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The recent pandemic has substantially changed the approach to the prevention of cardiovascular diseases in women. Women have been significantly impacted by the changes that occurred during the pandemic and the quarantine adopted to prevent the spread of the disease. Changes involved prevention both through the reduction of visits and preventive screening and through social and economic changes. It is necessary to adopt new cardiovascular prevention approaches focused on returning to healthy lifestyles, reducing stress and depression also using modern tools such as telemedicine, mobile phone applications and the web. These tools convey messages in a persuasive way especially in young and adult women. There is less impact of these new tools on older women towards whom it is important to adopt a more traditional approach. This review focuses on the new approach to cardiovascular prevention in women in light of the lifestyle changes recorded during the pandemic and which led to an increase in obesity examines the effects on the cardiovascular system induced by stress and depression and analyses the new high blood pressure guidelines and indications that are specific to women., (Copyright © 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: To evaluate cardiac sympathetic innervation in hypertensive patients with left ventricular (LV) hypertrophy (H) and aortic stenosis (AS) submitted to transcatheter aortic valve implantation (TAVI)., Methods and Results: Twenty-two hypertensive elders (82 ± 5 years) with severe AS and significant LVH (> 122 g·m -2 in women and > 149 g·m -2 in men) were compared with 14 patients with uncomplicated essential hypertension (HT) with similar degree of LVH and 10 controls. 123 I-metaiodobenzylguanidine (MIBG) and 99m Tc-tetrofosmin SPECT acquisitions were obtained to assess sympathetic innervation and LV perfusion. The innervation/perfusion mismatch score was taken as an indicator of cardiac sympathetic dysfunction. The imaging protocol was repeated 6 months after TAVI. Regional MIBG uptake was more heterogeneous in HT and AS patients than controls, and therefore, innervation/perfusion mismatch score was higher in both AS (9 ± 8) and HT (5 ± 2) than controls (1 ± 1, P < .001). On multivariate analysis, significant LVH was the major predictor of impaired LV sympathetic innervation (OR 19.45, 95% CI 1.87-201.92; P = .013). After TAVI, no differences in measures of LV sympathetic innervation were evident, although only a marginal LV mass reduction was observed (- 5.4 ± 2.4 g)., Conclusions: Cardiac sympathetic innervation is impaired in patients with LVH, either with AS or not, and is not impacted significantly by TAVI procedure., (© 2020. American Society of Nuclear Cardiology.)

Aim: This review represents a joint effort of the Italian Societies of Cardiology (SIC) and Diabetes (SID) to define the state of the art in a field of great clinical and scientific interest which is experiencing a moment of major cultural advancements, the cardiovascular risk management in type 2 diabetes mellitus., Data Synthesis: Consists of six chapters that examine various aspects of pathophysiology, diagnosis and therapy which in recent months have seen numerous scientific innovations and several clinical studies that require extensive sharing., Conclusions: The continuous evolution of our knowledge in this field confirms the great cultural vitality of these two cultural spheres, which requires, under the leadership of the scientific Societies, an ever greater and effective collaboration., Competing Interests: Conflicts of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

: Arterial hypertension, a widespread disease, whose prevalence increases with age, represents a major risk factor for cardiovascular events, causing damage in several organs, including the heart. In this context, echocardiography has a clear and pivotal role, being able to assess cardiac morphology and detect haemodynamic changes induced by this disease. 2018 European Society of Cardiology/European Society of Hypertension guidelines on AH identified main echo parameters such as left ventricular mass, relative wall thickness and left atrial volume, for detecting cardiac organ damage. The present review highlights the advantage of additional echocardiographic parameters such as diastolic measurement and both thoracic and abdominal aortic dimensions. An overlook on aortic valve should also be suggested to detect aortic regurgitation and stenosis, both frequent complications in hypertensive patients. In this kind of comprehensive assessment, the combination of standard and advanced echocardiography (speckle tracking echocardiography and, with a lesser extent, three-dimensional echocardiography) could be considered to improve the diagnostic accuracy, stratify prognosis and address management in arterial hypertension.

Aim: We combined cardiopulmonary exercise test (CPET) and exercise stress echocardiography (ESE) to identify early haemodynamic and metabolic alterations in patients with hypertension (HT) with and without heart failure with preserved ejection fraction (HFpEF)., Methods and Results: Fifty stable HFpEF-HT outpatients (mean age 68 ± 14 years) on optimal medical therapy, 63 well-controlled HT subjects (mean age 63 ± 11 years) and 32 age and sex-matched healthy controls (mean age 59 ± 15 years) underwent a symptom-limited graded ramp bicycle CPET-ESE. The acquisition protocol included left ventricular cardiac output, global longitudinal strain, E/e', peak oxygen consumption (VO 2 ), non-invasive arterial-venous oxygen content difference (AVO 2 diff) and lung ultrasound B-lines. There was a decline in peak VO 2 from controls (24.4 ± 3 mL/min/kg) to HFpEF-HT (15.2 ± 2 mL/min/kg), passing through HT (18.7 ± 2 mL/min/kg; P < 0.0001). HFpEF-HT displayed a lower peak cardiac output (9.8 ± 0.9 L/min) compared to HT (12.6 ± 1.0 L/min; P = 0.02) and controls (13.3 ± 1.0 L/min; P = 0.01). Peak AVO 2 diff was reduced in HFpEF-HT and HT (13.3 ± 2 and 13.5 ± 2 mL/dL vs. controls: 16.9 ± 2 mL/dL; P < 0.0001). A different left ventricular contractility was observed among groups, expressed as low-load global longitudinal strain (-16.8 ± 5% in HFpEF-HT, -18.2 ± 3% in HT, and 20.9 ± 3% in controls; P < 0.0001), and distribution of E/e' and B-lines [HFpEF-HT: 13.7 ± 3 and 16, interquartile range (IQR) 10-22; HT: 9.5 ± 2 and 8, IQR 4-10; controls: 6.2 ± 2 and 0, IQR 0-2; P < 0.0001]., Conclusions: Reduced peak VO 2 values in HT with and without HFpEF may be the result of decreased AVO 2 diff. CPET-ESE can also identify mild signs of left ventricular systo-diastolic dysfunction and pulmonary congestion, promoting advances in personalized therapy., (© 2020 European Society of Cardiology.)

Despite the availability of anti-hypertensive medications with proven efficacy and good tolerability, many hypertensive patients have blood pressure (BP) levels not at the goals set by international societies. Some of these patients are either non-adherent to the prescribed drugs or not optimally treated. However, a proportion has resistant hypertension (RH) defined as office BP above goal despite the use of ≥3 antihypertensive medications at maximally tolerated doses (one ideally being a diuretic). Diagnosis of RH based upon office measurements, however, needs confirmation through 24-h BP monitoring to exclude "white coat" RH since cardiovascular events and mortality rates follow mean ambulatory BPs. Standardized combination therapy based upon angiotensin converting enzyme inhibitors or angiotensin receptor blockers, amlodipine or other dihydropiridine calcium channel blockers and thiazide or thiazide-like diuretics has been advocated to treat RH with spironolactone as preferred fourth add-on drug. Interventional procedures such as renal denervation have been devised to treat RH and tested with insofar not positive results in series of patients not responding to medical treatment. It is unclear whether RH constitutes a specific phenotype of EH or should rather be considered a more serious form of uncontrolled hypertension. Whatever the case, its presence associates with an increased cardio- and cerebrovascular risk and deserves, therefore, particular care.

Aim: Functional analysis and measurement of left atrium are an integral part of cardiac evaluation, and they represent a key element during non-invasive analysis of diastolic function in patients with hypertension (HT) and/or heart failure with preserved ejection fraction (HFpEF). However, diastolic dysfunction remains quite elusive regarding classification, and atrial size and function are two key factors for left ventricular (LV) filling evaluation. Chronic left atrial (LA) remodelling is the final step of chronic intra-cavitary pressure overload, and it accompanies increased neurohormonal, proarrhythmic and prothrombotic activities. In this systematic review, we aim to purpose a multi-modality approach for LA geometry and function analysis, which integrates diastolic flow with LA characteristics and remodelling through application of both traditional and new diagnostic tools., Methods: The most important studies published in the literature on LA size, function and diastolic dysfunction in patients with HFpEF, HT and/or atrial fibrillation (AF) are considered and discussed., Results: In HFpEF and HT, pulsed and tissue Doppler assessments are useful tools to estimate LV filling pressure, atrio-ventricular coupling and LV relaxation but they need to be enriched with LA evaluation in terms of morphology and function. An integrated evaluation should be also applied to patients with a high arrhythmic risk, in whom eccentric LA remodelling and higher LA stiffness are associated with a greater AF risk., Conclusion: Evaluation of LA size, volume, function and structure are mandatory in the management of patients with HT, HFpEF and AF. A multi-modality approach could provide additional information, identifying subjects with more severe LA remodelling. Left atrium assessment deserves an accurate study inside the cardiac imaging approach and optimised measurement with established cut-offs need to be better recognised through multicenter studies., (© 2017 John Wiley & Sons Ltd.)

