Valentina Trimarco

L41Q polymorphism of the G protein coupled receptor kinase 5 is associated with left ventricular apical ballooning syndrome.

Altered response to acute catecholamine increase in the synaptic cleft is considered to be the mechanism underlying transient left ventricular apical ballooning syndrome (LVABS). –3 Cardiac adrenergic receptors (ARs) of the b1 and b2 subtypes activate myocytes by coupling to the Ga subunit of the heterotrimeric Gs protein, but on the other hand they also promote G protein coupled receptor kinase (GRK)-mediated phosphorylation of bAR with the intent to shut-off signalling. The impact on cardiac function of genetic variants of molecules involved in the intracellular pathways of bAR signalling has been extensively investigated. –8

Cooperation Between Insulin and Leptin in the Modulation of Vascular Tone

Abstract—High levels of insulin and leptin have been reported in human hypertension, suggesting a role for these metabolic hormones in blood pressure homeostasis. These hormones interact on intermediate metabolism, but nothing is known about their interaction at the vascular level. Our data demonstrate that insulin (0.6 nmol/L) is able to enhance vasodilation induced by leptin (10−11 to 10−6 mol/L; percentage change in maximal vasodilation, 39±3% vs 26±2%; n=6, P <0.03) but not by acetylcholine. Moreover, we demonstrate by 4,5-diaminofluorescein (DAF)-2 that insulin potentiates leptin-induced nitric oxide (NO) release. Finally, Western blotting studies show that insulin enhances the leptin-induced phosphorylation of Akt in Ser473 and Thr308 and of endothelial NO synthase in Ser1177. In conclusion, our data demonstrate that insulin and leptin cooperate in the modulation of vascular tone through enhancement of endothelial NO release. This phenomenon could have a major impact on the regulation of the cardiovascular system, principally in those clinical conditions characterized by endothelial NO dysfunction and metabolic disorders, such as arterial hypertension.

Resveratrol Improves Vascular Function in Patients With Hypertension and Dyslipidemia by Modulating NO Metabolism

Epidemiological studies have demonstrated that the Mediterranean diet, which is rich in resveratrol, is associated with a significantly reduced risk of cardiovascular disease. However, the molecular mechanisms that underlie the beneficial effects of resveratrol on cardiovascular function remain incompletely understood. Therefore, we set out to identify the molecular target(s) mediating the protective action of resveratrol on vascular function. To this end, we performed vascular reactivity studies to evaluate the effects of resveratrol on superior thyroid artery obtained from 59 patients with hypertension and dyslipidemia. We found that resveratrol evoked vasorelaxation and reduced endothelial dysfunction through the modulation of NO metabolism via (1) an 5′ adenosine monophosphate–activated protein kinase–mediated increase in endothelial NO synthase activity; (2) a rise in tetrahydrobiopterin levels, which also increases endothelial NO synthase activity; and (3) attenuation of vascular oxidative stress, brought about by overexpression of manganese superoxide dismutase via an nuclear factor erythroid–derived 2-like 2–dependent mechanism. The effects of resveratrol on acetylcholine vasorelaxation were also tested in vessels from patients with nonhypertensive nondyslipidemia undergoing thyroid surgery. In this setting, resveratrol failed to exert any effect. Thus, our finding that resveratrol reduces endothelial dysfunction, an early pathophysiological feature and independent predictor of poor prognosis in most forms of cardiovascular disease, supports the concept that the risk of vascular events could be further reduced by adherence to a set of dietary and behavioral guidelines.

Increased basal nitric oxide release despite enhanced free radical production in hypertension

Introduction Although in hypertension a defect in stimulated nitric oxide (NO) is well established, little is known about basal NO levels. Thus, we measured directly in vessels from normotensive [Wistar–Kyoto (WKY)] rats and spontaneously hypertensive rats (SHR) both basal and stimulated NO production using a novel technique [4,5-diaminofluorescein (DAF-2) fluorescence]. Methods Isolated vessels were exposed to the fluorescent probe DAF-2. After the technique was validated with increasing doses of acetylcholine in the presence and absence of NG-nitro-L-arginine methyl ester (l-NAME), we measured NO production in vessels from WKY rats and SHR in the same experimental setting. Finally, to explore the impact of reactive oxygen species (ROS) on NO release, we analysed the effect of an antioxidant, such as ascorbic acid, on basal and stimulated NO in aortic rings of WKY rats and SHR. Results Aortic rings from SHR exhibited a higher basal NO production and a lower responsiveness to agonist-induced NO release as compared with those observed in WKY rats. Also in resistance vessels such as mesenteric arteries, basal NO production was higher in hypertension. In hypertensive rats, ascorbic acid was able to further increase basal NO release and recovered the impaired stimulated NO production, whereas no effect was detected in normotensive rats. Conclusions Our data reveal an increased basal NO availability in hypertension despite the increased production of ROS, suggesting a greater complexity in hypertensive endothelial dysfunction when the analysis is focused on direct NO measurement.

