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Background: The Italian Society of Echography and Cardiovascular Imaging (SIECVI) conducted a national survey to understand the volumes of activity, modalities and stressors used during stress echocardiography (SE) in Italy., Methods: We analyzed echocardiography laboratory activities over a month (November 2022). Data were retrieved through an electronic survey based on a structured questionnaire, uploaded on the SIECVI website., Results: Data were obtained from 228 echocardiographic laboratories, and SE examinations were performed in 179 centers (80.6%): 87 centers (47.5%) were in the northern regions of Italy, 33 centers (18.4%) were in the central regions, and 61 (34.1%) in the southern regions. We annotated a total of 4057 SE. We divided the SE centers into three groups, according to the numbers of SE performed: <10 SE (low-volume activity, 40 centers), between 10 and 39 SE (moderate volume activity, 102 centers) and ≥40 SE (high volume activity, 37 centers). Dipyridamole was used in 139 centers (77.6%); exercise in 120 centers (67.0%); dobutamine in 153 centers (85.4%); pacing in 37 centers (21.1%); and adenosine in 7 centers (4.0%). We found a significant difference between the stressors used and volume of activity of the centers, with a progressive increase in the prevalence of number of stressors from low to high volume activity ( P = 0.033). The traditional evaluation of regional wall motion of the left ventricle was performed in all centers, with combined assessment of coronary flow velocity reserve (CFVR) in 90 centers (50.3%): there was a significant difference in the centers with different volume of SE activity: the incidence of analysis of CFVR was significantly higher in high volume centers compared to low - moderate - volume (32.5%, 41.0% and 73.0%, respectively, P < 0.001). The lung ultrasound (LUS) was assessed in 67 centers (37.4%). Furthermore for LUS, we found a significant difference in the centers with different volume of SE activity: significantly higher in high volume centers compared to low - moderate - volume (25.0%, 35.3% and 56.8%, respectively, P < 0.001)., Conclusions: This nationwide survey demonstrated that SE was significantly widespread and practiced throughout Italy. In addition to the traditional indication to coronary artery disease based on regional wall motion analysis, other indications are emerging with an increase in the use of LUS and CFVR, especially in high-volume centers., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Cardiovascular Echography.)

Background: The Italian Society of Echocardiography and Cardiovascular Imaging (SIECVI) conducted a national survey to understand better how different echocardiographic modalities are used and accessed in Italy., Methods: We analyzed echocardiography laboratory activities over a month (November 2022). Data were retrieved via an electronic survey based on a structured questionnaire, uploaded on the SIECVI website., Results: Data were obtained from 228 echocardiographic laboratories: 112 centers (49%) in the northern, 43 centers (19%) in the central, and 73 (32%) in the southern regions. During the month of observation, we collected 101,050 transthoracic echocardiography (TTE) examinations performed in all centers. As concern other modalities there were performed 5497 transesophageal echocardiography (TEE) examinations in 161/228 centers (71%); 4057 stress echocardiography (SE) examinations in 179/228 centers (79%); and examinations with ultrasound contrast agents (UCAs) in 151/228 centers (66%). We did not find significant regional variations between the different modalities. The usage of picture archiving and communication system (PACS) was significantly higher in the northern (84%) versus central (49%) and southern (45%) centers ( P < 0.001). Lung ultrasound (LUS) was performed in 154 centers (66%), without difference between cardiology and noncardiology centers. The evaluation of left ventricular (LV) ejection fraction was evaluated mainly using the qualitative method in 223 centers (94%), occasionally with the Simpson method in 193 centers (85%), and with selective use of the three-dimensional (3D) method in only 23 centers (10%). 3D TTE was present in 137 centers (70%), and 3D TEE in all centers where TEE was done (71%). The assessment of LV diastolic function was done routinely in 80% of the centers. Right ventricular function was evaluated using tricuspid annular plane systolic excursion in all centers, using tricuspid valve annular systolic velocity by tissue Doppler imaging in 53% of the centers, and using fractional area change in 33% of the centers. When we divided into cardiology (179, 78%) and noncardiology (49, 22%) centers, we found significant differences in the SE (93% vs. 26%, P < 0.001), TEE (85% vs. 18%), UCA (67% vs. 43%, P < 0001), and STE (87% vs. 20%, P < 0.001). The incidence of LUS evaluation was similar between the cardiology and noncardiology centers (69% vs. 61%, P = NS)., Conclusions: This nationwide survey demonstrated that digital infrastructures and advanced echocardiography modalities, such as 3D and STE, are widely available in Italy with a notable diffuse uptake of LUS in the core TTE examination, a suboptimal diffusion of PACS recording, and conservative use of UCA, 3D, and strain. There are significant differences between northern and central-southern regions and echocardiographic laboratories that pertain to the cardiac unit. This inhomogeneous distribution of technology represents one of the main issues that must be solved to standardize the practice of echocardiography., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Cardiovascular Echography.)

