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Measuring blood pressure (BP) and investigating arterial hemodynamics are essential in understanding cardiovascular disease and assessing cardiovascular risk. Several methods are used to measure BP in the doctor's office, at home, or over 24 h under ambulatory conditions. Similarly, several noninvasive methods have been introduced for assessing arterial structure and function; these methods differ for the large arteries, the small ones, and the capillaries. Consequently, when studying arterial hemodynamics, the clinician is faced with a multitude of assessment methods whose technical details, advantages, and limitations are sometimes unclear. Moreover, the conditions and procedures for their optimal implementation, and/or the reference normality values for the parameters they yield are not always taken into sufficient consideration. Therefore, a practice guideline summarizing the main methods and their use in clinical practice is needed. This expert group position paper was developed by an international group of scientists after a two-day meeting during which each of the most used methods and techniques for blood pressure measurement and arterial function and structure evaluation were presented and discussed, focusing on their advantages, limitations, indications, normal values, and their pragmatic clinical application., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Document Reviewers: Luis Alcocer (Mexico), Christina Antza (Greece), Mustafa Arici (Turkey), Eduardo Barbosa (Brazil), Adel Berbari (Lebanon), Luís Bronze (Portugal), John Chalmers (Australia), Tine De Backer (Belgium), Alejandro de la Sierra (Spain), Kyriakos Dimitriadis (Greece), Dorota Drozdz (Poland), Béatrice Duly-Bouhanick (France), Brent M. Egan (USA), Serap Erdine (Turkey), Claudio Ferri (Italy), Slavomira Filipova (Slovak Republic), Anthony Heagerty (UK), Michael Hecht Olsen (Denmark), Dagmara Hering (Poland), Sang Hyun Ihm (South Korea), Uday Jadhav (India), Manolis Kallistratos (Greece), Kazuomi Kario (Japan), Vasilios Kotsis (Greece), Adi Leiba (Israel), Patricio López-Jaramillo (Colombia), Hans-Peter Marti (Norway), Terry McCormack (UK), Paolo Mulatero (Italy), Dike B. Ojji (Nigeria), Sungha Park (South Korea), Priit Pauklin (Estonia), Sabine Perl (Austria), Arman Postadzhian (Bulgaria), Aleksander Prejbisz (Poland), Venkata Ram (India), Ramiro Sanchez (Argentina), Markus Schlaich (Australia), Alta Schutte (Australia), Cristina Sierra (Spain), Sekib Sokolovic (Bosnia and Herzegovina), Jonas Spaak (Sweden), Dimitrios Terentes-Printzios (Greece), Bruno Trimarco (Italy), Thomas Unger (The Netherlands), Bert-Jan van den Born (The Netherlands), Anna Vachulova (Slovak Republic), Agostino Virdis (Italy), Jiguang Wang (China), Ulrich Wenzel (Germany), Paul Whelton (USA), Jiri Widimsky (Czech Republic), Jacek Wolf (Poland), Grégoire Wuerzner (Switzerland), Eugene Yang (USA), Yuqing Zhang (China)., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: We tested the hypothesis that chronic treatment with the direct renin inhibitor aliskiren improves vascular function in resistance and conduit arteries of type two diabetic and hypertensive patients., Method: Sixteen patients with mild essential hypertension and with a previous diagnosis of noninsulin-dependent diabetes mellitus were included in the study. Patients were then randomized to aliskiren (150 mg once daily, n = 9), or ramipril (5 mg once daily, n = 7). Each patient underwent a biopsy of the subcutaneous tissue and small arteries were dissected and mounted on a pressurized micromyograph to evaluate endothelium dependent vasorelaxation in response to acetylcholine ± N omega-nitro-L-arginine methyl ester hydrochloride in vessels precontracted with norepinephrine. Endothelial function has been quantified also in large conduit arteries by flow-mediated dilation., Results: A similar office blood pressure-lowering effect was observed with the two drugs, although changes in DBP were not statistically significant in the ramipril group. Aliskiren significantly improved endothelium-dependent relaxation in subcutaneous resistance arteries, as well as increased flow-mediated dilation in conduit arteries, whereas the effects induced by ramipril did not reach statistical significance. Only aliskiren significantly increased the expression of p1177-endothelial nitric oxide synthase in the endothelium. Both aliskiren and ramipril had a negligible effect on markers of oxidative stress., Conclusion: Aliskiren restored endothelial function and induced a more prompt peripheral vasodilation in hypertensive and diabetic patients possibly through the increased production of nitric oxide via the enhanced expression and function of the active phosphorylated form of endothelial nitric oxide synthase.

: High-normal blood pressure (BP) is associated with an increased risk of cardiovascular disease, however the cost-benefit ratio of the use of antihypertensive treatment in these patients is not yet clear. Some dietary components and natural products seems to be able to significantly lower BP without significant side effects. The aim of this position document is to highlight which of these products have the most clinically significant antihypertensive action and wheter they could be suggested to patients with high-normal BP. Among foods, beetroot juice has the most covincing evidence of antihypertensive effect. Antioxidant-rich beverages (teas, coffee) could be considered. Among nutrients, magnesium, potassium and vitamin C supplements could improve BP. Among nonnutrient-nutraceuticals, soy isoflavones could be suggested in perimenopausal women, resveratrol in insulin-resistant patients, melatonin in study participants with night hypertension. In any case, the nutracutical approach has never to substitute the drug treatment, when needed.

: Document reviewers: Guy De Backer (ESC Review Co-ordinator) (Belgium), Anthony M. Heagerty (ESH Review Co-ordinator) (UK), Stefan Agewall (Norway), Murielle Bochud (Switzerland), Claudio Borghi (Italy), Pierre Boutouyrie (France), Jana Brguljan (Slovenia), Héctor Bueno (Spain), Enrico G. Caiani (Italy), Bo Carlberg (Sweden), Neil Chapman (UK), Renata Cifkova (Czech Republic), John G. F. Cleland (UK), Jean-Philippe Collet (France), Ioan Mircea Coman (Romania), Peter W. de Leeuw (The Netherlands), Victoria Delgado (The Netherlands), Paul Dendale (Belgium), Hans-Christoph Diener (Germany), Maria Dorobantu (Romania), Robert Fagard (Belgium), Csaba Farsang (Hungary), Marc Ferrini (France), Ian M. Graham (Ireland), Guido Grassi (Italy), Hermann Haller (Germany), F. D. Richard Hobbs (UK), Bojan Jelakovic (Croatia), Catriona Jennings (UK), Hugo A. Katus (Germany), Abraham A. Kroon (The Netherlands), Christophe Leclercq (France), Dragan Lovic (Serbia), Empar Lurbe (Spain), Athanasios J. Manolis (Greece), Theresa A. McDonagh (UK), Franz Messerli (Switzerland), Maria Lorenza Muiesan (Italy), Uwe Nixdorff (Germany), Michael Hecht Olsen (Denmark), Gianfranco Parati (Italy), Joep Perk (Sweden), Massimo Francesco Piepoli (Italy), Jorge Polonia (Portugal), Piotr Ponikowski (Poland), Dimitrios J. Richter (Greece), Stefano F. Rimoldi (Switzerland), Marco Roffi (Switzerland), Naveed Sattar (UK), Petar M. Seferovic (Serbia), Iain A. Simpson (UK), Miguel Sousa-Uva (Portugal), Alice V. Stanton (Ireland), Philippe van de Borne (Belgium), Panos Vardas (Greece), Massimo Volpe (Italy), Sven Wassmann (Germany), Stephan Windecker (Switzerland), Jose Luis Zamorano (Spain).The disclosure forms of all experts involved in the development of these Guidelines are available on the ESC website www.escardio.org/guidelines.

