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Competing Interests: Declaration of competing interest The conflict of interest declaration of authors are compiled into one file that can be found on the ESH website: https://www.eshonline.org/guidelines/2023-guidelines/. ESH received no financial support for the generation of this guidelines.

Introduction: Achieving hypertension control is beneficial regardless of age. Fixed-combination pills have the potential of increasing adherence to treatment, improving the benefit/risk ratio, and simplifying therapy, with resulting convenience especially in the elderly., Aim: We examined real-world antihypertensive treatment adherence and hypertension control rates in a cohort of Italian elderly individuals, enrolled in a prospective, pragmatic awareness-raising campaign on blood pressure (BP)., Methods: 13196 treated hypertensive elderly (mean age 73.2±7.5 years, 55.5% women) were recruited through opportunistic sampling, answered a brief questionnaire on antihypertensive therapy, and were followed-up for 6 months, when BP was measured as per routine care. Controlled hypertension was defined as BP < 140/90 mmHg. Real-world treatment adherence and hypertension control rates were evaluated at 6 months according to different treatment patterns (fixed-dose versus free combinations), using Yates correction for continuity to assess likelihood estimates for differences between treatments., Results: 10551 participants (80%) were on a single-pill therapy and 3445 were on a fixed combination therapy of two (24.8%) or three (1.3%) drugs. Individuals on a fixed combination therapy were more adherent to treatment than the counterparts (p < 0.001). Full adherence increased with the number of drugs/pill among single-pill users (47.5%, 68.5%, and 100% with 1, 2, or 3 drugs/pill; p < 0.001). Hypertension control rates were 70% and 65.2% (p = 0.001) according to fixed or free combinations of two drugs and 71% and 63.9% (p = 0.321) for fixed or free combinations of three drugs., Conclusions: Real-world data suggest that simplified treatment strategies and use of fixed combinations improve adherence to antihypertensive therapy and BP control in the elderly., (© 2021. The Author(s).)

Hypertensive emergencies are those situations where very high blood pressure (BP) values are associated with acute organ damage, and therefore, require immediate, but careful, BP reduction. The type of acute organ damage is the principal determinant of: (i) the drug of choice, (ii) the target BP, and (iii) the timeframe in which BP should be lowered. Key target organs are the heart, retina, brain, kidneys, and large arteries. Patients who lack acute hypertension-mediated end organ damage do not have a hypertensive emergency and can usually be treated with oral BP-lowering agents and usually discharged after a brief period of observation.

Introduction: Masked uncontrolled hypertension (MUCH) carries an increased risk of cardiovascular (CV) complications and can be identified through combined use of office (O) and ambulatory (A) blood pressure (BP) monitoring (M) in treated patients. However, it is still debated whether the information carried by ABPM should be considered for MUCH management. Aim of the MASked-unconTrolled hypERtension management based on OBP or on ambulatory blood pressure measurement (MASTER) Study is to assess the impact on outcome of MUCH management based on OBPM or ABPM., Methods and Analysis: MASTER is a 4-year prospective, randomised, open-label, blinded-endpoint investigation. A total of 1240 treated hypertensive patients from about 40 secondary care clinical centres worldwide will be included -upon confirming presence of MUCH (repeated on treatment OBP <140/90 mm Hg, and at least one of the following: daytime ABP ≥135/85 mm Hg; night-time ABP ≥120/70 mm Hg; 24 hour ABP ≥130/80 mm Hg), and will be randomised to a management strategy based on OBPM (group 1) or on ABPM (group 2). Patients in group 1 will have OBP measured at 0, 3, 6, 12, 18, 24, 30, 36, 42 and 48 months and taken as a guide for treatment; ABPM will be performed at randomisation and at 12, 24, 36 and 48 months but will not be used to take treatment decisions. Patients randomised to group 2 will have ABPM performed at randomisation and all scheduled visits as a guide to antihypertensive treatment. The effects of MUCH management strategy based on ABPM or on OBPM on CV and renal intermediate outcomes (changing left ventricular mass and microalbuminuria, coprimary outcomes) at 1 year and on CV events at 4 years and on changes in BP-related variables will be assessed., Ethics and Dissemination: MASTER study protocol has received approval by the ethical review board of Istituto Auxologico Italiano. The procedures set out in this protocol are in accordance with principles of Declaration of Helsinki and Good Clinical Practice guidelines. Results will be published in accordance with the CONSORT statement in a peer-reviewed scientific journal., Trial Registration Number: NCT02804074; Pre-results., Competing Interests: Competing interests: GP: honoraria as lecturer for Pfizer, Daiichi Sankyo, Menarini, Omron Healthcare. EA-R: honoraria and/or support from Menarini, Servier, Recordati,Guidotti,Malesci, Ferrer, DOC gen, Bruno farm. GLB: principal investigator (FIDElio)-Bayer, Steering committee (CREDENCE(Janssen), SONAR (AbbVie)-Consultant for Merck, Relypsa, Vascular Dynamics, Elceyx, Bayer, Janssen, AbbVie. FC: collaboration with Smart Solutions Technologies S.A.; AMICUS; Boston Scientific International S.A . ADS: honoraria as lecturer for Abbott, Daiichi-Sankyo, Lacer, Menarini, and Pfizer. MD: Honoria from Recordati and Servier. TK: Research grants Karolinska Institutet from Amgen, Medtronic, Pfizer, and Record, all outside the presented work. SL: Honoraria for lecturing from Axelife, Daichi-Sankyo, Fukuda-Denshi, Menarini, Novartis, Omron, Servier and Recordati. GM: honoraria aslecturer Actavis, Amgen, Boehringer Ingelheim, CVRx, Daiichi Sankyo, Ferrer, Medtronic, Menarini, Merck, Novartis, Recordati, Sanofi,Servier. RJM: has received BP Monitors forresearch use from Omron. JR: hasbeen paid as lecturer by Daiichi Sankyo, Menarini, BoehringerIngelheim, MSD. MYR: Lecture honoraria from Pfizer,LG Life Sciences, Bayer Korea, Hanmi Pharm. Co., Yuhan Co., Boryung Pharmaceutical Co., Research grant fromBoryung Pharmaceutical Co. and Dong-A Pharmaceutical Co., CJ HealthCare Co. GS: Conductedvalidation studies for various manufacturers; advised manufacturerson device development. JGW: lecture and consulting fees from Bayer, Daiichi-Sankyo, Novartis,Omron, Pfizer, Sanofi, and Servier. AZ: Honoraria from Menarini International., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The reduction of echocardiographic left ventricular (LV) mass and the change toward a less concentric geometry during antihypertensive treatment are independently associated with a better prognosis. Blood pressure-lowering treatment may reduce cardiac hypertrophy, although different effect on changes of LV mass have been reported among antihypertensive drug classes, while changes in echocardiographic evaluated LV geometry have not been systemically evaluated. It is not yet clear whether antihypertensive drugs may influence LV geometry. Our aim was to compare the effects of diuretics (D), beta-blockers (BB), calcium channel blockers (CCB), angiotensin-converting enzyme inhibitors (ACE-I), and angiotensin receptor blockers (ARBS) on relative wall thickness (RWT) in patients with hypertension on the basis of prospective, randomized comparative studies., Methods: MEDLINE, and the ISI Web of Sciences were searched for randomized clinical trials evaluating LV mass and geometry at baseline and end follow-up. We have performed a pooled pairwise comparisons of the effect of the 5 major drug classes on relative wall thickness changes, and of each drug class versus other classes statistically combined., Results: We selected 53 publications involving 7684 patients. A significant correlation was observed between percent changes from baseline to end of treatment in LV mass and those in systolic BP (r = 0.44, p < 0.001). Reduction of LV mass was significantly greater with CCB than with BB (P <  0.02) without other significant differences between drug classes. Percent changes in RWT were related to percent changes in LV mass/LVmass index (r = 0.68, p = 0.016) and of SBP (r = 0.64 p < 0.033). RWT decreased during treatment with all classes of drugs, except the combination of BB and D; the decrease of RWT was less with diuretics and sympatholytic drugs., Conclusions: In studies evaluating the effect of different classes of antihypertensive drugs on LV mass, the reduction of relative wall thickness seems to be less during treatment with diuretics., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The main goal of treating hypertension is to reduce blood pressure to physiological levels and thereby prevent risk of cardiovascular disease and hypertension-associated target organ damage. Despite reductions in major risk factors and the availability of a plethora of effective antihypertensive drugs, the control of blood pressure to target values is still poor due to multiple factors including apparent drug resistance and lack of adherence. An explanation for this problem is related to the current reductionist and 'trial-and-error' approach in the management of hypertension, as we may oversimplify the complex nature of the disease and not pay enough attention to the heterogeneity of the pathophysiology and clinical presentation of the disorder. Taking into account specific risk factors, genetic phenotype, pharmacokinetic characteristics, and other particular features unique to each patient, would allow a personalized approach to managing the disease. Personalized medicine therefore represents the tailoring of medical approach and treatment to the individual characteristics of each patient and is expected to become the paradigm of future healthcare. The advancement of systems biology research and the rapid development of high-throughput technologies, as well as the characterization of different -omics, have contributed to a shift in modern biological and medical research from traditional hypothesis-driven designs toward data-driven studies and have facilitated the evolution of personalized or precision medicine for chronic diseases such as hypertension., (© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