: Structural changes in left and right cardiac chambers that occur in arterial hypertension (AH) may lead to an increased risk of atrial fibrillation. Considering that AH is currently the most common cardiovascular disease in the general population, it represents a major risk factor for atrial fibrillation development. This review explores the complex relationship between atrial fibrillation and AH, starting from its pathophysiological basis. It focuses on the role of echocardiography in the management of hypertensive and atrial fibrillation patients, with emphasis on what should be evaluated about left ventricular remodeling, diastolic and systolic function, left atrial (LA) size and function and right ventricular deformation in patients with AH.

Among the risk factors associated to metabolic syndrome (MetS), hypertension shows the highest prevalence in Italy. We investigated the relationship between the newly identified serum γ-glutamyltransferase (GGT) fractions, b- s- m- f-GGT, and risk factors associated to MetS in hypertensive patients. A total of ninety-five consecutive hypertensive patients were enrolled. GGT fractions were analysed by gel-filtration chromatography, and hepatic steatosis was evaluated by ultrasound. MetS was diagnosed in 36% of patients. Considering the whole group, b- and f-GGT showed the highest positive correlation with BMI, glucose, triglycerides and insulin, and the highest negative correlation with HDL cholesterol. While both serum triglycerides and insulin were independently associated with b-GGT levels, only triglycerides were independently associated with f-GGT. The values of b-GGT activity increased with steatosis grade (g0 = 1.19; g2 = 3.29; ratio g2/g0 = 2.75, p < 0.0001 linear trend). Patients with MetS showed higher levels of b-GGT, m-GGT and f-GGT [median (25 th -75 th ) U/L: 3.19 (1.50-6.59); 0.55 (0.26-0.81); 10.3 (9.1-13.6); respectively] as compared to subjects presenting with one or two MetS criteria [1.75 (0.95-2.85), p < 0.001; 0.33 (0.19-0.60), p < 0.05; 8.8 (7.0-10.6), p < 0.001]. Our data point to a potential role for b- and f-GGT fractions in identifying MetS patients among hypertensive subjects, thus providing a minimally invasive blood-based tool for MetS diagnosis.

Speckle tracking echocardiography (STE) is an imaging technique applied to the analysis of left atrial function. STE provides a non-Doppler, angle-independent and objective quantification of left atrial myocardial deformation. Data regarding feasibility, accuracy and clinical applications of left atrial strain are rapidly gathering. This review describes the fundamental concepts of left atrial STE, illustrates its pathophysiological background and discusses its emerging role in systemic arterial hypertension.

Severe acute arterial hypertension is usually defined as 'hypertensive crisis', although 'hypertensive emergencies' or 'hypertensive urgencies', as suggested by the Joint National Committee and the European Society of Hypertension, have completely different diagnostic and therapeutic approaches.The prevalence and demographics of hypertensive emergencies and urgencies have changed over the last four decades, but hypertensive emergencies and urgencies are still associated with significant morbidity and mortality.Different scientific societies have repeatedly produced up-to-date guidelines; however, the treatment of hypertensive emergencies and urgencies is still inappropriate, with potential clinical implications.This review focuses on hypertensive emergencies and urgencies management and treatment, as suggested by recent data.

The present review is addressed to analyse the complex interplay between left ventricle and arterial tree in hypertension. The different methodological approaches to the analysis of ventricular vascular coupling in the time and frequency domain are discussed. Moreover, the role of hypertension-related changes of arterial structure and function (stiffness and wave reflection) on arterial load and how ventricular-vascular coupling modulates the process of left ventricular adaptation to hypertension are analysed.The different interplay between vascular bed and left ventricle emerges as the pathophysiological basis for the development of the multiple patterns of ventricular structural adaptation in hypertension and provides a pathway for the interpretation of systolic and diastolic functional abnormalities observed in hypertensive patients. Targeting the therapeutic approach to improve ventricular-vascular coupling may have relevant impact on reversing left ventricular hypertrophy and improving systolic and diastolic dysfunction.

Systemic hypertension is highly prevalent in stable coronary artery disease, a pervasive comorbidity complicating the diagnostic performance and interpretation of non-invasive provocative tests in chest pain patients because of the ischaemic signals generated, despite normal or near normal coronary arteries, by hearts structurally readapted by long-term exposure to raised systemic blood pressure. Additional and unresolved problems posed by arterial hypertension in patients with stable coronary artery disease regard the benefits of antihypertensive treatment due to reports of irrelevant, if not detrimental, effect of blood pressure (BP) lowering in averting coronary relapses as well as the lack of association between BP levels and incident coronary events in survivors from acute myocardial infarction. Uncertainties extend to BP-independent cardioprotective effects of antihypertensive drugs, although the efficacy of renin-angiotensin system blockers in the long-term prevention of cardiovascular events in stable coronary artery disease patients has been shown by several studies, particularly when combined with amlodipine, a dihydropiridine calcium channel blocker. In contrast, the long-term effect of beta-blockers, the antihypertensive class most used in that clinical category, is not supported by strong evidence except that generated in patients with systolic dysfunction and early postmyocardial infarction recovery periods.

History of hypertension is a frequent finding in patients with acute myocardial infarction (AMI) and its recurring association with female sex, diabetes, older age, less frequent smoking and more frequent vascular comorbidities composes a risk profile quite distinctive from the normotensive ischemic counterpart.Antecedent hypertension associates with higher rates of death and morbid events both during the early and long-term course of AMI, particularly if complicated by left ventricular dysfunction and/or congestive heart failure. Renin-angiotensin-aldosterone system blockade, through either angiotensin-converting enzyme inhibition, angiotensin II receptor blockade or aldosterone antagonism, exerts particular benefits in that high-risk hypertensive subgroup.In contrast to the negative implications carried by antecedent hypertension, higher systolic pressure at the onset of chest pain associates with lower mortality within 1 year from coronary occlusion, whereas increased blood pressure recorded after hemodynamic stabilization from the acute ischemic event bears inconsistent relationships with recurring coronary events in the long-term follow-up.Whether antihypertensive treatment in post-AMI hypertensive patients prevents ischemic relapses is uncertain. As a matter of fact, excessive diastolic pressure drops may jeopardize coronary perfusion and predispose to new acute coronary events, although the precise cause-effect mechanisms underlying this phenomenon need further evaluation.

Background: By increasing the intracellular prooxidant burden, gamma-glutamyltransferase (GGT) may accelerate atherosclerotic vascular disease. That noxious influence may be reflected by circulating enzyme levels, a correlate of cardiovascular risk factors, and a predictor of incident events. To evaluate this hypothesis, we tested the association between circulating GGT and common carotid intima-media thickness (CIMT), a surrogate index of systemic atherosclerotic involvement, in a large and well-characterized group of patients at risk of cardiovascular disease (CVD)., Patients: This study analyzed 548 patients with hypertension and/or diabetes and a widely prevalent history of CVD. Subjects with known hepatic disease and abnormal GGT values were excluded., Methods: CIMT (B-mode ultrasonography) values were the mean of four far-wall measurements at both common carotids. Metabolic syndrome (MetS) was diagnosed according to National Cholesterol Education Program-Adult Treatment Panel III criteria. Due to inherent sex-related differences in GGT levels, the data were analyzed separately in males and females in samples dichotomized by the median., Results: The age-adjusted CIMT values did not differ by GGT levels in males or females. In contrast, the carotid wall was consistently thicker in patients with a history of CVD and MetS independent of age and concurrent GGT values. In both sexes, GGT was associated with key components of the MetS such as triglycerides, fasting plasma glucose, and body mass index., Conclusion: The data collected in this mixed group of hypertensive and/or diabetic patients with widely prevalent history of CVD do not support the concept of a direct pathophysiological link between GGT levels within reference limits and atherosclerotic involvement.

Background: Consistent evidence shows an impact of systemic haemodynamic overload on the right ventricle, but its functional and structural consequences have received scarce attention for several reasons including the difficult application of conventional imaging techniques due to the complex shape and orientation of that cardiac chamber., Aims: To evaluate whether mild to moderate, uncomplicated hypertension associates with abnormal right ventricular structure and function and how those changes relate to homologous changes in the left ventricle. Data were acquired by steady-state free-precession cardiac MRI, the state of the art tool for the morphological and functional evaluation of the right ventricle., Materials and Methods: Twenty-five (12 women) uncomplicated, untreated, essential hypertensive patients were compared with 24 (13 women) sedentary normotensive controls of comparable age. Wall thickness, indexed ventricular mass, end-diastolic volumes, early peak filling rate, a correlate of diastolic relaxation, and ejection fraction were measured at both ventricles. Remodelling index, the ratio of ventricular mass to end-diastolic volume, was used as an index of concentricity., Results: Right ventricular mass index, ventricular wall thickness and remodelling index were greater in hypertensive subjects and associated with reduced peak filling rate, a pattern consistent with concentric right ventricular remodelling. In the hypertensive group, positive, highly significant biventricular correlations existed between indexed mass, early peak filling rate and ejection fraction., Conclusions: Systemic hypertension associates with concentric right ventricular remodelling and impaired diastolic function, confirming that the unstressed ventricle is not immune to the effects of systemic hypertension. Structural and functional right ventricular adaptation to systemic hypertension tends to parallel the homologous modifications induced by systemic haemodynamic overload on the left ventricle.