Anomalies of the coronary arteries represent rare congenital disorders, which are characterized by a wide spectrum of clinical manifestations. Usually, they are asymptomatic, but sometimes they cause myocardial ischemia or sudden cardiac death. Here, we describe the case of a patient who suffered from angina. Coronary angiography revealed an ectopic origin of the left anterior descending coronary artery from the proximal trait of the right coronary artery and the left circumflex artery, originating from the left sinus; the whole coronary tree was free of atherosclerosis. To better define the coronary anatomy, we performed computed tomography angiography with a three-dimensional reconstruction. The patient was discharged from the clinic after 48 h under optimal medical treatment., (© 2019 S. Karger AG, Basel.)

High levels of uric acid (UA) are associated with type-2 diabetes and cardiovascular disease. Recent pieces of evidence attributed to UA a causative role in the appearance of diabetes and vascular damage. However, the molecular mechanisms by which UA induces these alterations have not been completely elucidated so far. Among the mechanisms underlying insulin resistance, it was reported the role of a transmembrane glycoprotein, named either ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) or plasma cell antigen 1, which is able to inhibit the function of insulin receptor (I R ) and it is overexpressed in insulin-resistant subjects. In keeping with this, we stimulated human umbilical vein endothelial cells (HUVECs) with insulin and UA to investigate the effects of UA on insulin signaling pathway, testing the hypothesis that UA can interfere with insulin signaling by the activation of ENPP1. Cultures of HUVECs were stimulated with insulin, UA and the urate transporter SLC22A12 (URAT1) inhibitor probenecid. Akt and endothelial nitric oxide synthase (eNOS) phosphorylation levels were investigated by immunoblotting. ENPP1 binding to I R and its tyrosine phosphorylation levels were tested by immunoprecipitation and immunoblotting. UA inhibited insulin-induced Akt/eNOS axis. Moreover, UA induced ENPP1 binding to I R that resulted in an impairment of insulin signaling cascade. Probenecid reverted UA effects, suggesting that UA intracellular uptake is required for its action. In endothelial cells, UA directly interferes with insulin signaling pathway at receptor level, through ENPP1 recruitment. This evidence suggests a new molecular model of UA-induced insulin resistance and vascular damage.

Coronary calcification is a hard challenge for the interventional cardiologist, as it is associated with incomplete stent expansion and frequently stent failure. In recent years, innovative techniques, such as rotational atherectomy, have been developed to treat coronary calcification. However, these are burdened with an increased procedural risk. We report the case of a 60-year-old Caucasian man treated 1 month before at another center with primary coronary angioplasty and stenting of the ramus intermedius for coronary syndrome. Coronary angiography showed a critical stenosis of the left main coronary artery as well as critical calcified stenosis of the left anterior descending artery and the diagonal branch. Coronary calcification was treated with rotational atherectomy that preceded the angioplasty and stenting. Because of persistence of the symptomatology, coronary angiography was repeated 1 month later and showed a critical calcified restenosis of the ramus intermedius at the site of the previous stenting. Considering the high risk of traditional atherectomy, we performed lithotripsy-enhanced disruption of calcium beyond the stents with the Shockwave Coronary Lithoplasty System. The Shockwave Coronary Lithoplasty System has been introduced recently in order to treat calcified coronary lesions with greater safety. The procedure allows most calcified coronary lesions to be treated with simplicity and safety. This system employs sound waves, similar to those used for treating kidney stones, to crush the calcified lesions. We present the first case described to date in whom this technique was successfully used to treat calcified restenosis in a previous stent., (© 2019 S. Karger AG, Basel.)

We report the case of a stent under-expansion due to heavily calcified plaque treated with the shockwave lithoplasty system. A 77-year-old woman underwent coronary angiography, and intravascular ultrasound revealed stent under-expansion due to calcified plaque. Shockwave lithoplasty balloon was used to disrupt calcium deposits around the stent, thereby allowing a correct stent expansion with an excellent angiographic and intravascular ultrasound result., (© 2018 S. Karger AG, Basel.)