: 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.

The introduction of Vascular Endothelial Growth Factor (VEGF) signaling pathway inhibitor treatment has highlighted the role of the baseline activity of the VEFG system for blood pressure regulation. VEGF signaling pathway is associated with hypertension and proteinuria. Activation of the endothelin system, endothelial dysfunction and capillary rarefaction are among the underlying mechanisms possibly explaining the rise in blood pressure and, to some extent, also the renal injury. The hypertension induced by VEGF signaling pathway inhibition is, usually, responsive to treatment. Recommendations about the management of cardiovascular toxicity in patients receiving VEGF signaling pathway inhibitors include a formal cardiovascular risk assessment before initiation of VEGF signaling pathway inhibitor treatment, active monitoring of blood pressure and cardiac toxicity throughout treatment, with more frequent monitoring during the first cycles of therapy, given that marked and unpredictable blood pressure rises can occur early after treatment with a VEGF signaling pathway inhibitor, and aggressive management of blood pressure elevations and early symptoms and signs of cardiac toxicity to prevent clinically limiting complications. In patients with preexisting hypertension, the blood pressure target for initiating VEGF signaling pathway inhibitor treatment should be <140/90 mmHg. Blockers of the renin-angiotensin system and calcium channel antagonists are among the drugs to be preferably used in these clinical conditions.

Combinations between an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) and hydrochlorothiazide (HCTZ) are among the recommended treatments for hypertensive patients uncontrolled by monotherapy. Four randomized, double-blind, parallel group studies with a similar design, including 1469 hypertensive patients uncontrolled by a previous monotherapy and with ≥1 cardiovascular risk factor, compared the efficacy of a combination of a sulfhydryl ACE inhibitor (zofenopril at 30 or 60 mg) or an ARB (irbesartan at 150 or 300 mg) plus HCTZ 12.5 mg. The extent of blood pressure (BP)-lowering was assessed in the office and over 24 h. Pleiotropic features of the treatments were evaluated by studying their effect on systemic inflammation, organ damage, arterial stiffness, and metabolic biochemical parameters. Both treatments similarly reduced office and ambulatory BPs after 18-24 weeks. In the ZODIAC study a larger reduction in high sensitivity C reactive protein (hs-CRP) was observed under zofenopril (-0.52 vs. +0.97 mg/dL under irbesartan, p = 0.001), suggesting a potential protective effect against the development of atherosclerosis. In the ZENITH study the rate of carotid plaque regression was significantly larger under zofenopril (32% vs. 16%; p = 0.047). In the diabetic patients of the ZAMES study, no adverse effects of treatments on blood glucose and lipids as well as an improvement of renal function were observed. In patients with isolated systolic hypertension of the ZEUS study, a slight and similar improvement in renal function and small reductions in pulse wave velocity (PWV), augmentation index (AI), and central systolic BP were documented with both treatments. Thus, the fixed combination of zofenopril and HCTZ may have a relevant place in the treatment of high-risk or monotherapy-treated uncontrolled hypertensive patients requiring a more prompt, intensive, and sustained BP reduction, in line with the recommendations of current guidelines.

