With respect to structural and functional cardiac disorders, heart failure (HF) is divided into HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Oxidative stress contributes to the development of both HFrEF and HFpEF. Identification of a broad spectrum of reactive oxygen species (ROS)-induced pathways in preclinical models has provided new insights about the importance of ROS in HFrEF and HFpEF development. While current treatment strategies mostly concern neuroendocrine inhibition, recent data on ROS-induced metabolic pathways in cardiomyocytes may offer additional treatment strategies and targets for both of the HF forms. The purpose of this article is to summarize the results achieved in the fields of: (1) ROS importance in HFrEF and HFpEF pathophysiology, and (2) treatments for inhibiting ROS-induced pathways in HFrEF and HFpEF patients. ROS-producing pathways in cardiomyocytes, ROS-activated pathways in different HF forms, and treatment options to inhibit their action are also discussed.

Beta-blockers and inhibitors of the renin-angiotensin-aldosterone system improve survival and reduce morbidity in people with heart failure with reduced left ventricular ejection fraction (LVEF); a review of the evidence is required to determine whether these treatments are beneficial for people with heart failure with preserved ejection fraction (HFpEF).

To assess the effects of beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor neprilysin inhibitors, and mineralocorticoid receptor antagonists in people with HFpEF.

We updated searches of CENTRAL, MEDLINE, Embase, and one clinical trial register on 14 May 2020 to identify eligible studies, with no language or date restrictions. We checked references from trial reports and review articles for additional studies.  SELECTION CRITERIA: We included randomised controlled trials with a parallel group design, enrolling adults with HFpEF, defined by LVEF greater than 40%.

We used standard methodological procedures expected by Cochrane.

We included 41 randomised controlled trials (231 reports), totalling 23,492 participants across all comparisons. The risk of bias was frequently unclear and only five studies had a low risk of bias in all domains. Beta-blockers (BBs) We included 10 studies (3087 participants) investigating BBs. Five studies used a placebo comparator and in five the comparator was usual care. The mean age of participants ranged from 30 years to 81 years. A possible reduction in cardiovascular mortality was observed (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.62 to 0.99; number needed to treat for an additional benefit (NNTB) 25; 1046 participants; three studies), however, the certainty of evidence was low. There may be little to no effect on all-cause mortality (RR 0.82, 95% CI 0.67 to 1.00; 1105 participants; four studies; low-certainty evidence). The effects on heart failure hospitalisation, hyperkalaemia, and quality of life remain uncertain. Mineralocorticoid receptor antagonists (MRAs) We included 13 studies (4459 participants) investigating MRA. Eight studies used a placebo comparator and in five the comparator was usual care. The mean age of participants ranged from 54.5 to 80 years. Pooled analysis indicated that MRA treatment probably reduces heart failure hospitalisation (RR 0.82, 95% CI 0.69 to 0.98; NNTB = 41; 3714 participants; three studies; moderate-certainty evidence). However, MRA treatment probably has little or no effect on all-cause mortality (RR 0.91, 95% CI 0.78 to 1.06; 4207 participants; five studies; moderate-certainty evidence) and cardiovascular mortality (RR 0.90, 95% CI 0.74 to 1.11; 4070 participants; three studies; moderate-certainty evidence). MRA treatment may have little or no effect on quality of life measures (mean difference (MD) 0.84, 95% CI -2.30 to 3.98; 511 participants; three studies; low-certainty evidence). MRA treatment was associated with a higher risk of hyperkalaemia (RR 2.11, 95% CI 1.77 to 2.51; number needed to treat for an additional harmful outcome (NNTH) = 11; 4291 participants; six studies; high-certainty evidence). Angiotensin-converting enzyme inhibitors (ACEIs) We included eight studies (2061 participants) investigating ACEIs. Three studies used a placebo comparator and in five the comparator was usual care. The mean age of participants ranged from 70 to 82 years. Pooled analyses with moderate-certainty evidence suggest that ACEI treatment likely has little or no effect on cardiovascular mortality (RR 0.93, 95% CI 0.61 to 1.42; 945 participants; two studies), all-cause mortality (RR 1.04, 95% CI 0.75 to 1.45; 1187 participants; five studies) and heart failure hospitalisation (RR 0.86, 95% CI 0.64 to 1.15; 1019 participants; three studies), and may result in little or no effect on the quality of life (MD -0.09, 95% CI -3.66 to 3.48; 154 participants; two studies; low-certainty evidence). The effects on hyperkalaemia remain uncertain. Angiotensin receptor blockers (ARBs) Eight studies (8755 participants) investigating ARBs were included. Five studies used a placebo comparator and in three the comparator was usual care. The mean age of participants ranged from 61 to 75 years. Pooled analyses with high certainty of evidence suggest that ARB treatment has little or no effect on cardiovascular mortality (RR 1.02, 95% 0.90 to 1.14; 7254 participants; three studies), all-cause mortality (RR 1.01, 95% CI 0.92 to 1.11; 7964 participants; four studies), heart failure hospitalisation (RR 0.92, 95% CI 0.83 to 1.02; 7254 participants; three studies), and quality of life (MD 0.41, 95% CI -0.86 to 1.67; 3117 participants; three studies). ARB was associated with a higher risk of hyperkalaemia (RR 1.88, 95% CI 1.07 to 3.33; 7148 participants; two studies; high-certainty evidence). Angiotensin receptor neprilysin inhibitors (ARNIs) Three studies (7702 participants) investigating ARNIs were included. Two studies used ARBs as the comparator and one used standardised medical therapy, based on participants' established treatments at enrolment. The mean age of participants ranged from 71 to 73 years. Results suggest that ARNIs may have little or no effect on cardiovascular mortality (RR 0.96, 95% CI 0.79 to 1.15; 4796 participants; one study; moderate-certainty evidence), all-cause mortality (RR 0.97, 95% CI 0.84 to 1.11; 7663 participants; three studies; high-certainty evidence), or quality of life (high-certainty evidence). However, ARNI treatment may result in a slight reduction in heart failure hospitalisation, compared to usual care (RR 0.89, 95% CI 0.80 to 1.00; 7362 participants; two studies; moderate-certainty evidence). ARNI treatment was associated with a reduced risk of hyperkalaemia compared with valsartan (RR 0.88, 95% CI 0.77 to 1.01; 5054 participants; two studies; moderate-certainty evidence).