Background: The evaluation of the morphological characteristics of small resistance arteries in humans is challenging. The gold standard method is generally considered to be the measurement by wire or pressure micromyography of the media-to-lumen ratio of subcutaneous small vessels obtained by local biopsies. However, noninvasive techniques for the evaluation of retinal arterioles were recently proposed; in particular, two approaches, scanning laser Doppler flowmetry (SLDF) and adaptive optics, seem to provide useful information; both of them provide an estimation of the wall-to-lumen ratio (WLR) of retinal arterioles. Moreover, a noninvasive measurement of basal and total capillary density may be obtained by videomicroscopy/capillaroscopy. No direct comparison of these three noninvasive techniques in the same population was previously performed; in particular, adaptive optics was never validated against micromyography., Methods: In the current study, we enrolled 41 controls and patients: 12 normotensive lean controls, 12 essential hypertensive lean patients, nine normotensive obese patients and eight hypertensive obese patients undergoing elective surgery. All patients underwent a biopsy of subcutaneous fat during surgery. Subcutaneous small resistance artery structure was assessed by wire micromyography and the media-to-lumen ratio was calculated. WLR of retinal arterioles was obtained by SLDF and adaptive optics. Functional (basal) and structural (total) microvascular density was evaluated by capillaroscopy before and after venous congestion., Results and Conclusion: Our data suggest that adaptive optics has a substantial advantage over SLDF in terms of evaluation of microvascular morphology, as WLR measured with adaptive optics is more closely correlated with the M/L of subcutaneous small arteries (r = 0.84, P < 0.001 vs. r = 0.52, P < 0.05, slopes of the relations: P < 0.01 adaptive optics vs. SLDF). In addition, the reproducibility of the evaluation of the WLR with adaptive optics is far better, as compared with SLDF, as intraobserver and interobserver variation coefficients are clearly smaller. This may be important in terms of clinical evaluation of microvascular morphology in a clinical setting, as micromyography has substantial limitations in its clinical application due to the local invasiveness of the procedure.

Backgroud and Purpose: Wall-to-lumen ratio of retinal arterioles (W/L ratio) might serve as an in-vivo parameter of microvascular damage. No study has investigated the relationship between carotid stiffness and W/L ratio of retinal arteries. Therefore, the aim of the current study was to assess the correlation between local carotid stiffness, as assessed by echotracking technique, and W/L ratio of retinal arterioles, as assessed by noninvasive flowmetry in normotensive patients and in patients with primary hypertension., Methods: Two hundred and twenty-seven patients underwent renal arteries W/L ratio and local carotid-pulse wave velocity (carotid PWV) measurement. One hundred and fifteen patients had a diagnosis of primary hypertension, whereas 112 were normotensive patients., Results: W/L ratio and carotid PWV were both related with clinic SBP (r = 0.17, P < 0.05; r = 0.50, P < 0.001), clinic pulse pressure (r = 0.22, P < 0.001; r = 0.55, P < 0.001), carotid SBP (r = 0.18, P < 0.05; r = 0.51, P < 0.001) and carotid pulse pressure (r = 0.24, P < 0.001; r = 0.56, P < 0.001). W/L ratio was correlated with carotid PWV (r = 0.18, P < 0.005). At multivariate analysis, carotid PWV remained independently associated with W/L ratio., Conclusion: In hypertensive and normotensive patients, carotid stiffness is significantly correlated with W/L ratio of retinal arteries, independently of possible confounders.

: European Society of Hypertension/European Society of Cardiology guidelines recommend calculation of estimated glomerular filtration rate and evaluation of urinary albumin excretion rate as routine tests in the initial evaluation and during the follow-up of all hypertensive patients. However, from a clinical point of view, renal ultrasound - a noninvasive, readily available and cheap imaging modality - could contribute to the better evaluation of a hypertensive patient by identifying common causes of secondary hypertension (HTN) originating from the kidney and more recently by detecting renal injury in severe or long-standing essential HTN by measuring renal resistive indexes. The purpose of this review is to summarize the actual evidence which could support a larger use of renal ultrasound in the work-up of patients with newly diagnosed HTN.

: Arterial hypertension accounts for the largest amount of attributable cardiovascular mortality worldwide, and risk stratification in hypertensive patients is of crucial importance to manage treatment and prevent adverse events. Asymptomatic involvement of different organs in patients affected by hypertension represents an independent determinant of cardiovascular risk, and the identification of target organ damage is recommended to further reclassify patients' risk. Noninvasive cardiovascular imaging is progressively being used and continues to provide new technological opportunities to target organ damage evaluation at early stage. The aim of this article is to provide the community of cardiology with an update on appropriate and justified use of noninvasive imaging tests in the growing population of hypertensive patients.

: Antihypertensive, lipid lowering, antidiabetic and antiplatelet treatments all substantially reduce the risk of cardiovascular morbid and fatal events. In real life, however, effective implementation of these treatments is rare, and thus their contribution to cardiovascular prevention is much less than it could be, based on research data. This article reviews the pros and cons of cardiovascular prevention by the polypill approach. It is argued that the high prevalence of individuals with a multifactorial risk profile provides a strong rationale for a therapeutic strategy based on the combination in a single tablet of drugs against different risk factors. It is further argued that other important favourable arguments exist. First, in real-life adherence to all above treatments is very low, leading to a major increase in the incidence and risk of cardiovascular outcomes. Second, although a large number of factors are involved, adherence is adversely affected by the complexity of the prescribed treatment regimen and can be considerably improved by treatment simplification. Third, recent studies in patients with a history of manifest cardiovascular disease have documented that different cardiovascular drugs can be combined in a single tablet with no loss of their individual efficacy or unexpected inconveniences and this does favour adherence to treatment and multiple risk factor control, supporting use of the polypill in secondary cardiovascular prevention. It is finally also mentioned, however, that the polypill may have some drawbacks and that at present no evidence is available that this approach reduces cardiovascular outcome to a greater degree than standard treatment strategies. Trials are under way to provide an answer to this question and thus allow the therapeutic value of this approach to be known.

Background: The ocular fundus examination is infrequently and poorly performed in the emergency department (ED) clinical settings, placing patients at risk for missed diagnosis of hypertensive emergencies. The aim of this study was to investigate the feasibility of the ocular fundus photography with a smartphone small optical device in an ED setting and to compare it with a traditional ocular fundus examination., Methods: The study included 52 consecutive patients (mean age 69 ± 16 years, 50% women) presenting to a hospital ED with an acute increase in blood pressure (SBP > 180 and/or DBP > 100 mmHg). When admitted to the ED all patients had mydriatic ocular fundus examination obtained by a medical student (observer 1) using both a traditional ophthalmoscope and a commercially available ocular fundus smartphone device (D-Eye, Si14 S.p.A., Padova, Italy), to assess the presence of grade III and IV Keith Wegener retinopathy. All ocular fundus images and videos recorded with the D-Eye system were analyzed by two independent expert (ophthalmologist - observer 2) and inexpert (medical student - observer 1) observers. A quantitative score of hemorrages, exudates and/or papillary edema was used (0 absent, 1 early, 2 moderate, 3 severe and 4 very severe). The Cohen K coefficient was used to assess the interobserver concordance index., Results: The mean duration of ocular fundus examination was 130 ± 39 and 74 ± 31 s for traditional ophthalmoscopy and for smartphone D-Eye, respectively. No relevant abnormalities of the ocular fundus were detected by traditional ophthalmoscopy, performed by observer 1, whereas a significant number of abnormal ocular fundus findings were detected by the use of the D-Eye device in 17 and 19 patients by observer 1 and observer 2, respectively. The K coefficient value ranged from 0.66 to 0.77 (good concordance) for the assessment of hemorrhages and exudates, and from 0.89 to 0.90 (optimal concordance) for the evaluation of presence and severity of papilledema., Conclusion: Our results show that a new small smartphone device (D-Eye) may be feasible in an ED setting for the fundoscopic examination, detecting a significant number of abnormal ocular fundus. The reliability of relevant ocular fundus abnormalities seems to be superior in respect to traditional retinal fundoscopy.

