The VO(2)-on kinetics in constant load exercise sub-anaerobic threshold reflects endothelial function and dysfunction in muscle microcirculation.

To propose a test to evaluate endothelial function, based on VO(2) on-transition kinetics in sub-anaerobic threshold (AT) constant load exercise, we tested healthy subjects and patients with ischemic-hypertensive cardiopathy by two cardiopulmonary tests on a cycle ergometer endowed with an electric motor to overcome initial inertia: a pre-test and, after at least 24 h, one 6 min constant load exercise at 90 % AT. We measured net phase 3 VO(2)-on kinetics and, by phase 2 time constant (tau), valued endothelial dysfunction. We found shorter tau in repeated tests, shorter time between first and second test, by persisting endothelium-dependent arteriolar vasodilatation and/or several other mechanisms. Reducing load to 80 % and 90 % AT did not produce significant changes in tau of healthy volunteers, while in heart patients an AT load of 70 %, compared to 80 % AT, shortened tau (delta=4.38+/-1.65 s, p=0.013). In heart patients, no correlation was found between NYHA class, ejection fraction (EF), and the two variables derived from incremental cycle cardio-pulmonary exercise, as well as between EF and tau; while NYHA class groups were well correlated with tau duration (r=0.92, p=0.0001). Doxazosin and tadalafil also significantly reduced tau. In conclusion, the O(2) consumption kinetics during the on-transition of constant load exercise below the anaerobic threshold are highly sensitive to endothelial function in muscular microcirculation, and constitute a marker for the evaluation of endothelial dysfunction.

Serum uric acid and its relationship with metabolic syndrome and cardiovascular risk profile in patients with hypertension: insights from the I-DEMAND study.

BACKGROUND AND AIMS: The independent role of serum uric acid (SUA) as a marker of cardio-renal risk is debated. The aim of this study was to assess the relationship between SUA, metabolic syndrome (MS), and other cardiovascular (CV) risk factors in an Italian population of hypertensive patients with a high prevalence of diabetes. METHODS AND RESULTS: A total of 2429 patients (mean age 62 ± 11 years) among those enrolled in the I-DEMAND study were stratified on the basis of SUA gender specific quartiles. MS was defined according to the NCEP-ATP III criteria, chronic kidney disease (CKD) as an estimated GFR (CKD-Epi) <60 ml/min/1.73 m(2) or as the presence of microalbuminuria (albumin-to-creatinine ratio ≥2.5 mg/mmol in men and ≥3.5 mg/mmol in women). The prevalence of MS, CKD, and positive history for CV events was 72%, 43%, and 20%, respectively. SUA levels correlated with the presence of MS, its components, signs of renal damage and worse CV risk profile. Multivariate logistic regression analysis revealed that SUA was associated with a positive history of CV events and high Framingham risk score even after adjusting for MS and its components (OR 1.10, 95% CI 1.03-1.18; P = 0.0060; OR 1.28, 95% CI 1.15-1.42; P < 0.0001). These associations were stronger in patients without diabetes and with normal renal function. CONCLUSIONS: Mild hyperuricemia is a strong, independent marker of MS and high cardio-renal risk profile in hypertensive patients under specialist care. Intervention trials are needed to investigate whether the reduction of SUA levels favorably impacts outcome in patients at high CV risk.

The need for combination antihypertensive therapy to reach target blood pressures: what has been learned from clinical practice and morbidity-mortality trials?

Pharmacological treatment of hypertension represents a cost-effective way for preventing cardiovascular and renal complications. To benefit maximally from antihypertensive treatment blood pressure (BP) should be brought to below 140/90 mmHg in every hypertensive patient, and even lower (< 130/80 mmHg) if diabetes or renal disease co-exists. Most of the time such targets cannot be reached using monotherapies. This is especially true in patients who exhibit a high cardiovascular risk. The co-administration of two agents acting by different mechanisms considerably increases BP control. Such preparations are not only efficacious, but also well tolerated, and some fixed low-dose combinations have a tolerability profile similar to placebo. This is for instance the case for the preparation containing the angiotensin-converting enzyme inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), a fixed low-dose combination that has recently been shown in controlled interventional trials to be more effective than monotherapies in reducing albuminuria, regressing cardiac hypertrophy and improving macrovascular stiffness. Fixed-dose combinations are becoming more and more popular and are even proposed by current hypertension guidelines as a first-line option to treat hypertensive patients.