There is evidence that MRA and ARNI treatment in HFpEF probably reduces heart failure hospitalisation but probably has little or no effect on cardiovascular mortality and quality of life. BB treatment may reduce the risk of cardiovascular mortality, however, further trials are needed. The current evidence for BBs, ACEIs, and ARBs is limited and does not support their use in HFpEF in the absence of an alternative indication. Although MRAs and ARNIs are probably effective at reducing the risk of heart failure hospitalisation, the treatment effect sizes are modest. There is a need for improved approaches to patient stratification to identify the subgroup of patients who are most likely to benefit from MRAs and ARNIs, as well as for an improved understanding of disease biology, and for new therapeutic approaches.

Information regarding efficacy of the angiotensin II receptor blocker, telmisartan, for treatment of proteinuria in dogs is limited.

To evaluate the antiproteinuric efficacy of telmisartan, as compared to enalapril, in dogs with chronic kidney disease and persistent, renal proteinuria.

Thirty-nine client-owned dogs with chronic kidney disease and urinary protein-to-creatinine ratio (UPC) > 0.5 (if azotemic) or ≥ 1.0 (if nonazotemic).

In this prospective, randomized, double-masked clinical trial, dogs were block randomized, according to presence or absence of azotemia and systemic arterial hypertension, to receive telmisartan (1.0 mg/kg PO q24h), or enalapril (0.5 mg/kg PO q12h), and followed for 120 days. Up-titration of study drug dosage on days 30 and 60, and addition of the other study drug at day 90, were performed if UPC > 0.5 was noted at these visits. Percentage change in UPC relative to baseline was calculated for all time points. Data are presented as median (range).

Thirty-nine (20 telmisartan-treated, 19 enalapril-treated) dogs were included. At day 30, percentage change in UPC was greater for telmisartan-treated (-65% [-95% to 104%]) vs enalapril-treated (-35% [-74% to 87%]) dogs (P = .002). Among dogs persistently proteinuric at earlier visits, telmisartan remained superior to enalapril at days 60 (P = .02) and 90 (P = .02). No difference in percentage change in UPC between study groups was observed at day 120, when combination therapy was allowed. Combination therapy resulted in relevant azotemia in 4/13 (31%) dogs.

Telmisartan might be a suitable first-line therapy for dogs with renal proteinuria.

The effect of dual renin-angiotensin system (RAS) inhibition in heart failure (HF) is still controversial. Systematic reviews have shown that dual RAS blockade may reduce mortality and hospitalizations, yet it has been associated with the increased risk of renal dysfunction (RD). Surprisingly, although RD in patients with HF is frequent, the effect of combining RAS inhibitors in HF patients with RD has never been studied in a meta-analysis.

A systematic review and meta-analysis of randomized clinical trials involving HF patients with RD who received dual blockade analyzing death, cardiovascular (CV) death or HF hospitalization, and adverse events.

Out of 2258 screened articles, 12 studies were included (34,131 patients). Compared with monotherapy, dual RAS inhibition reduced hazard ratio of death to 0.94 (p=0.07) and significantly reduced CV death or HF hospitalization to 0.89 (p=0.0006) in all individuals, and to 0.86 (p=0.005) in patients with RD and to 0.91 (p=0.04) without RD. Nevertheless, dual RAS blockade significantly increased the risk of renal impairment (40%), hyperkalemia (44%), and hypotension (42%), although discontinuation of treatment occurs only in 3.68% versus 2.19% (p=0.00001).

Dual RAS inhibition therapy reduces the risk of CV death or HF hospitalization. However, cautions monitoring for specific adverse events may be warranted.

Beta-blockers and inhibitors of the renin-angiotensin aldosterone system improve survival and reduce morbidity in people with heart failure with reduced left ventricular ejection fraction. There is uncertainty whether these treatments are beneficial for people with heart failure with preserved ejection fraction and a comprehensive review of the evidence is required.

To assess the effects of beta-blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor neprilysin inhibitors, and mineralocorticoid receptor antagonists in people with heart failure with preserved ejection fraction.

We searched CENTRAL, MEDLINE, Embase and two clinical trial registries on 25 July 2017 to identify eligible studies. Reference lists from primary studies and review articles were checked for additional studies. There were no language or date restrictions.

We included randomised controlled trials with a parallel group design enrolling adult participants with heart failure with preserved ejection fraction, defined by a left ventricular ejection fraction of greater than 40 percent.

Two review authors independently selected studies for inclusion and extracted data. The outcomes assessed included cardiovascular mortality, heart failure hospitalisation, hyperkalaemia, all-cause mortality and quality of life. Risk ratios (RR) and, where possible, hazard ratios (HR) were calculated for dichotomous outcomes. For continuous data, mean difference (MD) or standardised mean difference (SMD) were calculated. We contacted trialists where neccessary to obtain missing data.

37 randomised controlled trials (207 reports) were included across all comparisons with a total of 18,311 participants.Ten studies (3087 participants) investigating beta-blockers (BB) were included. A pooled analysis indicated a reduction in cardiovascular mortality (15% of participants in the intervention arm versus 19% in the control arm; RR 0.78; 95% confidence interval (CI) 0.62 to 0.99; number needed to treat to benefit (NNTB) 25; 1046 participants; 3 studies). However, the quality of evidence was low and no effect on cardiovascular mortality was observed when the analysis was limited to studies with a low risk of bias (RR 0.81; 95% CI 0.50 to 1.29; 643 participants; 1 study). There was no effect on all-cause mortality, heart failure hospitalisation or quality of life measures, however there is uncertainty about these effects given the limited evidence available.12 studies (4408 participants) investigating mineralocorticoid receptor antagonists (MRA) were included with the quality of evidence assessed as moderate. MRA treatment reduced heart failure hospitalisation (11% of participants in the intervention arm versus 14% in the control arm; RR 0.82; 95% CI 0.69 to 0.98; NNTB 41; 3714 participants; 3 studies; moderate-quality evidence) however, little or no effect on all-cause and cardiovascular mortality and quality of life measures was observed. MRA treatment was associated with a greater risk of hyperkalaemia (16% of participants in the intervention group versus 8% in the control group; RR 2.11; 95% CI 1.77 to 2.51; 4291 participants; 6 studies; high-quality evidence).Eight studies (2061 participants) investigating angiotensin converting enzyme inhibitors (ACEI) were included with the overall quality of evidence assessed as moderate. The evidence suggested that ACEI treatment likely has little or no effect on cardiovascular mortality, all-cause mortality, heart failure hospitalisation, or quality of life. Data for the effect of ACEI on hyperkalaemia were only available from one of the included studies.Eight studies (8755 participants) investigating angiotensin receptor blockers (ARB) were included with the overall quality of evidence assessed as high. The evidence suggested that treatment with ARB has little or no effect on cardiovascular mortality, all-cause mortality, heart failure hospitalisation, or quality of life. ARB was associated with an increased risk of hyperkalaemia (0.9% of participants in the intervention group versus 0.5% in the control group; RR 1.88; 95% CI 1.07 to 3.33; 7148 participants; 2 studies; high-quality evidence).We identified a single ongoing placebo-controlled study investigating the effect of angiotensin receptor neprilysin inhibitors (ARNI) in people with heart failure with preserved ejection fraction.