Remodelling of subcutaneous small resistance arteries, as indicated by an increased media-to-lumen ratio, is frequently present in hypertensive, obese, or diabetic patients. The increased media-to-lumen ratio may impair organ flow reserve. This may be important in the maintenance and, probably, also in the progressive worsening of hypertensive disease. The presence of structural alterations represents a prognostically relevant factor, in terms of development of target organ damage or cardiovascular events, thus allowing us a prediction of complications in hypertension. In fact, media-to-lumen ratio of small arteries at baseline, and possibly their changes during treatment may have a strong prognostic significance. However, new, non-invasive techniques are needed before suggesting extensive application of the evaluation of remodelling of small arteries for the cardiovascular risk stratification in hypertensive patients. Some new techniques for the evaluation of microvascular morphology in the retina, currently under clinical investigation, seem to represent a promising and interesting future perspective. The evaluation of microvascular structure is progressively moving from bench to bedside, and it could represent, in the near future, an evaluation to be performed in all hypertensive patients, to obtain a better stratification of cardiovascular risk, and, possibly, it might be considered as an intermediate endpoint in the evaluation of the effects of antihypertensive therapy, provided that a demonstration of a prognostic value of non-invasive measures of microvascular structure is made available.

Aim: Our aim was to investigate the prevalence and the prognostic significance for fatal and nonfatal cerebrovascular and cardiovascular events of different ECG criteria for left ventricular hypertrophy (LVH) in normal weight, overweight and obese patients in an adult Italian population., Methods: A total of 18 330 adults (mean age 54 ± 11 years, 55% women, 53% hypertensive patients) were analyzed from the Moli-sani cohort. Obesity was defined using the ATPIII criteria. ECG-LVH was defined according to 2013 ESC-ESH guidelines., Results: The age and sex adjusted prevalence of ECG-LVH did not differ from normal weight patients to class 1-3 obesity patients, when Cornell-voltage criterion was used. In overweight and obese patients, as compared with normal weight patients, a progressively lower prevalence of ECG-LVH was observed when the Sokolow-Lyon index was used, whereas a higher prevalence was shown by using the aVL R-wave voltage (>11 and >5.7 mm) and the Cornell-voltage-QRS duration product. The incidence of cardiovascular events was significantly greater in patients with ECG LVH diagnosis by the Cornell voltage [hazard ratio 1.89, 95% confidence interval (CI) 1.05-3.39] and the Cornell product (hazard ratio 1.87, 95% CI 1.31-2.67). After adjusting for different confounders (age, sex, cigarette, hypertension, hypercholesterolemia, diabetes, income, education, occupational class and physical activity) and for BMI categories, only the Cornell product remained significantly associated with a higher incidence of cardiovascular events (hazard ratio 1.66; 95% CI 1.16-2.38). The predictive significance of different LVH criteria was assessed across BMI categories; after adjusting for confounders, no LVH criteria were significantly associated with an increased risk of cardiovascular events in obese patients; Cornell-product LVH remained an independent predictor of events in normal weight and overweight individuals (hazard ratio 2.63; 95% CI 1.10-6.28 and hazard ratio 2.72; 95% CI 1.52-4.25, respectively)., Conclusion: Our results confirm that ECG LVH prevalence may differ according to the criteria used across BMI categories in a low cardiovascular risk cohort. The use of different LVH criteria according to BMI categories may improve cardiovascular risk stratification in a general population independently of several confounding factors.

Increasing prevalence of hypertension (HTN) in children and adolescents has become a significant public health issue driving a considerable amount of research. Aspects discussed in this document include advances in the definition of HTN in 16 year or older, clinical significance of isolated systolic HTN in youth, the importance of out of office and central blood pressure measurement, new risk factors for HTN, methods to assess vascular phenotypes, clustering of cardiovascular risk factors and treatment strategies among others. The recommendations of the present document synthesize a considerable amount of scientific data and clinical experience and represent the best clinical wisdom upon which physicians, nurses and families should base their decisions. In addition, as they call attention to the burden of HTN in children and adolescents, and its contribution to the current epidemic of cardiovascular disease, these guidelines should encourage public policy makers to develop a global effort to improve identification and treatment of high blood pressure among children and adolescents.

Background and Objectives: The SBP values to be achieved by antihypertensive therapy in order to maximize reduction of cardiovascular outcomes are unknown; neither is it clear whether in patients with a previous cardiovascular event, the optimal values are lower than in the low-to-moderate risk hypertensive patients, or a more cautious blood pressure (BP) reduction should be obtained. Because of the uncertainty whether 'the lower the better' or the 'J-curve' hypothesis is correct, the European Society of Hypertension and the Chinese Hypertension League have promoted a randomized trial comparing antihypertensive treatment strategies aiming at three different SBP targets in hypertensive patients with a recent stroke or transient ischaemic attack. As the optimal level of low-density lipoprotein cholesterol (LDL-C) level is also unknown in these patients, LDL-C-lowering has been included in the design., Protocol Design: The European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment trial is a prospective multinational, randomized trial with a 3 × 2 factorial design comparing: three different SBP targets (1, <145-135; 2, <135-125; 3, <125  mmHg); two different LDL-C targets (target A, 2.8-1.8; target B, <1.8  mmol/l). The trial is to be conducted on 7500 patients aged at least 65 years (2500 in Europe, 5000 in China) with hypertension and a stroke or transient ischaemic attack 1-6 months before randomization. Antihypertensive and statin treatments will be initiated or modified using suitable registered agents chosen by the investigators, in order to maintain patients within the randomized SBP and LDL-C windows. All patients will be followed up every 3 months for BP and every 6 months for LDL-C. Ambulatory BP will be measured yearly., Outcomes: Primary outcome is time to stroke (fatal and non-fatal). Important secondary outcomes are: time to first major cardiovascular event; cognitive decline (Montreal Cognitive Assessment) and dementia. All major outcomes will be adjudicated by committees blind to randomized allocation. A Data and Safety Monitoring Board has open access to data and can recommend trial interruption for safety., Sample Size Calculation: It has been calculated that 925 patients would reach the primary outcome after a mean 4-year follow-up, and this should provide at least 80% power to detect a 25% stroke difference between SBP targets and a 20% difference between LDL-C targets.

Background and Objectives: It is well established by a large number of randomized controlled trials that lowering blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) by drugs are powerful means to reduce stroke incidence, but the optimal BP and LDL-C levels to be achieved are largely uncertain. Concerning BP targets, two hypotheses are being confronted: first, the lower the BP, the better the treatment outcome, and second, the hypothesis that too low BP values are accompanied by a lower benefit and even higher risk. It is also unknown whether BP lowering and LDL-C lowering have additive beneficial effects for the primary and secondary prevention of stroke, and whether these treatments can prevent cognitive decline after stroke., Results: A review of existing data from randomized controlled trials confirms that solid evidence on optimal BP and LDL-C targets is missing, possible interactions between BP and LDL-C lowering treatments have never been directly investigated, and evidence in favour of a beneficial effect of BP or LDL-C lowering on cognitive decline is, at best, very weak., Conclusion: A new, large randomized controlled trial is needed to determine the optimal level of BP and LDL-C for the prevention of recurrent stroke and cognitive decline.