Background: It has been demonstrated that circulating endothelial progenitor cells (EPCs) number reflects the endogenous vascular repair ability, with the EPCs pool declining in presence of cardiovascular risk factors. Several drugs, including dihydropyridine calcium channel blockers, have been reported to elicit antioxidant and anti-inflammatory properties, as well as to improve vascular remodeling and dysfunction. However, no data are available about the effects of lercanidipine on EPCs. The aim of the present study was therefore to investigate the effects of short-term treatment with lercanidipine on circulating EPCs, as well as on indices of inflammation and oxidative stress., Patients and Methods: Twenty essential hypertensive patients were included in the study and treated for 4 weeks with lercanidipine 20 mg per day orally. Investigations were performed in basal condition, after appropriate wash out of previous treatments, and after 4 weeks of lercanidipine treatment. Inflammatory and oxidative stress markers were assessed by ELISA technique. Lin-/7AAD-/CD34+/CD133+/VEGFR-2 + and Lin-/7AAD-/CD34+/VEGFR-2 + cells were identified by flow cytometry and considered as EPCs. EPCs cells were expressed as number of cells per million Lin-mononuclear cells., Results: Circulating EPCs were significantly increased after lercanidipine treatment (CD34+/CD133+/VEGFR-2 + cells: 78.3 ± 64.5 vs 46.6 ± 32.8; CD34+/VEGFR-2+: 87996 ± 165116 vs 1026 ± 1559, respectively, p < 0.05). A modest reduction in circulating indices of inflammation was also observed., Conclusions: In conclusion, lercanidipine is able to increase the number of circulating EPCs, possibly through a reduction of low-grade inflammation.

Estimates of blood pressure (BP) control in real life are not systematically collected in Italy. We evaluated trends in systolic/diastolic BP levels, as well as prevalence, awareness, treatment, and control rates of hypertension among adult individuals visiting open checkpoints during the 2004 to 2014 annual editions of World Hypertension Day. Hypertension was defined as BP level ≥140/90 mm Hg or use of antihypertensive medication, whereas BP control was defined as BP level <140/90 mm Hg. We included 10,051 individuals (53.2% female, age 56.2±16.8 years, body mass index 25.7±7.6 kg/m(2) , systolic/diastolic BP 131.9±18.6/79.1±10.5 mm Hg). Hypertension prevalence and treatment were substantially unchanged, whereas awareness appears to increase over time. Controlled hypertension in diagnosed treated patients increased from 50.0% in 2004-2010 to 55.5% in 2011-2012 towards 57.6% in 2013-2014. This analysis provides real-life snapshots of hypertension over the years in the occasion of World Hypertension Day, showing increased awareness and improved control rates among treated hypertensive patients attending open checkpoints during 2004 to 2014 in Italy., (©2015 Wiley Periodicals, Inc.)

It was previously demonstrated that metabolic syndrome in humans is associated with an impairment of insulin signalling in circulating mononuclear cells. At least in animal models of hypertension, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) may correct alterations of insulin signalling in the skeletal muscle. In the first study, we investigated the effects of a 3-month treatment with an ARB with additional PPARγ agonist activity, telmisartan, or with a dihydropyridine calcium channel blocker, nifedipine, on insulin signalling in patients with mild-moderate essential hypertension. Insulin signalling was evaluated in mononuclear cells by isolating them through Ficoll-Paque density gradient centrifugation and protein analysis by Western Blot. An increased expression of mTOR and of phosphorylated (active) mTOR (p-mTOR) was observed in patients treated with telmisartan, but not in those treated with nifedipine, while both treatments increased the cellular expression of glucose transporter type 4 (GLUT-4). We also investigated the effects of antihypertensive treatment with two drug combinations on insulin signalling and oxidative stress. Twenty essential hypertensive patients were included in the study and treated for 4 weeks with lercanidipine. Then they were treated for 6 months with lercanidipine + enalapril or lercanidipine + hydrochlorothiazide. An increased expression of insulin receptor, GLUT-4 and an increased activation of p70S6K1 were observed during treatment with lercanidipine + enalapril but not with lercanidipine + hydrochlorothiazide. In conclusion, telmisartan and nifedipine are both effective in improving insulin signalling in human hypertension; however, telmisartan seems to have broader effects. The combination treatment lercanidipine + enalapril seems to be more effective than lercanidipine + hydrochlorothiazide in activating insulin signalling in human lympho-monocytes.

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: In most treated patients with hypertension, a two or more drug combination is required to achieve adequate blood pressure (BP) control. In our study we assessed whether the combination of zofenopril + hydrochlorothiazide (HCTZ) was at least as effective as irbesartan + HCTZ in essential hypertensives with at least one additional cardiovascular risk factor, uncontrolled by a previous monotherapy., Methods: After a 2-week placebo washout, 361 treated hypertensive patients [office sitting diastolic BP (DBP), ≥90 mmHg], aged 18-75 years, were randomized double blind to 18-week treatment with zofenopril 30 mg plus HCTZ 12.5 mg or irbesartan 150 mg plus HCTZ 12.5 mg once daily, in an international, multicenter study. After the first 6 and 12 weeks, zofenopril and irbesartan doses could be doubled in non-normalized subjects. The primary study end point was the office sitting DBP reduction after 18 weeks of treatment. Secondary end points included office systolic BP (SBP), ambulatory BP and high sensitivity C-reactive protein (hs-CRP)., Results: The between-treatment difference for office DBP averaged to +1.0 (95% CI -0.4, +0.8) mmHg (P = 0.150), the upper limit of the 95% confidence interval being inferior to the protocol-defined non-inferiority limit (3 mmHg). In the subset of patients with valid ambulatory BP, no difference in 24-h average DBP [n = 181; 6.7 (8.7, 4.6) zofenopril + HCTZ vs. 6.3 (8.8, 3.7) mmHg irbesartan + HCTZ, P = 0.810] and SBP reductions [11.7 (15.4, 8.0) vs. 12.6 (17.2, 8.0) mmHg, P = 0.758] were observed between the two treatment groups. hs-CRP was reduced by zofenopril + HCTZ [-0.52 (-1.05, 0.01) mg/L], while it was increased by irbesartan plus HCTZ [0.97 (0.29, 1.65) mg/L, P = 0.001 between treatments]., Conclusion: In previously monotherapy-treated, uncontrolled patients with hypertension, zofenopril 30-60 mg + HCTZ 12.5 mg is as effective as irbesartan 150-300 mg plus HCTZ 12.5 mg, with the added value of a potential protective effect against vascular inflammation.