Tissue factor (TF), the physiologic initiator of blood coagulation, may contribute to the increased risk of thrombotic complications that characterizes arterial hypertension, as suggested by hypertensive animal models showing evidence for TF activation, and clinical studies in hypertensive patients at higher cardiovascular risk with increased circulating levels of TF and thrombogenic microparticles. Angiotensin II stimulates TF expression both in vitro and in vivo, an effect abolished by ACE or angiotensin II receptor inhibition. Moreover, renin-angiotensin system blockers, including aliskiren, a direct renin inhibitor, are able to modulate TF expression in monocytes and vascular endothelial cells activated by inflammatory cytokines. This behavior is suggestive of anti-inflammatory and anti-thrombotic properties of renin-angiotensin system blockers, and is compatible with the possibility that blocking local renin-angiotensin system activation might downregulate TF, thus reducing the risk of ischemic complications in hypertensive patients.

Aims: To analyse the relationship between increasing systemic blood pressure (BP) and right ventricular (RV) function as assessed by two-dimensional strain imaging., Methods and Results: Longitudinal peak strain and strain rate (SR) were sampled by speckle-tracking methodology at the RV free wall and interventricular septum (IVS) and RV and left ventricular (LV) structure and function were evaluated by conventional echo-Doppler sonography in 89 never-treated, non-obese subjects with office BP values varying from the optimal to mildly hypertensive range. Data were analysed by 24 h systolic BP (SBP) tertiles (cut-offs: 117 and 130 mmHg, n = 29, 30, and 30, respectively), thus partitioning subjects with optimal BP from those with high-normal and mildly increased values. RV peak systolic strain and early diastolic SR decreased in the mid-BP third without further changes in the upper tertile. IVS thickened gradedly by increasing systemic 24 h SBP; posterior wall remodelled to a lesser extent and poorly related to BP load and LV mass index did not change. RV and IVS systolic and diastolic strain indices associated inversely with increasing septal thickness. Conventional right and left indices of global ventricular function, left atrial size, and estimated systolic pulmonary pressure did not differ., Conclusion: Two-dimensional strain-assessed RV function is sensitive to increased systemic BP, even at levels below the conventional diagnostic limits for arterial hypertension. Subclinical RV systolic and diastolic abnormalities paralleled BP-driven septal remodelling, perhaps as a reflection of the crucial role played by IVS in RV function.

Background: Prehypertension predicts established hypertension. In this study, the aim was to analyze left ventricular (LV) mechanics in borderline prehypertensive (pre-HT) and hypertensive (HT) subjects through two-dimensional (2D)-strain echocardiography and then evaluate possible relations between cardiac parameters and insulin metabolism (homeostasis model assessment of insulin resistance (HOMA(IR))., Methods: Seventy-four consecutive newly diagnosed, untreated HT were divided, on the basis of their office blood pressure (BP) measurements, confirmed by ambulatory BP monitoring (ABPM), in 41 borderline pre-HT (ABPM: 122.5 +/- 6.7/76.2 +/- 5.2 mm Hg) and 33 never-treated mild HT (ABPM: 138.3 +/- 7.3/87.6 +/- 7.1 mm Hg). Thirty-three healthy normotensive (NT) controls (ABPM: 114.8 +/- 6.3/73.1 +/- 6.1 mm Hg) (P < 0.0001) were also studied (NT). All subjects performed 2D color Doppler and pulsed-wave tissue Doppler imaging (PW-TDI)., Results: Left ventricular mass (LVM) was significantly higher in pre-HT (39.2 +/- 8.7 g/m(2.7)) and in HT (43.6 +/- 8.5 g/m(2.7)) compared with NT (30.9 +/- 7.4 g/m(2.7)) (P < 0.0001). A mild LV diastolic dysfunction was found both with Doppler mitral flow velocity and PW-TDI at mitral annulus level analysis. Longitudinal 2D strain in pre-HT (-18.9% +/- 3.4) and in HT (-18.0% +/- 3.3) was significantly lower than in NT (-23.9% +/- 3.0) (P < 0.002). These LV abnormalities were associated with systolic ABPM, LVM, and HOMA(IR)., Conclusions: Early abnormalities of LV longitudinal systolic deformation were found both in pre-HT and HT, together with a mild LV diastolic dysfunction. In both groups this early cardiac systolic and diastolic dysfunction is associated to insulin resistance, systolic pressure load, and cardiac remodeling.

Purpose: To analyze the relationship between increasing systemic blood pressure (BP) and right ventricular (RV) function., Subjects and Methods: Ninety-eight never-treated, nonobese patients with BP values varying from the optimal to the mild hypertensive range. Peak early diastolic (Em) and systolic (Sm) velocities were recorded at the tricuspid and mitral annuli by tissue Doppler imaging (TDI); global RV and left ventricular (LV) structure and function by conventional echo-Doppler sonography; insulin sensitivity by homeostasis model assessment (HOMA) index. Data were analyzed by 24-h systolic BP (cut-offs 117 and 130 mmHg), thus partitioning an optimal BP from an intermediate high-normal and an upper mildly increased BP stratum., Results: Em decreased in the mid-third and decelerated further in association with reduced Sm in the upper BP tertile; both correlated negatively to septal thickness and positively to homologous TDI-derived LV indices. RV and LV indices of global ventricular function, estimated pulmonary pressure, HOMA did not differ by systemic BP., Conclusion: RV diastolic and systolic function deteriorates in response to slightly increased systemic BP. The process paralleled homologous changes at the LV side and was driven by interventricular septum remodeling, perhaps as a reflection of its role in RV function and biventricular interdependence. Insulin sensitivity seemed to play no relevant role.

Background: Elevated levels of the proinflammatory cytokine soluble CD40 ligand (sCD40L) were reported in subjects with diabetes, impaired glucose tolerance, metabolic syndrome (MS), obesity, and insulin resistance. Metabolic abnormalities might also account for increased sCD40L in subjects with essential hypertension., Methods: Several metabolic and vascular correlates of sCD40L levels have been investigated in 90 nondiabetic never-treated essential hypertensive men., Results: Median sCD40L level was 8.7 ng/ml (interquartile range: 4.9-11.7). On the basis of sCD40L, subjects were divided by tertiles (thresholds at 6.6 and 11.0 ng/ml). The three groups did not differ for age, body mass index (BMI), smokers, blood pressure (BP), prevalence of nondippers, lipids and lipoproteins, renal function, and albuminuria. Carotid intima-media thickness (IMT: 0.79 +/- 0.22, 0.83 +/- 0.29, and 0.85 +/- 0.30 mm) and percentage of subjects with wall thickening (IMT >0.9 to <1.3 mm: 23, 27, and 27%, respectively) were superimposable in the three groups. No differences were observed in high-sensitivity C-reactive protein (hs-CRP) and no correlation emerged between sCD40L and hs-CRP. An increase through sCD40L tertiles emerged for basal insulin (11.2 +/- 5.6, 14.7 +/- 7.7, and 16.8 +/- 13.5 microU/ml, P = 0.10) and fasting glucose (95 +/- 11, 103 +/- 16, and 105 +/- 14 mg/dl, P = 0.028). Consistently, along with the increase in sCD40L, a worsening in insulin sensitivity was observed, which was expressed as homeostasis model assessment for insulin sensitivity (HOMA%S: 99 +/- 52, 77 +/- 43, and 72 +/- 35, P < 0.05), composite insulin sensitivity index (ISIcomp; Matsuda index: 5.11 +/- 2.65, 3.61 +/- 1.98, and 3.28 +/- 1.87, P = 0.025), or oral glucose insulin sensitivity (OGIS) index (OGIS: 421 +/- 67, 386 +/- 90, and 362 +/- 72, P = 0.004)., Conclusions: In newly diagnosed hypertensive men, sCD40L levels are inversely related to insulin sensitivity, with no correlation with BP, other cardiovascular risk factors, or the degree of subclinical atherosclerosis.

Background: Polymorphisms within the gene for transforming growth factor (TGF)-beta-1, a pro-fibrogenic cytokine pathophysiologically involved in hypertension and hypertensive target damage, might modulate the biological activity of the encoded protein. Through that mechanism, they might contribute to microalbuminuria, a marker of subclinical renal damage and a correlate of systemic inflammation and endothelial dysfunction in hypertension, a possibility never before tested. For this reason, we assessed the association of four TGF-beta-1 polymorphic variants (C-509T, Leu(10)-->Pro, Arg(25)-->Pro, Thr(263)-->Ile) with albuminuria in uncomplicated essential hypertensive men, using (circulating active + acid-activatable latent) TGF-beta-1 levels as an indirect index of their in vivo biological activity. Because of the close pathophysiological link of TGF-beta-1 with the renin-angiotensin system, we also tested the behaviour of the angiotensin converting enzyme (ACE) deletion/insertion (D/I) polymorphism., Methods: Albuminuria (three overnight collections), office and 24-h BP, left ventricular mass index (LVMI), BMI, renal function, glucose, lipids, plasma TGF-beta-1 (n = 162, ELISA) were measured in 222 genetically unrelated, never-treated, uncomplicated Caucasian hypertensive men. ACE D/I polymorphisms were analysed by the polymerase chain reaction technique or a 5' nuclease assay with further restriction analysis when required., Results: Urine albumin levels or microalbuminuria (albuminuria > or =15 microg/min) did not differ by TGF-beta-1 genotypes, but both parameters were more frequent in ACE D/D homozygotes. Plasma TGF-beta-1 was similar across genetic backgrounds and was unrelated to albuminuria. Cardiovascular, renal, metabolic parameters were homogeneously distributed across genotypes., Conclusions: In contrast to its link with the ACE D/I genotype, microalbuminuria was independent of TGF-beta-1 polymorphism in this group of never-treated, uncomplicated essential hypertensive men.