Aims: It has been demonstrated previously that inflammation in perivascular adipose tissue (PVAT) may be implicated in vascular dysfunction. The aim of this study was to investigate the functional responses of small mesenteric arteries in a hyperphagic animal model of obesity after chronic treatment with melatonin, an endogenous hormone with antioxidant and vasculoprotective properties., Methods and Results: Ten obese mice (ob/ob) and 10 control lean mice (CLM) were treated with melatonin 100  mg/kg per day in the drinking water for 8 weeks. Mesenteric small resistance arteries were dissected and mounted on a wire myograph and a concentration-response to norepinephrine was evaluated in vessels with intact PVAT and after PVAT was removed and in the presence of iberiotoxin, a selective blocker of BKCA channels as well as under conditions of induced hypoxia in vitro. The presence of PVAT reduced the contractile response to norepinephrine in both ob/ob and CLM; however, the effect was significantly reduced in ob/ob. The anticontractile effect of PVAT completely disappeared with iberiotoxin preincubation. After melatonin treatment, inflammation was significantly ameliorated, and the contractile response in ob/ob and CLM was significantly reduced when PVAT was removed. Anticontractile effect of PVAT that is lost in obesity can be rescued using melatonin. A reduced expression of adiponectin and adiponectin receptor was observed in perivascular fat of ob/ob, whereas significant increase was observed in ob/ob treated with melatonin., Conclusion: Melatonin seems to exert a protective effect on arteries from both ob/ob and CLM, counteracting the adverse effect of hypoxia and iberiotoxin.

Background: Because of their lower cost, healthcare systems recommend physicians to prefer generic products, rather than brand-name medicaments. There is then considerable interest and debate concerning safety and effectiveness of generic products. Few studies have compared patients treated with brand-name and generic drugs for adherence to treatment, with somewhat inconsistent results. The primary objective of this study was to compare the risk of discontinuing antihypertensive drug therapy in patients treated with generic or brand-name agents., Methods: The 101,618 beneficiaries of the Healthcare system of Lombardy, Italy, aged 18 years or older who were newly treated on monotherapy with antihypertensive generic or brand-name drugs during 2008, were followed until the earliest date among those of the occurrence of treatment discontinuation to whatever antihypertensive drug therapy (outcome), or censoring (death, emigration, 12 months after treatment initiation). Hazard ratios of discontinuation associated with starting on generic or brand-name products (intention-to-treat analysis), and incidence rate ratio of discontinuation during periods on generic and brand-name products (as-treated analysis) were respectively estimated from a cohort and self-controlled case series analyses., Results: Patients who started on generics did not experience a different risk of discontinuation compared with those starting on brand-name agents (hazard ratio: 1.00; 95% confidence interval 0.98-1.02). Discontinuation did not occur with different rates during periods covered by generics or brand-name agents (incidence rate ratio: 1.01; 95% confidence interval 0.96-1.11) within the same individuals. A number of sensitivity and subgroup analyses confirmed the robustness of these findings., Conclusion: Generic products are not responsible for the high rate of discontinuation from antihypertensive drug therapy. Assuming therapeutic equivalence, clinical implication is of prescribing generic drug therapies.

Introduction: The aim of the study was to assess the age-specific, sex-specific, and region-specific average sodium and potassium intake and its association with anthropometric characteristics in a sample of the Italian adult hypertensive population., Methods: A total of 1232 hypertensive patients were recruited consecutively by 47 centers recognized by the Italian Society of Hypertension. The enrolled participants were on stable antihypertensive treatment. Anthropometric indices, blood pressure, 24-h urinary sodium, and potassium excretion were measured and used as proxy for the average daily sodium and potassium intake., Results: The average sodium intake was 172  mmol (or 10.1  g of salt/day) among men and 138 (or 8.1) among women, with no difference among geographical areas. Over 90% of men and 81% of women had a consumption higher than the recommended standard dietary intake of 5  g/day. The average potassium intake was 63 and 56  mmol, respectively in men and women, again without geographical differences, nearly 92% of men and 95% of women having an intake lower than the recommended intake (100  mmol/day or 3.9  g/day). There was a significant trend to a gradual decrease in sodium intake with age in both sexes (P <0.001). There was also a direct association between BMI and sodium intake in both sexes, this association being independent of age (P < 0.001)., Conclusion: In this national sample of the Italian hypertensive population, dietary sodium intake was largely higher and potassium intake much lower than the recommended intakes, and this was true for all geographical areas. Overweight and obese hypertensive patients had particularly high sodium intakes.

Objectives: Renal dysfunction is associated with an increased risk of cardiovascular events in hypertensive patients. Chronic kidney disease (CKD) and left ventricular hypertrophy (LVH) are both independent prognostic factors for cardiovascular events. The relation between changes in renal function and/or cardiac structure with subsequent prognosis has not yet been definitely assessed, and the aim of this study was to evaluate the relationships between renal and cardiac target-organ damage not only at baseline but also during treatment, and their influence on cardiovascular prognosis in hypertensive patients., Methods: Among 436 uncomplicated hypertensive individuals, 246 with a baseline and follow-up (last examination 68 ± 34 months apart) echocardiogram and creatinine measurements were followed for an additional 55 ± 29 months. All patients received treatment by their family doctor. After the last follow-up echocardiogram, a first major cardiovascular event occurred in 54 patients., Results: By multivariate Cox regression analysis, persistence and development of LVH from baseline to follow-up [adjusted hazard ratio 2.36, 95% confidence interval (CI) 1.03-3.68, P = 0.041] and persistence/development of CKD (estimated glomerular filtration rate according to the Modification of Diet in Renal Disease formula <60 ml/min) (adjusted hazard ratio 1.94, 95% CI 1.12-3.87, P = 0.021) from baseline to follow-up were identified as independent predictors of cardiovascular events., Conclusion: This study indicates that in hypertensive patients free of cardiovascular disease, both persistence or development of a reduced renal function and of LVH represent independent prognostic factors of cardiovascular events.

Although it is recognized that the cause of hypertension can be various, once blood pressure has become established structural changes emerge in the systemic vasculature. In medium- and large-sized vessels, as in the left ventricle, there is clear histological evidence of hypertrophy of the medial smooth muscle layers but, downstream in small arteries, which modulate vascular resistance, other changes occur. In essential hypertension, the smooth muscle cells of small vessels are restructured around a smaller lumen, but there is no evidence of hypertrophy or hyperplasia of the vascular wall. In secondary forms of hypertension, which tend to be representative of severer forms of the disease, hypertrophic remodelling is observed. Similarly, in non-insulin-dependent diabetes mellitus, irrespective of whether blood pressure accompanies this disorder or not, hypertrophy is also seen. The presence of architectural alterations in the vascular wall of small arteries may have a strong prognostic significance in patients, and this may be over and above all other known cardiovascular risk factors. Although it is yet to be established whether regression of such changes should be a goal of effective antihypertensive therapy, there is a body of evidence emerging indicating that different classes of antihypertensive drug have a varied effect on reversing vascular structure both in humans and animal models of genetic and experimental hypertension. However, at present, there are no data available concerning the prognostic impact of regressing vascular structural alterations in hypertension, and this must be an urgent research priority.

Background: The prognostic role of endothelial dysfunction, as evaluated by flow-mediated vasodilatation of the brachial artery, has been demonstrated in patients at very high risk. We aimed to investigate whether flow-mediated vasodilatation predicts cardiovascular events in uncomplicated hypertensive patients., Methods and Results: A total of 172 prospectively identified uncomplicated hypertensive patients (age 56 +/- 8 years, 41% women, 48 with diabetes mellitus type 2) were studied. At baseline all patients were untreated and underwent baseline standard laboratory examination. A standard echocardiogram was performed for the evaluation of left ventricular anatomy and function and patients with systolic dysfunction or left ventricular wall motion abnormalities were excluded. Endothelial function was measured as flow-mediated vasodilatation of the brachial artery using high-resolution ultrasound. Patients were followed for 95 +/- 37 months (range 2-136 months). A first nonfatal or fatal cardiovascular event occurred in 32 patients. The incidence of cardiovascular events was 1.4 and 3.1 per 100 patient-years in patients with a flow-mediated vasodilatation below and above the median value (4.7%), respectively (P < 0.005 by the log-rank test). In Cox analysis, controlling for age, sex, glycemia, cholesterol, smoking, BMI, systolic and diastolic blood pressure at baseline and left ventricular mass index, a low flow-mediated vasodilatation conferred an increased risk of cardiovascular events (odds ratio 2.67, 95% confidence interval 1.17 to 6.1, P = 0.02)., Conclusion: The presence of endothelial dysfunction, as evaluated by flow-mediated vasodilatation of the brachial artery, identifies hypertensive patients at increased risk of nonfatal and fatal cardiovascular events.