Only 20-30% out of the treated hypertensive patients in Europe are achieving blood pressure (BP) control. Among other recognized factors, these poor results could be attributable to the fact that for many doctors it is very difficult to detect which is the predominant hemodynamic cause of the hypertension (hypervolemia, hyperinotropy or vasoconstriction). The aim of the study was to use non-invasive thoracic electrical bioimpedance (TEB) to evaluate hemodynamic modulators and subsequent hemodynamic status in uncontrolled hypertensive patients, receiving at least two antihypertensive drugs. A number of 134 uncontrolled hypertensive patients with essential hypertension were evaluated in nine European Hypertension Excellence centers by means of TEB (the HOTMAN(®) System). Baseline office systolic and diastolic BP averaged 156/92 mmHg. Hemodynamic measurements show that almost all patients (98.5%) presented at least one altered hemodynamic modulator: intravascular hypervolemia (96.4%) and/or hypoinotropy (42.5%) and/or vasoconstriction (49.3%). Eleven combinations of hemodynamic modulators were present in the study population, the most common being concomitant hypervolemia, hypoinotropy and vasoconstriction in 51(38%) patients. Six different hemodynamic states (pairs of mean arterial pressure and stroke index) were found. Data suggest that there is a strong relation between hypertension and abnormal hemodynamic modulators. This method might be helpful for treatment individualization of hypertensive patients.

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.

Regardless of the mechanisms that initiate the rise of blood pressure, the development of structural changes in the systemic vasculature is the end result of established hypertension. Indices of small resistance artery structure, such as the ratio of tunica media to internal lumen, may have a strong prognostic significance in hypertensive patients, over and above all other known cardiovascular risk factors. Hence, the regression of vascular alterations seems to be an appealing goal for antihypertensive treatment. Different antihypertensive drugs may have different effects on vascular structure. Complete normalization of small resistance artery structure was demonstrated in hypertensive patients after long-term and effective antihypertensive therapy with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium antagonists. Little or no improvement was observed with beta-blockers or diuretics. Evidence from several studies suggests that some antihypertensive drugs are more effective than others in reversing microvascular structural alterations in hypertension.

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.

Arterial stiffness plays a key role in the pathophysiology of the cardiovascular system. Some indices of arterial stiffness (pulse wave velocity, augmentation index, characteristics of central blood pressure waveform) may be presently calculated and evaluated in the clinical setting. Age and blood pressure are the two major clinical determinants of increased arterial stiffness, while molecular determinants of arterial stiffness are related to fibrotic components of the extracellular matrix, mainly elastin, collagen and fibronectin. Increased arterial stiffness has been consistently observed in conditions such as hypertension, dyslipidemia and diabetes. Arterial stiffness evaluated by means of carotid-femoral pulse wave velocity yielded prognostic significance beyond and above traditional risk factors. A more favorable effect of calcium channel blockers, diuretics and ACE inhibitors compared with beta-blockers on indices of arterial stiffness was observed in several studies. It is conceivable that newer beta-blockers with additional vasodilating properties, such as nebivolol, which has favorable effects on carbohydrate and lipid metabolism, as well as on endothelial function and on oxidative stress, may have favorable effects on arterial stiffness, compared with atenolol. In fact, in recent studies, nebivolol was demonstrated to improve artery stiffness to a greater extent than older beta-blockers. Because endothelial dysfunction and increased arterial stiffness play an important role in the early atherosclerotic processes and are associated with poor outcomes and increased mortality, independently of blood pressure, the ability of nebivolol to enhance release of endothelium-derived nitric oxide, and consequently improve endothelial function and arterial stiffness, may have significant clinical implications for the use of this agent in the treatment of hypertension and cardiovascular diseases.

Inappropriate left ventricular mass (LVM; ie, the value of LVM exceeding individual needs to compensate hemodynamic load) predicts the risk of cardiovascular (CV) events, independent of risk factors, either in the presence or in the absence of traditionally defined LV hypertrophy. The relation between changes in appropriateness of LVM during antihypertensive treatment and subsequent prognosis was evaluated in 436 prospectively identified uncomplicated hypertensive subjects, with a baseline and follow-up standard clinical evaluation, laboratory examinations, and echocardiogram (last examination: 6+/-3 years apart), followed for additional 4.5+/-2.5 years. The appropriateness of LVM to cardiac workload was calculated by the ratio of observed LVM to the value predicted for individual sex, height, and stroke work at rest. At baseline, low or appropriate LVM (

beta-Adrenoceptor antagonists (beta-blockers) have historically been considered an effective and safe option for first-line treatment of hypertension. However, very recently, it has been proposed that beta-blockers should no longer be considered suitable for first-line therapy in the patient with uncomplicated hypertension because of unfavourable morbidity and mortality data. New evidence from recent clinical studies of nebivolol, a third-generation highly selective beta(1)-blocker with additional endothelial nitric oxide (NO)-mediated vasodilating activity, confirms previous findings that this drug differs from other beta-blockers. The combined mechanisms of beta-adrenoceptor antagonism and NO-mediated vasodilation may potentiate the blood pressure-lowering effect of this agent, and confer a broader favourable metabolic profile, which may be clinically relevant for hypertensive patients. The antioxidant properties of nebivolol and its neutral or even favourable effects on both carbohydrate and lipid metabolism are well documented. These properties consistently differentiate nebivolol from nonvasodilating beta-blockers such as atenolol, metoprolol or bisoprolol. Therapeutic indications for beta-blockers include a wide range of co-morbidities found in hypertensive patients, including ischaemic heart disease, tachyarrhythmias and heart failure. Given that the majority of hypertensive patients require more than one drug to control blood pressure, the multiple mechanisms of action and favourable metabolic profile of nebivolol could make it an alternative therapeutic option for hypertensive patients requiring beta-adrenoceptor therapy.

Left ventricular (LV) mass and geometry predict risk for cardiovascular events in hypertension. Regression of LV hypertrophy (LVH) may imply an important prognostic significance. The relation between changes in LV geometry during antihypertensive treatment and subsequent prognosis has not yet been determined. A total of 436 prospectively identified uncomplicated hypertensive subjects with a baseline and follow-up echocardiogram (last examination 72+/-38 months apart) were followed for an additional 42+/-16 months. Their family doctor gave antihypertensive treatment. After the last follow-up echocardiogram, a first cardiovascular event occurred in 71 patients. Persistence of LVH from baseline to follow-up was confirmed as an independent predictor of cardiovascular events. Cardiovascular morbidity and mortality were significantly greater in patients with concentric (relative wall thickness > or =0.44) than in those with eccentric geometry (relative wall thickness <0.44) in patients presenting with LVH (P=0.002) and in those without LVH (P=0.002) at the follow-up echocardiogram. The incidence of cardiovascular events progressively increased from the first to the third tertile of LV mass index at follow-up (partition values 91 and 117 g/m2), but for a similar value of LV mass index it was significantly greater in those with concentric geometry (OR: 4.07; 95% CI: 1.49 to 11.14; P=0.004 in the second tertile; OR: 3.45; 95% CI: 1.62 to 7.32; P=0.001 in the third tertile; P<0.0001 in concentric versus eccentric geometry). Persistence or development of concentric geometry during follow-up may have additional prognostic significance in hypertensive patients with and without LVH.