The clinical correlates and risk profile of prediabetes (fasting plasma glucose (FPG) values in the upper normal limits but below the diabetic threshold) in hypertension, an insulin-resistant, prodiabetogenic condition, are scarcely known. For this reason, we evaluated 982 non-diabetic (FPG,<126 mg 100 ml(-1) and no antidiabetic treatment) referred hypertensive patients without a history of cardiovascular disease grouped by mild (100-109 mg 100 ml(-1)) and advanced (110-125 mg 100 ml(-1)) dysglycaemia compared with normal FPG (<100 mg 100 ml(-1)). FPG, total and high density lipoprotein (HDL) cholesterol, triglycerides and total white blood cell count were assessed by standard methodologies; 10-year predicted coronary heart disease (CHD) risk was approximated by the Framingham risk score (FRS). Metabolic syndrome (MetS) was diagnosed by standard categorical criteria using either 110 or 100 mg 100 ml(-1) as a threshold for impaired fasting glucose (IFG). FPG was above 110 in 13% and between 100 and 109 in 20% of patients. In both dysglycaemic groups, perturbed glucose homeostasis was associated with abnormally high fasting triglycerides, low HDL cholesterol, obesity, worse CHD risk profile and higher white blood cell count. MetS was highly prevalent and its distribution pattern was markedly influenced by the definitions of IFG based on different FPG cutoffs. Thus, even mildly perturbed glucose homeostasis associates with atherogenic dyslipidaemia, obesity and adverse risk profile in non-diabetic hypertensive patients. Because of its prediabetic nature, dysglycaemia should prompt measures to prevent new-onset diabetes, although the role of IFG as an independent risk factor awaits specifically designed intervention trials.

Abnormal vasoconstriction of the lesser circulation characterizes a subset of patients with essential hypertension, a possible effect of mechanisms, such as enhanced sympathetic tone, increased delivery of blood-borne vasoconstrictor substances or abnormal local release of vasoactive factors, acting on both sides of the circulation or to backward transmission of increased pressure due to stiffer left ventricles with more advanced diastolic dysfunction. Elevated systemic pressure also associates with thickening of the right ventricle, a central element of the low-pressure system. Right ventricular remodelling develops in parallel with a similar process occurring at the left side, likely as a result of ventricular interdependence under the influence of trophic factors targeting both ventricles, though other mechanisms, including increased pulmonary afterload, may also be operative. By and large independent of the extent of structural remodelling of both ventricles, systemic hypertension also conditions an impaired filling rate of the right ventricle that accompanies a similar phenomenon at the left side. Thus, quite in contrast with the common and simplistic assumption of a separate behaviour of the two ventricles, the right-sided cardiovascular system is not immune to the effect of systemic hypertension, a concept whose clinical and pathophysiological implications require further studies.

Metabolic syndrome, a cluster of metabolic abnormalities with visceral obesity and insulin resistance as its central component, is highly prevalent among hypertensive patients. Hypertension complicated by metabolic syndrome is associated with an increased risk of cardiovascular disease and new-onset Type II diabetes mellitus that further aggravates the prognostic outlook. Such a complex condition requires a multifactorial intervention including blood pressure lowering, improvement of the adverse metabolic profile and delayed onset of new diabetes. In this respect, doxazosin and other alpha-1 adrenoceptor blocking agents are of interest given their effect on the lipid profile in dyslipidemic, obese hypertensive patients, either diabetic or not. Doxazosin improves insulin sensitivity, apparently by accelerating insulin and glucose disposal through vasodilatation of skeletal muscle vascular beds. Whether long-term treatment with the drug might delay, or possibly prevent, incident Type II diabetes in hypertension complicated by metabolic syndrome is an intriguing possibility to be tested in appropriately designed clinical trials.

Background: The Glu298Asp, T786C and 4a/4b genetic polymorphisms within the endothelial nitric oxide synthase (e-NOS) gene may predispose to hypertension, ischaemic heart disease and renal damage, possibly by reducing the generation of nitric oxide (NO), a fundamental substance in renal and cardiovascular biology. That same mechanism may contribute to raise albuminuria, a correlate of endothelial dysfunction and a marker of early kidney damage and poor cardiovascular prognosis in patients with hypertension. To assess that hypothesis, we evaluated the association of albuminuria with eNOS genotypes and their interacting potential with the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism. We also tested their impact on systemic NO availability, as reflected by endothelial-mediated forearm vasodilatation., Methods: Albuminuria (three overnight collections), blood pressure, body mass index, renal function, glucose, lipids and prevalence of the metabolic syndrome were measured in 235 genetically unrelated, never-treated, uncomplicated white men with essential hypertension. Endothelial function was assessed in a patient subgroup (n = 94) by measuring plethysmographic forearm blood flow vasodilatation in response to intra-arterial acetylcholine with sodium nitroprusside as a control. Polymerase chain reaction or a 5' nuclease assay were used to characterize the eNOS and ACE I/D variants., Results: Albuminuria or microalbuminuria (albuminuria > or = 15 microg/min) showed no association with eNOS polymorphisms either per se or after accounting for the co-existing ACE I/D genetic configuration. Forearm responses to acetylcholine did not differ by eNOS polymorphisms. Cardiovascular, renal, metabolic parameters were homogeneously distributed across different genetic backgrounds., Conclusion: eNOS polymorphisms apparently play no role in promoting hypertensive renal damage, and do not influence endothelial-mediated vasodilatation in never-treated men with essential hypertension.

A D/D (deletion/deletion) polymorphism within the ACE (angiotensin 1-converting enzyme) gene increases the risk of microalbuminuria, a predictor of atherosclerotic vascular disease, in essential hypertension. It is unknown, however, whether this genetic profile is accompanied by disturbed macromolecular permeability of systemic capillary endothelium, possibly in the context of generalized endothelial dysfunction. In the present study, the ACE gene polymorphism was determined by PCR in 79 never-treated uncomplicated hypertensive men and 16 normotensive men as controls. Evaluation variables were TERalb (transcapillary escape rate of albumin; the 1-h decline rate of intravenous (125)I-albumin, a measure of integrity of systemic capillary endothelium), albuminuria and forearm vasodilation to intra-arterial acetylcholine, an index of NO (nitric oxide)-mediated vasomotion, in addition to a series of sensitive parameters of albumin permeation (blood pressure, metabolic status and smoking habits). Analyses were done by comparing D/D homozygotes with grouped I/D (insertion/deletion) and I/I (insertion/insertion) subjects. TERalb was higher in D/D hypertensives, who had higher albuminuria, more frequent microalbuminuria and comparable forearm responsiveness to intra-arterial acetylcholine. Fasting glucose and insulin, insulin sensitivity, 24-h blood pressure, smoking habits and metabolic parameters did not differ between the two groups. TERalb and urine albumin values were positively associated in the hypertensive subjects. In conclusion, ACE D/D homozygosis, independently of several confounding factors, associates with higher TERalb in men with essential hypertension. This may reflect noxious genetic influences on systemic vascular permeability, a critical control mechanism for atherogenesis in the absence of grossly impaired NO-mediated arteriolar responsiveness. The parallel behaviour of TERalb and albuminuria suggests some shared genetically mediated determinant of renal and systemic microvascular abnormalities in hypertension.

Background: A single-nucleotide polymorphism (Gly460Trp) within the alpha-adducin gene (ADD1) may influence several renal phenotypes, including salt sensitivity, susceptibility to renal failure, the renal haemodynamics and confer a worse cardiovascular risks profile. However, its relationship with microalbuminuria, a marker of early renal and cardiovascular damage and an independent predictor of morbid events in hypertension, is unknown. For this reason, we related the ADD1 genetic polymorphism to urine albumin levels and other clinical variables in essential hypertensive men. The angiotensin-converting enzyme (ACE) insertion/deletion (ID) polymorphism was also evaluated because of its interactive potential with the ADD1 genotype., Methods: Albuminuria (three overnight collections), echocardiographic left ventricular mass index, blood pressure, body mass index, renal function, glucose and lipids were measured in 238 genetically unrelated, never treated, uncomplicated Caucasian essential hypertensive men. Polymerase chain reaction or a 5' nuclease assay were used to characterize the ACE ID and ADD1 Gly460Trp variants, respectively., Results: Microalbuminuria (albuminuria >or= 15 microg/min) was more frequent in patients with the ACE DD variant, but only in those with a ADD1 Gly460Gly background. In contrast, urine albumin did not differ by ACE ID genotype in the presence of mutated ADD1 Trp alleles. ADD1 polymorphisms per se were not associated with albuminuria. Cardiovascular, renal, metabolic parameters were homogeneously distributed among different genetic backgrounds., Conclusions: ACE DD and ADD1 Gly460Gly polymorphisms may jointly influence albuminuria in hypertensive men, 460Gly homozygosis facilitating or, possibly, the 460Trp allele mitigating the noxious renal impact of the ACE DD genotype. The data highlight further the complex pathophysiological implications of microalbuminuria in hypertension.