Guía Europea de Prevención Cardiovascular en la Práctica Clínica (y II) / Spanish adaptation of the European Guidelines on Cardiovascular Prevention (and II)

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Left ventricular and carotid structure in untreated, uncomplicated essential hypertension: results from the Assessment Prognostic Risk Observational Survey (APROS).

The impact of hypertension on left ventricular (LV) and vascular structure and the relation of left ventricular hypertrophy (LVH) with vascular changes in untreated essential hypertensives has not been fully explored. This study investigated the prevalence of structural abnormalities of LV and carotid arteries and their determinants in a large population of untreated, uncomplicated essential hypertensive patients. The Assessment of Prognostic Risk Observational Survey was a multicentre (44 centres) prospective study including 1142 untreated hypertensives classified as low or medium cardiovascular risk on the basis of the routine diagnostic work-up recommended by the 1999 World Health Organization/International Society of Hypertension guidelines. All patients underwent ultrasound examinations of the heart and carotid arteries. LVH and carotid structural changes were diagnosed when: (1) LV mass index exceeded 125 g/m(2) in men and 110 g/m(2) in women; (2) there was at least one plaque (focal thickening>1.3 mm) in any segment of either carotid artery or a diffuse common carotid intima-media thickness (IMT) (average of IMT>/=0.8 mm) was present. Overall, 1074 patients (504 women, mean age 48.1+/-11.4 years) completed the study with ultrasonographic examinations of good technical quality. The prevalences of LVH and LV concentric remodelling in the total population were 26.8 and 10.7%, respectively. Eccentric hypertrophy was more prevalent than concentric hypertrophy (15.2 vs 11.6%). One or more carotid plaques or thickening were present in 27.4% of the patients. A stepwise increase in IM thickness occurred from the lowest values in patients with normal cardiac mass and geometry (0.68 mm) to intermediate in those with LV remodelling (0.76 mm) and eccentric LVH (0.81 mm) and to the highest level in patients with concentric LVH (0.87 mm). Patients with LV concentric remodelling and concentric LVH had a significantly greater relative carotid wall thickness than those with normal geometry and eccentric LVH (0.25 and 0.26 vs 0.18 and 0.19, respectively, P<0.01). According to a multivariate analysis age, blood glucose, systolic BP and pulse pressure were the main independent predictors of LVH, while age, systolic BP and total cholesterol were the variables with the greatest impact on IM thickening. To conclude, this study shows that: (1) altered patterns of LV structure and geometry and carotid structural changes occur in a large fraction of patients with untreated essential hypertension; (2) there is a significant association between carotid wall thickening and LVH; (3) the probability of LVH or carotid thickening is significantly greater in elderly, in patients with higher systolic BP and in patients with associated metabolic risk factors.

[Management of hypertensive patients with left ventricular hypertrophy]. / Prise en charge des hypertendus ayant une hypertrophie ventriculaire gauche.

CARDIOVASCULAR RISK OF LEFT VENTRICULAR HYPERTROPHY: Because of the rhythmic, mechanical and ischemic risk related to it, the left ventricular hypertrophy (LVH) is considered to be a major independent risk factor for cardiovascular disease which should be screened for and treated early. In patients with type 2 diabetes, left ventricular hypertrophy is mainly due to high blood pressure, but also to reduced elasticity of the large vessels, defective vasomotricity and dysfunction of the arterial endothelium. Obesity, elevated blood viscosity, hyperinsulinism and/or autonomous cardiac neuropathy can also have a favoring effect. THE LIVE STUDY: Is the first multicentric European study comparing the efficacy of a thiazide-like diuretic, slow-release indapamid, with a converting enzyme inhibitor, enalapril 20 mg, on the reduction of the left ventricular mass index (LVMI) in hypertensive subjects with LVH. The study involved a randomized centralized reading of the echocardiograms as well as a randomized and blinded reading at the end of the study. DEMONSTRATED SUPERIORITY OF INDAPAMID SR: The LIVE study clearly demonstrated the superiority of indapamid SR over enalapril 20 mg in reducing the LVMI in hypertensive subjects with LVH while the blood pressure lowering effect was comparable for the two treatments.