There is evidence that MRA treatment reduces heart failure hospitalisation in heart failure with preserverd ejection fraction, however the effects on mortality related outcomes and quality of life remain unclear. The available evidence for beta-blockers, ACEI, ARB and ARNI is limited and it remains uncertain whether these treatments have a role in the treatment of HFpEF in the absence of an alternative indication for their use. This comprehensive review highlights a persistent gap in the evidence that is currently being addressed through several large ongoing clinical trials.

Cardiac autonomic neuropathy (CAN) is a common and often-underdiagnosed complication of diabetes mellitus (DM). CAN is associated with increased mortality, cardiovascular disease, chronic kidney disease, and morbidity in patients with DM, but despite these significant consequences CAN often remains undiagnosed for a prolonged period. This is commonly due to the disease being asymptomatic until the later stages, as well as a lack of easily available screening strategies. In this article, we review the latest developments in the epidemiology, pathogenesis, diagnosis, consequences, and treatments of CAN in patients with DM.

Overactivity of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathophysiology of heart failure (HF) and chronic kidney disease (CKD). RAAS antagonists can significantly improve clinical outcomes, but monotherapy blocks but one step of the RAAS and can be bypassed through compensatory mechanisms. Providing more complete RAAS blockade by deploying drugs with complementary actions seemed logical - hence the practice of using dual (or triple) RAAS inhibitors. However, RAAS antagonists also exhibit dose-limiting side effects, including acute kidney injury, hyperkalaemia and hypotension, which blunt their overall effectiveness. Despite achieving better RAAS blockade, several trials failed to show clinical outcome improvements. Patients with concomitant CKD and HF (cardiorenal syndrome) are at the greatest risk of these adverse events and therefore the least able to benefit, yet they also have the worst prognosis. This paradox, where those most in need have fewest therapeutic options, poses three questions which are the focus of this review: whether (i) novel therapies that prevent adverse effects can restore therapeutic benefits to patients who would otherwise be RAAS-therapy intolerant, (ii) there are any validated alternatives to their use and (iii) newer approaches to the detection of fluid congestion are ready for implementation.

The role of angiotensin (Ang) (1-7) on the vasoconstrictor effect induced by angiotensins could be different in the presence of an ACE inhibitor or an ARB because Ang II is formed through several pathways. Therefore, the role of Ang (1-7) in Ang I and Ang II contraction was evaluated in aortas from Wistar rats after 48-hour coronary occlusion treated with captopril or losartan.

Concentration-response curves to Ang I or Ang II were conducted in the absence or presence of Ang (1-7) and A779: a) sham group; b) 48-hour coronary occlusion; c) treated with captopril or d) losartan (3.1 mg/kg, i.m.).

Captopril caused a significant increase in the contractile effect of Ang I and Ang II, while losartan reduced it. The presence of Ang (1-7) in the captopril group showed a reduction of the contraction compared to the sham group, while the treatment with losartan did not show a significant difference. Ang (1-7) presents effects different from Ang I or Ang II.

Ang (1-7) showed a modulatory role, suggesting Ang I did as well after treatment with an ACE inhibitor but not with an AT1 receptor antagonist.

Cardiac autonomic neuropathy (CAN) is an often overlooked and common complication of diabetes mellitus. CAN is associated with increased cardiovascular morbidity and mortality. The pathogenesis of CAN is complex and involves a cascade of pathways activated by hyperglycaemia resulting in neuronal ischaemia and cellular death. In addition, autoimmune and genetic factors are involved in the development of CAN. CAN might be subclinical for several years until the patient develops resting tachycardia, exercise intolerance, postural hypotension, cardiac dysfunction and diabetic cardiomyopathy. During its sub-clinical phase, heart rate variability that is influenced by the balance between parasympathetic and sympathetic tones can help in detecting CAN before the disease is symptomatic. Newer imaging techniques (such as scintigraphy) have allowed earlier detection of CAN in the pre-clinical phase and allowed better assessment of the sympathetic nervous system. One of the main difficulties in CAN research is the lack of a universally accepted definition of CAN; however, the Toronto Consensus Panel on Diabetic Neuropathy has recently issued guidance for the diagnosis and staging of CAN, and also proposed screening for CAN in patients with diabetes mellitus. A major challenge, however, is the lack of specific treatment to slow the progression or prevent the development of CAN. Lifestyle changes, improved metabolic control might prevent or slow the progression of CAN. Reversal will require combination of these treatments with new targeted therapeutic approaches. The aim of this article is to review the latest evidence regarding the epidemiology, pathogenesis, manifestations, diagnosis and treatment for CAN.

To compare the long term efficacy and adverse events of dual blockade of the renin-angiotensin system with monotherapy.

Systematic review and meta-analysis.

PubMed, Embase, and the Cochrane central register of controlled trials, January 1990 to August 2012.

Randomised controlled trials comparing dual blockers of the renin-angiotensin system with monotherapy, reporting data on either long term efficacy (≥ 1 year) or safety events (≥ 4 weeks), and with a sample size of at least 50. Analysis was stratified by trials with patients with heart failure versus patients without heart failure.

33 randomised controlled trials with 68,405 patients (mean age 61 years, 71% men) and mean duration of 52 weeks were included. Dual blockade of the renin-angiotensin system was not associated with any significant benefit for all cause mortality (relative risk 0.97, 95% confidence interval 0.89 to 1.06) and cardiovascular mortality (0.96, 0.88 to 1.05) compared with monotherapy. Compared with monotherapy, dual therapy was associated with an 18% reduction in admissions to hospital for heart failure (0.82, 0.74 to 0.92). However, compared with monotherapy, dual therapy was associated with a 55% increase in the risk of hyperkalaemia (P<0.001), a 66% increase in the risk of hypotension (P<0.001), a 41% increase in the risk of renal failure (P=0.01), and a 27% increase in the risk of withdrawal owing to adverse events (P<0.001). Efficacy and safety results were consistent in cohorts with and without heart failure when dual therapy was compared with monotherapy except for all cause mortality, which was higher in the cohort without heart failure (P=0.04 v P=0.15), and renal failure was significantly higher in the cohort with heart failure (P<0.001 v P=0.79).