Renal dysfunction is an independent predictor for cardiovascular morbidity and mortality. We investigated whether chronic hepatitis C virus (HCV) infection and the related insulin resistance/hyperinsulinemia influence renal function in comparison with a group of healthy subjects and with another group with metabolic syndrome. We enrolled 130 newly diagnosed HCV outpatients matched for age and gender with 130 patients with metabolic syndrome and 130 healthy subjects. Renal function was evaluated by calculation of glomerular filtration rate (e-GFR, mL/min/1.73 m(2)) using the CKD-EPI equation. The following laboratory parameters were measured: fasting plasma glucose and insulin, total, LDL- and HDL-cholesterol, triglyceride, creatinine, and HOMA to evaluate insulin sensitivity. HCV patients with respect to both healthy subjects and metabolic syndrome patients have a decreased e-GFR: 86.6 ± 16.1 vs 120.2 ± 23.1 mL/min/1.73 m(2) (P < 0.0001) and 94.9 ± 22.6 mL/min/1.73 m(2) (P = 0.003), respectively. Regarding biochemical variables, HCV patients, in comparison with healthy subjects, have a higher triglyceride level, creatinine, fasting insulin and HOMA (3.4 ± 1.4 vs 2.6 ± 1.3; P < 0.0001). At linear regression analysis, the correlation between e-GFR and HOMA is similar in the metabolic syndrome (r = -0.555, P < 0.0001) and HCV (r = -0.527, P < 0.0001) groups. At multiple regression analysis, HOMA is the major determinant of e-GFR in both groups, accounting for, respectively, 30.8 and 27.8 % of its variation in the metabolic syndrome and HCV. In conclusion, we demonstrate that HCV patients have a significant reduction of e-GFR and that insulin resistance is the major predictor of renal dysfunction.

Aims: Normoglucose tolerant (NGT) subjects with a 1-h postload plasma glucose (PLPG) value ≥155 mg/dL have an increased risk of type-2 diabetes and subclinical organ damage. Heart rate variability (HRV) reflects cardiac autonomic balance, frequently impaired in course of diabetes. At this time, no data support the association between 1-h PLPG and HRV; thus, we investigated the possible association between 1-h PLPG and HRV., Methods: We enrolled 92 never-treated hypertensive subjects (56 women, 36 men), aged 55 ± 9.8 years. During OGTT, the patients underwent electrocardiographic recordings to evaluate HRV in the time domain (SDNN). Insulin sensitivity was assessed by Matsuda index., Results: Among participants, 56 were NGT, 20 had impaired glucose tolerance (IGT), and 16 had type-2 diabetes. According to the 1-h PLPG cutoff point of 155 mg/dL, we divided NGT subjects into: NGT < 155 (n = 38) and NGT ≥ 155 (n = 18). Glucose tolerance status was associated with a significant (P < 0.0001) increase in PLPG and insulin and the reduction in Matsuda index. In all groups, the SDNN values significantly (P < 0.0001) decreased during the first hour of OGTT. A complete recovery in NGT groups was observed at the end of the second hour; in IGT and type-2 diabetes, SDNN remained significantly lower with respect to baseline values. At multiple regression analysis, Matsuda index resulted in the only determinant of SDNN modification, explaining the 12.3 % of its variability., Conclusions: Our data demonstrate that during OGTT, sympathovagal balance is acutely affected by both glucose and insulin modifications. Particularly, NGT ≥ 155 subjects behave in the same way of IGT and type-2 diabetes patients.

Background: Uric acid (UA) is a risk factor for cardiovascular (CV) disease. In post-menopause UA levels are increased and strongly associated with subclinical organ damage. We investigated the prognostic significance of UA levels in predicting CV morbidity and mortality in post-menopausal women., Methods: We considered 645 post-menopausal outpatients not taking hormone replacement therapy or any drugs interfering with UA levels. We evaluated major adverse cardiovascular events (MACE) as primary endpoint, with coronary, stroke or total events as secondary endpoint. Survival curves for tertiles of UA were obtained by using the Kaplan-Meier and Mantel methods. Effect of prognostic factors on survival was evaluated by multivariable Cox regression model, considering P<0.05 as statistically significant., Results: During a mean (SD) follow-up at 72.5 (23.5) months, there were 90 new CV events (2.31%): 62 coronary and 28 cerebrovascular events. The rate of nonfatal CV events (3.15% versus 2.03% and 1.52%, P=0.009) as well as that of MACE (3.23% versus 2.11% and 1.59%, P=0.011) were significantly higher in the third tertile than in the other two groups. Interestingly, cerebrovascular (1.15% versus 0.62% and 0.30%, P=0.027) but not coronary events were significantly different among the three groups. In the Cox regression model, UA was independently and strongly associated with the incident risk of MACE (HR=1.248, P=0.001), cerebrovascular (HR=1.657, P<0.0001) and total events (HR=1.391, P<0.0001)., Conclusions: In post-menopause, independently of other CV risk factors and menopause duration, UA levels are associated with increased risk of death and MACE, in particular cerebrovascular but not coronary events., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