[Arterial hypertension in elderly individuals]. / Hypertension artérielle du sujet âgé.

EMERIAU STUDY IN ELDERLY HYPERTENSIVE PATIENTS: This multicenter, randomized, double-blind European study was conducted in 524 elderly patients of mean aged 72 years in three parallel treatment arms (indapamid SR 1.5 mg, amlopidine 5 mg hydrochlorothiazide 25 mg). The study demonstrated an equivalent antihypertensive effect for the three treatment arms and with a mean reduction in diastolic pressure of 23 mmHg. In the indapamid SR group, the rate of normalization was higher, both for elevated systolic-diastolic pressure and elevated systolic pressure, alone. HYVET STUDY: This is an ongoing randomized, double-blind trial designed to confirm the beneficial effect of antihypertensive treatment with indapamid SR in very elderly patients (> 80 years old).

Fixed combinations of delapril plus indapamide vs fosinopril plus hydrochlorothiazide in mild to moderate essential hypertension.

This 12-week randomized, parallel-group, multicenter study compared fixed combinations of delapril (D) 30 mg plus indapamide (I) 2.5 mg and fosinopril (F) 20 mg plus hydrochlorothiazide (H) 12.5 mg in 171 adult patients with mild to moderate essential hypertension. After a 2-week placebo run-in, sitting and standing systolic (SBP) and diastolic blood pressure (DBP) was measured by conventional sphygmomanometry. The primary efficacy endpoint was the percentage of normalized (sitting DBP < or =90 mm Hg) and responder (sitting DBP reduction of 10 mm Hg or DBP < or =90 mm Hg) patients. Treatment effects were analyzed in the intention-to-treat (ITT; n = 171) and the per-protocol (PP; n = 167) populations. The percentage of normalized and responder patients did not differ significantly between the D + I (87.4% and 92%) and the F + H (81% and 86.9%) ITT groups. Similar results were seen in the PP population. In ITT and PP patients, sitting and standing SBP and DBP values were comparable at baseline in the two groups and were significantly (P<.01) and similarly reduced at weeks 4, 8, and 12. Neither treatment induced reflex tachycardia, and both regimens were well tolerated. Four patients in the F + H group dropped out because of adverse events. In this study, the efficacy and safety of D + I were comparable to those of F + H in patients with mild to moderate essential hypertension.

The role of losartan in cost-effective hypertension control.

Despite recent guidelines emphasising the need for aggressive treatment in patients with elevated blood pressure, the control of hypertension in Europe and the USA is poor, imposing a considerable burden in terms of patient morbidity and mortality, and associated healthcare costs. A major factor contributing to the suboptimal control of hypertension is the failure of patients to adhere to their prescribed therapy. Drug side-effects are an important cause of non-compliance and prescribing a well-tolerated agent that promotes good compliance is therefore the key to the cost-effective management of hypertension. Several studies have demonstrated that patients are more likely to remain on therapy with the angiotensin II antagonist losartan than other antihypertensives. Although the acquisition costs of new antihypertensives such as losartan are greater than for older drugs, such costs represent only a small proportion of the total cost of prescribing antihypertensive therapy. When accessory costs are also considered, the total cost of care with newer antihypertensives is comparable with those for diuretics. The costs involved if therapy has to be switched due to unacceptable side-effects also need to be taken into account when assessing relative cost effectiveness. Furthermore, savings may accrue from the non-haemodynamic benefits of losartan, such as improved cognitive function and renal protection. Further studies will increase awareness of the true cost effectiveness of antihypertensive drugs.

Pharmacoeconomic challenges in disease management of hypertension.