Hypertensive target organ damage predicts incident diabetes mellitus

Aims Whether patients with hypertensive preclinical cardiovascular disease (CVD) are at higher risk of incident diabetes has never been studied. Methods and results We assessed incident diabetes in 4176 hypertensive non-diabetic patients (age 58.7 ± 8.9 years, 58% male) with ≥1 year follow-up (median: 3.57 years; inter-quartile range: 2.04–7.25). Left ventricular (LV) hypertrophy (LVH) was defined as LV mass index (LVMi) ≥51 g/m2.7. Carotid atherosclerosis (CA) was defined as intima-media thickness >1.5 mm. During follow-up, diabetes developed in 393 patients (9.4%), more frequently in those with than without initial LVH or CA (odds ratio = 1.97 and 1.67, respectively; both P < 0.0001). In the Cox regression, the presence of either initial LVH or CA was associated with higher hazard of diabetes [hazards ratio (HR) = 1.30 and 1.38, respectively; both P = 0.03], independently of the type and number of anti-hypertensive medications, initial systolic blood pressure (P < 0.001), body mass index, fasting glucose, family history of diabetes (all P < 0.0001), and therapy with β-blockers. The presence of one of the, or both, markers of preclinical CVD increased the chance of incident diabetes by 63 or 64%, respectively (both P < 0.002), independently of significant confounders, a result that was confirmed (HR = 1.70 or 1.93, respectively; both P < 0.0001) using ATPIII metabolic syndrome (HR = 2.73; P < 0.0001) in the Cox model. Conclusion Initial LVH and CA are significant predictors of new onset diabetes in a large population of treated hypertensive patients, independently of initial metabolic profile, anti-hypertensive therapy, and other significant covariates. This sequence may be attributable to risk factors common to preclinical CVD and diabetes, but a vascular origin of diabetes cannot be excluded.

Cross-Talk Between PKA and Akt Protects Endothelial Cells From Apoptosis in the Late Ischemic Preconditioning

Objective—The aim of this study was to explore the molecular mechanisms involved in late preconditioning-induced cell protection in endothelial cells. Methods and Results—Preconditioning (PC) was induced by exposing bovine aortic endothelial cells (BAECs) to 3 cycles of 15 minutes of hypoxia followed by 15 minutes of reoxygenation. A 12-hour period of hypoxia induced cell death in 60% of BAECs (48±5% apoptosis, 12±4% necrosis). Early and late PC decreased hypoxia-induced apoptotic (25±5% and 28±4%, respectively) and necrotic (6±3%, and 8±2%, respectively) cell death. Consistently, hypoxia-induced caspase-3 cleavage was reduced by PC. Pretreatment with H89 (protein kinase A [PKA] inhibitor), LY294002 (phosphatidyl-inositol-3-kinase [PI3K] inhibitor), and N-acetyl-cysteine (antioxidant) abrogated late PC-induced cell protection, whereas inhibition of protein kinase C by Go6983, and of nitric oxide synthesis by L-NAME,1400W and bovine eNOS siRNA did not. In addition, in early and late PC, PKA physically interacted with the phosphorylated form of Akt, suggesting that PKA is required for Akt phosphorylation. Expression of PKA and Akt dominant negative mutants inhibited ischemic late PC-induced protection, indicating that these kinases play a key role in late PC-mediated cell protection. Conclusions—Late ischemic PC protects BAECs against hypoxia through PKA- and PI3K-dependent activation of Akt.

The Glu27 allele of the β2 adrenergic receptor increases the risk of cardiac hypertrophy in hypertension

Objective Cardiac and vascular remodeling occur in response to hypertension. Genetic background appears to modify the development of target organ damage (TOD). We evaluated the impact on hypertension-associated TOD of a highly polymorphic gene with elevated significance for the regulation of the cardiovascular system, the β2AR gene. Methods We recruited 775 hypertensives (mean ± SE: age 53.5 ± 0.5, from 20 to 84 years; female 32.7%; systolic (SBP)/diastolic (DBP) blood pressure: 159 ± 1.2/101 ± 0.6 mmHg) referred to the departmental outpatient clinic and screened them for the Arg16Gly, Gln27Glu, and Ile164Thr variants of β2AR gene. We performed association analyses on clinical, anamnesis, anthropometrical and biochemical parameters as well as cardiac and vascular ultrasound. Results We found that the three polymorphisms did not affect blood pressure levels. Cardiac TOD appeared to be related to the Glu27 variant. In fact, the Glu27 allele associates with a 1.4-fold higher risk of developing cardiac hypertrophy, and directly correlated with larger systolic and diastolic left ventricle internal diameters. Vascular TOD was not affected by the three polymorphisms. Ancillary to our finding we observed that the Glu27 variant is associated with a higher incidence of dyslipidemia. Conclusions Our data indicate that β2AR gene polymorphisms participate in the determination of cardiac TOD associated with hypertension.