Objective: Grading of hypertension severity by fundoscopic appearance is difficult and inaccurate. We investigated whether essential hypertension (EHT) and malignant phase hypertension (MHT) were associated with quantifiable abnormalities of the topology and architecture of the retinal circulation., Methods: The topology and architecture of the retinal microvasculature were compared in images from 20 normotensive subjects, 20 patients with EHT and 20 patients with MHT. Digitized retinal photographs were analysed by a novel multiscale image analysis method using a semi-automated program to quantify geometrical and topological properties of arteriolar and venular trees., Results: EHT was associated with an increase in the arteriolar length-to-diameter ratio (P < 0.01). There were also alterations in arteriolar topology indicative of rarefaction, including a marked reduction in the number of terminal branches in EHT (P < 0.01). These changes in the arteriolar network were exaggerated in MHT and there was also increased venular tortuosity and venular rarefaction in MHT compared with normotensive subjects., Conclusions: Hypertension is associated with marked topological alterations in the retinal vasculature, and quantification of these changes may be a useful novel approach to the assessment of target organ damage in hypertension.

Background: The study was conducted to evaluate the vascular effects of chlorthalidone, a distal tubule-acting natriuretic agent, in hypertensive patients with nondiabetic metabolic syndrome, an insulin-resistant condition characterized by endothelial dysfunction and high risk for diabetes mellitus development., Methods: Thirteen untreated hypertensive patients with Adult Treatment Panel-III-defined nondiabetic metabolic syndrome were assigned to 3-month treatment with chlorthalidone. The end-points were baseline and post-treatment evaluation of (1) forearm blood flow (strain-gauge plethysmography) responses to graded intra-arterial acetylcholine infusion to test endothelial-mediated vasomotor function, with sodium nitroprusside as a control for endothelium-independent vasodilatation; (2) minimum forearm vascular resistance, the ratio of mean blood pressure and maximal blood flow in response to 13-minute arterial occlusion, as a hemodynamic correlate of arteriolar structure; and (3) transcapillary albumin escape rate (the 1-hour decay rate of (125)I-albumin, 6-8 microC ev) as a measure of systemic capillary permeability. Additional measurements included baseline and posttreatment lipids, fasting, and postload glucose and insulin as well as the homeostasis model assessment, an index of insulin sensitivity., Results: Chlorthalidone reduced blood pressure, augmented acetylcholine-mediated vasodilatation, decreased minimum forearm resistance, and slowed the transcapillary albumin escape rate. Metabolic parameters did not change significantly except for an increase in low-density lipoprotein cholesterol levels., Conclusions: Chlorthalidone improved endothelial function, reversed abnormal arteriolar structure, and slowed albumin permeation in hypertensive patients with nondiabetic metabolic syndrome.

Background: Global risk status more than BP values per se drive nowadays treatment decisions and increasing emphasis is given to the role of lipid control in hypertension (HT). However, the distribution of circulating low density lipoproteins (LDL) levels as a function of risk profile and lipid-lowering treatment in hypertensive patients is unclear., Methods: We analysed 1196 patients (677 males, age range: 20-80 years) referred to our Hypertension Unit with treatment history and a complete dataset (systolic blood pressure levels, being on anti-hypertensive treatment or not, total and high density lipoproteins (HDL) cholesterol, smoking status, sex, age) for 10-year absolute coronary heart disease (CHD) risk stratification by National Cholesterol Education Program (NCEP)/ATP III guidelines. LDL cholesterol <25.9 mmol/L (100 mg/dL) was the target for high-risk patients (vascular diseases, diabetes, hypertension with multiple risk factors at CHD risk >20%/10 years). LDL <33.6 mmol/L (130 mg/dL) and 41.4 mmol/L (160 mg/dL) were the thresholds for intermediate (10-20%/10 years) and low (<10%/10 years) CHD risk., Results: At referral, 78% of high-risk patients were above target LDL and, overall, 56% had LDL cholesterol above the desired risk-specific thresholds. Lipid-lowering treatment was prescribed in 19% in whom LDL was actually higher than the untreated group., Conclusions: LDL cholesterol was out of target in most of a large series of referred high-risk hypertensive patients and LDL levels were largely unsatisfactory even in those undergoing lipid-lowering treatment. The data show the intensive effort still needed to implement global risk-oriented prevention strategies in hypertensive populations.

Aims: To evaluate the vascular effects of doxazosin, an alpha-1 antagonist, in hypertensive patients with metabolic syndrome in whom the drug has previously been shown to exert beneficial metabolic actions on lipids and insulin metabolism., Experimental Protocol: Twelve untreated non-diabetic hypertensive patients with National Cholesterol Education Program (NCEP) ATP-III defined metabolic syndrome were assigned to three-months of treatment with doxazosin (5.5 +/- 1.9 mg/die). Study variables were measured at baseline and after treatment. End-points: forearm blood flow (strain-gauge plethysmography) responses to graded intra-arterial acetylcholine and sodium nitroprusside infusion to test endothelium-dependent and independent vasodilatation respectively. Minimum forearm vascular resistance, the ratio of mean blood pressure and post-ischaemic maximal blood flow, as an index of arteriolar structure; transcapillary albumin escape rate (the 1-h decay rate of I-albumin, 6-8 microC ev) as a measure of systemic capillary permeability. Lipids, fasting and post-glucose insulin were measured at baseline and after treatment., Results: Doxazosin reduced blood pressure, augmented acetylcholine-mediated vasodilatation, decreased minimum resistance and, although not to a statistically significant extent, transvascular albumin leakage increased high-density lipoprotein (HDL) cholesterol while triglycerides and post-stimulative hyperinsulinemia decreased., Conclusions: Doxazosin improved endothelial-mediated vasomotor function and reversed abnormal arteriolar structure in hypertensive patients with metabolic syndrome while improving lipid profile and blunting post-glucose hyperinsulinemia.

Unlabelled: Background- Albuminuria and C-reactive protein (CRP), a marker of systemic low-grade inflammation, are frequently elevated in essential hypertension and predict cardiovascular prognosis independent of conventional risk factors. However, in spite of their potentially important links, the interrelationships between the 2 parameters have not been explored in depth in hypertensive patients., Methods and Results: Albuminuria (the mean of 3 overnight urine collections), high-sensitive CRP (hs-CRP), 24-hour blood pressure (BP), weight, lipids, poststimulative (75 g PO) plasma glucose, insulin, and insulin sensitivity by the homeostasis model assessment model were evaluated in 220 never treated, nondiabetic, uncomplicated essential hypertensive men. Albuminuria > or =15 microg/min was defined as microalbuminuria and hs-CRP values above and below median (2.3 mg/L) as high and low, respectively. Concentric left ventricular hypertrophy was diagnosed by echocardiography, and a full-blown metabolic syndrome was identified in presence of hypertension and at least 3 of following: obesity, subclinical hyperglycemia, low high-density lipoprotein (HDL) and high triglycerides. Microalbuminuria was present in 54 patients, 29 with high hs-CRP characterized by higher 24-hour systolic BP, postload glucose, body mass index, lower HDL cholesterol, more frequent metabolic syndrome, concentric LVH, and active smoking than those with either isolated microalbuminuria (n=27) or normoalbuminuria., Conclusions: Microalbuminuria accompanied by evidence of subclinical inflammation is a strong correlate of metabolic abnormalities in essential hypertension and identifies a patient subset at very high cardiovascular risk. In contrast, isolated microalbuminuria may represent a distinct pathophysiological condition characterized by a more benign profile and possibly a better prognosis.

The mitral annulus velocities of Doppler transmitral flow and pulsed-wave tissue Doppler imaging (TDI) were sampled by echocardiography for the assessment of left ventricular (LV) diastolic function in 118 never-treated essential hypertensive patients with normal systolic function and compared with those of 59 normotensive healthy subjects matched for age and sex. A selected group (n = 26) of the hypertensive study population was observed after 1 year of pharmacologic antihypertensive treatment to determine the behavior of TDI parameters in relation to eventual regression of LV hypertrophy (LVH). We found that the TDI early myocardial diastolic wave (E(m)) was significantly lower both in concentric and eccentric LVH. In addition, TDI late myocardial diastolic wave (A(m)) was significantly higher in concentric remodeling and concentric and eccentric hypertrophy. The TDI E(m)/A(m) ratio was significantly lower in all geometric remodeling subgroups. The E/A ratio Doppler transmitral flow velocity measured showed that of the 118 patients, only 32 (25%) could really be discriminated from normal, whereas individual analysis for TDI E(m)/A(m) at the mitral annulus septal level showed that of 118 patients 108 (91%) could be discriminated from normal P < .001). The LV mass was significantly less after 1 year of treatment (LVH regression), and TDI parameters showed a trend toward normalization, in particular of TDI E(m)/A(m) at the annular septal level. Pulsed-wave TDI analysis could enable not only the early assessment of whether a patient is still in an adaptive or compensatory phase before transition to irreversible damage (pathologic phase) but also the detection of precocious LV global diastolic dysfunction. With regard to this, more extensive randomized studies are needed to evaluate the effect of different pharmacologic treatments (calcium antagonists, beta-blockers, angiotensin I and II inhibitors) on TDI parameters.