We have evaluated the effects of an ACE inhibitor, enalapril (ENA) and of an angiotensin II receptor blocker, losartan (LOS), administered either at hypotensive or non-hypotensive dosage, on the cardiac and renal structure of spontaneously hypertensive rats (SHR). Forty-eight rats were included in the study: eight SHR were treated with low-dose (ld, 1 mg/kg/day) ENA; eight with low-dose (ld, 0.5 mg/kg/day) LOS; eight with high-dose (hd, 25 mg/kg/day) ENA; eight with high-dose (hd, 15 mg/kg/day) LOS; while eight Wistar-Kyoto (WKY) and eight SHR were kept untreated (unt). Treatment was given from the 4th to the 12th week of age. Systolic blood pressure (SBP) was measured non-invasively every week. The left ventricular weight to body weight (RLVM) and the left + right kidney weight (RKW) to body weight was measured, and the cardiac and glomerular interstitial collagen content was evaluated using sirius red staining and image analysis. In addition, cardiac metalloproteinases activity (43 kDa MMP, MMP-2, and MMP-9) was evaluated by zymography. A significant reduction in RLVM was observed in SHR given ENA hd or LOS hd. Cardiac collagen was significantly reduced in SHR ENA hd and SHR LOS hd as well as in SHR LOS ld, but not in SHR ENA ld. The 43 kDa MMP collagenase activity was greater in WKY unt compared with SHR unt, being normalized only in SHR ENA hd. The gelatinase activity of MMP-9 showed a trend similar to 43 kDa MMP, but differences between SHR and WKY unt were only of borderline statistical significance. No difference among groups was observed in MMP-2 activity. No significant differences in RKW was observed between groups. However, the collagen content in the glomerular perivascular space was significantly reduced in all treated groups, including those given ld, compared with SHR unt. In conclusion, LOS and ENA showed a similar preventive effect on the increase of RLVM in SHR, but, at least in part, different effects on the extracellular matrix in different organs, being cardiac collagen less sensitive to low dose (ld) ACE inhibition.

The increased peripheral resistance in hypertension results from arteriolar vasoconstriction, increased media-to-lumen (M/L) ratio of small resistance arteries, and rarefaction (reduction in density) of microvessels. Numerous neurohumoral and hormonal factors are involved in causing structural and functional changes in the microcirculation in hypertension, including the renin-angiotensin-aldosterone system, remodelling of the extracellular matrix, increased growth of the smooth muscle cells of the media, and elevated collagen and fibronectin deposition. Although a wide variety of pharmacological agents can decrease blood pressure (BP) in hypertension, they vary in their ability to reverse structural and functional changes in the microcirculation. ACE inhibitors have consistently been shown to regress microvascular changes but findings with calcium antagonists have been variable and beta-adrenoceptor blockers appear to have no effect. In studies with ACE inhibitors, improvements in the M/L ratio and endothelial function of small resistance arteries have been recorded in both animal models of hypertension and human subcutaneous arteries obtained by biopsy of gluteal tissue from patients with essential hypertension. Recent studies with the very low-dose combination of perindopril and indapamide have indicated that these agents act synergistically to restore normal microvascularisation and reverse capillary rarefaction in the coronary circulation of hypertensive rats, and normalise coronary blood flow reserve in humans with hypertension. The additional benefit accruing from regression of structural and functional abnormalities in critical vascular beds such as coronary or renal circulations of patients with chronic hypertension may well become an important factor in selection of antihypertensive therapy, as complications such as ischaemic episodes and other target organ damage may be prevented and the BP-lowering effect of treatment may be extended such that it continues even after withdrawal. However, whether improvements in microcirculatory structure and function will be associated with improved morbidity and mortality outcomes in patients with chronic hypertension has yet to be firmly established.

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.

The aim of the present study was to compare the effects of a long-acting dihydropyridine (amlodipine) and a nondihydropyridine (verapamil) on autonomic function in patients with mild to moderate hypertension. A total of 145 patients with a diastolic blood pressure (BP) between 95 and 110 mm Hg received 8 weeks of verapamil sustained release (240 mg) and amlodipine (5 mg) in a prospective randomized, double blind, cross-over study, both after 4 weeks of placebo. The 24-h autonomic balance was measured by analysis of 24-h heart rate variability and short-term autonomic control of BP by baroreflex sensitivity measurements. Plasma norepinephrine was sampled at rest. Blood pressure was equally reduced from 153/100 mm Hg to 139/91 mm Hg with verapamil and 138/91 mm Hg with amlodipine, P = .50/.59. The low- to high-frequency ratio (LF/HF), reflecting sympathovagal balance, was higher with amlodipine than with verapamil (4.66 v 4.10; P = .001). Baroreflex function was improved by both treatments; however, baroreflex sensitivity (BRS) was significantly higher with verapamil than with amlodipine (8.47 v 8.06 msec/mm Hg; P = .01). Plasma norepinephrine (NE) level was higher with amlodipine than with verapamil (1.59 v 1.32 nmol/L; P < .0001). Amlodipine induces a shift in sympathovagal balance, as measured by heart rate variability indices and plasma NE, toward sympathetic predominance compared with vagal predominance with verapamil. Short-term autonomic control of BP, as assessed by BRS, is more effectively improved by verapamil than by amlodipine. These contrasting effects on autonomic function suggest that the nondihydropyridine calcium antagonist verapamil may have additional beneficial effects beyond lowering BP compared with the dihydropyridine amlodipine.

