Journal of hypertension. Supplement : official journal of the International Society of Hypertension最新文献

Clinical trials have shown that effective control of blood pressure reduces the risk of cardiovascular events in high-risk patients. For example, data from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study show significant reductions in the incidence of cardiac events, stroke and all-cause mortality in patients in whom blood pressure control was achieved compared with those in whom blood pressure remained uncontrolled. Although the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) demonstrated no significant difference in cardiovascular mortality and morbidity between patients receiving diuretics, calcium channel blockers or angiotensin-converting enzyme (ACE) inhibitors, this finding might have been confounded by differences in the blood pressure reductions achieved with the three treatments. Other studies have consistently shown that newer antihypertensive agents, such as ACE inhibitors and calcium channel blockers, reduce cardiovascular events to a similar, or possibly greater, extent as older therapies, such as diuretics and beta-blockers. In particular, ACE inhibitors appear to offer additional benefits beyond blood pressure reduction in terms of reducing cardiovascular events and producing renoprotective effects. Angiotensin II receptor blockers (ARBs) have been less extensively studied, but there is evidence already that they have heart failure, stroke and renoprotective benefits. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) is currently comparing the effects of the ARB telmisartan 80 mg and the ACE inhibitor ramipril 10 mg, alone and in combination, on cardiovascular events in high-risk patients.

Incidences of potentially life-threatening cardiovascular events display a diurnal pattern, tending to be higher in the morning than at other times of day. The recording of blood pressure at pre-defined intervals under everyday circumstances is facilitated by ambulatory blood pressure monitoring (ABPM). This technique shows that systolic and diastolic blood pressures display a circadian rhythm in most individuals. Typically, at the end of the night on arousal, blood pressure surges. This surge coincides with increased cardiovascular events. A recent prospective study conducted in Japan, where the incidence of stroke is high, provides further evidence for the link between cardiovascular events and morning blood pressure surge. Prevalence of both silent ischaemic events and multiple cerebrovascular infarcts was highest among the elderly subjects studied, with the largest increase in blood pressure on awakening. An increased risk of cardiovascular morbidity and mortality is also seen in 'non-dippers' (i.e. individuals in whom the normal nocturnal fall in blood pressure is absent or blunted). ABPM is superior to clinic blood pressure in predicting cardiovascular morbidity and mortality, and this suggests that 24-h blood pressure control may be necessary to gain complete benefit from blood pressure-lowering therapy. Antihypertensive agents with a long duration of action have the potential to provide blood pressure control throughout the dosing interval and thus cover the critical early morning period when the blood pressure surges. Clinical studies that have compared telmisartan with shorter-acting angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors demonstrate that telmisartan has a sustained duration of action, with proven efficacy over the entire 24-h period between doses, including the critical early morning period.

Recognition that cardiovascular risk factors, such as hypertension, dyslipidaemia and diabetes mellitus, often cluster together has focused attention on the concept of total cardiovascular risk. Most current hypertension management guidelines emphasize the importance of assessing and managing the total risk in an individual patient. Due to the presence of additional risk factors, target-organ damage and associated clinical conditions, patients may be at high risk of cardiovascular events even when their blood pressure is normal or high-normal (systolic blood pressure 130-139 mmHg, diastolic blood pressure 80-89 mmHg). Such high-risk patients, although common in clinical practice, are often under-diagnosed. Intensive hypertensive therapy is recommended for high-risk patients. In most cases, this will necessitate combination therapy with two or more drugs. Moreover, antihypertensive therapy should form one component of a multifactorial approach aimed at treating all reversible risk factors. In the future, research should be aimed at controlling or reversing subclinical target-organ damage, the ultimate aim being to prevent the progression of cardiovascular risk in individuals at low or medium risk.

Although there has been a decline in the incidence of ischaemic heart disease in Western Europe, North America and Australia/New Zealand, it remains a major cause of morbidity and mortality worldwide due to rapidly increasing incidences in developing countries. Prevention is key to reducing the burden of this disease. The INTERHEART study performed in 52 countries around the world has shown that the major risk factors are tobacco smoking, elevated apolipoprotein A, hypertension, diabetes mellitus, abdominal obesity, psychosocial factors, low fruit and vegetable intake, physical inactivity and alcohol consumption. Strategies for prevention by reducing risk factors are applicable universally. Individual healthcare providers can implement primary and secondary preventive measures to individual patients. Primary prevention involves the avoidance of disease in high-risk subjects free of disease, whereas the purpose of secondary prevention is to avoid recurrence of myocardial infarction. The general principle is to encourage improved and proven lifestyle measures and to prescribe evidence-based effective medications. Primary prevention requires greater investment and planning to identify people at high risk, plus the implementation of life-style intervention and pharmacological prevention. In both situations, strategies will have to be tailored to suit individual countries and economies. Life-style measures (i.e. sensible diet, physical exercise and smoking cessation) are effective and need to be promoted. Compliance with preventive measures is achievable. Primordial prevention, which involves reducing the prevalence of risk factors, rests mainly on public education, media, legislation and government policy, and is very dependent on individual governments' commitment and determination. It requires promoting a healthier life-style in the population as a whole by encouraging people to seek alternatives and making them available.

