Raffaele Izzo

The use of a telematic connection for the follow-up of hypertensive patients improves the cardiovascular prognosis

Background Inadequate blood pressure (BP) control could be due to incorrect management of hypertensives caused by the lack of interaction between general practitioners (GP) and hypertension specialists. Objectives To test the effectiveness on BP and total cardiovascular risk (TCVR) control of an internet-based digital network connecting specialists and GPs. Methods We created a network among the Hypertension Clinic, Federico II University (Naples, Italy), 23 hospital-based hypertension clinics and 60 GPs from the area (CampaniaSalute Network, CS). Randomized GPs enrolled in CS could update online records of patients (n = 1979). As a control, we included 2045 patients referred to the specialist clinics by GPs from outside the network. All patients completed a 2-year follow-up. Results CS provided a larger reduction in BP [systolic/diastolic BP (SBP/DBP): 7.3 ± 0.4/5.4 ± 0.3 versus 4.1 ± 0.4/3.1 ± 0.26 mmHg, CS versus control; P < 0.001 for both] and percentage of patients with BP < 140/90 mmHg (CS versus control: baseline, 33 versus 34%, NS; end of follow-up, 51 versus 47%, χ2 = 13.371; P < 0.001). A European Society of Hypertension–European Society of Cardiology (ESH/ESC) TCVR score was calculated [from 1 (average) to 5 (very high TCVR)]. The CS group showed a reduction in the mean TCVR score (CS: from 3.5 ± 0.02 to 3.2 ± 0, P < 0.01, ANOVA; control group: 3.5 ± 0.03 to 3.4 ± 0.03, NS) and, accordingly, fatal and non-fatal major cardiovascular events (MACE) were less frequent (2.9 versus 4.3%; χ2 = 5.047, P < 0.02). CS predicts fewer MACE in multiple binary regression analysis (β:−7.27, P < 0.008) reducing the risk for MACE compared to control [odds ratio (OR): 0.838; 95% confidence interval (CI): 0.73–0.96]. Conclusion Our results support the idea that telemedicine can achieve better control of BP and TCVR.

The PlA1/A2 polymorphism of glycoprotein IIIa and cerebrovascular events in hypertension: Increased risk of ischemic stroke in high-risk patients

Objective The platelet GPIIIa plays a pivotal role in platelet aggregation. Previous studies showed an association between the GPIIIa PlA1/A2 polymorphism and coronary thrombosis, while there is only contrasting evidence about its role in stroke. We explored the possibility that this polymorphism represents a risk factor for stroke in hypertensive patients. Methods We studied two populations. In loco, we genotyped 140 hypertensive control individuals and 28 hypertensive patients with ischemic stroke. Furthermore, we performed an analysis of previously published data of 451 Sardinian hypertensive patients, already characterized and genotyped. Results Association analysis revealed that the PlA2 distribution was similar between hypertensive patients with and without stroke, but when considering a more homogeneous population of high-risk hypertensive patients, defined according to ESH/ESC 2003 guidelines, we observed that the frequency of the PlA2 allele was higher among stroke versus nonstroke patients (stroke, 46.4%; nonstroke, 22.6%; P = 0.01). The multiple regression analysis taking into account this polymorphism among other factors known to contribute to ischemic stroke confirmed the PlA2 allele as an additive risk factor for stroke (B = 0.986, Wald = 4.943, P < 0.03), increasing the risk of stroke by 2.9 (95% confidence interval = 1.23–6.85, P < 0.02). Similar results were obtained in the Sardinian population: in hypertensive patients with three or more risk factors, PlA2 increases the risk (odds ratio = 2.8, 95% confidence interval = 1.3–6.0, P < 0.001) and is an additive risk factor for stroke (B = 1.073, Wald = 6.920, P < 0.01). Conclusions Our data suggest that the PlA2 polymorphism is a genetic determinant of ischemic stroke in a selected high-risk hypertensive population.

Insulin modulation of an endothelial nitric oxide component present in the alpha2- and beta-adrenergic responses in human forearm.