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

Recent studies showed that in diabetic hypertensive patients, administration of angiotensin-converting enzyme (ACE)-inhibitors or calcium antagonists can effectively lower blood pressure (BP) and prevent diabetes-related cardiovascular complications with no adverse metabolic effects. We sought to assess the antihypertensive and metabolic effects of the new dihydropyridine calcium antagonist manidipine (M) in patients with diabetes mellitus and essential hypertension as compared with the ACE inhibitor enalapril (E). After 3 weeks of placebo, 101 (62 men; age range, 34-72 years) hypertensives with type II diabetes mellitus were randomized to M 10-20 mg or E 10-20 mg, od, for 24 weeks. At the end of the placebo period and the active-treatment phase, BP was measured with a mercury sphygmomanometer (office, O) and over the 24 h by ambulatory (A) monitoring. ABP recordings were analyzed to obtain 24-h, day (6 a.m. to midnight), and night (midnight to 6 a.m.) average systolic (S) and diastolic (D) BP and heart rate (HR) values. Homogeneity of the antihypertensive effect over the 24 h was assessed by the smoothness index [SI: i.e., the ratio between the average of the 24 hourly BP changes after treatment and the corresponding standard deviation (the higher the SI, the more uniform is the BP control by treatment over the 24 h]. The O SBP and DBP were significantly (p < 0.01) and similarly reduced by M (16 +/- 10 and 13 +/- 6 mm Hg, n = 49) and E (15 +/- 10 and 13 +/- 6 mm Hg, n = 45). The percentage of patients whose O DBP was reduced < or = 85 mm Hg (i.e., the value indicated to be the optimal DBP goal in diabetic hypertensives) was similar for M (37%) and E (40%). The reduction of 24-h BP also was similar between M (n = 38) and E (n = 38) for both drugs (systolic, 6 +/- 11 and 8 +/- 10 mm Hg; diastolic, 5 +/- 8 and 5 +/- 7; NS, M vs. E). The antihypertensive effect was distributed in a similar homogeneous fashion throughout the dosing interval, as shown by the similar SI values (M, 0.6 +/- 1.2 for SBP and 0.6 +/- 0.9 for DBP; E, 0.6 +/- 0.8 for SBP and 0.5 +/- 0.7 for DBP; NS, M vs. E). O and A HR were unchanged by either treatment. Markers of glucose and lipid metabolism and renal function were not significantly modified by treatment both with M and with E. In the diabetic hypertensives, M was as effective and metabolically neutral as the ACE-inhibitor E.

Objective: The aim of this study was to compare the efficacy and tolerability of the new angiotensin-converting enzyme (ACE) inhibitor moexipril and the calcium antagonist nitrendipine in postmenopausal women with mild to moderate hypertension., Methods: After a 4-week placebo run-in period, 93 postmenopausal women (age range 44-70 years) with primary hypertension were randomized to receive moexipril 15 mg once daily or nitrendipine 20 mg once daily for 8 weeks. The mean sitting systolic (SSBP) and sitting diastolic blood pressures (SDBP) at baseline were 161.3/103.0 mmHg in the moexipril group, and 162.2/102.3 mmHg in the nitrendipine group., Results: After the 8 weeks of treatment, the SSBP/SDBP reductions were -21.2/-15.2 mmHg in the moexipril group and -18.2/-13.6 mmHg in the nitrendipine group. Blood pressure responses were adequate in 82.2% of the moexipril-treated patients and in 80.9% in the nitrendipine-treated group. Adverse events were more frequent with nitrendipine than with moexipril. The most common adverse events in the nitrendipine group were headache (23.4%), flushing (21.3%) and ankle oedema (14.9%). In the moexipril group the most common adverse event was cough (8.9%)., Conclusion: The results of the study suggest that moexipril and nitrendipine are equieffective in the given dosages. In the patient population of postmenopausal women, the ACE inhibitor moexipril appears to have an advantage over the calcium antagonist nitrendipine with regard to tolerability.

off aim of our study was to evaluate the effect of antihypertensive treatment on flow-mediated dilation (FMD)of a large artery, a noninvasive estimate of endothelial function, in hypertensive patients. In 78 consecutive hypertensive patients (40%men; age range, 42 to 67 years) we measured by a high-resolution ultrasound system the changes of brachial artery diameter during reactive hyperemia and after sublingual glyceryl trinitrate (400 microg); brachial artery flow velocity was measured by pulsed Doppler. The results of 2 studies are reported. In the first study, this procedure was repeated in 58 patients after 6 and 12 months of treatment with a combination of antihypertensive drugs; in a second study, the FMD was assessed in 20 patients after 2 months of monotherapy with either nifedipine or hydrochlorothiazide. In the first study, FMD was significantly increased after treatment compared with baseline (from 3.1+/-3% at baseline to 6.5+/-4.5% at 6 months and to 8.12+/-4. 6% at 12 months; P<0.001 by ANOVA), concomitant with blood pressure reduction (from 162+/-24/102+/-13 mm Hg to 141+/-12/89+/-6 mm Hg and to 141+/-9/89+/-6 mm Hg; P<0.001 by ANOVA); significant changes of endothelium-independent dilation were also observed, but only after 12 months of treatment (from 14.2+/-4.8 at baseline to 15.5+/-4.7 at 6 months and 16.8+/-5.9% at 12 months; P=0.03 by ANOVA). In the second study, FMD was significantly increased during nifedipine treatment as compared with baseline (from 5+/-6.18% at baseline to 9. 45+/-3.94%, P<0.001), while it did not change in patients receiving hydrochlorothiazide (from 5.15+/-5.28% at baseline to 4.69+/-4.34%, NS). No significant changes of endothelium-independent dilation were observed with both drugs (from 17.10+/-2.4% to 18.14+/-3.76% and from 18.73+/-4.07% to 17.46+/-4.27% during nifedipine and hydrochlorothiazide, respectively, NS). Thus, in essential hypertensive patients an improvement of the impaired FMD of the brachial artery, evaluated by noninvasive ultrasound, may be observed after long-term, effective blood pressure reduction, suggesting a beneficial effect of antihypertensive treatment on endothelial function. It seems that beyond blood pressure control, a calcium antagonist may be more effective than a diuretic in this respect.

We evaluated the effects on cardiovascular structure of the angiotensin-converting enzyme (ACE) inhibitor enalapril and of the angiotensin II receptor blocker losartan, administered either at hypotensive or nonhypotensive dosage in spontaneously hypertensive rats (SHR). SHR were treated from ages 4 to 12 weeks with low-dose (1 mg x kg(-1) x d(-1)) enalapril, low-dose (0.5 mg x kg(-1) x d(-1)) losartan, high-dose (25 mg x kg(-1) x d(-1)) enalapril, or high-dose (15 mg x kg(-1) x d(-1)) losartan. Untreated WKY and SHR were also studied. Rats were killed at 13 weeks of age, and the heart was weighed. Mesenteric small arteries were dissected and mounted on a micromyograph for determination of media thickness and lumen diameter. In fixed arteries, cell volume, number of cells per segment length, and number of cell layers were measured using the unbiased "disector" method. Systolic blood pressure was significantly reduced by the high doses of both drugs, but the hypotensive effect was greater with enalapril than with losartan (P<0.05). In the high-dose enalapril and losartan groups, there were similar reductions in relative left ventricular mass, media/lumen ratio, and number of cell layers of resistance arteries; however, there were no differences in the cell volume or number of cells per segment length of resistance arteries. Low-dose enalapril did not affect systolic blood pressure or any of the structural parameters. The results show that the hypotensive effects of both losartan and enalapril were associated with outward remodeling of resistance arteries at the cellular level. The effect of losartan on resistance artery structure was equal to that of enalapril, despite the smaller hypotensive effect.