No data exist concerning a possible association between CHADS2 or CHA2DS2-VASc scores and atrial fibrillation (AF). In this prospective observational study, we tested the hypothesis whether thromboembolic risk scores predict AF. We investigated 3549 subjects, 1829 men and 1720 women, aged 60.7 ± 10.6 years, without baseline AF. Patients with thyroid disorders were excluded. CHADS2 and CHA2DS2-VASc scores were evaluated as categorical variables. To test the effect of some clinical confounders on incident AF, we constructed different models including clinical and laboratory parameters. During follow-up (53.3 ± 18.1 months), 546 subjects developed AF (4.5 events/100 patient-years). Progressors to AF are older, have a higher body mass index (BMI), blood pressure, LDL-cholesterol, and glucose. Hypertension, metabolic syndrome, diabetes and carotid wall thickening were more common among AF cases than among control subjects. In the final Cox-regression model, variables that remained significantly associated with incident AF were BMI (HR = 1.022, 95% CI = 1.008-1.037), LDL-cholesterol (HR = 1.032, 95% CI = 1.008-1.056), CHA2DS2-VASc score (HR = 1.914, 95% CI = 1.439-2.546), and CHADS2 score (HR = 2.077, 95% CI = 1.712-2.521). In conclusion, CHADS2 and CHA2DS2-VASc scores are independent predictors of AF.

Current guidelines suggest the use of low doses of acetylsalicylic acid (ASA) for patients with diabetes mellitus (DM) in primary prevention. However, the evidences demonstrating the beneficial effect of ASA in primary prevention are conflicting. In this pilot study, we evaluated in a group of diabetic patients, in primary prevention, the impact of ASA treatment on oxidative stress and vascular function. We enrolled 22 newly diagnosed diabetic patients, without any previous clinical evidence of cardiovascular disease, to receive, in primary prevention, ASA (100 mg/daily). We tested, in basal condition, after 4 weeks of ASA administration and after 4 weeks of pharmacological washout, the impact of ASA treatment on endothelial function, assessed by a semipletysmographic method, measuring the main oxidative stress parameters related to it. As expected, after 4 weeks of treatment, ASA induced a significant reduction of plasma thromboxane-A2, as a consequence of cyclooxygenase-1 inhibition. By contrast, ASA significantly increased the plasma and urine 8-iso-PGF2α, a well-known prothrombotic molecule, parallel to an increase of plasma NOX2 levels. The enhancement of this oxidative pathway is associated with a significant impairment of endothelial vasodilation, assessed by reactive hyperemia index (RHI). The pharmacological washout reverted all parameters to basal condition. Our findings suggest that ASA utilization for primary prevention in diabetic patients causes a significant increase of oxidative stress burden impairing the vascular function. Present data, if confirmed on a larger population, could permanently discourage the use of the ASA for the primary prevention in patients with DM.