Objective: Spontaneously hypertensive rats are an example of an animal model of genetic hypertension with insulin resistance. The aim of this study was to investigate insulin signaling in the heart and in the skeletal muscle of spontaneously hypertensive rats, as well as to evaluate the effects of renin-angiotensin system blockade., Design and Methods: We investigated eight untreated spontaneously hypertensive rats of 12 weeks of age and eight age-matched normotensive Wistar-Kyoto controls. In addition, eight spontaneously hypertensive rats were treated for 8 weeks with the angiotensin receptor blocker olmesartan, and eight spontaneously hypertensive rats with the angiotensin-converting enzyme inhibitor enalapril. The heart and a skeletal muscle (quadriceps femoris) were promptly dissected and frozen. Insulin signaling was evaluated by Western blot analysis of involved proteins; in addition, microvessel density was indirectly evaluated by immunohistochemistry., Results: Blood pressure values were normalized by both olmesartan and enalapril. In the heart, no statistically significant difference in the expression of proteins involved in insulin signaling was observed between untreated spontaneously hypertensive rats and Wistar-Kyoto controls. On the contrary, in the skeletal muscle of untreated spontaneously hypertensive rats, we noted a significant reduction of insulin receptors, of insulin-receptor substrate-1, and of phosphorylated-mammalian target of rapamycin. The treatment with olmesartan normalized insulin signaling, including expression of glucose transporter-4, whereas the treatment with enalapril was ineffective for the insulin receptor and less effective than olmesartan on the insulin-receptor substrate-1, phosphorylated-mammalian target of rapamycin and glucose transporter-4. There was a significant reduction in microvessel density in the skeletal muscle of spontaneously hypertensive rats compared with Wistar-Kyoto controls, and this was completely prevented by both olmesartan and enalapril., Conclusion: These results suggest that changes in insulin signaling occur in the skeletal muscle but not in the heart of untreated spontaneously hypertensive rats. In the skeletal muscle, insulin signaling was restored by olmesartan, whereas enalapril was less effective. Effective antihypertensive treatment with olmesartan or enalapril was associated with prevention of microvascular rarefaction.

Background: Data on the performance of the tests used to confirm the diagnosis of primary aldosteronism (PA) are limited., Objective: To prospectively investigate the accuracy of the saline infusion test (SIT)., Methods: Three hundred and seventeen (26.9%) out of 1125 patients screened in the PAPY study underwent measurement of plasma aldosterone, cortisol and renin activity after infusion of 2 l of isotonic saline intravenously over 4 h. They comprised patients with a baseline aldosterone/renin ratio (ARR) > 40 and one every four patients not fulfilling such criterion. The area under the receiver-operator characteristic curves (AUC) of aldosterone values after SIT was used as a measure of accuracy for diagnosing PA, aldosterone-producing adenoma (APA) or idiopathic hyperaldosteronism (IHA)., Results: One hundred and twenty (37.9%) patients had PA that was due to an APA in 46 (38.3%) and to IHA in 74 (61.7%). No untoward effect occurred with the SIT. The AUC (0.811 +/- 0.026, 0.878 +/- 0.040 and 0.784 +/- 0.034 for identification of PA, APA and IHA, respectively) was higher (P < 0.0001) than that under the diagonal. By sensitivity/specificity versus criterion values plot, the best aldosterone cut-off values for identifying APA and IHA were 6.75 and 6.91 ng/dl, respectively. However, even at these optimal cut-offs, sensitivity and specificity were moderate because of values overlapping between patients with and without the disease. Moreover, there were no differences of AUC and aldosterone cut-offs between APA and IHA., Conclusion: In a multicenter study the SIT was safe and specific for excluding PA, but had no place for discriminating between an APA and IHA.

Background: The appropriateness of left ventricular (LV) mass to cardiac workload may be calculated by the ratio of observed LV mass to the value predicted for an individual's sex, height, and stroke work at rest., Objective: To investigate test-retest reproducibility of observed/predicted LV mass in a single patient., Design and Methods: We measured intraclass correlation and interval of agreement between two M-mode tracings, recorded both at the same session and 3-10 days apart in 200 participants (45 +/- 13 years, body mass index 25 +/- 4 kg/m; 99 hypertensive and 101 normotensive; 50% of each group were women) in 16 centres in Italy. Tracings were read by two observers in each centre., Results: The values of observed/predicted LV mass value ranged from 40.78 to 215.50%. On the same day, the within-observer 90% interval of agreement between tracings 1 and 2 was -23 to +20%. For day-to-day test-retest within-observer variability (average three cycles), the 90% interval of agreement of the observed/predicted LV mass was -30 to +32%. The 90% interval of agreement of test-retest between-observer variability was -25 to +25%. The categorical consistency of retest in the identification of subjects with appropriate LV mass, classified in the first study (i.e. > 73% and < 128%), was 90% (k = 0.87)., Conclusion: Measurement of the appropriateness of LV mass in single patients allows acceptable risk stratification, with a coefficient of consistency similar to that reported for LV mass. The probability of a true change (90% chance) in observed/predicted LV mass over time is maximized for a single-reader difference greater than 22%, although lesser differences might also have clinical relevance.

Objectives: To evaluate and correlate the effects of long-term antihypertensive treatment on left ventricular (LV) mass and carotid structural changes in a large group of essential hypertensive patients, participating in the European Lacidipine Study on Atherosclerosis (ELSA)., Design: In four (Brescia, Glasgow, Naples and Pisa) of 23 centres participating in the ELSA study, an echocardiographic examination was performed at baseline and repeated, until the end of the 4-year study, in essential hypertensive patients, followed-up for carotid quantitative ultrasound examination of intima-media thickness (IMT), after random allocation to treatment with either lacidipine or atenolol (and added hydrochlorothiazide, as required for control of blood pressure)., Methods: M-mode, two-dimensional guided echocardiography was used to measure left ventricular (LV) wall thickness and dimensions, from which LV mass was calculated, using an anatomically validated formula (Penn Convention) and indexed to body surface area (left ventricular mass index, LVMI). The echocardiographic tracings were blindly evaluated in a single reading centre (Brescia). Bilateral IMT was measured at the site of common carotid and bifurcation far walls (CBMmax)., Results: At baseline, cardiac and carotid ultrasound scans were available in 278 patients (mean age 54 +/- 7 years, 57% males, 22% obese). A significant correlation was observed between baseline LVMI and CBMmax (r = 0.22, P < 0.001), independent of age. In multivariate analysis, CBMmax and mean 24-h pulse pressure were most strongly associated with baseline LVMI. A significant reduction in LVMI was observed both during lacidipine (n = 96) (-12.5% reduction) and atenolol (n = 78) (-13.9% reduction) treatments (up to 4 years) (P < 0.001 for both, without significant differences between treatments). Changes in LVMI were not related to changes in carotid wall thickness. In multivariate analysis, baseline LV mass and mean 24-h systolic blood pressure changes were significantly associated with changes in LV mass., Conclusions: In this large, long-term controlled study, antihypertensive treatment with atenolol or lacidipine was accompanied by a similar and significant decrease in LV mass. Treatment-induced changes in LV mass were related to baseline LV mass and changes in 24-h mean systolic blood pressure, without any correlation with changes in carotid structure. In the whole ELSA population, carotid IMT changes have been shown to be unrelated to blood pressure reduction, but significantly influenced by the type of antihypertensive treatment.