The SILVER (Study of Irbesartan in Left VEntricular hypertrophy Regression) trial is designed to test the hypothesis that the newly developed angiontensin-II receptor antagonist, irbesartan, will produce a greater reduction in left ventricular (LV) mass than felodipine ER, in a population of hypertensive patients defined by seated diastolic blood pressure (SeDBP) in the range 95-115 mmHg or seated systolic blood pressure (SeSBP) in the range 160-200 mm Hg. A population of 360 men and women of non-childbearing potential, >18 years of age, with hypertension, newly diagnosed or after a 3-week washout from previous anti-hypertensive or vasodilator therapies, will be randomised at approximately 80-90 European sites. Add-on therapy with hydrochlorothiazide and atenolol will be allowed for blood pressure control. Patients will be studied by two-dimensional and M-mode echocardiography at baseline (central validation of LV hypertrophy), on randomisation day, and after 6 and 12 months randomised therapy. Blinded analysis of echocardiograms will be performed at a central laboratory, which will provide measurements of the LV mass index (LVMI), determined by M-mode readings according to Devereux formula and using the Penn convention. The primary end-point of the study will be the change in LVMI from baseline to 12 months. The study power is 90% to detect differences between groups from baseline of approximately 8 g/m2.

The aim of this study was to evaluate the effect of the calcium antagonist Nifedipine GITS in a double-blind, randomized comparison with the diuretic hydrochlorothiazide (HCTZ) on reduction of left ventricular (LV) mass and minimal vascular resistance in a group of essential hypertensives with left ventricular hypertrophy (LVH). The effects on blood pressure and on echocardiographic LV functional parameters were also analysed. After two months of randomized treatment with Nifedipine GITS or HCTZ, if diastolic blood pressure was > 90 mmHg, a combination of the two drugs was given and was continued for 24 weeks. M-mode, 2D-guided echocardiography was used to measure LV mass index (LVMI) according to the "Penn convention". Minimal vascular resistance was measured in the forearm, from arterial pressure and maximal blood flow, using a strain gauge plethysmography. All examinations were performed before and after 8 and 24 weeks of treatment. Changes in LVMI were analysed at 8 weeks and at 24 weeks in patients receiving monotherapy ("according to protocol" analysis), and also at the end of treatment in patients taking Nifedipine or HCTZ monotherapy or the combination of the two drugs ("intention to treat" analysis). Both Nifedipine and HCTZ significantly reduced systolic and diastolic blood pressure (p < 0.001), without any significant difference between the two drug treatments. Heart rate was not significantly modified by either treatment. A progressive decrease in LVMI was observed after 8 and 24 weeks of treatment with Nifedipine monotherapy (ANOVA, p = 0.03), while the decrease in LVMI during HCTZ treatment did not progress further at 24 weeks (ANOVA, p = 0.49). A significant reduction of minimal vascular resistance was observed in patients treated with Nifedipine GITS monotherapy (ANOVA, p = 0.001), but not in the HCTZ group (ANOVA, p = 0.06). Comparison of changes of forearm minimal vascular resistance, considering baseline values, could demonstrate a greater effect during Nifedipine monotherapy as compared to HCTZ monotherapy. In conclusion, in a group of hypertensive patients with LVH, treatment for 24 weeks with Nifedipine GITS alone or in combination with HCTZ induced a significant reduction in LVMI and of forearm vascular structural changes, as evaluated by minimal vascular resistance. The decrease of minimal vascular resistance was significantly greater in patients treated with Nifedipine monotherapy, as compared to those given HCTZ.

Background: In cross-sectional studies, ambulatory blood pressure (ABP) correlates more closely than clinic BP with the organ damage of hypertension. Whether ABP predicts development or regression of organ damage over time better than clinic BP, however, is unknown., Methods and Results: In 206 essential hypertensive subjects with left ventricular hypertrophy (LVH), we measured clinic supine BP, 24-hour ABP, and left ventricular mass index (LVMI, echocardiography) before and after 12 months of treatment with lisinopril (20 mg UID) without or with hydrochlorothiazide (12.5 or 25 mg UID). Measurements included random-zero, clinic orthostatic, and home BP. In all, 184 subjects completed the 12-month treatment period. Before treatment, clinic supine BP was 165 +/- 15/105 +/- 5 mm Hg (systolic/diastolic), 24-hour average BP was 149 +/- 16/95 +/- 11 mm Hg, and LVMI was 158 +/- 32 g/m2. At the end of treatment, they were 139 +/- 12/87 +/- 7 mm Hg, 131 +/- 12/83 +/- 10 mm Hg, and 133 +/- 26 g/m2, respectively (P < .01 for all). Before treatment, LVMI did not correlate with clinic BP, but it showed a correlation with systolic and diastolic 24-hour average BP (r = .34/.27, P < .01). The LVMI reduction was not related to the reduction in clinic BP, but it was related to the reduction in 24-hour average BP (r = .42/.38, P < .01). Treatment-induced changes in average daytime and nighttime BPs correlated with LVMI changes as strongly as 24-hour BP changes. No substantial advantage over clinic supine BP was shown by clinic orthostatic, random-zero, and home BP., Conclusions: In hypertensive subjects with LVH, regression of LVH was predicted much more closely by treatment-induced changes in ABP than in the clinic BP. This provides the first longitudinally controlled evidence that ABP may be clinically superior to traditional BP measurements.

The presence of left ventricular hypertrophy (LVH) in hypertensive patients, recognized clinically by electrocardiography or echocardiography, is an adverse prognostic sign and a powerful predictor of cardiovascular morbidity and mortality, independent of blood pressure and other cardiovascular risk factors. Several pathophysiological changes accompany the myocytic growth and fibrosis that characterize hypertensive LVH and have been invoked to explain the association of LVH with increased cardiovascular risk. These include: impairment of diastolic function, and probably also of systolic performance, at least during exercise; reduced coronary blood flow reserve; predisposition to ventricular arrhythmias; alteration in cardiac autonomic nervous system activity. All these data have led to the opinion that regression of LVH should be a major goal in the treatment of hypertensive patients and might predict an improvement in prognosis.