BACKGROUND AND AIMS. Arterial stiffness evaluated as pulse wave velocity, is an early marker of vascular damage and an independent predictor for cardiovascular events. We investigated if the insulin resistance/hyperinsulinemia chronic hepatitis C virus infection-related could influence arterial stiffness. METHODS. We enrolled 260 outpatients matched for age, body mass index, gender, ethnicity: 52 with never-treated uncomplicated chronic hepatitis C virus infection (HCV(+)), 104 never-treated hypertensives (HT) and 104 healthy subjects (NT). Pulse wave velocity was evaluated by a validated system employing high-fidelity applanation tonometry. We also measured: fasting plasma glucose and insulin, total, LDL- and HDL-cholesterol, triglyceride, creatinine, e-GFR-EPI, HOMA, quantitative HCV-RNA. RESULTS. HCV(+) patients with respect to NT had an increased pulse wave velocity (7.9 ± 2.1 vs 6.4 ± 2.1 m/s; P < 0.0001), similar to that observed in HT group (8.8 ± 3.2 m/s). HCV(+) patients, in comparison with NT, had higher triglyceride, creatinine, fasting insulin and HOMA (3.2 ± 1.3 vs 2.5 ± 1.0; P < 0.0001). At linear regression analysis, the correlation between pulse wave velocity and HOMA was similar in HT (r = 0.380, P < 0.0001) and HCV(+) (r = 0.369, P = 0.004) groups. At multiple regression analysis, HOMA resulted the major determinant of pulse wave velocity in all groups, explaining respectively 11.8%, 14.4% and 13.6% of its variation in NT, HT and HCV(+). At correlational analysis hepatitis C virus-RNA and HOMA demonstrated a strong and linear relationship between them, explaining the 72.4% of their variation (P = 0.022). CONCLUSIONS. We demonstrated a significant and direct correlation between HOMA and pulse wave velocity in HCV(+) patients, similar to that observed in hypertensives., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background & Aims: Left ventricular hypertrophy (LVH), is an independent predictor for cardiovascular events. We investigated if chronic hepatitis C virus (HCV) infection and the related insulin resistance (IR)/hyperinsulinemia could influence the increase of left ventricular mass (LVM)., Methods: We enrolled 260 outpatients matched for age, body mass index, gender, ethnicity: 52 with never-treated uncomplicated chronic HCV infection (HCV(+)), 104 never-treated hypertensives (HT) and 104 healthy subjects (NT). LVM was calculated according to the Devereux formula and indexed for body surface area. The following laboratory parameters were measured: fasting plasma glucose and insulin, total, LDL- and HDL-cholesterol, triglyceride, creatinine, e-GFR-EPI, HOMA. Quantitative HCV-RNA was assessed by PCR., Results: HCV(+) patients with respect to healthy normotensive subjects had an increased LVMI (100 ± 23 vs. 83 ± 15 g/m(2); p < 0.0001), similar to that observed in HT group (103 ± 25 g/m(2)). Regarding biochemical variables, HCV(+) patients, in comparison with normotensive healthy subjects, had higher triglyceride, creatinine, fasting insulin and HOMA (3.2 ± 1.3 vs. 2.5 ± 1.0; p < 0.0001). At linear regression analysis, the correlation between LVMI and HOMA was similar in HT (r = 0.528, p < 0.0001) and HCV(+) (r = 0.489, p < 0.0001) groups. At multiple regression analysis, HOMA resulted the major determinant of LMVI in all groups, explaining respectively 21.8%, 27.8%, and 23.9% of its variation in NT, HT and HCV(+). At correlational analysis HCV-RNA and HOMA demonstrated a strong and linear relationship between them, explaining the 72.4% of their variation (p = 0.022)., Conclusions: We demonstrated a significant and direct correlation between HOMA and LVMI in patients with chronic HCV infection, similar to that observed in hypertensives., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: In this prospective population-based study, we tested the possible interaction between chronic kidney disease (CKD) and left atrium volume index (LAVI) in predicting incident atrial fibrillation (AF)., Methods: We enrolled 3549 Caucasian subjects, 1829 men and 1720 women, aged 60.7 ± 10.6 years, without baseline AF and thyroid disorders. Echocardiographic left ventricular mass and LAVI were measured. Renal function was calculated by estimated glomerular filtration rate (e-GFR). To test the effect of some clinical confounders on incident AF, we constructed different models including clinical and laboratory parameters. AF diagnosis was made by standard electrocardiogram or 24-h ECG-Holter, hospital discharge diagnoses, and by the all-clinical documentation., Results: During the follow-up (53.3 ± 18.1 months), 546 subjects developed AF (4.5 events/100 patient-years). Progressors to AF were older, had a higher body mass index, blood pressure, LDL-cholesterol, glucose, cardiac mass, and LAVI, and had lower e-GFR. Hypertension, metabolic syndrome, diabetes, cardiac hypertrophy and CKD were more common among AF cases than controls. In the final Cox regression model, variables that remained significantly associated with AF were: cardiac hypertrophy (HR=1.495, 95% CI=1.215-1.841), renal disease (HR=1.528, 95% CI=1.261-1.851), age (HR=1.586, 95% CI=1.461-1.725) and LAVI (HR=2.920, 95% CI=2.426-3.515). The interaction analysis demonstrated a synergic effect between CKD and cardiac hypertrophy (HR=4.040, 95% CI=2.661-6.133), as well as between CKD and LAVI (HR=4.875, 95% CI=2.699-8.805). The coexistence of all three subclinical organ damages significantly increases the arrhythmic risk (HR=7.185, 95% CI=5.041-10.240)., Conclusions: Our data demonstrate that LAVI and CKD significantly interact in a synergic manner in increasing AF risk., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background and Aims: Normoglucosetolerants (NGT) are considered at low risk, even if a 1-h post-load glucose (PLG) value ≥ 155 mg dl(-1) identifies NGTs at high risk of type-2 diabetes (T2D) and sub-clinical organ damage. Specific dietary factors may affect insulin sensitivity and the risk of T2D. However, it is unknown whether dietary components affect 1-h PLG in hypertensive NGT. Therefore, we investigate the effect of dietary patterns on 1-h PLG., Methods and Results: We selected 188 subjects (94 NGTs < 155 mg dl(-1) and 94 NGTs ≥ 155 mg dl(-1) PLG), well matched for age, gender and body mass index (BMI). Insulin sensitivity was evaluated using the Matsuda index. Dietary intake was quantified by a semiquantitative food frequency questionnaire (FEQ) validated in the European Investigation into Cancer and Nutrition (EPIC) study. The NGT ≥ 155 group had significantly reduced insulin sensitivity (40.3 ± 19.8 vs. 73.3 ± 28.8; P < 0.0001). With the exclusion of total calories, lipids, alcohol and fiber consumption we observed a significant difference, between groups, in starch (214.1 ± 52.4 vs. 268.8 ± 71.8 g; P < 0.0001), saturated (27.4 ± 8.7 vs. 24.1 ± 8.5 g; P = 0.009), monounsaturated (45.5 ± 8.9 vs. 48.8 ± 10.7 g; P = 0.023) and polyunsaturated fatty acids (FAs) (14.5 ± 4.0 vs. 16.8 ± 4.7 g; P < 0.0001), fructose (14.5 ± 5.3 vs. 11.2 ± 4.8 g; P < 0.0001), and oligosaccharides (103.2 ± 26.6 vs. 89.9 ± 29.2 g; P = 0.001) consumption. In the whole population, starch was the major predictor of 1-h PLG, explaining 23.2% of variation (P < 0.0001). In the NGT < 155 group, fructose was the strongest predictor, accounting for 15.4% of the variation; BMI, gender and polyunsaturated FAs added another 6.6%, 3.6% and 3.2%, respectively. In the NGT ≥ 155 group, saturated and polyunsaturated FAs were retained as the major predictors of 1-h PLG, explaining 18.2% and 11.4% of the variation., Conclusions: The present data demonstrate that dietary patterns affect 1-h PLG, remarking the importance of both quantitative and qualitative composition of a diet., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Endothelial dysfunction represents an independent predictor for clinical events. Genetic background may promote deleterious alterations of endothelial physiology. The aim of the study was to investigate the relationship between the rs1050283 polymorphism in the 3'-UTR of OLR1/LOX-1 gene and endothelial dysfunction in 178 never-treated hypertensive patients and 36 healthy subjects. The rs1050283 C/T single nucleotide polymorphism was detected, by TaqMan allelic discrimination assay. The influence of polymorphism on gene transcription rate was tested in 12 heterozygous hypertensive patients, by using an allelic imbalance assay. Forearm blood flow (FBF) was measured during intra-arterial infusion of acetylcholine (ACh), and sodium nitroprusside at increasing doses. Analysis of endothelium-dependent and endothelium-independent vasodilatation was tested according to rs1050283 polymorphism. In hypertensive patients, ACh-stimulated FBF is significantly reduced in T allele carriers (P < 0.0001), even when the allelic imbalance assay indicates an overexpression of C allele. In healthy subjects, there is no significant difference for ACh-dependent vasodilatation among genotypic groups (P = 0.660). In essential hypertensive patients, the T allele of OLR1/LOX-1 gene is strongly associated with an impaired endothelium-dependent vasodilatation, a powerful predictor of cardiovascular events.