Although dual blockade of the renin-angiotensin system may have seemingly beneficial effects on certain surrogate endpoints, it failed to reduce mortality and was associated with an excessive risk of adverse events such as hyperkalaemia, hypotension, and renal failure compared with monotherapy. The risk to benefit ratio argues against the use of dual therapy.

The most common risk factors for heart failure are hypertension and myocardial infarction. Angiotensin receptor blockers (ARBs) attenuate the deleterious effects of angiotensin II. Valsartan is a once or twice daily ARB that is FDA-approved for hypertension, LV dysfunction post-myocardial infarction and congestive heart failure as both an adjunct in ACE-inhibitor tolerant, and alternative in ACE-I intolerant patients.

This article presents a comprehensive review of the literature regarding the pharmacokinetics and pharmacodynamics of valsartan, with particular attention paid to the post-myocardial infarction population.

Valsartan is a safe, well-tolerated and readily titratable ARB. In addition to its vasodilatory effects there are pleotropic effects associated with the ARB such as modulation of a number of neurohormonal regulators, cytokines and small molecules. Given the clear evidence-based benefits above and beyond its hypertensive properties, it has the potential, if priced appropriately, to grow in its impact as a pharmacotherapeutic long after its patent expires.

Angiotensin II type 1 receptor antagonists (ARBs) are widely used as a substitute for angiotensin-converting enzyme inhibitors (ACEIs) to treat patients without heart failure, but their effect on cardiovascular morbidity and mortality has not been clearly determined. A systematic review and meta-analysis was undertaken to determine the impact of ARBs on cardiovascular outcomes in high-risk patients without heart failure.

A computerized literature search was carried out using PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, and EMBASE, from January 1990 to April 2008. The following search terms were used: 'hypertension', 'clinical trial', 'sartan', 'ARB', 'angiotensin receptor antagonist', 'losartan', 'candesartan', 'valsartan', 'irbesartan', 'eprosartan', 'telmisartan', 'olmesartan', 'coronary disease', 'coronary heart disease', 'myocardial infarction', 'cardiovascular disease', 'cerebrovascular disease', and 'stroke'. Criteria for inclusion of clinical trials in our meta-analysis were the use of a randomized control group not receiving an ARB and the availability of outcome data for any one of four endpoints: myocardial infarction (MI), stroke, cardiovascular death, and all-cause death (these were not always pre-specified endpoints in all trials). Out of 45 potentially relevant studies, 37 trials met the inclusion criteria. We tabulated all occurrences of these four adverse outcomes.

Homogenous subgroups were combined by means of a fixed-effects model, while heterogenous subgroups were not combined. In the subgroup without heart failure, ARBs, when compared with the control group, had an odds ratio of 1.09 (95% CI 1.00, 1.18; p = 0.05) for MI. Other endpoints, namely, cardiovascular death and all-cause death, did not reach statistical significance. There was a clear trend for fewer strokes in the ARB group, but these studies were clearly heterogenous, and therefore a pooled risk estimate was not computed.

After pooling more than 89 000 patients, there is no evidence to suggest that ARBs confer cardiovascular protection akin to ACEIs, and the results that emerged are not in favor of ARB therapy in terms of its use as a substitute for ACEIs in non-heart failure patients. ARBs may have a small benefit in terms of stroke risk, but the studies are heterogenous, making it very difficult to quantify this effect. Given that ACEIs protect against both stroke and MI, caution is advised in the use of ARBs as a substitute for ACEIs in patients without a heart failure indication, who are tolerant of an ACEI.

Chronic heart failure (HF) is a prevalent world-wide. Angiotensin receptor blockers (ARBs) are widely prescribed for chronic HF although their role is controversial.

To assess the benefit and harm of ARBs compared with ACE inhibitors (ACEIs) or placebo on mortality, morbidity and withdrawals due to adverse effects in patients with symptomatic HF and left ventricular systolic dysfunction or preserved systolic function.

Clinical trials were identified by searching CENTRAL, HTA, and DARE , (The Cochrane Library 2010 Issue 3), as well as MEDLINE (2002 to July 2010), and EMBASE (2002 to July 2010). Reference lists of retrieved articles and systematic reviews were checked for additional studies not identified by the electronic searches.

Double blind randomised controlled trials in men and women of all ages who have symptomatic (NYHA Class II to IV) HF and: 1) left ventricular systolic dysfunction, defined as left ventricular ejection fraction (LVEF) ≤40%; or 2) preserved ejection fraction, defined as LVEF >40%.

Two authors independently assessed risk of bias and extracted data from included studies.

Twenty two studies evaluated the effects of ARBs in 17,900 patients with a LVEF ≤40% (mean 2.2 years). ARBs did not reduce total mortality (RR 0.87 [95% CI 0.76, 1.00]) or total morbidity as measured by total hospitalisations (RR 0.94 [95% CI 0.88, 1.01]) compared with placebo.Total mortality (RR 1.05 [95% CI 0.91, 1.22]), total hospitalisations (RR 1.00 [95% CI 0.92, 1.08]), MI (RR 1.00 [95% CI 0.62, 1.63]), and stroke (RR 1.63 [0.77, 3.44]) did not differ between ARBs and ACEIs but withdrawals due to adverse effects were lower with ARBs (RR 0.63 [95% CI 0.52, 0.76]). Combinations of ARBs plus ACEIs increased the risk of withdrawals due to adverse effects (RR 1.34 [95% CI 1.19, 1.51]) but did not reduce total mortality or total hospital admissions versus ACEI alone.Two placebo-controlled studies evaluated ARBs in 7151 patients with a LVEF >40% (mean 3.7 years). ARBs did not reduce total mortality (RR 1.02 [95% CI 0.93, 1.12]) or total morbidity as measured by total hospitalisations (RR 1.00 [95% CI 0.97, 1.05]) compared with placebo. Withdrawals due to adverse effects were higher with ARBs versus placebo when all patients were pooled irrespective of LVEF (RR 1.06 [95% CI 1.01, 1.12]).