Hypertension is known to be associated with an increase in the wall/lumen ratio (W/L) of the resistance arteries. Growth, eutrophic remodelling and changes in arterial distensibility can all contribute to an increase W/L. Wall stress may stimulate growth, whereas remodelling and/or reduced distensibility may be the result of prolonged contraction. Impaired or overwhelmed pressure-induced myogenic constriction, causing increased wall stress, may explain the small artery growth seen in diabetes and secondary hypertension, respectively. We find that small artery growth is a greater predictor of cardiovascular events than an increased W/L.

Background and Aim: Increased vascular resistance is a hallmark of hypertension and involves structural alterations, which may entail smooth muscle cell hypertrophy or hyperplasia, or qualitative or quantitative changes in extracellular matrix (ECM) proteins. Since the renin-angiotensin-aldosterone system modulates these changes, we investigated the effects of 8 weeks of treatment with an angiotensin-converting enzyme (ACE) inhibitor, ramipril (RAM), or a dual ACE and neutral endopeptidase (NEP) inhibitor, MDL-100240 (MDL), on mesenteric small artery structure and ECM proteins in mRen2-transgenic rats (TGRs), an animal model of hypertension with severe cardiovascular damage., Materials and Methods: Thirty-five 5-week-old rats were included in the study: six TGRs received RAM; five TGRs RAM + the bradykinin receptor inhibitor, icatibant; six TGRs, MDL; and five TGRs MDL + icatibant, while eight TGRs and five normotensive Sprague-Dawley controls were kept untreated. Mesenteric small arteries were dissected and mounted on a micromyograph. The media-to-lumen ratio (M/L) was then calculated. Vascular metalloproteinase (MMP) content was evaluated by zymography., Results: In untreated TGRs severe hypertension was associated with inward eutrophic remodelling of small arteries. Both RAM and MDL prevented the increase in blood pressure and M/L and decreased MMPs. Icatibant blunted the effect of MDL on BP, M/L and MMPs., Conclusions: Changes in collagenase activity induced by ramipril and MDL are associated with prevention of small artery structural alterations in TGRs. Furthermore, MDL-induced enhancement of bradykinin could play a role in both the prevention of vascular structural alterations and in the stimulation of MMPs.

Background: A limited number of studies have evaluated the effect of angiotensin II receptor antagonists (AIIAs) on left ventricular hypertrophy (LVH) in comparison with other antihypertensive drugs, and no large study has compared AIIAs with angiotensin-converting enzyme inhibitors (ACEIs)., Methods and Results: The CATCH (Candesartan Assessment in the Treatment of Cardiac Hypertrophy) study was a multicenter prospective randomized double-blind trial comparing the effects of candesartan cilexetil (8-16 mg once daily) and enalapril (10-20 mg once daily) with possible addition of hydrochlorothiazide (12.5-25 mg once daily) on echocardiographic left ventricular mass index (LVMI), in 239 hypertensives with LVH (LVMI 120 g/m2 in men and 100 g/m2 in women). Two-dimensionally guided M-mode echocardiograms were carried out at screening (recruiting scan), randomization (baseline scan) and after 24 and 48 weeks of treatment. Baseline and treatment echocardiograms were read at two central labs without knowledge of the scan time sequence. In intention-to-treat (ITT) analyses (196 patients), systolic and diastolic blood pressures (SBP, DBP) were significantly and equally reduced by the two treatments. Candesartan and enalapril reduced LVMI to the same extent, i.e. by 15.0 and 13.1 g/m2 (-10.9 and -8.4%; P<0.001 for both). The proportion of patients achieving normalization of LVMI was non-significantly higher with candesartan (36.3 versus 28.6%). Similar results were obtained in per-protocol (PP) analyses. Cough incidence was lower with candesartan ( P<0.03)., Conclusions: CATCH is the first large study comparing the effects of an AIIA and an ACEI on LVMI. Candesartan cilexetil was found to be equally effective as enalapril in reducing SBP, DBP and LVMI in hypertensives with LVH, according to both ITT and PP analyses.

Objective: To investigate the effects of the dual angiotensin-converting enzyme (ACE) + neutral endopeptidase (NEP) inhibitor, MDL-100,240 (MDL), on hypertension and cardiovascular damage in male heterozygous transgenic Ren2 rats., Methods: Blood-pressure-matched 5-week-old transgenic rats were allocated to receive a placebo, MDL (40 mg/kg body weight) or ramipril (5 mg/kg body weight) for 8 weeks. During the last 4 weeks, the bradykinin B2 receptor antagonist, icatibant (0.5 mg/kg body weight), was also administered subcutaneously via osmotic minipumps to 50% of the transgenic rats receiving MDL or ramipril. We measured blood pressure, heart weight, structural changes in the aorta and small resistance mesenteric arteries, and the plasma concentrations of adrenomedullin, aldosterone, atrial natriuretic peptide and cGMP. To verify if MDL could regress long-standing hypertension and full-blown cardiovascular damage, 3-month-old transgenic rats received MDL subcutaneously (3 and 10 mg/kg body weight, osmotic minipumps) for 4 weeks., Results: Compared with placebo, MDL decreased blood pressure (P < 0.001) and prevented left ventricular hypertrophy (P < 0.001), being as effective as ramipril. Hypertrophy and dilatation of the aorta and hypertrophy of the resistance arterioles were all prevented by MDL. Plasma aldosterone was decreased by MDL (P < 0.001), but not by ramipril. Icatibant blunted the decrease in blood pressure (P < 0.001), decreased cGMP concentrations and blunted the decrease in cross-sectional area of the resistance arteries in MDL-treated, but not in ramipril-treated, transgenic rats. In 3-month-old transgenic rats, MDL normalized blood pressure, regressed left ventricular hypertrophy and decreased adrenomedullin concentrations., Conclusions: The dual ACE+NEP inhibitor MDL prevented and regressed severe hypertension and cardiovascular damage, even in this model of severe angiotensin II-dependent hypertension with pronounced cardiovascular damage. Enhancement of the effects of bradykinin has a role in such favourable outcomes.

Objective: To prospectively evaluate the interrelationships between left ventricular (LV) geometry and structural characteristics of the vessel wall in small resistance arteries in patients with consecutive primary and secondary hypertension., Methods: In 14 patients with phaeochromocytoma, 12 with primary aldosteronism, 25 with renovascular, 25 with essential hypertension and 12 normotensive controls, an echocardiographic study for the measurement of LV mass index and relative wall thickness (RWT) was performed. Morphological characteristics of small resistance arteries (relaxed diameter < 300 microm) were directly evaluated by a micromyographic technique., Results: A total of 25 patients had normal LV mass and geometry, 28 patients had normal RWT (< 0.45) and 23 patients had a RWT >or= 0.45; all normotensive subjects had normal LV mass and geometry. Media to lumen ratio (M/L) in subcutaneous small arteries was greater in hypertensive patients with concentric LV hypertrophy in respect to normotensives (ANOVA P = 0.01) and hypertensives with normal LV geometry (ANOVA P = 0.05). In the whole group of hypertensive patients the correlation coefficient between M/L and LV mass index was 0.33 (P < 0.05); the correlation coefficient between M/L and RWT was 0.46 (P < 0.01) and it was higher in primary aldosteronism (r = 0.67) and renovascular hypertension patients (r = 0.46)., Conclusions: A close relation between morphology of subcutaneous small resistance arteries and LV geometric patterns may be observed in hypertensive patients; this relationship is more evident when the renin-angiotensin-aldosterone system is activated.