Objective: Aims of this study were to: (1) demonstrate whether quantitative myocardial contrast echocardiography could detect an index of myocardial blood flow reserve through the analysis of refilling curves generated by microbubble transit into myocardium both at rest and after vasodilatation induced by dipyridamole; and (2) explore with this method myocardial microcirculatory function in two different models (ie, patients with essential hypertension and control subjects)., Methods: Two groups of strictly age-matched men were studied (case-control study): 12 patients who were adults (28.2 +/- 0.2 years) and asymptomatic with never-treated essential hypertension, a mild degree of left ventricular hypertrophy, and normal left ventricular function; and 12 control subjects. Quantitative myocardial contrast echocardiography was performed in all study participants. We used second-generation ultrasound microbubbles as echocardiography contrast agent. Real-time color-coded power modulation was performed with a phased-array system interfaced to a S3 transducer (1.3-3.6 MHz)., Results: In control subjects there was little increase in myocardial blood volume (30%) between basal and hyperemic status (P <.05); in patients with hypertension this parameter increased by 22% (P <.05). Myocardial blood velocity increased after dipyridamole by 270% in control subjects (P <.01), whereas for patients with hypertension this parameter increased only by 150% (P <.02). The index of myocardial blood flow reserve was significantly lower for patients with hypertension than in control subjects (3.3 +/- 0.3 vs 4.4 +/- 0.3, respectively; P <.01)., Conclusion: Results of our study documented that myocardial microcirculation in young adult patients with hypertension showed an early impairment in the vasodilatation capacity of the resistance arterioles under dipyridamole-induced hyperemia, as demonstrated by a reduction of myocardial blood flow reserve. Myocardial blood velocity increased after dipyridamole induction in control subjects, whereas patients with hypertension showed a significantly lesser increase. Myocardial blood flow reserve was significantly lower for patients with hypertension because of an early impairment in vasodilatation capacity of resistance arterioles under dipyridamole-induced hyperemia.

Purpose: Metabolic Syndrome as defined by ATP III criteria, a constellation of risk factors associated with insulin resistance, predisposes to premature atherosclerosis and early coronary events. Whether that negative risk profile is associated with endothelial dysfunction remains to be established., Materials and Methods: Transcapillary escape rate of albumin (TERalb), a measure of capillary permeability and integrity of systemic capillary endothelium, and forearm vasodilation to intra-arterial acetylcholine (ACH), an index of nitric oxide (NO)-mediated vasomotor dysfunction, were assessed in 24 non-diabetic, uncomplicated hypertensive men with Metabolic Syndrome according to ATP III criteria (hypertension with at least two additional traits such as high triglycerides, low HDL, abdominal obesity, impaired fasting or post-load plasma glucose). Twelve age-matched lean normal hypertensive patients with normal lipid and glucose profile and nine normotensive subjects were the controls. All patients underwent lipids determination and fasting and post-OGTT insulin assessment; HOMA-IR was the index of insulin resistance., Results: TERalb was higher in hypertensive patients with Metabolic Syndrome, without differences between hypertensive and normotensive controls. Blood pressure (BP), lipids, plasma glucose, insulin levels and HOMA-IR were unrelated to TERalb. Responses to acetylcholine were selectively attenuated in metabolic patients and, on an individual basis, related only to HDL cholesterol levels, independent of LDL cholesterol, BP, body size, triglycerides, and HOMA-IR values. No relationship existed between responses to acetylcholine and TERalb., Conclusions: Altered systemic capillary permeability characterizes insulin-resistant hypertensive patients with Metabolic Syndrome. That defect, which may promote early atherosclerosis development, coexists with blunted endothelial-mediated vasodilation, indicating a pervasive abnormality of endothelial function.

Aims: To compare the effect of amlodipine, a prototype dihydropyridine calcium-channel blocker with lercanidipine, a newer dihydropyridine compound with lipophilic properties, on dependent oedema generation and interference with skin blood flow vasomotion in hypertensive patients., Design: Single-blind, sequence-randomized, cross-over comparison of amlodipine and lercanidipine. Drugs were given at equipotent doses (10 mg daily and 20 mg daily, respectively) in 22 never-treated mild-to-moderate hypertensive men (age: 48 +/- 5 years). Each treatment was administered for 2 weeks with a 2-week intervening period to restore baseline values., Main Outcome Measures: Dependent oedema formation was quantified through leg weight changes (water displacement method). Blood pressure (the mean of at least 10 determinations) was recorded by an automated oscillometric device and skin blood flow (laser Doppler flowmetry) measured at the dorsum of the foot, both supine and with the limb passively placed 50 cm below the heart level, to evaluate the behaviour of cutaneous postural vasoconstriction, an autoregulatory mechanism that minimizes gravitational increases in capillary pressure and avoids fluid extravasation when standing., Results: Leg weight was increased by both drugs, but the increase was significantly greater during treatment with amlodipine than with lercanidipine. Blood pressure decreased to a similar extent and postural vasoconstriction was antagonized comparably during both treatments., Conclusions: The oedema-forming potential of amlodipine is greater than that induced by lercanidipine, a difference which emerged in the presence of a comparable drop in blood pressure and could not be attributed to interference with postural vasoconstrictor mechanisms.

Background: Rather unique amongst the prognostic predictors, microalbuminuria (MA, albuminuria: 15-200 microg min-1) is associated with several cardiovascular risk factors including left ventricular hypertrophy (LVH). The relationship, usually assumed to reflect an increased blood pressure (BP) load on the heart and the kidney, may, however, represent more than a haemodynamic correlate., Methods: To evaluate this possibility, we related MA to left ventricular mass index (LVMI) and other functional and structural echocardiographic parameters, office and 24-h BP, weight, lipids and smoking status in 330 never treated nondiabetic hypertensive men., Results: The risk of MA increased linearly by ascending quartiles of LVMI and was 2.3-fold higher in the presence of LVH after adjustment for age, left atrial size, mean fractional shortening. Systolic BP, either office or 24 h, and smoking status were the only additional independent predictors in multivariate logistic regression models. The BP-adjusted risk of MA was about twofold higher in patients with LVH, either concentric or eccentric, and neutral in those with concentric remodelling compared with normal geometry., Conclusions: The association between elevated LVMI and MA independent of several other potential confounders, systolic BP in particular, is consistent with the existence of cardiac albuminuric factors, possibly of hormonal nature, which are to be identified more precisely. The extent to which LVH explains the predictive power of MA for morbid events independent of the BP load remains unknown.

Objective: To evaluate the relationship of albuminuria and microalbuminuria (overnight urine albumin > or = 15 micro g/min) with insulin resistance and related metabolic abnormalities in patients with essential hypertension., Design: Cross-sectional evaluation of 271 (age range, 19-77 years) never-treated, non-diabetic, uncomplicated hypertensive men., Main Outcome Measures: Triplicate overnight urine albumin determination and homeostasis model assessment (HOMA) of insulin resistance as a surrogate measure of insulin sensitivity. Additional parameters were fasting and post-load circulating glucose and insulin, lipids, body mass index, blood pressure and echocardiographic left ventricular mass., Results: HOMA, fasting and post-challenge glucose and insulin, percentages of glucose-intolerant patients, triglycerides and high-density lipoprotein cholesterol levels did not differ across ascending urine albumin quartiles. Body mass index, blood pressure and ventricular mass were significantly greater in the upper quartiles, and the prevalence of obesity fivefold more frequent in the top as compared with the bottom urine albumin fourth. The statistical trend was unchanged after adjustment for HOMA, while accounting for systolic blood pressure and left ventricular mass by co-variance analysis abolished it. Eighty-eight patients bearing the phenotypic traits of the metabolic syndrome and a striking degree of insulin resistance and hyperinsulinemia showed urine albumin rates and prevalence of microalbuminuria comparable with the 183 patients who were not affected by that syndrome., Conclusions: Albuminuria is independent of insulin resistance and other phenotypic components of the metabolic syndrome in never-treated, non-diabetic essential hypertensive men. Microalbuminuria is more frequent in obese hypertensives but this association is explained by higher blood pressure more than insulin resistance.

The study was carried out in two different models of left ventricular hypertrophy: athlete's heart and essential arterial hypertension. Three groups of strictly age-matched males were studied: one group of 10 young adult untreated essential hypertensive patients (H), a second group of 10 athletes (A), and a group of 10 healthy individuals as controls (C). A Sonos 5500 echograph with S4 harmonic transducer was used with Levovist (ultrasonic tracer) before and after dipyridamole injection; digitised images of quantitative myocardial contrast echocardiography were collected with Power Harmonic Doppler. Angio images were analysed using dedicated PC software by placing a region-of-interest on the septum. Peak intensity, half-time (HT), the area under the curve of appearance and disappearance of microbubbles at 2/3 of PI, both in absolute and indexed values (/LVMi), were sampled. The per cent increase of PI after dipyridamole was significantly higher in C (+73%, P < 0.01) than in H (+31%) and in A (+33%) (P < 0.05). The area of appearance was significantly lower in H in comparison with C and A, both at rest and after vasodilatation. The disappearance area after dipyridamole was significantly higher in C and in A (+124%) than in H (+104%) (P < 0.05). Some hypothesis could be made: an impairment in the coronary microcirculatory function in hypertensive patients could be because of an in-crease in the arteriolar resistance. Angiogenesis and several different functional adaptations are the mechanisms that allow an optimal distribution of oxygen and of substrates to the hypertrophied myocardium of the athletes.