In patients with symptomatic HF and systolic dysfunction or with preserved ejection fraction, ARBs compared to placebo or ACEIs do not reduce total mortality or morbidity. ARBs are better tolerated than ACEIs but do not appear to be as safe and well tolerated as placebo in terms of withdrawals due to adverse effects. Adding an ARB in combination with an ACEI does not reduce total mortality or total hospital admission but increases withdrawals due to adverse effects compared with ACEI alone.

Activation of the renin-angiotensin-aldosterone system (RAAS) is the primary etiologic event in the development of hypertension in people with diabetes mellitus. Modulation of the RAAS has been shown to slow the progression and even cause regression of the microvascular and macrovascular complications associated with diabetes mellitus. Early pharmacotherapy with agents that decrease RAAS activation in the adipose tissue have had a dramatic impact on the prevalence of diabetes related complications. Recent data show that preventing the development of "angry fat" can prevent not just hypertension but also type 2 diabetes mellitus and its associated complications. This review updates what is known about angry fat and the role of RAAS inhibition in preventing the metabolic sequelae of local RAAS activation.

Angiotensin II receptor blockers have been proven to be beneficial in left ventricular failure. In patients with a morphologic right ventricle supporting the systemic circulation, its efficacy has not yet been established.

We designed a multicenter, prospective, randomized, double-blind, placebo-controlled trial studying the effect of valsartan in patients with a systemic right ventricle due to a congenitally or surgically corrected transposition of the great arteries. The primary end point is the change in right ventricular ejection fraction as measured by cardiovascular magnetic resonance or multidetector row cardiac computed tomography in case of pacemaker patients.

This large prospective, double-blind, randomized, placebo-controlled trial will establish the role of angiotensin II receptor blockers (valsartan) in the treatment of patients with a systemic right ventricle.

Activation of the renin-angiotensin-aldosterone system (RAAS) results in vasoconstriction, muscular (vascular and cardiac) hypertrophy and fibrosis. Established arterial stiffness and cardiac dysfunction are key factors contributing to subsequent cardiovascular and renal complications. Blockade of RAAS has been shown to be beneficial in patients with hypertension, acute myocardial infarction, chronic systolic heart failure, stroke and diabetic renal disease. An aggressive approach for more extensive RAAS blockade with combination of two commonly used RAAS blockers [ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)] yielded conflicting results in different patient populations. Combination therapy is also associated with more side effects, in particular hypotension, hyperkalaemia and renal impairment. Recently published ONTARGET study showed ACEI/ARB combination therapy was associated with more adverse effects without any increase in benefit. The Canadian Hypertension Education Program responded with a new warning: 'Do not use ACEI and ARB in combination'. However, the European Society of Cardiology in their updated heart failure treatment guidelines still recommended ACEI/ARB combo as a viable option. This apparent inconsistency among guidelines generates debate as to which approach of RAAS inhibition is the best. The current paper reviews the latest evidence of isolated ACEI or ARB use and their combination in cardiovascular diseases, and makes recommendations for their prescriptions in specific patient populations.

Inhibition of the renin-angiotensin-aldosterone system (RAAS) is a key strategy in treating hypertension and cardiovascular and renal diseases. However, RAAS inhibitors (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone receptor antagonists, and direct renin inhibitors) increase the risk of hyperkalemia (serum potassium >5.5 mmol/L). This review evaluates the effects on serum potassium levels of RAAS inhibitors. Using PubMed, we searched for clinical trials published up to December 2008 assessing the effects on serum potassium levels of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone receptor antagonists, and direct renin inhibitors, alone and in combination, in patients with hypertension, heart failure (HF), or chronic kidney disease (CKD); 39 studies were identified. In patients with hypertension without risk factors for hyperkalemia, the incidence of hyperkalemia with RAAS inhibitor monotherapy is low (< or =2%), whereas rates are higher with dual RAAS inhibition ( approximately 5%). The incidence of hyperkalemia is also increased in patients with HF or CKD (5% to 10%). However, increases in serum potassium levels are small ( approximately 0.1 to 0.3 mmol/L), and rates of study discontinuation due to hyperkalemia are low, even in high-risk patient groups (1% to 5%). Patients with HF or CKD are at greater risk of hyperkalemia with RAAS inhibitors than those without these conditions. However, the absolute changes in serum potassium are generally small and unlikely to be clinically significant. Moreover, these patients are likely to derive benefit from RAAS inhibition. Rather than denying them an effective treatment, electrolyte levels should be closely monitored in these patients.

The addition of the angiotensin II type 1 receptor blocker (ARB) candesartan to a angiotensin-converting enzyme inhibitor (ACEI) has been associated with improved clinical outcomes in patients with heart failure. However many do not tolerate combination therapy and concerns have been raised regarding excessive neurohormonal inhibition.

The majority of patients with chronic heart failure are not eligible or do not tolerate combination therapy with an ACEEI and ARB.

We prospectively evaluated 115 consecutive patients with heart failure (median age 74 y; 74% males; mean left ventricular ejection fraction 30%) within a district general hospital for eligibility and tolerance to combination therapy using candesartan in addition to recommended doses of an ACEI.

Overall, 109 (95%) were ineligible to initiate candesartan. The most frequent reasons were that, despite best efforts at optimization, 77% of patients were unable to achieve recommended doses of an ACEI, 29% were relatively asymptomatic, 20% had symptomatic hypotension, and 35% were already taking an ARB due to previous ACEI "intolerance." Overall, 6 (5%) of patients satisfied the eligibility criteria of whom 3 (3% of total) were already taking "optimal" doses of an ARB in addition to an ACEI. The remaining 3 patients commenced the titration schedule with candesartan. All 3 patients failed the first titration phase (4 mg once daily) within 2 weeks of initiation, due to the development of hyperkalemia.

The use of combination therapy with an ARB in addition to recommended doses of ACEI does not appear feasible in patients with heart failure in the general population, as the vast majority are not eligible.

Clinical trials have shown organ-protective effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs); however, cardiovascular mortality and morbidity rates, and decline in renal function remain high. In the ONTARGET trial in patients with hypertension at high cardiovascular risk, ACE inhibitor/ARB combination therapy provided no significant clinical outcome benefits over monotherapy, and was associated with a worse safety and tolerability profile. These results raise the question of whether ACE inhibitor/ARB, direct renin inhibitor (DRI)/ACE inhibitor and DRI/ARB combinations are of clinical value.

