Activation of the AT1 angiotensin II (Ang II) receptors has various effects including vasoconstriction, hypertrophy, and possibly hyperplasia of vascular smooth muscle cells and cardiomyocytes and increase in extracellular collagen matrix synthesis. These actions lead to the development of cardiovascular hypertrophy and fibrosis, as well as arterial stiffness, which are some key factors in the development of the cardiovascular and renal complications. In clinical studies, it has been shown that renin–angiotensin blockade has direct and specific implications in the evolution of heart failure, coronary disease, stroke, and hypertensive and diabetic renal disease. The beneficial cardiovascular and renal effects of blocking the renin–angiotensin–aldosterone system reported in numerous clinical trials may be at least partially related to the actions of these drugs on cardiovascular and renal fibrosis, and arterial stiffness. These effects are now well-established and lead the international medical societies to propose the use of the renin–angiotensin system (RAS) blockers as initial treatment (both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers) in several cardiovascular, metabolic, and renal disorders such as hypertension, heart failure, and proteinuria.
Hypertension in association with oxidative stress belongs to the most discussed topics within the literature on cardiovascular diseases. It is generally believed that elevated production of reactive oxygen species (ROS) plays an important role in hypertension, but clinical studies on chronic antioxidant therapy of hypertension fail to confirm this hypothesis. This discrepancy may be partly determined by the different effects of short and long-lasting treatment with antioxidants or scavengers. Elevated ROS production in hypertension need not be only harmful. It may also stimulate the activity of the antioxidant defence system and improve the nitric oxide (NO)/cyclic 3′, 5′-guanosine monophosphate pathway, resulting in the establishment of a new equilibrium between enhanced oxidative load and the stimulated NO pathway, thus maintaining sufficient NO bioavailability. It has been suggested that antioxidant treatment might be beneficial for a short time, until increased NO generation predominates over ROS production. Further weakening of ROS formation by antioxidants may attenuate nuclear factor kappa B activation resulting in decreased endothelial NO synthase expression and activity. Prolonged antioxidant therapy may thus attenuate the beneficial regulatory effect of ROS, leading to decreased NO generation and the re-establishment of the undesirable disproportion between deleterious and protective forces. As a consequence prolonged antioxidant treatment in human hypertension may fail to provide the expected clinical profit.
Objectives The effects of indapamide, a thiazide-like diuretic, and captopril, an angiotensin-converting enzyme inhibitor, on spontaneous hypertension and the development of left ventricular hypertrophy (LVH), nitric oxide generation and oxidant status were investigated. Methods Six-week-old male spontaneously hypertensive rats (SHR) were treated with indapamide (1 mg/kg per day) or captopril (10 mg/kg per day) or a combination of indapamide plus captopril. After the 6-week treatment, nitric oxide synthase (NOS) activity, the expression of NOS isoform proteins, conjugated dienes concentration and relaxation responses of the femoral artery were analyzed. Results Indapamide and captopril partly prevented a blood pressure increase in young SHR. Captopril in contrast to indapamide reduced LVH. The effect of the combined indapamide and captopril treatment on the prevention of hypertension was additive. Combined indapamide and captopril treatment increased NOS activity and endothelial NOS protein expression in the aorta and decreased conjugated dienes concentration in the kidney compared with the indapamide monotherapy group. Indapamide and indapamide and captopril treatment increased acetylcholine-induced relaxation of the femoral artery. Conclusion Whereas captopril reduced LVH, indapamide enhanced NOS activity and decreased oxidative damage in the case of the combined treatment. It is concluded that the complex protective effects of the combined indapamide plus captopril treatment on hypertension may be exerted via its effects on blood pressure, hypertrophy and vasorelaxation.