Hypertension is a major global economic burden. Blood pressure management remains one of the most cost-effective methods of cardiovascular risk factor reduction. However, current hypertension management strategies remain sub-optimal and blood pressure remains poorly controlled in a high proportion of patients. Conventional economic studies in well controlled clinical trial settings have not adequately assessed factors such as non-compliance, switching and discontinuation of treatment which have an important impact on the costs of antihypertensive therapy in actual clinical practice. Furthermore, most conventional, randomized clinical studies may not fully reveal long-term benefits (e.g reductions in end-organ damage) which may be associated with newer therapeutic strategies. First-line use of rational, low-dose combination therapy can offer important advantages in terms of improved efficacy, tolerability and compliance, with reduced end-organ damage compared with conventional monotherapy. For newer hypertension management strategies, comprehensive pharmacoeconomic studies are needed which consider all of these important factors. Early economic analyses which failed to consider some of these newer issues should not hinder the more widespread use of novel strategies, including first-line low-dose combination therapy.

Statins and blood pressure regulation.

Hypertension and high serum cholesterol levels are two of the most relevant risk factors for cardiovascular diseases. A combined increase in both risk factors has been reported in a significant proportion of patients with coronary artery disease. Statins are the most widely used drugs to treat hypercholesterolemia, and they interact with blood pressure control in different populations of hypertensive patients. A significant reduction in blood pressure associated with the use of statins has been described in patients with untreated hypertension and in patients treated with antihypertensive drugs, particularly angiotensin converting enzyme inhibitors and calcium channel blockers. The effect of statins on blood pressure control has also been reported in diabetic patients. The mechanisms responsible for the hypotensive effect seem to be largely independent of the effect of statins on lipid profile, and are probably related to their interaction with endothelial function or angiotensin II receptors. The capacity of statins to improve blood pressure control could be a useful consideration for an integrated approach to better prevention of cardiovascular diseases.

Anti-ischemic effects of angiotensin-converting enzyme inhibitors: a future therapeutic perspective.

The renin-angiotensin system and angiotensin-converting enzyme (ACE) are increasingly being implicated in the pathogenesis of coronary artery disease and its sequelae and the potential of ACE inhibitors to protect the heart is a topic that has emerged recently as a matter for scientific discussion. Experimental and clinical studies have shown the beneficial effects of ACE inhibitors on the metabolism, function and structure of healthy and damaged hearts and these data support the concept of both primary and secondary cardioprotection with this class of drugs. Animal studies have demonstrated the potential beneficial effects of ACE inhibition at a variety of sites, including improvement of endothelial function, inhibition of platelet aggregation, prevention of atherosclerotic lesions and inhibition of myointimal proliferation, extending the concept to a more general definition of cardiovascular protection with ACE inhibitors involving both the heart and the vessels. ACE inhibitors prevent stimulation of smooth muscle cell angiotensin-II (A-II) receptors, thereby blocking both contractile and proliferative actions of A-II. In addition, ACE inhibition of kininase inhibits the breakdown of bradykinin, a direct stimulant of nitric oxide release from the intact endothelial cell. Thus, at the cellular level ACE inhibition shifts the balance of ongoing mechanisms in favour of those promoting vasodilatory, anti-aggregatory, antithrombotic and antiproliferative effects. Although these data have not all been validated in human studies, the reduction of ischemic events in studies of ACE inhibition in left ventricular dysfunction (LVD) and, more recently, also in patients without LVD, cannot be explained solely by improved hemodynamics, and it is possible that actions on the endothelium, the atherosclerotic process and platelets are at least in part responsible. So, the available data underlie the potential benefits of ACE inhibition in the field of ischemic heart disease and atherosclerosis; the results of ongoing studies in humans looking more directly at the influence of ACE inhibitors in this setting are awaited with interest.

Pharmacoeconomics of hypertension management: the place of combination therapy.