We explored in 51 normal subjects, distributed in various series of experiments, whether endothelium nitric oxide may play a role in insulin modulation of alpha2- and beta-adrenergic- evoked vascular responses. In particular, we examined the forearm blood flow response (FBF, ml.min-1.dl-1) to intrabrachial infusion of BHT-933 (0.5, 1, and 2 microg.min-1.dl-1) or isoproterenol (1, 3, and 6 ng. min-1.dl-1) in control conditions, during intrabrachial infusion of insulin alone (0.05 mU.kg-1.min-1) and associated with l-N-monomethylarginine (L-NMMA) (0.05 microg.min-1.dl-1), a nitric oxide synthase inhibitor. In control conditions both BHT-933 and isoproterenol induced a dose-dependent vascular response. Local hyperinsulinemia (deep venous plasma insulin 68.5+/-4 microU/ml) did not change basal FBF whereas attenuated BHT-933 vasoconstriction and enhanced isoproterenol vasodilation. L-NMMA reduced basal FBF and abolished the insulin effect on BHT-933 and isoproterenol response. To clarify whether a nitric oxide component is included in alpha2- and beta-adrenergic response and may be responsible for insulin vascular effect, we further examined BHT-933 and isoproterenol responses during nitric oxide inhibition. Interestingly, L-NMMA potentiated the BHT-933 vasoconstriction and attenuated the isoproterenol vasodilation and, in these conditions, insulin was no more able to exhibit its vascular effects. Finally, to rule out the possibility that the conteracting effect of L-NMMA may not be specifically related to insulin action, dose-response curves to phenylephrine (0.5, 1, and 2 microg.min-1.dl-1) or sodium nitroprusside (1, 2, and 4 microg.min-1.dl-1) were also performed. Both insulin and L-NMMA were unable to alter the phenylephrine-induced vasoconstriction and the sodium nitroprusside vasodilation. In conclusion, our data demonstrate an endothelial nitric oxide component in the alpha2- and beta-adrenergic vascular responses which is the target of the insulin vascular action.

Does Information on Systolic and Diastolic Function Improve Prediction of a Cardiovascular Event by Left Ventricular Hypertrophy in Arterial Hypertension

Left ventricular (LV) mass (LVM) is the most important information requested in hypertensive patients referred for echocardiography. However, LV function also predicts cardiovascular (CV) risk independent of LVM. There is no evidence that addition of LV function significantly improves model prediction of CV risk compared with LVM alone. Thus, composite fatal and nonfatal CV or cerebrovascular events were evaluated in 5380 hypertensive outpatients (2336 women, 298 diabetics, and 1315 obese subjects) without prevalent CV disease (follow-up: 3.5±2.8 years). We compared 5 risk models using Cox regression and adjusting for age and sex: (1) LV mass normalized for height in meters2.7 (LVMi); (2) LVMi, concentric LV geometry, by relative wall thickness (>0.43), ejection fraction, and transmitral diastolic pattern (by thirtiles of mitral deceleration index); (3) LVMi, LV geometry, midwall shortening, and mitral deceleration index thirtiles; (4) as No. 2 with the addition of left atrial dilatation (>23 mm); and (5) as No. 3 with the addition of left atrial dilatation. Individual hazard functions were compared using receiving operating characteristic curves and z statistics. Areas under the curves increased from 0.60 in the model with the sole LVMi to 0.62 in the others (all P values for differences were not significant). The additional information on systolic and diastolic function decreased the contribution (Wald statistics) of LVMi in the Cox model without improving the model ability to predict CV risk. We conclude that risk models with inclusion of information on LV geometry and systolic and diastolic function, in addition to LVMi, do not improve the prediction of CV events but rather redistribute the impact of individual predictors within the risk variance.

Insufficient control of blood pressure and incident diabetes

OBJECTIVE Incidence of type 2 diabetes might be associated with preexisting hypertension. There is no information on whether incident diabetes is predicted by blood pressure control. We evaluated the hazard of diabetes in relation to blood pressure control in treated hypertensive patients. RESEARCH DESIGN AND METHODS Nondiabetic, otherwise healthy, hypertensive patients (N = 1,754, mean ± SD age 52 ± 11 years, 43% women) participated in a network over 3.4 ± 1 years of follow-up. Blood pressure was considered uncontrolled if systolic was ≥140 mmHg and/or diastolic was ≥90 mmHg at the last outpatient visit. Diabetes was defined according to American Diabetes Association guidelines. RESULTS Uncontrolled blood pressure despite antihypertensive treatment was found in 712 patients (41%). At baseline, patients with uncontrolled blood pressure were slightly younger than patients with controlled blood pressure (51 ± 11 vs. 53 ± 12 years, P < 0.001), with no differences in sex distribution, BMI, duration of hypertension, baseline blood pressure, fasting glucose, serum creatinine and potassium, lipid profile, or prevalence of metabolic syndrome. During follow-up, 109 subjects developed diabetes. Incidence of diabetes was significantly higher in patients with uncontrolled (8%) than in those with controlled blood pressure (4%, odds ratio 2.08, P < 0.0001). In Cox regression analysis controlling for baseline systolic blood pressure and BMI, family history of diabetes, and physical activity, uncontrolled blood pressure doubled the risk of incident diabetes (hazard ratio [HR] 2.10, P < 0.001), independently of significant effects of age (HR 1.02 per year, P = 0.03) and baseline fasting glucose (HR 1.10 per mg/dl, P < 0.001). CONCLUSIONS In a large sample of treated nondiabetic hypertensive subjects, uncontrolled blood pressure is associated with twofold increased risk of incident diabetes independently of age, BMI, baseline blood pressure, or fasting glucose.