Objective: To assess whether regression of left ventricular hypertrophy (LVH) can be used as a surrogate end-point for morbid events in hypertension treatment trials., Design and Methods: Statistical, epidemiologic and treatment trial literature was reviewed to identify the criteria that should be met by a surrogate end-point and to determine whether these criteria are met by existing data on the regression of LVH., Results: Relevant criteria include: (1) a consistent relationship between LVH and subsequent morbid events; (2) prediction of lower or higher complication rates by LVH regression or progression; (3) evidence that the relationship between LVH regression/progression and morbidity/mortality is consistent in different populations and with different treatments; and (4) demonstration of a quantitative relationship that allows prediction of a change in clinical risk from a measured change in LVH. The results of seven electrocardiographic and 10 echocardiographic studies with a total of about 20000 subjects have shown consistently higher risks of morbid events in subjects with than without LVH (odds ratios 1.4-5.4). The available data (four studies, 1145 subjects) suggest that morbid events will occur in a higher proportion of subjects in whom LVH progresses (13-59%) rather than regresses (7-12%). However, the latter data are derived almost entirely from white subjects, predominantly male, with incomplete knowledge of interim treatment and blood pressure in most instances; no information on the mathematical relationship between change in LVH and subsequent morbidity and mortality is yet available., Conclusions: A strict definition of the information required to establish a fully adequate surrogate end-point for morbid events in antihypertensive has been partially but not completely satisfied. The consistent relationship between baseline LVH and subsequent morbid events and the initial evidence of a parallelism between LVH change and prognosis need to be supplemented by additional studies that examine the latter relationship in diverse populations under varied treatments, and which examine the quantitative relationship between measured change in LVH and the subsequent rates of morbid events. Additional data will come from ongoing treatment trials (approximately 12 000 subjects) and observational studies (approximately 8000 subjects) with serial assessments of LVH.

Available data support the hypothesis that antihypertensive drugs may determine a significant regression of cardiac and vascular structural changes. Antihypertensive drugs that inhibit the renin-angiotensin or, to a lesser extent, the adrenergic system may more consistently and promptly reduce left ventricular hypertrophy (LVH) and vascular structural changes. It is possible that all antihypertensive agents, when used for long enough periods, will reduce LV mass, whereas only certain drugs will reduce mass within a period of few months, so that any difference among classes of antihypertensive drugs is more quantitative than absolute. However, a rapid reversal of LVH may be particularly important because reducing blood pressure in the presence of an elevated LV mass may be associated with impairment of coronary perfusion. Structural changes of small resistance arteries play a significant role in the genesis of increased vascular resistance in hypertension and in the maintainance of high blood pressure values. Studies in humans have demonstrated that minimal vascular resistance can be reduced with the use of different antihypertensive drugs, while a complete normalization of the media: lumen ratio was observed only with ACE inhibitors. Further studies are needed to assess the true clinical impact, in terms of reduced morbidity and mortality of reversal of cardiovascular structural changes in hypertensive patients. However, available studies indicate that reversal of LVH reduces the pathological consequences of increased left ventricular mass, and preliminary data suggest that complete regression of LVH may be associated to a decreased risk for cardiovascular events.

Objective: The aim of the present study was to assess the prognostic value of changes in left ventricular hypertrophy in hypertensive patients with time., Design: Two hundred and fifteen uncomplicated hypertensive patients underwent a high-quality baseline echocardiogram for left ventricular anatomy evaluation and in 151 of those patients the echocardiographic examination was repeated 10 +/- 1.4 years after the initial study., Methods: Left ventricular mass index changes were evaluated, in relation to the incidence of non-fatal cardiovascular events, adjusted for traditional cardiovascular risk factors., Results: According to the presence or absence of left ventricular hypertrophy (left ventricular mass index > 134 g/m2 in men and > 110 g/m2 in women) at baseline and at the end of follow-up study, patients were divided into four groups: with normal left ventricular mass at both examinations (n = 78), with regression of left ventricular hypertrophy (n = 32), with persistence of left ventricular hypertrophy (n = 34) and with hypertrophy development (n = 7). After adjustment for traditional cardiovascular risk factors, the cumulative incidence of non-fatal cardiovascular events was significantly higher in the group of patients without regression of left ventricular hypertrophy. Cox survival analysis showed the presence of left ventricular hypertrophy at the end of follow-up study to be the most important factor related to cardiovascular events., Conclusions: The present findings strongly indicate that the lack of decrease or the increase of left ventricular mass after antihypertensive treatment can be associated with a higher risk for cardiovascular events, which is significantly reduced and almost normalized by complete regression of left ventricular hypertrophy.

The vasoprotective activity of lacidipine has been demonstrated both in animals and humans. Results from several studies indicate that vital organ perfusion is maintained, or even increased, during lacidipine administration. Left ventricular hypertrophy (LVH) represents an independent risk factor for cardiovascular events. Lacidipine has been shown to reduce LVH significantly within 3 months of initiation of treatment. In addition, systolic function, as evaluated by ejection fraction and fractional shortening of the left ventricle, is unchanged after 6 months of treatment with lacidipine. Diastolic function may also be improved by this treatment. In large arteries, lacidipine can reverse the abnormal arterial compliance observed in patients with essential hypertension. Other studies, in spontaneously hypertensive rats, have shown that lacidipine can significantly reduce the elevated media/lumen ratio of small resistance arteries. In conclusion, lacidipine possesses vascular selectivity and its effect in essential hypertension is characterized by vasodilation and by the maintenance, or even improvement, in vital organ perfusion.

Left ventricular hypertrophy (LVH) in hypertension is initially a useful compensatory process, but it can also represent the first step toward a pathologic process that leads to the development of congestive heart failure. In fact, epidemiologic studies have documented that LVH in essential hypertension represents an independent risk factor for cardiovascular morbidity and mortality. Reversing or even preventing LVH, through a reduction of elevated blood pressure values and modification of some other pathogenetic factors, should represent a major therapeutic goal for the treatment of hypertensive patients. It has been demonstrated that different classes of antihypertensive drugs do not have the same effect in reducing left ventricular mass, probably because, beyond the control of blood pressure, their pharmacologic interference with the adrenergic system, the renin-angiotensin-aldosterone system, or other growth factors can influence the development and the reduction of cardiac hypertrophy. Two recent meta-analyses of the principal regression studies have indicated that angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists, followed by drugs capable of reducing sympathetic nervous system activity, are most effective in decreasing LV mass. The results of experimental and clinical studies have demonstrated that the reversal of cardiac hypertrophy is associated with an improvement of the functional consequences of increased LV mass. Further studies are needed to verify whether the reversal of LVH per se increases survival rate in patients with essential hypertension.