, hypertensive patients with and without diastolic dysfunction. Methods: Eighty-eight patients were enrolled, 46 of whom had diastolic dysfunction (early/atrial peak wave velocity [E/A] ratio <1 or deceleration time (DT) >240ms in patients aged <55 years, or E/A ratio <0.8 and DT >240ms in patients aged ≥55 years). After a 2-week run-in period, patients received nebivolol 5mg once daily for 3 months. Endothelium-dependent and -independent vasodilation was assessed with brachial artery ultrasound at the end of the run-in and treatment periods. Results: After treatment with nebivolol, flow-mediated dilation increased significantly in both patients with diastolic dysfunction (from 10.32 ± 1.32% to 12.82 ± 1.20%, p < 0.001) and those without diastolic dysfunction (from 11.09 ± 1.12% to 12.72 ± 1.06%, p < 0.001) so that there was no statistically significant difference between the two groups. Nebivolol was well tolerated, with no adverse events reported during the treatment period. Conclusion: Nebivolol can improve endothelial-dependent vasodilation in hypertensive patients with and without diastolic dysfunction, and suggests that endothelial and diastolic dysfunction are early manifestations of hypertension.

The revised role of ACE-inhibition after myocardial infarction in the thrombolytic/primary PCI era

Many studies have investigated the process of left ventricular (LV) dilatation and the effects of angiotensin-converting enzyme (ACE) inhibitors after myocardial infarction (MI). It has been generally accepted that progression of LV dilatation is a major predictor of heart failure and death after MI. Also, attenuation of LV dilatation is thought to be one of the main mechanisms by which ACE inhibitors (ACE-Is) produce their beneficial effects. However, evidence for this hypothesis came from studies that were performed before thrombolytic therapy and primary percutaneous coronary intervention (PCI) were routinely used after acute MI. Nowadays, reperfusion is obtained much more frequently and LV dilatation after MI has become less prevalent. Nevertheless, ACE-Is proved effective in reducing cardiac morbidity and mortality. Therefore, mechanisms other than attenuation of LV dilatation, such as anti-atherosclerotic effects or plaque stabilisation, may explain the long-term beneficial effects of ACE-Is after MI. In the present overview, we evaluate the role of LV dilatation and the effects of ACE-Is after MI in the thrombolytic/primary PCI era and provide recommendations on ACE-I use in clinical practice.

9C.07: MULTICENTRE RANDOMISED, DOUBLE BLIND, EVALUATION OF NEBIVOLOL PLUS HCTZ AND IRBESARTAN PLUS HCTZ IN THE TREATMENT OF ISOLATED SYSTOLIC HYPERTENSION IN THE ELDERLY: THE NEHIS STUDY.

Objective: According to the 2013 ESH/ESC guidelines combination drug treatment is recommended in the treatment of isolated systolic hypertension (ISH) to improve blood pressure (BP) control. The present study was aimed at comparing the antihypertensive effects, tolerability and side effects profile of nebivolol/hydrochlorothiazide vs irbesartan/hydrochlorothiazide combination in elderly patients with ISH. Design and method: 124 ISH patients aged 69.1 ± 3.1 (mean ± SEM) followed by 13 general practictioners in Netherlands and Belgium were enrolled and randomized in a double blind fashion to Nebivolol 5 mg/Hydrochlorothiazide 12.5 mg (NH, n = 62) or Irbesartan 150 mg/Hydrochlorothaizide 12.5 (IH,N = 62) once daily for a 12 week period on sitting office BP, ambulatory BP, 24 hour BP variability, pulse pressure, tolerability and safety profile. Results: 9 pts were withdrawn after randomization. After 12 weeks NH caused a significant greater reduction than IH in sitting SBP (-25.8 ± 1.6 vs -20.6 ± 1.7 mmHg, P < 0.03) and heart rate (HR, -7.0 ± 1.0 vs 2.5 ± 1 b/min, P < 0.01), while the decrease in diastolic and pulse BP showed a non significant tendency to be greater in NH than in IH (-7.4 ± 1.0 and -18.3 ± 1.5 vs -5.0 ± 0.09 and -15.7 ± 1.7 mmHg, P = NS for both). The magnitude of the 24-h, day-time and night-time SBP reduction was almost superimposable in the 2 groups, while HR reduction induced by NH was significantly (P < 0.001) greater during the 24-h, the daytime as well as the nighttime period than that induced by IH. NH caused a significantly greater reduction than IH in 24-h SBP variability, both when expressed as standard deviation (-4.4 ± 2.7 ± vs -2.2 ± 5.1 mmHg, P < 0.02) or as coefficient of variation (-2.0 ± 2.6 vs -0.3 ± 3.4, P < 0.01). This was the case also for pulse pressure and mean BP. Both the 2 drug combinations were well tolerated. Conclusions: These data provide evidence that NH induces an office BP reduction greater than IN but similar effects throughout the 24 hours. NH, however, reduces, at variance from IH, 24-h systolic, mean and pulse BP variability, suggesting a greater protection against a variable known to adversely affect morbidity and mortality in hypertensive patients.