Angiotensin-converting enzyme (ACE) inhibitors are useful drugs for preventing cardiovascular disease and death in patients at risk. However, a significant proportion of patients experience side effects, mainly cough or less frequently angioedema, when treated with ACE inhibitors. Angiotensin receptor blockers (ARBs) are also useful drugs for treatment of hypertension, diabetic nephropathy and patients with left ventricular dysfunction or cardiac failure who are intolerant to ACE inhibitors. The Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) study examined the effect of a long-acting ARB, telmisartan, on cardiovascular events in a group of patients at high-risk for cardiovascular disease who were intolerant to ACE inhibitors. Five thousand nine hundred twenty-six patients with known intolerance to ACE inhibitors were randomized to telmisartan or placebo added to current treatments. The primary composite endpoint, a sum of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and hospitalization due to heart failure was nonsignificantly reduced in telmisartan-treated patients with respect to placebo (15.7 vs. 17%; relative risk reduction 8%). The key secondary endpoint (the primary endpoint excluding heart failure hospitalization) was reduced in telmisartan-treated patients by 13% (13 vs. 14.8%; P = 0.046). In conclusion, telmisartan reduces cardiovascular events in high-risk patients with the exception of heart failure hospitalization and can be considered as the first-line therapy in those intolerant to ACE inhibitors.
Prevention of diabetes represents an important therapeutic goal in current cardiovascular risk reduction strategies. Blockade of the renin-angiotensin system has been shown to markedly reduce the incidence of new-onset diabetes in different patient populations. Recent results from three large clinical endpoint trials with the angiotensin-II receptor blocker telmisartan regarding new-onset diabetes, atrial fibrillation, and left ventricular hypotrophy will be discussed. J Hypertens 27 (suppl 2): S36-S39 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
Hypertension control in populations, although improving, remains far from satisfactory, even though effective and inexpensive therapies are available. Among many factors responsible for this situation, poor adherence to treatment appears to be particularly important. Unfortunately, even if its causes have been quite well defined, this problem is still far from being solved in clinical practice. The present paper discusses the key issues related to treatment adherence, and discontinuation in hypertension, in the light of recent evidence coming from the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease trial (TRANSCEND).
Objective Melatonin was shown to reduce blood pressure, oxidative load and to increase nitric oxide bioavailability predisposing melatonin to have antiremodelling potential. Design The aim of this study was to show whether melatonin can reverse left ventricular remodelling in spontaneously hypertensive rats (SHR) and to compare this potential protective effect with captopril, spironolactone, or simvastatin. Methods Six groups of 3-month old rats (eight per group) were treated for 5 weeks: control untreated Wistar rats, control SHR, SHR plus melatonin (10 mg/kg per 24 h), SHR plus captopril (100 mg/kg per 24 h), SHR plus spironolactone (200 mg/kg per 24 h) and SHR plus simvastatin (10 mg/kg per 24 h). Their systolic blood pressure (SBP) was measured by the tail-cuff method. The relative weights of the left ventricle, nitric oxide synthase (NOS) activity, endothelial NOS and nuclear factor kappa B (NF-κB) protein expression, conjugated dienes concentration, level of collagenous proteins and hydroxyproline were measured. Results SBP was reduced by all drugs investigated but most prominently by captopril in SHR. The activity of NOS and endothelial NOS expression increased in the left ventricles of SHR compared with controls. Melatonin and spironolactone further increased NOS expression. Left ventricular oxidative load, estimated by NF-κB expression and conjugated dienes concentration, increased in SHR. Only melatonin reduced NF-κB expression and decreased conjugated diens concentration. Only captopril reduced left ventricular hypertrophy in SHR, whereas melatonin reduced collagenous protein concentration and hydroxyproline content in the left ventricle. Conclusion It is concluded that although melatonin, in comparison with captopril, did not reverse left ventricle hypertrophy, it reversed left ventricular fibrosis. This protection by melatonin may be caused by its prominent antioxidative effect.
The benefits of blood pressure control on the risks of major cardiovascular events are well established. In clinical trials conducted in patients with mild-to-moderate hypertension, the angiotensin II receptor blocker (ARB) telmisartan has been shown to provide reduction of blood pressure throughout the 24-h dosing interval. Clinical trials have also demonstrated that ARBs are effective agents in reducing the risk of cardiovascular mortality, stroke, heart failure and new-onset atrial fibrillation. Recently, the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study established that telmisartan reduces morbidity and mortality in a broad cross-section of patients at high risk for heart and vascular events, to an extent similar to that of the angiotensin-converting enzyme inhibitor ramipril. In addition, ONTARGET demonstrated that telmisartan is somewhat better tolerated than ramipril. Attributes such as effective blood pressure lowering, tolerability and convincing outcomes data mean that ARBs satisfy the requirements for first-line antihypertensive agents.