Pharmacological treatment of hypertension has been shown to reduce the risk of stroke, coronary events, heart failure and progression of renal disease. However, rates of successful blood pressure control remain low among treated patients while antihypertensive medication represents a large and increasing proportion of healthcare expenditure in many countries. Several influential pharmacoeconomic analyses have confirmed the cost effectiveness of conventional antihypertensive treatments, usually involving monotherapy with diuretics or beta-blockers, compared with alternative strategies. Recent research has shown that a considerable proportion of the total cost of antihypertensive treatment in general practice is due to factors such as inadequate blood pressure control, poor compliance with therapy, discontinuation and switching between therapies. These factors operate to a much lesser extent in well-conducted clinical trials, and have not been fully incorporated into most economic studies. Some novel strategies, particularly low dose combinations of antihypertensive agents, may offer advantages in terms of efficacy, reduced adverse effects and improved compliance with treatment. There is therefore a need for comprehensive pharmacoeconomic analyses of novel strategies, taking these additional factors into account. Until such studies are available, the wider use of low dose combination therapy and other novel strategies should not be held back on the basis of earlier economic studies that have not included all relevant considerations.

Beta-blockade in hypertension and congestive heart failure.

Hypertension is common and increases the risk of death from coronary artery disease and cerebral vascular disease. The reason for treating hypertension is to prevent the long-term complications of this disorder. Many studies of antihypertensive therapy have produced only modest reductions in coronary events; in particular, with the use of beta-blockers. Clinical trials and meta-analyses have shown a lesser effect of these drugs on primary prevention of coronary events, cardiovascular and total mortality with respect to other antihypertensive approaches based on the use of low-dose diuretic therapy, especially in the elderly, even if the reduction of stroke and heart failure (HF) were similar. New beta-blockers with vasodilating properties due to the capacity to enhance the release of endothelial nitric oxide, then lessening a contributory mechanism to the pathogenesis of atherosclerosis as endothelial damage and dysfunction, seem to possess considerable potential in the treatment of hypertension, particularly in terms of improvement of cardiovascular outcome of patients. In HF, there is now considerable interest in the therapeutic use of beta-blockade. Some recent clinical trials have demonstrated conclusive evidence of the beneficial effects of beta-blocker therapy on survival in chronic HF. As a result of these data, beta-blocker therapy has become part of standard therapy for patients with chronic HF, in addition to angiotensin-converting enzyme-inhibitors and diuretics. The treatment is, in general, well tolerated. There are, however, some unanswered questions. One is whether some beta-blockers may be better than others. The major mortality benefit is probably a class-effect of beta1-adrenoceptor blockade, but the differences between beta-blockers might be clinically relevant. For example, it is under debate whether ancillary properties of some beta-blockers, such as the capability of exerting antioxidant effects or enhancing the nitric oxide production, may contribute to the clinical effects of these drugs. Future clinical trials will report over the next few years and help to answer the question about differences in mortality effects among types of beta-blocking agents, thus correctly defining the precise role of these drugs in the wide spectrum of cardiovascular disease.

Healthcare benefits of very-low-dose combination treatment used in the management of hypertension.

There are several classes of effective pharmacological agents available for the treatment of hypertension. However, rates of successful blood pressure control remain low among treated patients, while antihypertensive medication represents a large and increasing proportion of healthcare expenditure in many countries. Several influential pharmacoeconomic analyses have confirmed the cost-effectiveness of conventional antihypertensive treatments, usually involving monotherapy using diuretics or beta-blockers, compared with alternative strategies. Recent research has shown that a considerable proportion of the total cost of antihypertensive treatment in general practice is attributable to factors such as inadequate blood pressure control, poor compliance with treatment, discontinuation of treatment, and switching between treatments. These factors are generally less influential in well-supervised clinical trials, and have not been fully incorporated into most economic studies. Some novel strategies, particularly the use of low-dose combinations of antihypertensive agents as first-line therapy, may offer advantages in terms of efficacy, reduced side effects, and improved compliance with treatment; these advantages would be predicted to result in improved cost-effectiveness. There is therefore a need for comprehensive pharmacoeconomic analyses of novel strategies, taking these additional factors into account. Until such studies are available, the wider use of low-dose combination treatments and other novel strategies should not be held back on the basis of findings of earlier economic studies that have not included all relevant considerations.

Effect of very early angiotensin-converting enzyme inhibition on left ventricular dilation after myocardial infarction in patients receiving thrombolysis: results of a meta-analysis of 845 patients. FAMIS, CAPTIN and CATS Investigators.