Background: Subclinical organ damage is a condition with an increased risk for fatal and nonfatal cardiovascular events. Particularly, endothelial dysfunction and left ventricular mass (LVM) are recognized as independent predictors of cardiovascular events in hypertensive patients. Besides, LVM in hypertensives is inversely related to forearm blood flow (FBF) responses to the endothelium-dependent vasodilating agent. We evaluated the role of endothelium-dependent vasodilation in the progression/regression of LVM in a group of hypertensive subjects., Methods: We enrolled 170 hypertensive outpatients (88 men, 92 women; age 47 ± 11 years). LVM was calculated with the Devereux formula and indexed by surface area (LVMI). Endothelium-dependent vasodilation was investigated by intra-arterial infusions of acetylcholine (ACh)., Results: During the follow-up blood pressure (BP) decreased from 150/91 ± 17/11 to 135/80 ± 14/9 mm Hg (P=0.0001), and LVMI from 120 ± 28 to 118 ± 28 g/m(2) (P=0.194). The mean annual rate of variation of LVMI was -0.38 ± 3.9 g/m(2), which was not statistically different in men and women. It was correlated with baseline ACh-stimulated FBF (r=-0.272, P=0.0001) and BMI (r=0.164, P=0.016). At multivariate analysis, FBF was the only baseline covariate that remained significantly associated with LVMI variation, also after correction for antihypertensive treatment and BP reduction. The interaction between baseline LVM and ACh-stimulated FBF was investigated in a multiple linear regression model showing that a fixed reduction in ACh-stimulated FBF (100%) induces different variation of annual rate of LVMI at different levels of baseline LVM., Conclusions: Our data demonstrate, for the first time, the role of endothelial function in the progression/regression of LVMI, independently of traditional cardiovascular risk factors and antihypertensive therapy., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Aims: Angiotensin II participates to the regulation of cardiovascular physiology and it is involved in molecular mechanisms of insulin resistance. Angiotensin (1-7), derived from angiotensin II metabolism, is able to counteract many of the haemodynamic and non-haemodynamic actions of angiotensin II. In this study, we investigated in human umbilical vein endothelial cells (HUVECs) the possible action of angiotensin (1-7) on the insulin signalling pathway., Methods and Results: We stimulated HUVECs with insulin, angiotensin II and angiotensin (1-7), testing the effects on endothelial nitric oxide synthase (eNOS) enzyme activation and on insulin receptor substrate-1 (IRS1) phosphorylation. Moreover, we analysed the involvement of angiotensin type1, type2, and Mas receptors in these actions. Finally, we measured the nitric oxide (NO) production, the intracellular cGMP and the PKG-related activity in HUVECs, and the subsequent functional vasoactive effect of angiotensin (1-7) in mesenteric arteries of mice. Angiotensin II inhibits the insulin-induced Akt and eNOS phosphorylation, reducing the NO production. On the other hand, angiotensin (1-7) counteracts the inhibitory effect of angiotensin II, being able to restore the insulin-induced Akt/eNOS activation and the NO production. This effect is mediated by the Mas receptor. The inhibitory effects of angiotensin II on insulin signalling are, at least in part, mediated by an increased serine phosphorylation of IRS₁. Angiotensin (1-7) inhibits the serine phosphorylation of IRS1 induced by angiotensin II., Conclusion: In endothelial cells angiotensin (1-7) counteracts the negative effects of angiotensin II on insulin signalling and NO production. The balance between angiotensin II and angiotensin (1-7) could represent a key mechanism in the pathophysiological processes leading to endothelial dysfunction and insulin-resistance.