Using PubMed and EMBASE databases, we conducted a systematic review of clinical trials published before June 2008 evaluating dual intervention with ACE inhibitors and ARBs, and compared these with trials of DRI/ACE inhibitor or DRI/ARB combinations.

A total of 70 studies met the inclusion criteria for this analysis. In patients with hypertension, ACE inhibitor/ARB combinations provided limited additional reductions in blood pressure (BP) over monotherapy. Outcomes benefits were unclear: VALIANT and ONTARGET demonstrated no enhanced outcome benefit of combination therapy over monotherapy; Val-HeFT and CHARM-Added showed reduced morbidity/mortality in patients with heart failure, but at the expense of poorer tolerability. Combination therapy with the DRI aliskiren and an ACE inhibitor or ARB provided significant additional BP reductions over monotherapy in patients with mild-to-moderate hypertension, and reduced surrogate markers of organ damage in patients with heart failure or diabetic nephropathy, with generally similar safety and tolerability to the component monotherapies. No morbidity and mortality data for DRI/ACE inhibitor or DRI/ARB combinations are currently available.

ACE inhibitor/ARB combinations showed equivocal effects on clinical outcomes. DRI/ACE inhibitor and DRI/ARB combinations reduced markers of organ damage, but longer-term trials are required to establish whether more complete renin--angiotensin--aldosterone system control with aliskiren-based therapy translates into improved outcome benefits.

In the present study, we investigated the efficacy and safety of candesartan cilexetil (candesartan) as "add-on" treatment in congestive heart failure (CHF) in daily practice.

In this open-label, multicenter study 414 CHF outpatients (NYHA II/III) with left ventricular ejection fraction (LVEF) < or = 40% and plasma brain natriuretic peptide (BNP) levels > 200 pg/ml at baseline were enrolled. Patients were treated with standard therapy including at least one angiotensin converting enzyme inhibitor in addition to another CHF drug; 91% of the patients received beta-blockers. Candesartan was uptitrated to 32 mg/day (target dose if tolerated) during 6 weeks followed by constant dosing over 16 weeks. The primary endpoint plasma BNP was significantly reduced by 25% at week 22 (from 394 to 295 pg/ml, P < 0.0001 vs. baseline). Candesartan produced early and sustained improvements of plasma BNP/NT-pro-BNP, LVEF, and quality of life (SF-36) compared to baseline. Of patients on beta-blockers, 37% improved towards NYHA II/I at week 22 (P < 0.0001) and 53.5% of the patients in NYHA III at baseline improved into NYHA II/I at week 22 (n = 232, P < 0.0001). Candesartan was well tolerated; no unexpected findings were reported besides known adverse reactions including hypotension, hyperkalemia, and serum creatinine elevations.

Candesartan "add-on" treatment provides a good benefit/risk ratio in CHF outpatients in daily practice, although high-risk patients should be managed with frequent monitoring of BP, serum potassium, and renal function.

The addition of an angiotensin receptor blocker (ARB) to an angiotensin-converting enzyme inhibitor (ACEI) in patients with heart failure remains controversial. A recent meta-analysis showed that the combination therapy reduces hospitalization without improved survival. Whether excess risk is associated with this strategy has not been fully explored. We sought to quantify the risk of adverse events of combination therapy (ACEI+ARB) versus ACEI alone.

MEDLINE, EMBASE, BIOSIS, and Cochrane databases were searched. Eligible studies were randomized, placebo-controlled trials of ACEI versus the combination of ACEI+ARB in patients with heart failure or left ventricular dysfunction. Included studies were reviewed to determine the frequency of adverse effects leading to discontinuation of therapy.

Nine trials that enrolled 18,160 patients met the inclusion criteria. A total of 9199 patients received combination therapy, and 8961 patients received an ACEI only. Patients receiving combination therapy had an increased risk of developing any adverse effect by 2.3% (relative risk [RR] = 1.27, 95% confidence interval [CI] = 1.15-1.40, P < .00001, I(2) = 15.9%, number needed to harm [NNH] = 42), hypotension by 1.1% (RR = 1.91, 95% CI = 1.37-2.66, P = .0002, I(2) = 26.6%, NNH = 89), worsening renal function by 1% (RR = 2.12, 95% CI = 1.30-3.46, P = .003, I(2) = 67.3%, NNH = 100), and hyperkalemia by 0.6% (RR = 4.17, 95% CI = 2.31-7.53, P < .00001, I(2) = 0%, NNH = 149). There was no difference in angioedema (RR = 0.88, 95% CI = 0.43-1.80, P = .72, I(2) = 0%) or cough (RR = 0.84, 95% CI = 0.65-1.09, P = .19, I(2) = 0%).

The current cumulative evidence suggests that patients with left ventricular dysfunction have an increased risk of adverse events leading to discontinuation on ACEI+ARB combination therapy compared with ACEI alone. This excess risk, coupled with a lack of consistent mortality benefit, suggests that ARBs should not routinely be added to ACEI therapy for left ventricular dysfunction. If chosen, the combination strategy may warrant closer patient monitoring to detect adverse effects.

Drug treatment of chronic heart failure is undergoing continuous modifications according to the data of new trials. Treatment has to be adjusted to current guidelines. The state of the art of medical treatment of chronic heart failure is addressed in this report.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are commonly prescribed for the management of hypertension. In addition, each of these drug classes has been shown to be effective in the treatment of congestive heart failure, proteinuric chronic kidney disease, and most recently the high-cardiac-risk profile patient. The individual success of each of these drug classes has fueled the theory that given together, the overall biologic effect of both would surpass that of either given alone. The foundation of this premise, although biologically plausible, has yet to be proven in a compelling enough fashion to support the everyday use of these two drug classes in combination. Additional clarifying studies are required to establish whether specific patient subsets exist that might benefit from such combination therapy.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are regularly prescribed for the management of hypertension. Each of these drug classes has also been shown to provide survival benefits for patients with heart failure, proteinuric chronic kidney disease, and/or a high cardiac risk profile. The individual gains seen with each of these drug classes have led to speculation that their combination might offer additive if not synergistic outcome benefits. The foundation of this hypothesis, although biologically possible, has thus far not been sufficiently well proven to support the everyday use of these 2 drug classes in combination. Additional outcomes trials, which are currently proceeding to their conclusion, may provide the necessary proof to support an expanded use of these 2 drug classes in combination.