Clinical evaluation of cardiovascular risk in patients with hypertension is evolving from independently assessing well-known, traditional risk factors (e.g. hypertension, hypercholesterolemia, obesity, diabetes mellitus, smoking) towards an integrated, multidisciplinary clinical approach, aimed at determining the global (or total) cardiovascular risk profile in each individual patient for planning early and effective strategies for cardiovascular prevention. A paradigmatic example is provided by hypertension, in which new clinical behaviour implies a shift from focusing only on high blood pressure levels towards a more integrated approach, aimed at identifying and reducing global cardiovascular risk, as is highlighted in the European Guidelines. This approach arises from the acknowledgement that a cluster of cardiovascular risk factors is the rule, rather than the exception in hypertension. In addition, major cardiovascular diseases often develop from a subclinical level, which can be discovered at an early stage, thus providing the opportunity promptly to intercept and treat high-risk patients early. Identification of organ damage and assessment of hypertension-related clinical conditions can further contribute to a more precise definition of an individual total cardiovascular risk profile, and to the decision on when, how and how much to treat patients with hypertension. Implementing a clinical behaviour based on global cardiovascular risk assessment will help to target global cardiovascular risk reduction, while maintaining specific therapeutic goals for individual risk factors. This synergistic approach holds the best promise for treating total cardiovascular risk and reducing the mounting global burden of cardiovascular disease associated with hypertension.
Inhibition of the renin-angiotensin system (RAS) either with an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) has been shown to be beneficial for cardiorenal protection. The combination of both is an exciting prospect and pathophysiologically plausible. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study provides evidence that dual blockade does not further reduce cardiovascular events or worsen renal outcomes. However, in patients with existing diabetic nephropathy, a trend towards a better outcome was observed. Therefore, combination of ARBs and ACEIs could be an alternative for selected patients, but not a standard approach in the management of chronic kidney disease. The benefits of dual blockade on hard renal endpoints remain to be shown.
'Hard' primary endpoints from randomized clinical trials, such as cardiovascular morbidity and mortality data are usually considered as the backbone of evidence for clinical practice guidelines. However, 'intermediate' or 'surrogate' endpoints, for example, biological or imaging markers are increasingly being recognized for their importance in stratifying risk and determining treatment strategy in clinical practice. In hypertension, use of validated surrogate endpoints, notably left ventricular hypertrophy (LVH), microalbuminuria, arterial stiffness and carotid intima-media thickness are discussed. These variables are among those assessed in clinical practice, and are considered as predictors of cardiovascular risk. Moreover, some antihypertensive therapies can reverse these organ-damage abnormalities and improve cardiovascular prognosis partly independently from their blood pressure lowering effect. Recognizing the importance of identifying subclinical organ damage in the prediction of cardiovascular risk provides further support to physicians making decisions in their daily clinical practice and offers possibilities for prospective studies on cardiovascular prevention in populations of middle age with low cardiovascular risk. In this article we overview the advantages and disadvantages of morbidity/mortality trials and 'hard' versus 'soft' endpoints. We also considered the relevance of analyzing not only primary endpoints but also secondary endpoints.
Renin-angiotensin system blockers have been shown to reduce stroke risk, partly independent of their blood pressure-lowering effect. The PReventiOn regimen For Effectively avoiding Second Strokes (PRoFESS) trial, ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized AssessmeNt Study in aCE-iNtolerant subjects with cardiovascular Disease (TRANSCEND) recently showed potential benefits of the angiotensin II receptor blocker, telmisartan, in reducing secondary strokes. In PRoFESS, 20 332 ischemic stroke patients were randomized to telmisartan 80 mg versus placebo and to two antiplatelets in a 2 x 2 factorial design. After a mean exposure of 2 years, telmisartan showed a nonsignificant lower rate of recurrent stroke versus placebo [880 versus 934; hazard ratio 0.95; 95% confidence interval (CI) 0.86-1.04]. In a post-hoc analysis, from 6 months, telmisartan significantly reduced the number of strokes versus placebo (533 versus 608; hazard ratio 0.88; 95% CI 0.78-0.99; P = 0.042). In the stroke subgroup of ONTARGET, telmisartan 80 mg showed a trend toward reducing recurrent stroke versus ramipril 10 mg (hazard ratio 0.91; 95% CI 0.79-1.05). In the TRANSCEND study, 5926 patients who were intolerant to angiotensin-converting enzyme inhibitors were treated with 80 mg telmisartan or placebo. In a combined analysis of PRoFESS and TRANSCEND, the incidence of the composite of stroke, myocardial infarction, or vascular death was 12.8% for telmisartan versus 13.8% for placebo (hazard ratio 0.91; 95% CI 0.85-0.98; P = 0.013).