Aims: Essential hypertension, as well as other established cardiovascular risk factors, is associated with endothelial dysfunction. Hypertensive patients with a nondipper circadian pattern have a greater risk of cerebrovascular and cardiovascular complications in comparison with those with a dipper circadian pattern. In this study, we evaluated the association between nondipper pattern and endothelial function in patients with essential hypertension., Methods: We evaluated the forearm blood flow (FBF) response to intraarterial acetylcholine (ACh), an endothelium-dependent vasodilator, and sodium nitroprusside (SNP), an endothelium-independent vasodilator, infusions in 190 hypertensive patients stratified according to dipper and nondipper status. The FBF was measured by strain-gauge plethysmography. Effects of oxidative stress on FBF were evaluated by intraarterial infusion of vitamin C. Ambulatory BP monitorings were obtained by a validated oscillometric device (SpaceLabs 90207 Monitor Inc., Issaquah, WA, USA)., Results: Systolic and diastolic blood pressures were higher during daytime and lower during night-time in dipper subjects than in nondippers. The peak percent increase in ACh-stimulated FBF was higher in dippers than in nondippers (473% vs. 228%, P < 0.001). The FBF responses to SNP were similar in dipper and nondipper patients. The FBF response to ACh during coinfusion of vitamin C was higher in nondippers rather than in dipper hypertensives., Conclusions: Present data demonstrate that endothelium-dependent vasodilation is impaired in patients who have nondipper hypertension. The effects of vitamin C on impaired ACh-stimulated vasodilation support the hypothesis that oxidative stress contributes to endothelial dysfunction of nondipper hypertensive patients., (© 2010 Blackwell Publishing Ltd.)