Objectives: In arterial hypertension, the spectrum of geometric patterns in the left ventricle may parallel the structural alterations detected in the carotid arteries and in subcutaneous small arteries. It has been also reported that hypertensive left ventricular hypertrophy (LVH) may be associated with endothelial dysfunction, as evaluated by the response of coronary or forearm vasculature to acetylcholine infusion. The aim of this study was to evaluate the flow-mediated vasodilatation (FMD) of the brachial artery, non-invasive estimate of endothelium-dependent vasodilatation according to left ventricular geometric adaptations in hypertensive patients., Methods and Results: In 16 normotensive (nine males, seven females, aged 40-68 years) and in 78 hypertensive subjects (50 males, 28 females, aged 42-67 years), we performed an echocardiographic study for the measurement of left ventricular mass index (LVMI) and relative wall thickness (RWT); we measured to a high resolution the brachial artery diameter at rest, during reactive hyperaemia (5 min of brachial artery occlusion) and after sublingual glyceril trinitrate (GTN); brachial artery flow velocity was measured by pulsed Doppler. Twenty-six hypertensive patients had a normal LVMI (LVMI < 51 g/ m2.7) and geometry (RWT < 0.44), five had concentric remodelling (RWT > or = 0.44), and concentric and eccentric LVH were observed in 19 and 28 patients, respectively. FMD was reduced in hypertensive patients as compared with normotensive subjects (P< 0.01). No correlation was found between FMD and LVMI (r= -0.078) or RWT (r = 0.049); in addition, no difference in FMD was found among the left ventricular geometric patterns in hypertensive patients., Conclusions: In hypertensives, the presence of endothelial dysfunction is not associated with the LVH or with different left ventricular geometric patterns, suggesting that different and independent mechanisms may be responsible for the presence of LVH and of endothelial dysfunction.

Objective: To investigate changes in left ventricular (LV) performance, as evaluated by measurement of midwall LV fractional shortening (FS), after reduction of cardiac hypertrophy., Design and Methods: Echocardiographic evaluation of LV anatomy and function was performed by M-mode echocardiography at baseline, after long-term antihypertensive therapy, and after treatment withdrawal in 68 asymptomatic hypertensive patients (50 males, 18 females, age range 22-62 years). Patients were divided according to the presence of LV hypertrophy (LVH) at baseline (LV mass index, LVMI, > or = 51 g/m(2.7))., Results: At baseline patients with concentric (relative wall thickness > 0.44) LV hypertrophy (n = 38) or remodelling (n = 7) had reduced midwall shortening with respect to patients with normal LV geometry (n = 4) or eccentric LVH (n = 19); no differences were observed for endocardial FS. After long-term treatment (average 15 months), in 11 patients LV mass remained within normal limits, in 45 patients LVH reduction was obtained, while in 12 patients LV mass remained persistently elevated. Midwall FS was significantly increased in patients with reduction of LVH both during treatment and after withdrawal of treatment, while it remained significantly lower in patients with persistently elevated LV mass. Changes in midwall fractional shortening were independently associated with modifications in relative wall thickness (P < 0.00001), with changes in end-diastolic dimensions (P < 0.0001) and those of LVMI (P< 0.02) as shown by multivariate analysis., Conclusion: LV midwall systolic performance significantly improved after reduction of LVH, even in the presence of high blood pressure values. Modifications in relative wall thickness are more independently associated with changes, in LV diastolic dimensions and mass, to midwall improvement

Objective: To investigate the clinical reliability of repeated measurements of left ventricular mass in a single patient., Design: We used test-retest reliability analysis, within-class correlation and interval of agreement measures., Methods: Two M-mode tracings (three consecutive cycles) were recorded in the same session and 3-10 days apart (5+/-2 days; mean +/- SD) in 261 participants (age 45+/-13 years, body mass index 24.7+/-3.6 kg/m2; 131 hypertensive and 130 normotensive; 50% of each group women) in 16 centres in Italy. The two tracings were read by two observers in each centre, after classification by a three-order quality score (1 = poor, 2 = sufficient, 3 = optimal)., Results: The average quality score was 2.11+/-0.71 (21% poor, 50% sufficient, 29% optimal). Left ventricular mass values ranged from 56 to 419 g (170+/-61 g). On the same day, within-observer 90% interval of agreement between tracing 1 and tracing 2 was -28 to +22 g (-17 to +11% of tracing 1). For day-to-day test-retest within-observer variability (average three cycles), the 90% interval of agreement was -30 to +35 g (-18 to +18%). This variability decreased to -13 to +12% at the 80% interval of agreement and -12 to +11% at the 75% interval of agreement. The 90% interval of agreement of test- retest between-observer variability was -26 to 30 g (-19 to +15%). A negligible regression toward the mean was identified. Categorical consistency of retest in the identification of hypertensive patients with left ventricular hypertrophy, classified in the first study, was 87% (k = 0.87)., Conclusions: Measurement of left ventricular mass in single patients allows reliable risk stratification on the basis of the presence of left ventricular hypertrophy. The probability of a true change in left ventricular mass over time is maximized for a single-reader difference greater than 18% of the initial value, although differences of 10-13% might also have clinical relevance.

Objective: To evaluate the interrelationships between structural alterations in the carotid arteries and left ventricular geometric patterns in a middle-aged general population., Design and Methods: We studied 223 untreated subjects (106 females, 117 males; aged 48-64 years) living in a small town in Northern Italy (Vobarno, Brescia), using a cross-sectional design. The left ventricular mass index was assessed by echocardiography, while the intima-media thickness and the occurrence of plaque were evaluated by ultrasound. Blood pressure was determined by clinic measurements and by 24 h noninvasive ambulatory blood pressure monitoring., Results: According to the presence of left ventricular hypertrophy (left ventricular mass index > 50 g/m2.7 in males and > 47 g/m2.7 in females) or concentric left ventricular remodelling (normal left ventricular mass index and relative wall thickness > 0.42), the subjects were divided into four groups: 124 subjects with normal left ventricular geometry, 73 subjects with left ventricular hypertrophy (55 with eccentric and 18 with concentric hypertrophy) and 26 subjects with concentric remodelling. The common carotid intima-media thickness and cross-sectional area were significantly greater in the subjects with concentric left ventricular hypertrophy (analysis of variance, P< 0.05) than in those with normal left ventricular geometry. A significantly higher number of plaques was observed in subjects with concentric and eccentric left ventricular hypertrophy., Conclusions: In a general population of unselected middle-aged subjects, the presence of concentric left ventricular hypertrophy was associated with an increase in intima-media thickness and with the presence of plaque in the carotid arteries, possibly contributing to the worse prognosis observed in this group of patients.

Objective: To introduce a new method, the smoothness index, for assessing the homogeneity of 24 h blood pressure reduction by antihypertensive treatment and to compare it with the trough : peak ratio; and to assess the ability of both indices to predict a reduction in the left ventricular mass index induced by treatment., Patients and Methods: In 174 patients with essential hypertension and left ventricular hypertrophy, enrolled in the Study on Ambulatory Monitoring of Pressure and Lisinopril Evaluation (SAMPLE), aged 20-65 years, we measured clinic blood pressure, 24 h ambulatory blood pressure and the left ventricular mass index (echocardiography) before and after treatment with lisinopril at 20 mg with the addition of 12.5 or 25 mg hydrochlorothiazide as needed to reach a sufficient blood pressure reduction. The following parameters were computed for systolic and diastolic ambulatory blood pressure: (1) hourly and 24 h blood pressure averages (+/- SD) at baseline and after 3 and 12 months of treatment; (2) hourly blood pressure changes from baseline after 3 and 12 months of treatment, and their average (+/- SD) over 24 h; (3) the trough : peak ratio after 3 and 12 months of treatment; and (4) the smoothness index after 3 and 12 months of treatment Similar calculations were also performed at the end of a final study month during which active treatment was withdrawn and placebo was substituted (n = 164)., Results: The smoothness index for systolic and diastolic ambulatory blood pressure computed after 3 months of treatment was more closely related to its corresponding values after 12 months of treatment than the trough : peak ratio values computed after the same time periods were (r = 0.68 versus 0.38 for systolic and 0.68 versus 0.42 for diastolic blood pressure, respectively). The smoothness index showed an inverse correlation with the 24 h standard deviation of systolic and diastolic blood pressure (r = -0.25 and -0.16, P < 0.01 and < 0.05, respectively, for 12 months of treatment), while the trough : peak ratio did not (r = -0.01 to -0.12, NS). A treatment-induced reduction in the left ventricular mass index was related to the smoothness index for systolic and diastolic blood pressure (r = -0.35 and -0.32, P< 0.001 with 12 months of treatment), but not to the corresponding trough : peak ratios., Conclusions: The smoothness index identifies the occurrence of a balanced 24 h blood pressure reduction with treatment and correlates with the favourable effects of treatment on left ventricular hypertrophy better than the commonly used trough : peak ratio.