Inhibiting the synthesis of angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) inhibitor treatment has long been established as the recommended therapy for heart failure (HF). As ACE inhibitors are only partially effective in blocking the formation of Ang II, additional treatment with selective Ang II receptor blockers (ARBs) promise additional benefits in patients with HF. This hypothesis is currently being evaluated in Val-HeFT, a large-scale, randomised, double-blind, placebo-controlled study on the effects of adding the highly selective ARB valsartan to usual therapy (diuretics, digoxin, beta-blockers, ACE inhibitors) for HF treatment.

Valsartan is an angiotensin receptor antagonist that specifically blocks the angiotensin II type 1 receptors. It is an effective and well-tolerated once-daily antihypertensive agent, with a tolerability profile similar to placebo. A recent series of large-scale clinical trials have shown the benefits of valsartan in disease states beyond hypertension. Based on the results of the Val-HeFT (Valsartan in Heart Failure Trial) and VALIANT (Valsartan in Acute Myocardial Infarction Trial) studies, valsartan is indicated for use in patients with heart failure and in patients post-myocardial infarction. Recently, in the VALUE (Valsartan Antihypertensive Long-term Use Evaluation) trial, valsartan was no more cardioprotective than calcium channel blockers, but was shown to reduce the risk of developing new-onset diabetes in hypertensive patients at high risk of cardiac events compared with calcium antagonist treatment. In diabetic patients with microalbuminuria, valsartan has been shown to have benefits beyond those attributable to blood pressure lowering alone.

Diabetic nephropathy is a major cause of diabetes related morbidity and mortality. The first part of the current review was published in the last issue of this journal and discussed the important role of the renin-angiotensin system (RAS) in diabetic nephropathy and the genetic influence on development of endstage renal disease (ESRD) in diabetic patients. This second part of the review focus on the potential improvement of the current treatment strategy to slow down the loss of kidney function using dual blockade of the RAS with both ACE-inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs). Substantial evidence from short-term studies using surrogate endpoints indicates a beneficial impact of dual blockade of the RAS, not obtainable with single agent blockade alone, both in diabetic and non-diabetic renal disease. This conclusion has been confirmed and extended in a longterm trial with regard to prevention of ESRD in non-diabetic renal disease. Results indicate that dual blockade of the RAS may further slow down, but not arrest progressive loss of renal function. However, studies defining the optimal dose of ACE-I / ARBs without additional adverse effects are essential to ensure relevant comparison with dual blockade therapy. Trials using primary renal endpoints in diabetic nephropathy are still needed, and will finally establish the role of dual blockade of the RAS in a clinical setting.

The benefits of angiotensin-converting enzyme (ACE) inhibitors for the treatment of congestive heart failure (CHF) are well-established. A newer class of medications, angiotensin II receptor blockers (ARBs), may be a suitable replacement for ACE inhibitors as a result of a more complete inhibition of angiotensin II and better tolerability among patients. To examine the current literature on the efficacy and safety of ARBs in the setting of CHF, a Medline search was conducted of the English language literature for the years 1987 to 2005. Clinical trials that reported data on cardiac outcomes were reviewed. The earlier trials were direct ARB to ACE inhibitor comparisons (ELITE I and ELITE II). These studies indicated that ARBs do not confer an improvement in cardiac outcomes over ACE inhibitors. RESOLVD, Val-HeFT, and the 3 separate trials of the CHARM program investigated the addition of an ARB to standard therapy. The RESOLVD trial showed no significant differences in clinical events among ACE inhibitor, ARB, and their combination. Although no mortality benefit was evident in the Val-HeFT trial, a substantial reduction in CHF rehospitalizations was reported among patients who were not receiving ACE inhibitor therapy. The CHARM-Overall program demonstrated a significant benefit in cardiovascular death and hospital admissions for CHF with the addition of ARB to standard therapy, a benefit that was more pronounced in patients with depressed left ventricular ejection fraction. In the setting of CHF, rates of cardiac outcomes do not differ substantially between ARBs and ACE inhibitors. However, their combination may improve outcomes for patients with CHF.

To investigate the effect of angiotensin converting enzyme inhibition (ACE-I) or angiotensin receptor blockade (ARB), and their combination, on both diabetic autonomic neuropathy (DAN) and left ventricular (LV) diastolic dysfunction (LVDD) in asymptomatic patients with diabetes mellitus (DM).

Sixty-two patients (34 women) with long-term DM (24 with Type 1) and DAN, aged 51.7+/-13.9 years, free of coronary artery disease (CAD) or arterial hypertension (HT) at baseline, were studied for a 12-month period. Diagnosis of DAN was established if two or more of the standard cardiovascular reflex tests (CRT) were abnormal. Patients were randomly allocated to quinapril (20 mg/day), losartan (100 mg/day), or quinapril plus losartan (20 mg/day+100 mg/day). LV systolic and diastolic function was assessed using radionuclide ventriculography (RNV) at baseline and after 12 months of treatment.

In all three treatment groups, abnormal CRT values were improved. In the quinapril group, the first third filling fraction (1/3FF, 48.9+/-17.8% vs. 39.2+/-12.9% at baseline, P=.005) was increased and the atrial contribution to ventricular filling (25.1+/-6.3 vs. 30.1+/-7.8, P=.027) was reduced in the losartan group; the peak filling rate (PFR) was improved (3.41+/-.62 vs. 3.11+/-.44 volumes/s, P=.05), and in the combination group, the 1/3FF (39.4+/-11.8% vs. 29.6+/-11.9%, P=.018) was markedly increased, while the time to peak filling (TPF; 147+/-42 vs. 184+/-33 ms, P=.02) and the TPF/filling time (TPF/FT; 32.5+/-6.2% vs. 38.2+/-5.7%, P=.016) were reduced.

Early ACE-I or ARB improve both DAN and LVDD in asymptomatic patients with Type 1 or 2 DM, after 1 year of treatment. Their combination may be slightly better than monotherapies on DAN and LVDD. The clinical importance of these effects should be validated by larger studies.