Several newer areas of hypertension research are presented in this supplement. First, the benefits of melatonin in the treatment of experimental hypertension including its cardioprotective effects are introduced. Second, the possible role of melatonin in the non-dipping blood pressure pattern is described. Third, two hypotheses discuss the potential reasons for the ineffectivness of antioxidants in hypertension treatment, and difficulties associated with interpretations of experimental findings in the model of the spontaneously hypertensive rat (SHR). Finally, interactions of indapamide with the nitric oxide system in SHR, the protective effect of angiotensin II type 1 receptor blockade against alterations in insulin-resistant rats, and the deleterious effect of a low protein diet on kidney maturation with the development of hypertension are presented.
Objective Melatonin was shown to reduce blood pressure, enhance nitric oxide availability and scavenge free radicals. There is, however, a shortage of data with respect to the effect of melatonin on pathological left ventricular remodelling associated with haemodynamic overload. Design We investigated whether melatonin was able to prevent left ventricular hypertrophy (LVH) and fibrosis associated with NG-nitro-L-arginine-methyl ester (L-NAME)-induced hypertension. Methods Four groups of male Wistar rats were investigated: control, L-NAME (50 mg/kg per day), melatonin (10 mg/kg per day) and L-NAME plus melatonin. Blood pressure was measured non-invasively each week. After 5 weeks of treatment the animals were killed and nitric oxide synthase (NOS) activity, endothelial and inducible NOS expression, the level of collagenous proteins, hydroxyproline and conjugated dienes in the left ventricle were determined. Results The administration of L-NAME inhibited NOS activity, increased conjugated dienes concentration, elevated blood pressure and induced LVH and fibrosis (indicated by increased collagenous proteins and hydroxyproline levels). The addition of melatonin to L-NAME treatment failed to prevent the attenuation of NOS activity and the development of LVH and prevented hypertension only partly. The administration of melatonin, however, completely prevented the increase in conjugated dienes concentration and the development of left ventricular fibrosis. NOS expression was not different among experimental groups. Conclusion Melatonin prevented the development of left ventricular fibrosis and the increase in oxidative load in rats with L-NAME-induced hypertension. The antifibrotic effect of melatonin seems to be independent of its effects on NOS activity and might be linked to its antioxidant properties.
In patients with arterial hypertension and/or high cardiovascular risk, including patients with diabetes, chronic ischemic heart disease and kidney disease, the risk of heart failure decreases with blood pressure reduction and the use of drugs that inhibit the renin-angiotensin system (RAS) [angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)]. The heart failure incidence seen in ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) is in line with this observation. In ONTARGET, telmisartan and ramipril were equally effective in heart failure prevention and with the same blood pressure reduction. The low event rate, including the low incidence of heart failure in TRANSCEND with the greater use of diuretics in the placebo arm, may help to explain the absence of significant differences between telmisartan and placebo.
Clinical practice guidelines on the management of hypertension such as the 2007 European Society of Hypertension (ESH)/European Society of Cardiology (ESC) Guidelines were developed with the objective of allowing a greater number of patients with high blood pressure to be detected and effectively treated. The acceptance of hypertension guidelines and their implementation in clinical practice by ‘front-line’ physicians continues to be less than optimal for a variety of reasons, however, including the gap between academic guideline writers and those whose task it is to implement the guidelines, the physicians’ own attitudes and knowledge, the characteristics of the guideline itself, patient-related factors, and external barriers such as a lack of adequate resources. In Spain, a survey of the opinions of Spanish physicians on the 2007 ESH/ESC hypertension Guidelines found that there was agreement that the guidelines allow a better stratification of cardiovascular risk, better control of risk factors related to hypertension, better implementation of an individualized treatment programme, and facilitate choice of the best therapeutic approach for each patient, but there was no consensus that adherence to the guidelines achieves better control of hypertension or that it is more likely to prevent future cardiovascular events. In future, there needs to be a continuous process involving education and audit that takes into account the full spectrum of barriers to acceptance and implementation of hypertension guidelines to ensure that their full potential in reducing the strain on healthcare delivery systems imposed by undiagnosed, untreated and uncontrolled hypertension can be realized.