Background: Ultrasonic backscatter parameters were analyzed in hypertensive patients and divided into groups according to both severity of left ventricular hypertrophy (LVH) (group A: no LVH [n=52]; B: mild to moderate LVH [n=55]; and C: severe LVH [n=10]) and left ventricular geometry (normal geometry [n=44]; concentric remodeling [n=8]; concentric hypertrophy [n=25]; and eccentric hypertrophy [n=40])., Methods and Results: We studied 117 male, essential hypertensive patients and 19 normotensive, age-matched (40+/-5 years), healthy subjects who served as controls. Ambulatory and office blood pressure measurements were taken and 2-dimensional Doppler echocardiography and ultrasonic myocardial integrated backscatter (IBS) were performed. A group from the hypertensive study population (n=16) was observed after a period of pharmacological antihypertensive treatment to determine the behavior of backscatter parameters in relation to eventual regression of left ventricular mass (LVM). The cyclic variation index (CVIs) of the backscatter signal at the septum level was grouped according to each LVM level and was 29.4+/-9.3 (controls), 15+/-11 (group A), 9.5+/-10 (group B), and -1.5+/-8.6 (group C) (P<0.001). CVI septum values grouped according to left ventricular geometry were 15+/-11 (normal geometry), 12+/-7 (concentric remodeling), 7+/-11 (concentric hypertrophy), and 7.8+/-11 (eccentric hypertrophy) (P<0.01). Follow-up data demonstrate a significant reduction of LVM after therapy, as well as a significant increase in CVIs toward normal values., Conclusions: Hypertensive patients with higher LVM had the worst prognosis; in fact, those patients had the most significant CVI alterations. Regression of LVM subsequent to chronic pharmacological therapy induces a normalization of ultrasonic backscatter parameters. Ultrasonic tissue characterization (backscatter) analysis could allow early identification of patients at risk of developing complications of hypertensive cardiopathy.

A relationship may exist between endothelial-mediated vasodilation and tissue-type plasminogen activator (t-PA) release. However, the existing evidence is mainly based upon exogenous agonist administration, and needs testing under more physiological conditions. We evaluated the link between t-PA, the key fibrinolytic factor in man, and forearm reactive hyperemia, a model of endogenous endothelial-mediated vasodilation, in 13 uncomplicated hypertensive subjects and six elderly hypertensive patients with atherosclerotic peripheral vascular disease and hypercholesterolemia (i.e a group in whom post-ischemic hyperemia was probably defective because of dysfunctional endothelium). To characterize further the phenomenon, 29 additional uncomplicated hypertensive patients underwent intra-arterial drug infusions. Study variables were forearm blood flow (strain-gauge plethysmography), arterial and venous concentrations of t-PA mass concentrations, and calculated net release (forearm plasma flow x veno-arterial differences). Reactive hyperemia was induced by inflating a cuff midway between systolic and diastolic pressure for 10 min; blood and forearm blood flow were sampled before and after cuff release. Post-ischemic t-PA release increased in uncomplicated hypertensives, and did not change in hypercholesterolemic atherosclerotic patients in whom post-ischemic vasodilation was negligible. Local adenosine (n = 9), acetylcholine (n = 12) and bradykinin (n = 8) vasodilated similarly, but only bradykinin increased t-PA release. Thus, reactive hyperemia stimulates t-PA release, and that relationship is altered when endothelium is dysfunctional. Release of t-PA is independent of forearm vasodilatation, adenosine or biological products of muscarinic stimulation and may, perhaps, be related to the activity of the endogenous kininogen/kinin system., (Copyright 2003 Lippincott Williams & Wilkins)

Aims: The aims of the present study were: (a) to demonstrate whether quantitative myocardial contrast echocardiography can detect the increase in coronary flow induced by dipyridamole infusion vasodilation through the myocardial opacification due to the transit of microbubbles, both at rest and after dipyridamole induced vasodilation; (b) to explore the coronary microcirculatory function before and after dipyridamole in two different models: asymptomatic and relatively young hypertensive patients with a mild degree of left ventricular hypertrophy, and healthy controls., Methods and Results: Two groups of strictly age-matched males were studied (case-control study): 10, relatively young and asymptomatic essential hypertensive patients with a mild degree of left ventricular hypertrophy with a normal left ventricular function, and 10 healthy controls. The main findings were: the microbubbles' appearance area was significantly lower in hypertensive patients than in controls (P<0.05) because of a significantly lower time to peak. The peak intensity at rest was higher in hypertensives than in controls (P<0.05); but the per cent increase after vasodilatory stimulus was significantly higher in controls (+71% in controls vs +31% in hypertensives; P<0.05). The microbubbles' disappearance area was comparable in both groups at rest; the per cent increase of this parameter after dipyridamole was significantly higher in controls (+124%) than in hypertensives (+90%) (P<0.05). The results achieved in this study documented that the coronary microcirculation in hypertensive patients presenting a mild degree of left ventricular hypertrophy, explored with quantitative myocardial contrast echocardiography, showed a different behaviour in comparison with controls, in the vasodilatory response to dipyridamole., Conclusion: The coronary microcirculation in hypertensives showed a reduced vasodilation capacity of the resistance arterioles under dipyridamole induced vasodilatation, and a possible impairment of the endothelium dependent vasodilation. This happened despite an increase in the left ventricular mass, where the relation between capillary bed distribution and hypertrophied myocardium (rarefaction phenomenon) is not completely respected., (Copyright 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.)

It is not known if diastolic abnormalities are independent of systolic dysfunction in arterial hypertension. We studied three groups of 10 male subjects of comparable mean age (31.6 +/- 3.5 years), weight, and height: Athletes (A) (cyclists), essential hypertensive patients (H), and controls (C). Ultrasonic myocardial integrated backscatter signals (IBS) of the septum and the posterior wall were analyzed, while the systo-diastolic variation of the backscatter was considered as a cyclic variation index (CVI(ibs)). Myocardial velocities across the left ventricular major axis were sampled at septum and lateral wall levels by pulsed-wave Doppler tissue imaging (DTI). CVI(ibs) at the septum and the posterior wall were significantly lower in the hypertensive group in comparison with athletes and controls, who were comparable. Early diastolic myocardial velocity (E(m)) of the lateral wall and of the septum were significantly lower in hypertensives, while the late diastolic myocardial velocity (A(m)) was significantly higher in hypertensives in comparison with athletes. The E(m)/A(m) at the septum level was significantly lower in hypertensives in comparison with athletes and controls. Significant correlations were found between CVI and DTI parameters: CVI(ibs) and E(m)/A(m) septum (r = 0.50, P < 0.002). Furthermore, significant correlations were found between mean arterial pressure (MAP) and E(m)/A(m) septum (r = - 0.65, P < 0.001). Ultrasonic tissue characterization with the intrinsic contractility study and the evaluation of the regional diastolic function should, therefore, represent a new integrated diagnostic modality for the evaluation of left ventricular hypertrophied intramyocardial function. This study demonstrated that diastolic abnormalities of left ventricular function, in arterial hypertension, are related and progress with systolic intrinsic dysfunction.

This paper reviews the existing epidemiological and clinical evidence about the relationships of non-diabetic microalbuminuria with cardiovascular risk factors such as elevated blood pressure (BP), systolic particularly, cardiac hypertrophy, adverse metabolic status, smoking habits, elevated angiotensin II levels, endothelial dysfunction, acute and perhaps subclinical inflammation. Because of that unique property of reflecting the influence of so many clinically relevant parameters, microalbuminuria may legitimately be defined as an integrated marker of cardiovascular risk, an unique profile among the several prognostic predictors available to stratify risk in hypertensive patients. Recent cohort studies also showed associations with cardiovascular morbidity and mortality independently from conventional atherogenic factors. This behaviour, whose understanding still needs further elucidation, suggests to measure albuminuria and to screen patients at a higher absolute risk in whom preventive treatment is expected to be more beneficial than in those with a lower absolute risk.

Treatment with calcium channel blocker (CCB)s, dihydropyridines and others, is frequently complicated by dependent oedema in the absence of sodium retention or cardiac failure, a bothersome side effect of unclear aetiology. The present paper reviews our own and other work dealing with the antagonism exerted by such drugs on postural vasoconstriction, a mechanism triggered by limb venous congestion during orthostasis and controlled through a local sympathetic axo-axonic reflex and increased myogenic tone in response to changes in transmural pressure. By stabilising capillary pressure, postural vasoconstriction counteracts fluid hyperfiltration consequent to gravitational stimuli, and consistent evidence shows attenuation of this response by L-type calcium channel blockers. Interference with the postural reflex control of skin blood flow may therefore contribute to dependent oedema, although cannot entirely explain its development. Attenuation of postural vasoconstriction may amplify the fluid hyperfiltration induced by CCBs through other mechanisms, such as imbalanced intracapillary pressure or enhanced vascular permeability, which are the main factors determining net fluid filtration into the interstitial compartment.