Objective: Two subtypes of angiotensin II (ATII) receptor have been defined on the basis of their differential pharmacological and biochemical properties: ATII-type1 receptors (AT(1)-R) and ATII-type2 receptors (AT(2)-R). It has been hypothesized that part of the protective effects on the cardiovascular system of AT(1)-R blockers is mediated by an ATII-mediated overstimulation of AT(2)-R. We hypothesized that the inhibition of AT(1)-R has a stronger impact on insulin-induced nitric oxide (NO) production than ATII-mediated overstimulation of AT(2)-R. Therefore we studied the effect of the inhibition of AT(1)-R and AT(2)-R on ATII-mediated actions in Human Umbilical Vein Endothelial Cells (HUVECs)., Methods: We analyzed the phosphorylation state of IRS1 at Ser(616) and Ser(312) and on tyrosines after preincubation with PD123319, an inhibitor of AT(2)-R, alone and in combination with losartan, an inhibitor of AT(1)-R. In addition we measured eNOS and Akt activation through the evaluation of their phosphorylation at Ser(1177) and Ser(473) sites respectively., Results: ATII induces IRS-1 phosphorylation at Ser(312) and Ser(616) through the activation of JNK and ERK 1/2, resulting in the inhibition of the insulin-induced phosphorylation of IRS1 tyrosines, Akt and eNOS. Treatment of HUVECs with AT(1)-R inhibitor restored the insulin signaling leading to NO production, whereas AT(2)-R inhibitor did not have effects on NO production in presence of ATII., Conclusion: Our results demonstrate that in presence of AT(1)-R antagonist, the AT(2)-R blockage does not modify the effect obtained with the AT(1)-R inhibition alone. Therefore, a possible positive role of an AT(2)-R overstimulation in condition of AT(1)-R antagonism seems to be irrelevant., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: To address whether glucose tolerance status, and in particular 1-h postload plasma glucose levels, may affect diastolic function in 161 never-treated hypertensive white subjects. Impaired left ventricular relaxation, an early sign of diastolic dysfunction, represents the first manifestation of myocardial involvement in diabetic cardiomyopathy. A plasma glucose value ≥155 mg/dL for the 1-h postload plasma glucose during an oral glucose tolerance test (OGTT) is able to identify subjects with normal glucose tolerance (NGT) at high risk for type 2 diabetes and with subclinical organ damage., Research Design and Methods: Subjects underwent OGTT and standard echocardiography. Diastolic function was assessed by pulsed Doppler transmitral flow velocity and tissue Doppler imaging. Insulin sensitivity was assessed by Matsuda index., Results: Among the participants, 120 had NGT, 26 had impaired glucose tolerance (IGT), and 15 had type 2 diabetes. According to the 1-h postload plasma glucose cutoff point of 155 mg/dL, we divided NGT subjects as follows: NGT <155 mg/dL (n = 90) and NGT ≥155 mg/dL (n = 30). Those with NGT ≥155 mg/dL had higher left atrium dimensions (P < 0.0001) and isovolumetric relaxation time (IVRT) (P = 0.037) than those with NGT <155 mg/dL. By contrast, early/late transmitral flow velocity and all tissue Doppler parameters were significantly lower in those with NGT ≥155 mg/dL than in those with NGT<155 mg/dL. At multiple regression analysis, 1-h glucose was the major determinant of left atrium area, IVRT, septal e', septal e'-to-a' ratio, lateral e', and lateral e'-to-a' ratio., Conclusions: The main finding of this study is that 1-h postload plasma glucose is associated with left ventricular diastolic dysfunction. Subjects with NGT ≥155 mg/dL had significantly worse diastolic function than those with NGT<155 mg/dL.

Background and Aims: Non-alcoholic fatty liver disease, characterized by insulin resistance, has been correlated with several clinical and pathological manifestations, such as intima-media thickness. At present, no data are available regarding endothelial dysfunction, the first step in atherosclerosis, and non-alcoholic fatty liver disease. The aim of this study was to test a possible association between non-alcoholic fatty liver disease and endothelium-dependent vasodilation in a group of hypertensive patients., Methods and Results: A total of 40 never-treated uncomplicated hypertensive outpatients were enrolled. Patients underwent a complete clinical and biochemical work-up including ultrasonographic scanning to detect liver steatosis. Insulin sensitivity was estimated by using the homeostasis model assessment (HOMA) index. Endothelial function was assessed by strain-gauge plethysmography during intra-arterial infusion of increasing doses of acetylcholine and sodium nitroprusside. Endothelium-dependent vasodilation was significantly reduced in hypertensive patients with liver steatosis in comparison with those without. Statistical analysis demonstrated that the HOMA index was the strongest predictor of both endothelium-dependent vasodilation and liver steatosis. In particular, one point of HOMA accounts for 37.9% of forearm blood flow variation, and increases the risk of liver steatosis by 86.4%., Conclusion: Our data demonstrate that hypertensive patients with liver steatosis have a reduced endothelium-dependent vasodilation and highest insulin resistance. In keeping with this, it is possible to hypothesize that liver steatosis may be considered a marker of vascular damage in essential hypertension., (Copyright © 2009 Elsevier B.V. All rights reserved.)