Cardiovascular risk in relation to a new classification of hypertensive left ventricular geometric abnormalities.

Objectives: In 2010, the Dallas Heart Study proposed an upgrade of the left ventricular geometric classification proposed in 1991, by using left ventricular mass combined with end diastolic volumes, and introducing the new categories of dilated left ventricular hypertrophy (LVH). We adopted the new method to test the prognostic impact of the left ventricular geometric patterns from the new classification. Methods: We evaluated baseline anthropometric, laboratory and echocardiographic parameters of 8848 hypertensive patients from the Campania Salute Network (53 ± 12 years, 56% male), free of prevalent cardiovascular disease, valve disease and with ejection fraction ≥50%. Cut points for left ventricular mass index, relative wall thickness and left ventricular end-diastolic dimension (cm/m) were derived from our historical normal reference population. Composite cardiovascular end-points were cardiac death, fatal and nonfatal myocardial infarction and stroke. Results: Independent of confounders, eccentric dilated LVH, concentric nondilated LVH and concentric dilated LVH were associated with higher cardiovascular risk (hazard ratios between 2 and 9, all P < 0.01), mostly depending on the magnitude of LVM index. A volume load was present especially in dilated forms of LVH, the extent of which was important in the determination of harmful types of left ventricular geometry. Conclusion: Consideration of left ventricular dilatation in the evaluation of risk related to hypertensive left ventricular geometry reveals the importance of the extent of the volume load coexisting with the typical hypertensive pressure overload. At a given normal ejection fraction, the balance between the two hemodynamic components influences the shape of left ventricular geometric adaptation, the amount of left ventricular mass and the impact on prognosis.

Association of suboptimal blood pressure control with body size and metabolic abnormalities

Background Blood pressure control is disappointingly suboptimal in populations. Whether metabolic abnormalities influence blood pressure control is unclear. We evaluated the relationship between metabolic risk factors and blood pressure control in a large population of patients with hypertension. Methods From our Hypertension Centre, 4551 subjects (43.4% women; age 51 ± 12 years) were selected with available data for metabolic and cardiovascular evaluation (no prevalent cardiovascular disease), at the last control visit. A modified Adult Treatment Panel III definition of metabolic syndrome was adopted changing waist girth for body mass index (≥ 30 kg/m2). Blood pressure was considered controlled when supine office blood pressure was below 140/90 mmHg, or uncontrolled if this target was not achieved. Blood pressure control has been evaluated in relation to metabolic risk factors, adjusting for age, sex, and the number of antihypertensive medications. Results The metabolic syndrome phenotype was found in 1444 individuals (31.72%). The probability of uncontrolled blood pressure was 43% higher in patients with the metabolic syndrome than in those without, independently of covariates. This probability was also confirmed in 728 untreated patients. The probability of uncontrolled blood pressure significantly and independently increased with the increasing number of metabolic risk factors. Uncontrolled blood pressure was also independently associated with the prescription of more medications. Conclusion Insufficient control of blood pressure is independently associated with the presence of the metabolic syndrome. Blood pressure control worsens with the increasing number of metabolic risk factors associated with hypertension, despite the use of a greater number of medications.