OBJECTIVES: We sought to investigate the effect of angiotensin-converting enzyme (ACE) inhibition <9 h after myocardial infarction (MI) on left ventricular (LV) dilation in patients receiving thrombolysis. BACKGROUND: The ACE inhibitors reduce mortality after MI. Attenuation of LV dilation has been suggested as an important mechanism. METHODS: The data of 845 patients with three-month echocardiographic follow-up after MI were combined from three randomized, double-blind, placebo-controlled studies. The criteria for these studies included: 1) thrombolytic therapy; 2) ACE inhibition within 6 to 9 h; and 3) evaluation of LV dilation as the primary objective. RESULTS: The ACE inhibitor was started 3.2+/-1.7 h after the patients' first (mainly, 85%) anterior MI. After three months, LV dilation was not significantly attenuated by very early treatment with an ACE inhibitor. The diastolic volume index was attenuated by 0.5 ml/m2 (95% confidence interval [CI] -1.5 to 2.5, p = 0.61), and the systolic volume index by 0.5 ml/m2 (95% CI -1.0 to 1.9, p = 0.50). Subgroup analysis demonstrated that LV dilation was significantly attenuated by ACE inhibitor treatment for patients in whom reperfusion failed. In contrast, LV dilation was almost unaffected by ACE inhibitor treatment in successfully reperfused patients. CONCLUSIONS: We could not demonstrate attenuation of LV dilation in patients receiving thrombolysis by ACE inhibitor treatment within 6 to 9 h after MI. We speculate that very early treatment with an ACE inhibitor has a beneficial effect on LV remodeling only in patients in whom reperfusion failed. Other mechanisms may be responsible for the beneficial effects of ACE inhibitors in successfully reperfused patients after MI.

Patterns of hypertension management in Italy: results of a pharmacoepidemiological survey on antihypertensive therapy. Scientific Committee of the Italian Pharmacoepidemiological Survey on Antihypertensive Therapy.

OBJECTIVE: To collect statistically significant information on patterns of antihypertensive therapy in medical practice, with particular attention to the drugs used in the pharmacological management of hypertensive patients and the reasons for the limited achievement of therapeutic goals during treatment DESIGN: A survey conducted among general practitioners, specialists, and hypertensive patients. METHODS: A total of 28,000 physicians were contacted by letter and 3,394 declared their willingness to participate and received a questionnaire. Subsequently, 1,255 questionnaires suitable for analysis (corresponding to 37.0% of adhering physicians) were received. In addition, 4,612 questionnaires completed by patients were pooled and evaluated. The prevalence of hypertension was calculated from a base of 254,192 patients, seen by general practitioners. RESULTS: The prevalence of hypertension, defined as systolic blood pressure > or = 160 mmHg or diastolic blood pressure > or = 95 mmHg, or current treatment, was 19.7%. The average number of hypertensive patients in each general practitioner's file, covering the previous 12 months, was approximately 230. Physicians reported a 66% rate of discontinuation of treatment or switching to another drug. Physicians and patients both considered inadequate blood pressure control and side effects to be the two main reasons for switching antihypertensive therapy, but in opposite order. Furthermore, physicians indicated a prevalence of drug side effects between 10 and 20%, according to class of drug used, whereas 69% of patients reported to have experienced side effects. In the doctors' opinions, there were many reasons for poor patient adherence: complexity of the drug regimen, appearance of side effects, forgetfulness, reduced patient understanding of the need for long-term continuation of treatment, and refusal to accept a chronic pathological condition. CONCLUSIONS: The survey showed awareness of the disease among physicians and provides a representation of the experiences of both general practitioners and specialists, in addition to that of their patients. During antihypertensive therapy, a disconcerting degree of discontinuation and switching of drugs occurred. Insufficient blood pressure control and side effects accounted for most of the observed treatment changes. This survey revealed the existence of a gap between the physicians' perception of tolerability and the real experience of patients, a clear need for greater tolerability of treatments, and a need for an enhancement of patient-physician communication.