We are currently fighting a battle against a stroke epidemic. Implementation of new treatment strategies could save many patients in the future. The control of blood pressure is a major objective; however, choosing specific antihypertensive therapy (e.g. an agent blocking the renin-angiotensin system) is also important. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study demonstrates potential benefits beyond blood pressure reduction of prescribing an angiotensin II receptor blocker (ARB) compared with more established therapy in patients with left ventricular hypertrophy (LVH). Losartan-based therapy brought about regression of LVH and reduced incidences of fatal and non-fatal stroke by 25%, new-onset diabetes by 25% and atrial fibrillation by 30% more than atenolol-based therapy for a similar blood pressure control and better tolerability. The Study on COgnition and Prognosis in the Elderly (SCOPE) study, although difficult to interpret, does not contradict an ARB benefit beyond blood pressure lowering in primary prevention linked to targeting the angiotensin type 1 receptor. The findings of the MOrbidity and mortality after Stroke, Eprosartan compared with nitrendipine in Secondary prevention (MOSES) trial suggest clear-cut ARB benefits independent of blood pressure lowering in secondary stroke prevention. Experimental findings and other clinical evidence further support the benefits of ARBs in stroke prevention. Telmisartan is an ARB with a particularly interesting profile for stroke; given the 24-hour efficacy with more pronounced protection against the morning blood pressure surge and peroxisome proliferator-activated receptor-gamma activity at clinical doses. The unique properties of telmisartan for secondary stroke prevention are being tested in the Prevention Regimen For Effectively avoiding Second Strokes (PRoFESS) study.

Background: Numerous studies have demonstrated that activation of the angiotensin II type 1 (AT1) receptor plays an important role in the pathogenesis of cardiovascular diseases.

Results: AT1-receptor activation by angiotensin II is not only involved in the regulation of blood pressure, water and sodium homeostasis, and control of other neurohumoral systems, but also leads to excessive production of reactive oxygen species and to hypertrophy, proliferation, migration, and apoptosis of vascular cells. AT1-receptor-induced oxidative stress may cause nitric oxide inactivation, lipid oxidation, and activation of redox-sensitive genes, such as chemotaxis and adhesion molecules, pro-inflammatory cytokines, and matrix metalloproteinases, all of which are involved in the initiation and progression of endothelial dysfunction and manifested atherosclerosis. The expression levels of the AT1-receptor define the biological efficacy of angiotensin II. Many agonists, such as, for example, angiotensin II, growth factors, low-density lipoprotein cholesterol, insulin, glucose, estrogen, progesterone, reactive oxygen species, cytokines, nitric oxide, and many others, are known to regulate AT1-receptor expression in vascular cells. The pathophysiological relevance of dysregulated AT1-receptor expression has been demonstrated in many cell culture and animal studies and interventional trials in humans. Hypercholesterolemia, estrogen deficiency, and diabetes mellitus are associated with enhanced vascular AT1-receptor expression, increased oxidative stress, and endothelial dysfunction. Importantly, treatment with AT1-receptor blockers may inhibit the onset and progression of vascular oxidative stress and inflammation, endothelial dysfunction, atherosclerosis, and related organ damage.

Conclusion: Inhibition of AT1-receptor activation is presumably a primary treatment goal in patients suffering from cardiovascular risk factors or manifested atherosclerotic diseases.

Background: Randomized clinical trials in patients with chronic heart failure and reduced left ventricular ejection fraction (LVEF) have demonstrated the life-saving and symptomatic benefits of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and, in more selected patients, spironolactone. Despite these major advancements, the prevalence of heart failure continues to increase mainly as a consequence of aging populations. The development of angiotensin II type 1 receptor blockers (ARBs) provides a pharmacologically distinct mechanism of inhibiting the renin-angiotensin-aldosterone system. ARBs offer the potential to produce further clinical improvements for patients with heart failure above and beyond ACE inhibitors, as well as an alternative for those intolerant to an ACE inhibitor.