Effects of hormonal replacement therapy in postmenopausal hypertensive patients

OBJECTIVE To evaluate the effect of hormonal replacement therapy (HRT) on blood pressure (BP) in postmenopausal hypertensive women. METHODS Sixty women affected by hypertension were enrolled and randomized in two groups of treatment: transdermal continuous HRT in a sequential regimen (group A) and placebo (group P). At baseline, after 3 and 6 months of treatment, the BP with standard sphygmomanometer and with 24-h ambulatory recording method was evaluated in two periods (from day 10 through day 16 of the cycle and from day 20 through day 27 of the cycle). At the same time, we also evaluated total cholesterol, LDL-c, HDL-c, triglycerides, and fibrinogen levels. RESULTS After 3 and 6 months of treatment, no significant variations of systolic and diastolic BP measured with standard sphygmomanometer were detected in both groups. On the contrary, in group A in comparison with basal values and group P, and without difference between the two phases of treatment, the 24-h recording showed a significant (P<0.05) decrease in BP. No significant variations were detected in group P versus baseline. In particular, we observed in group A at 3 months of treatment a significant (P<0.05) decrease only in daytime BP in comparison with basal values and group P, without difference between the two phases of treatment. Indeed, the decrease in daytime BP was significant (P<0.05) for both systolic and diastolic BP. At 3 and 6 months a significant (P<0.05) decrease in total cholesterol, LDL-c and fibrinogen levels was detected in group A versus baseline and group P. HDL-c and triglyceride concentrations showed no significant variations. CONCLUSIONS The transdermal HRT induces a significant reduction of BP values and a favorable metabolic action in postmenopausal hypertensive patients.

Enhanced GRK2 Expression and Desensitization of βAR Vasodilatation in Hypertensive Patients

Increased levels of G protein coupled receptor kinase GRK2 appear to participate in hypertension presumably through the desensitization of β adrenergic receptors (βARs) that mediate vasodilatation. There are contrasting data on the occurrence of βAR desensitization in the vasculature, we therefore investigated βAR vasodilatation and desensitization in normotensives and in hypertensive humans. In blood lymphocytes, we assessed βAR signaling and GRK2 expression and found βAR signaling alterations and, consistent with desensitization, ncreased GRK2 levels in hypertensives. We studied in vivo vasodilatation to the βAR agonist isoproterenol (ISO) injected in the brachia artery in control conditions and during the concomitant infusion of heparin, a known in vitro nonspecific GRK inhibitor. ISO induced a dose‐dependent vasorelaxation that was attenuated in hypertensives indicating a loss of βAR signaling. Intra‐arterial infusion of heparin nhibited lymphocyte GRK2 activity and prevented desensitization of βAR vasodilatation in normotensives. In hypertensives, heparin restored vasodilatation to ISO, to levels observed in normotensives. Our results suggest that βAR desensitization does indeed occur at the vascular levels in vivo, and that heparin by acting as a GRK inhibitor prevents this in normotensives and restores impaired βAR vasodilation in hypertensives. We conclude that desensitization participates to impaired βAR vasodilation in hypertension.

Noradrenergic Vascular Hyper-Responsiveness in Human Hypertension Is Dependent on Oxygen Free Radical Impairment of Nitric Oxide Activity

BACKGROUND Noradrenergic vascular hyper-responsiveness is a hallmark of essential hypertension. To evaluate whether nitric oxide plays a role in the enhanced vascular response to norepinephrine in hypertension, we examined 32 hypertensives and 28 normotensives who were distributed in 3 experimental series. METHODS AND RESULTS In the first series, we measured the forearm blood flow (FBF) response to a norepinephrine infusion under control conditions and during the infusion of L-N-monomethylarginine (L-NMMA). Norepinephrine evoked dose-dependent vasoconstriction that was greater in hypertensives than in normotensives (maximum FBF, -61+/-1 versus -51+/-1%; P<0.01). During L-NMMA infusion, norepinephrine vasoconstriction was not modified in hypertensives; however, it was potentiated in normotensives (maximum FBF, -64+/-2%; P<0.01). In the second series, we tested whether norepinephrine vasoconstriction could be affected by an antioxidant such as ascorbic acid. Norepinephrine vasoconstriction was blunted by ascorbic acid administration only in hypertensives (maximum FBF, -49+/-3 versus -63+/-2%; P<0.01); the vasoconstriction became similar to that observed in normotensives. During ascorbic acid plus L-NMMA administration, the vascular response to norepinephrine increased to a similar extent in both study groups. To rule out the possibility that the effect of ascorbic acid on norepinephrine vasoconstriction could depend on adrenergic receptor-induced nitric oxide release, in the last series we inhibited endogenous nitric oxide and replaced it with an exogenous nitric oxide donor (sodium nitroprusside). Even in these conditions, ascorbic acid attenuated norepinephrine vasoconstriction only in hypertensives (maximum FBF, -50+/-2 versus -62+/-1%; P<0.01). CONCLUSIONS Our data demonstrate that noradrenergic vascular hyper-responsiveness in hypertension is dependent on an impairment of nitric oxide activity that is realized through norepinephrine-induced oxygen free radical production.