Objective: The aim of this study was to evaluate the spectral analysis of the heart rate in normotensive subjects and in hypertensive patients with and without left ventricular hypertrophy (LVH), under basal conditions and after a reduction in left ventricular mass., Subjects and Methods: In 12 normotensive subjects and 22 hypertensive patients (14 with and eight without LVH), we performed 24 h electrocardiogram Holter monitoring, ambulatory blood pressure monitoring and an echocardiographic study. Sequences of 512 R-R intervals, during daytime, afternoon and night-time periods, were taken for an evaluation of spectral analysis (Box-Jenkins method). We then calculated the absolute and percentage power spectral density of the peak centred at 0.10 Hz (low-frequency peak) and at 0.25 Hz (high-frequency peak)., Results: At baseline, a daytime to night-time decrease in the low-frequency peak was detected in normotensives (P < 0.01) and in hypertensives without LVH (P < 0.01), while no change was observed in hypertensives with LVH. The power spectral density low-frequency peak during the daytime and night-time was significantly greater in hypertensives with LVH than in those without LVH (P < 0.001) and in normotensive subjects (P < 0.001). Fourteen of these patients with LVH were given effective long-term antihypertensive treatment and were studied again 20 days after the treatment had been withdrawn, when blood pressure had increased to pretreatment values. In eight patients showing a reduction in LVH, we found a significant decrease in the power spectral density low-frequency peak and an increase in the high-frequency peak during daytime and night-time in respect to basal conditions, and circadian variations in the spectral indices of heart rate variability were restored. In contrast, in six patients without reversal of LVH, the power spectral density low-frequency peak did not change in respect to basal conditions and remained significantly higher in comparison with the patients with LVH regression., Conclusion: A reduction in LVH may be associated with restoration of daytime to night-time cardiac autonomic control, as evaluated by a power spectral analysis of the heart rate.

Objective: To compare the calculations of left ventricular mass according to thick-wall [American Society of Echocardiography (ASE) and Penn convention] and thin-wall (Wikstrand formula) models., Methods: We have reexamined the data from the cross-sectional study on the general population sample of Vobarno and from a prospective longitudinal study of hypertensive patients assessing the prognostic significance of changes in left ventricular mass during a follow-up period of 10 years on average (Brescia population)., Results: For the Vobarno and Brescia populations, we found a close relationship between values of left ventricular mass calculated by using a thin-wall ellipsoidal model (Wikstrand formula) and those calculated using a thick-wall model with Penn convention or ASE left ventricle measurements (r = 0.99, for both the Vobarno and Brescia populations). Highest values of Penn left ventricle mass were slightly underestimated by use of the thin-wall formula. The numbers of nonfatal cardiovascular events and the relative risks, evaluated by Cox proportional hazard models for 151 patients seen at follow-up did not differ for patients with persistence of left ventricular hypertrophy (LVH), those with regression of LVH, and those with normal left ventricle mass, both at baseline and at follow-up, when these different ways of measuring left ventricle mass and partition values for LVH were used., Conclusions: The calculation of left ventricle mass according to the ASE recommendations or to the Penn convention, both of which are based on the assumption that the left ventricle can be represented by a prolate ellipsoid with both the internal and external long axes twice the short axis, produces results similar to those obtained using an alternate formula for the calculation of left ventricle mass, considering wall thickness constant around the ellipsoidal cavity. The cardiovascular risk stratification, in relation both to baseline left ventricular mass and to its change during long-term antihypertensive treatment, does not differ significantly among the results of these three different calculations.

Background: Previous studies have shown that molecular variants of the cytoskeletal protein adducin may be involved in regulation of blood pressure both in genetic rat hypertension and in human essential hypertension., Objective: To investigate the relationship of genetic polymorphism of alpha-adducin with blood pressure, cardiovascular structure, and some biochemical indexes of cardiovascular risk in a sample of general population., Design and Methods: A sample of 246 subjects (124 men and 122 women, aged 57.7+/-3.7 years) was randomly chosen from a middle-aged population. Twenty-four-hour ambulatory blood pressure, as well as left ventricular mass (by echocardiographic methods) and carotid wall thickness (by B-mode ultrasound methods) were measured. DNA was extracted from peripheral blood samples; the Gly460Trp diallelic variant of human alpha-adducin was genotyped by polymerase chain reaction amplification and then allele-specific oligo hybridization., Results: A trend toward higher 24 h ambulatory blood pressure values in subjects not treated with antihypertensive drugs was observed among carriers of Trp460 allele, although the differences did not attain statistical significance (at closest, P = 0.066 for a dominant effect of Trp460 on systolic blood pressure). When blood pressure was considered a dichotomous variable, allowing the inclusion of treated hypertensives), a higher prevalence of Trp460 allele among hypertensives was observed (0.188 versus 0.106 among normotensives, P= 0.02). There was no evidence of association either of left ventricular mass or of common carotid wall thickness with Gly460Trp polymorphism., Conclusions: In this sample of a general population, the relationship of a genetic polymorphism of alpha-adducin with blood pressure values was rather weak. However, a population-based case-control analysis indicated that there was an association between Trp460 allele and hypertension, with a relative risk for subjects carrying at least one Trp460 allele of approximately 1.6. Further investigation of larger and different population samples in order to assess the role of adducin gene polymorphism as a marker of genetic predisposition to the development of hypertension is warranted.

Objective: To evaluate the functional responses of mesenteric small resistance arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rat controls to endothelin-1 (ET-1), in the presence and absence of an ET(A) receptor antagonist drug as well as to an ET(B) receptor agonist., Methods: Twenty rats aged 12 weeks were studied. They were 10 SHR and 10 WKY rats. Mesenteric small resistance arteries (relaxed diameter 100-180 microm) were dissected and mounted on a micromyograph (Mulvany's technique). A dose-response curve for response to ET-1 was plotted for cumulative concentrations (from 10(-11) to 10(-8) mol/l) in the presence and absence of 10(-6) mol/l FR 139317 (a selective antagonist of ET(A) receptors). In addition, the effects of 10(-7) mol/l N-succinyl-[Glu9, Ala11,15]-endothelin 1 fragment 8-21 (IRL 1620, a selective agonist of ET(B) receptors) were evaluated., Results: The response of ET-1 was greater in WKY rats than it was in SHR. Almost all the vasoconstrictor effect of ET-1 could be prevented by addition of FR 139317, whereas the agonist of ET(B) receptors had no effect (no change in active force)., Conclusions: The contractile effects of ET-1 on mesenteric small resistance arteries of SHR and WKY rats are mediated mostly by ET(A) receptors, whereas ET(B) receptors play a minor role, if any. It is possible, however, that a vasoconstrictor effect of ET(B) receptors on the smooth muscle could be masked by the concomitant stimulation of endothelial ET(B) vasodilator receptors.