Methods: The Candesartan in Heart failure--Assessment of Reduction in Mortality and morbidity (CHARM) programme was designed as three parallel, randomized, double-blind, placebo-controlled clinical trials comparing candesartan with placebo in three different but complementary populations of patients with symptomatic heart failure.

Results: In patients with intolerance to an ACE inhibitor and an LVEF of 40% or less (the CHARM-Alternative trial), candesartan reduced cardiovascular mortality and hospitalizations for heart failure by 23% (P < 0.001). In patients with an LVEF of 40% or less treated with an ACE inhibitor (the CHARM-Added trial), candesartan reduced cardiovascular death and hospitalization for chronic heart failure by 15% (P = 0.011). In patients with a LVEF greater than 40% (the CHARM-Preserved trial), hospitalizations for heart failure and new-onset diabetes were significantly reduced.

Conclusion: The CHARM programme, together with evidence from mechanistic studies and from other large trials with ARBs, constitutes a firm basis for including an ARB in the therapeutic arsenal in the treatment for chronic heart failure.

Principal results of the Study on COgnition and Prognosis in the Elderly (SCOPE) were published in 2003. Blood pressure reduction was pronounced in both the candesartan and control groups, with little difference. With candesartan-based treatment, compared with control, the relative risk of non-fatal stroke was 0.72 (P = 0.04) and of major cardiovascular events 0.89 (P = 0.19). There were no significant differences in cognitive outcomes. We have reviewed recent subgroup analyses in SCOPE. Cardiovascular endpoints were analysed in patients who did not receive add-on treatment after random allocation to groups (post hoc) and in patients with certain characteristics at baseline, such as age, sex, diabetes, isolated systolic hypertension, or a history of stroke. Cognitive endpoints were analysed in patients with baseline Mini Mental State Examination (MMSE) score 24-28, and in those examined with more extensive investigations than the MMSE. In patients without add-on treatment, there were significant risk reductions in the candesartan group in major cardiovascular events [relative risk (RR) 0.68, 95% confidence interval (CI) 0.51 to 0.92] and mortality (RR 0.73, 95% CI 0.57 to 0.95). In other subgroups, the relative risks for major cardiovascular events and stroke were generally consistent with those in the entire study population. However, risk reductions in the candesartan group were particularly marked in patients with a history of stroke. In patients with MMSE score 24-28 at baseline, the score declined significantly less in the candesartan group (between-group difference 0.49, 95% CI 0.02 to 0.97). Cardiovascular outcome benefit of candesartan-based treatment was most evident in patients without add-on treatment and in those with a history of stroke. Results in other subgroups were generally consistent with those in the entire SCOPE study population. In patients with slightly low cognitive function at baseline, the MMSE score declined less in the candesartan group.

Blockade of the renin-angiotensin system has become crucial in the management of type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus, especially in patients who are at risk of nephropathy. In this review, we address the issue of why the renin system and its blockade are so important. As in many complex processes, diabetic nephropathy reflects an interaction between genetic factors and environmental factors. Recent research has uncovered a number of environmental factors; control of these factors should contribute to improved management. The renin system is important in patients with diabetes mellitus because so many relevant factors converge on the intrarenal renin system.

Background: Effects of angiotensin II type 1 receptor blockers (ARBs) to improve endothelial dysfunction may be due to mechanisms in addition to the reduction of high blood pressure per se. Endothelial dysfunction is characterized by vascular inflammation that contributes to clinically significant atherosclerosis and by an increased tendency for thrombus formation. Hypertensive patients have impaired endothelial functions that have positive predictive power with respect to future cardiovascular events.

Objectives: The present review will focus on multiple mechanisms underlying vascular and metabolic effects of ARBs that may synergize to prevent or regress atherosclerosis, onset of diabetes, and coronary heart disease.

Conclusions: Angiotensin II accelerates the development of atherosclerosis by activating angiotensin II type 1 receptors that then promote superoxide anion generation and oxidative stress, leading to activation of nuclear transcription factor and endothelial dysfunction. Activation of angiotensin II type 1 receptors also stimulates increased expression of plasminogen activator inhibitor type 1 and tissue factor. Endothelial dysfunction associated with the metabolic syndrome and other insulin-resistant states is characterized by impaired insulin-stimulated production of nitric oxide from the endothelium and decreased blood flow to skeletal muscle. Increasing insulin sensitivity therefore improves endothelial function, and this may be an additional mechanism whereby ARBs decrease the incidence of coronary heart disease and the onset of diabetes. Adiponectin serves to link obesity with insulin resistance. In addition, adiponectin has anti-atherogenic properties.