Background: Ultrasound tissue characterization studies realized through integrated backscatter analysis with end-diastolic sampling in hypertensive cardiopathy have demonstrated that abnormalities in the left ventricular myocardial ultrasonic texture are present in extreme forms of left ventricular hypertrophy (LVH). Such abnormalities are not evident in the athlete's heart. The aim of the present study was to analyze the ultrasonic backscatter myocardial indexes both as peak end-diastolic signal intensity and as cardiac-cyclic variation in two models of LVH: hypertensive cardiopathy and athlete's heart., Methods: Three groups of 10 subjects each, all men of mean age (31.6+/-3.5 years), and of comparable weight and height, were analyzed. Group A comprised 10 cyclists of good professional level, while hypertensive patients were grouped in Group H. Both groups presented a comparable left ventricular mass (LVM). Group C included 10 healthy subjects acting as controls. The men with hypertension were selected on the basis of the results of ambulatory monitoring of the blood pressure according to ISH-World Health Organization guidelines (International Society of Hypertension). A 2D-color Doppler echocardiography with a digital echograph Sonos 5500 (Agilent Technologies, Andover, Massachusetts, USA), was carried out on all the subjects in the study for conventional analysis of the LVM and function. The ultrasonic myocardial integrated backscatter signal (IBS) was analyzed with an 'acoustic densitometry' module implemented on a AT echograph. The signal was also sampled with a region of interest (ROI) placed at interventricular septum and at posterior left ventricular wall level. The systo-diastolic variation of the backscatter was also considered, as cyclic variation index (CVIibs)., Results: According to the inclusion criteria, the LVM was comparable in groups A and H, but it was significantly higher than group C (left ventricular mass (body surface) (LVMbs)=154.5+/-18.7 (A), 146.8+/-25.5 (H), 101.4+/-12.4 (C), p < 0.001). The end-diastolic IBS did not show significant statistical differences among the three groups. The CVI(IBS) both at septum (30.5+/-5.3 (A), 13.2+/-13.1 (H), 27.2+/-7.3(C), p < 0.002) and posterior wall level (43.7+/-9.1 (A), 16.5+/-12.1 (H), 40.7+/-9.1 (C), p < 0.001) though, was significantly lower in the hypertensive patients than in both the athletes and the control group, where the results were comparable., Conclusion: A significant alteration of the myocardial CVIibs (both for septum and posterior wall) was found in the hypertensive model. This was probably the expression of an alteration in the intramural myocardial function.

Microalbuminuria (UAE) may be considered a marker of systemic vascular dysfunction, while pulse pressure (PP) is an indicator of the stiffness of vascular conduits. Both these parameters, together with left ventricular hypertrophy (LVH), are linked to cardiovascular morbidity in hypertensive patients. The aim of this study was the analysis of the possible relationships among UAE, PP, and LVH with ultrasonic myocardial textural parameters, which are altered in hypertensives patients. A group of male (n = 70) essential hypertensive patients (mean age: 58 +/- 7 yr) was analyzed with a group of age-comparable normotensive healthy subjects as controls (n = 32). Ambulatory blood pressure monitoring (ABPM) was performed with an oscillometric monitor; UAE was measured by nephelometry. A conventional 2D-Doppler echocardiography (to analyze left ventricular mass: LVM) and a quantitative analysis of the echocardiographic digitized imaging with the use of a calibrated digitization system (to calculate the septum and the posterior wall textural parameters) were performed on all subjects. The myocardial mean gray level was calculated to derive the cyclic variation index (CVI). The CVI was significantly lower in hypertensives both for the septum (- 16.3 +/- 22.8 vs 34.7 +/- 15.3%; p < 0.001) and for the posterior wall (- 15.2 +/- 23.6 vs 38.2 +/- 15.4%; p < 0.001). A significant negative correlation was found between logUAE and the CVI of the septum (r = -0.42; p < 0.001), between the PP and the CVI of the septum (r = -0.40; p < 0.002) and between the CVI and the LVM (r = -0.38; p < 0.001). Multiple regression analysis having as dependent variable the CVI at septum level showed as significantly related independent variables: PP (p < 0.01), logUAE (p < 0.001), and LVM (p < 0.05) (multiple R: 0.76, squared multiple R: 0.57; p < 0.001). It was found that LVM, logUAE, and PP are all correlated with textural parameters, and the CVI can be considered a sensitive parameter in the identification of an abnormal myocardial texture in hypertension. A high level of arterial stiffness and the presence of vascular dysfunction in essential hypertension could participate in the determination of myocardial alterations and permit the identification of patients with the worst prognosis in terms of morbidity or mortality due to cardiovascular events.

Background: The reasons why microalbuminuria (albuminuria > or = 15 microg/min), an expression of a renal microcirculatory abnormality, predicts cardiovascular disease in essential hypertension are unsettled. To test the hypothesis that microalbuminuria represents a marker of subclinical atherosclerosis, we evaluated its association with common carotid artery (CCA) intima media thickness (IMT), a measure of preclinical atherosclerosis and an independent predictor of cardiac and cerebrovascular events, in uncomplicated essential hypertensive individuals., Materials and Methods: Albuminuria, ultrasonographic CCA IMT (the mean of six bilateral far wall measurements within 1.5 cm proximally to the flow divider), brachial blood pressure (BP), smoking habits and lipids were evaluated in 136 stage 1-3 untreated essential hypertensive men free of cardiovascular disease., Results: CCA IMT did not differ between normo- (n = 99) and microalbuminuric (n = 37) patients. The correlation between CCA IMT and albuminuria was not significant, and the prevalence of microalbuminuria across IMT quartiles was not different. Microalbuminuric patients showed higher systolic BP and that parameter was the only independent correlate in a multivariate logistic regression model including also age, CCA IMT, diastolic BP, lipids and smoking habits as independent variables and microalbuminuria as the dependent one., Conclusion: This cross-sectional study in hypertensive subjects free of cardiovascular disease has shown a dissociation between microalbuminuria and CCA IMT, a surrogate measure of subclinical atherosclerosis, and a parameter linearly related to cardiovascular events. The data do not support the theory of microalbuminuria as a surrogate measure of subclinical atherosclerosis, while confirming the importance of systolic BP levels as an independent correlate of increased albuminuria in essential hypertension. Journal of Human Hypertension (2000) 14, 831-835

Background: Left ventricular hypertrophy (LVH) and the geometric shape of the left ventricle are well-established important risk factors for cardiovascular morbidity and mortality in the hypertensive population. Videodensitometry is an alternate echocardiographic approach to the study of myocardial structural and functional alterations in essential hypertension., Objectives: To analyze the behavior of the ultrasonic videodensitometric parameter for various subgroups of a hypertensive population; first according to the severity of LVH (group A, without LVH; group B, with mild-to-moderate LVH; and group C, with severe LVH) and second according to geometric adaptation of left ventricle to pressure-volume overload of essential hypertension (group NG, normal geometry; group CR, concentric remodeling; group CH, concentric hypertrophy; and group EH, eccentric hypertrophy)., Methods: For 70 male, essential hypertensive patients and 32 normotensive healthy subjects matched for age (58 +/- 7 years) and sex as controls (group N) we performed ambulatory blood pressure measurements for the evaluation of 24 h mean systolic and diastolic blood pressures, conventional two-dimensional Doppler echocardiography to evaluate left ventricular performance and left ventricular mass index, and digitization of left ventricular parasternal long-axis echocardiographic images. For regions of interest selected within the septum and the posterior wall, the mean gray levels were calculated at end-systole and end-diastole. The resulting values were used to estimate the percentage cyclic variation index (CVI)., Results: The results according to left ventricular mass index were CVI for septum group N 34.7 + 16.3%; group A - 0.18 +/- 16%, group B - 13 +/- 19%, and group C - 22 +/- 12% (P < 0.001); and CVI of posterior wall, group N 38.2 +/- 15.4%, group A -0.75 +/- 16%, group B -16 +/- 16% and group C -16 +/- 13% (P< 0.001). According to left ventricular geometry CVI for septum were group NG 0.6 +/- 24%, group CR 1.9 +/- 17%; group CH - 25.4 +/- 18%, and group EH -17.1 +/- 20% (P < 0.01). CVI of posterior wall were group NH -5.8 + 24%, group CR 6.4 +/- 23%, group CH -29 +/- 20%, group EH -20 +/- 21 (P < 0.01)., Conclusions: Our results demonstrate that subjects with high left ventricular masses and those with concentric hypertrophy, which have the worst prognostic impacts, have the most significant changes in CVI. Furthermore, videodensitometric findings are quite different even among the subgroups with mild-to-moderate left ventricular hypertrophy and eccentric hypertrophy. Therefore this videodensitometric approach could provide some useful information for better definition of cardiovascular risk in hypertension.