The Heart Outcomes Prevention Evaluation study established the angiotensin-converting enzyme inhibitor ramipril, versus placebo, for prevention of cardiovascular events in high-risk patients. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) was later conducted in similar high-risk patients using multifactorial treatment to control hypertension, platelet aggregation, and dyslipidemia, while comparing ramipril, telmisartan, or their combination, without placebo. In ONTARGET, the first angiotensin II receptor blocker-based study to be performed in a broader population of patients without congestive heart failure and/or left ventricular hypertrophy/dysfunction, telmisartan provided cardiovascular protection that was noninferior to ramipril. However, greater blockade of the renin-angiotensin system, using their combination, was not superior to ramipril alone. Telmisartan was better tolerated than ramipril in this high-risk population: notably, the incidence of cough and angioedema was significantly lower with telmisartan alone. Thus, telmisartan provides comparable efficacy to ramipril with less adverse events, which may encourage patient compliance.
Objectives Plasma melatonin concentrations in non-dipping patients show a blunted daily rhythm. Melatonin has a capacity to improve disturbances in biological rhythms. Hypertensive TGR(mRen2)27 (TGR) rats with an upregulated renin–angiotensin system and inverted blood pressure profile were used to elucidate whether melatonin is able to influence the control of blood pressure. Design Melatonin was administered in drinking water to normotensive Sprague–Dawley (SD) and hypertensive TGR rats during the dark phase of the light: dark cycle 12: 12 for 4 weeks. Methods The effect of melatonin on blood pressure was monitored, and the expression of clock genes per2 and bmal1 and melatonin receptor MT1 in the suprachiasmatic nucleus (SCN) and the heart was measured by real time polymerase chain reaction during a 24-h cycle. Results and conclusion The administration of melatonin did not influence clock gene expression in the SCN but its effect on clock gene expression in the heart was phase dependent in both SD and TGR rats. Melatonin administration did not decrease the expression of melatonin receptors in the SCN and the heart. Melatonin did not decrease blood pressure in TGR rats but influenced the peripheral oscillator in the heart independently of the SCN. A modified function of molecular circadian oscillators in the heart can interfere with anticipation and disturb the adaptation of this organ to pressure overload.
Impaired kidney function increases the risk of cardiovascular morbidity and mortality. Coexistence of hypertension and type 2 diabetes increases the risk of kidney damage, hypertension being an independent risk factor for kidney disease progression. Angiotensin II, through its inflammatory, proliferative, and thrombotic effects, adversely affects renal perfusion and increases oxidative stress, thus playing a pivotal role in kidney disease progression. Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors improve markers of kidney disease and slow kidney disease progression in diabetic and nondiabetic patients; this kidney protection may be in addition to their antihypertensive activity in those with advanced proteinuric nephropathy. Key beneficial effects of ARBs and ACE inhibitors throughout the kidney disease continuum are primarily explained by blood pressure lowering effects and partially by their direct blockade of angiotensin II. Recent studies have shown that telmisartan, an ARB with high lipophilicity and the longest half-life compared with other ARBs, provides benefits on markers of cardiovascular risk, that is, microalbuminuria and slowing of early-stage nephropathy.
Hypertension is one of the most important causes of cardiovascular morbidity and mortality and its treatment is a major focus of primary and secondary disease prevention strategies. The treatment of hypertension continues to evolve and the need for guidance on the use of newer screening tools, techniques for blood pressure measurement and different classes of drug therapies led to the first European guidelines for the management of arterial hypertension being issued in 2003 by the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC). The first update of these guidelines in 2007 crystallized much of the modern thinking about the evaluation and treatment of patients with hypertension with a sharp focus on detailed assessment of subclinical organ damage and cardiovascular disease risk, as well as differential blood pressure treatment targets and thresholds for those at different levels of risk. This review focuses on the 2007 ESH/ESC Guidelines, highlighting the evolution of treatment strategies in order to meet the challenge of improving blood pressure control in Europe. In particular, development of patient-centred treatment strategies, the benefits of blood pressure lowering, drug-specific influences over clinical outcomes, recommendations for the pharmacological treatment of hypertension and the role of combination therapies are discussed.