Effects of nutraceuticals on prevalence of metabolic syndrome and on calculated Framingham Risk Score in individuals with dyslipidemia

Background Nutraceuticals (NUTs) are forms of compounds with biological activity and are used to improve health in dosage largely exceeding those obtainable in food. Objectives To investigate whether addition of NUTs to lifestyle management including diet counseling improves lipid profile and reduces cardiovascular risk and prevalence of metabolic syndrome (MetS). Methods One thousand, three hundred and eighty, 18–80-year-old nondiabetic participants with dyslipidemia, with or without MetS not requiring pharmacological therapy were assigned to diet; after 2 weeks, 690 patients were also given NUT combination over other 8 weeks. Fasting plasma glucose and lipid compounds were measured by standard methods. Waist circumference, systolic and diastolic blood pressure (BP) were measured at each visit. MetS was defined according to ATPIII guidelines. Ten-year risk of coronary heart disease was calculated using the Framingham Risk Score (FRS). Results At baseline, NUT patients were older and more dyslipidemic than placebo, with no difference in other cardiovascular risk factors and prevalence of MetS. After 8 weeks, high-density lipoprotein (HDL) cholesterol was increased and diastolic BP, waist girth, triglycerides, total and non-HDL cholesterol were significantly reduced in NUT than in the placebo group, whereas systolic BP and fasting glucose did not change. Prevalence of MetS was also significantly lower in the NUT (36.1%) than in placebo (48.1%, P < 0.05) and reduction in the FRS greater (73.3 vs. 52%, respectively; P < 0.0001). Conclusion In a large clinical sample of patients with moderate cardiovascular risk, combination of NUT with dietary counseling reduces central obesity, improves lipid profile, diastolic BP and FRS, and decreases prevalence of MetS.

β2‐Adrenergic receptor polymorphisms and treatment‐induced regression of left ventricular hypertrophy in hypertension

Although blood pressure is considered the major determinant of left ventricular hypertrophy in hypertension, genetic variability is increasingly being considered among the factors influencing this complication. β2‐Adrenergic receptors (β2ARs) are up‐regulated in hypertension and largely polymorphic within the human population. Recently, we have shown that the Glu27 β2AR variant is strongly associated with cardiac hypertrophy in hypertension. The objective of this study is to verify whether this polymorphism also affects hypertrophy regression in response to antihypertensive therapy.

Cardiovascular ultrasound exploration contributes to predict incident atrial fibrillation in arterial hypertension: the Campania Salute Network.

BACKGROUND Interaction of cardiovascular (CV) risk factors with structural and hemodynamic alterations as combined promoters of atrial fibrillation (AF) is not yet well studied. We designed an observational, longitudinal, retrospective study to predict risk of incident AF by combination of CV risk profile, target organ damage and therapy in hypertensive patients. METHODS AND RESULTS We studied 7062 hypertensive patients without history of AF or prevalent CV disease, with ejection fraction (EF) of ≥50%, and no more than stage III chronic kidney disease. The patients were selected from an open registry, the Campania-Salute Network, collecting information from general practitioners and community hospitals, in the Campania Region, Southern Italy, networked with the Hypertension Center of Federico II University Hospital in Naples. The end-point of the present analysis was the detection of first episode of AF by ECG or hospital admission, at any point throughout follow-up (median 36months [IQR=10-74]). During follow-up, AF developed in 117 patients. Baseline older age, greater left atrial diameter (LAd), left ventricular mass (LVM), and intimal medial thickness (IMT) were independent predictors of AF (all p<0.0001), with no effect of CV risk factors. Beta-blockers and diuretics increased risk of incident AF; use of medications inhibiting renin-angiotensin system (RAS) reduced risk by 50% (all p<0.002). CONCLUSIONS Older age, increased LAd, and markers of target organ damage (increased LVM and IMT), identify the hypertensive phenotype at highest risk for AF. CV risk factors do not exhibit significant, independent association. Patients on anti-RAS therapy are exposed to lower risk of incident AF.