Impaired diastolic function is related to subjective symptoms, reduced exercise capacity, and poor prognosis in patients with congestive heart failure, and an angiotensin II type-I receptor blocker might have a beneficial effect on diastolic function in such patients with heart failure. A 53-year-old woman underwent valvuloplasty of the mitral valve and later presented with heart failure symptoms, including exertional dyspnea and easy fatigue. Although no pathological changes could be identified by radiography of the chest, electrocardiography, or routine echocardiography, the assessment of diastolic function with Doppler echocardiography revealed left ventricular diastolic dysfunction. Her neurohumoral parameters and left ventricular diastolic dysfunction improved after 1 month of treatment with Valsartan, an angiotensin II type-I receptor blocker, accompanied by improvement of her subjective symptoms. This case implies that angiotensin II type-I receptor blocker could improve left ventricular diastolic dysfunction and that Doppler echocardiography might be useful for detecting diastolic dysfunction in high-risk patients undergoing cardiac surgery.

Abnormal large artery function and increased pulsatile load are exacerbated by excess angiotensin-II acting through the AT1 receptor and contribute to the pathogenesis and progression of chronic heart failure (CHF).

To evaluate effects of the AT1 receptor blocker candesartan (N = 30) or placebo (N = 34) on pulsatile hemodynamics in participants with CHF in the CHARM program.

Noninvasive hemodynamics were assessed following 6 and 14 months of treatment and averaged. Using calibrated tonometry and aortic outflow Doppler, characteristic impedance was calculated as the ratio of the change in carotid pressure and aortic flow in early systole. Total arterial compliance was calculated by the diastolic area method. Brachial blood pressure, cardiac output and peripheral resistance did not differ between groups. Lower central pulse pressure in the candesartan group (57+/-20 vs. 67+/-17 mmHg, P = 0.043) was accompanied by lower characteristic impedance (200+/-78 vs. 240+/-74 dyne s/cm5, P = 0.039) and higher total arterial compliance (1.87+/-0.70 vs. 1.47+/-0.48 ml/mmHg, P = 0.008). Similar favorable differences were seen when analyses were stratified for ejection fraction (< or = 0.40 vs. >0.40) and baseline angiotensin converting enzyme inhibitor use.

Candesartan has a favorable effect on large artery function in patients with chronic heart failure.

To evaluate the effects of valsartan on cardiac sympathetic nerve activity, plasma brain natriuretic peptide (BNP) concentration, cardiac function, and symptoms in patients with congestive heart failure (CHF) by comparison with those of enalapril.

50 patients with CHF (left ventricular ejection fraction (LVEF) < 40%) were randomly assigned to valsartan (80 mg/day; n = 25) or enalapril (5 mg/day; n = 25). All patients were also treated with a loop diuretic. The delayed heart to mediastinum count (H/M) ratio, delayed total defect score (TDS), and washout rate were determined from (123)I-meta-iodobenzylguanidine (MIBG) images. Plasma BNP concentrations were measured before and after six months of treatment. The left ventricular end diastolic volume (LVEDV) and LVEF were also determined by echocardiography.

In patients receiving valsartan, TDS decreased from a mean (SD) of 43 (8) to 39 (10) (p < 0.01), H/M ratio increased from 1.70 (0.17) to 1.78 (0.22) (p < 0.05), washout rate decreased from 46 (11)% to 41 (10)% (p < 0.05), and plasma BNP concentration decreased from 237 (180) pg/ml to 143 (93) pg/ml (p < 0.05). In addition, LVEDV decreased from 172 (42) ml to 151 (45) ml (p < 0.05) and LVEF increased from 31 (7)% to 39 (10)% (p < 0.001). However, these parameters did not change significantly in patients receiving enalapril.

Plasma BNP concentration and (123)I-MIBG scintigraphic and echocardiographic parameters improved significantly after six months of treatment with valsartan. These findings indicate that valsartan can improve cardiac sympathetic nerve activity and left ventricular performance in patients with CHF.

Valsartan (Diovan) is a widely use angiotensin receptor blocker that prevents angiotensin II from binding to the subtype 1 receptor. Stimulation of the subtype 1 receptor is believed to mediate many of the deleterious effects accompanied by increased angiotensin II levels. Valsartan is effective in the treatment of hypertension, alone and in combination with hydrochlorothiazide. Valsartan is similarly as effective as angiotensin-converting enzyme (ACE) blockers following myocardial infarction accompanied with left ventricular dysfunction, and/or heart failure. For the treatment of congestive heart failure with left ventricular dysfunction, valsartan offers a reduction in mortality in patients not able to tolerate an ACE inhibitor and in combination with an ACE inhibitor, valsartan reduces morbidity (hospitalization for heart failure).

Angiotensin-converting enzyme (ACE) inhibitors have a central role in the management of heart failure, reflecting the contribution of the renin-angiotensin-aldosterone system to the pathophysiology of the condition. Angiotensin-receptor blockers (ARBs) bind specifically to the angiotensin type 1 receptor and may offer further benefits compared with ACE inhibitors. Candesartan, losartan and valsartan have all been evaluated in large clinical outcome trials in heart failure. They display marked differences in pharmacokinetics and receptor-binding properties that may contribute to observed differences in outcome. ELITE II found no significant difference in outcome with losartan as compared with captopril. In the Val-Heft trial, valsartan reduced heart failure hospitalisations when added to conventional therapy including an ACE inhibitor in most patients, but had no effect on mortality. The CHARM programme showed that candesartan reduced morbidity and mortality in heart failure with reduced systolic function, both when added to ACE inhibitor therapy or when used as an alternative in patients who are intolerant to ACE inhibitors. Moreover, the CHARM-preserved study suggested that candesartan is beneficial in patients with heart failure and preserved left-ventricular systolic function. A growing body of evidence show that ARBs are an important contribution to the pharmaceutical management of patients with heart failure.

We sought to evaluate the effects of angiotensin receptor blocker (ARB) on cardiac sympathetic nerve activity (CSNA) in patients with congestive heart failure (CHF) with a preserved left ventricular ejection fraction (LVEF).

Approximately 50% of patients with CHF have preserved LVEF. It is reported that ARB therapy improves CSNA in CHF patients and reduced LVEF. However, the effect of ARB therapy on CSNA evaluated by iodine-123 meta-iodobenzylguanidine ((123)I-MIBG) scintigraphy has not been determined in CHF patients with preserved LVEF.

We selected 50 patients with nonischemic CHF and LVEF >40% who were treated with standard therapy. Twenty-five patients were randomized to also receive candesartan, whereas the remaining 25 patients received placebo. The delayed heart/mediastinum count (H/M) ratio, delayed total defect score (TDS), and washout rate (WR) were determined by (123)I-MIBG scintigraphy before and six months after treatment. The LV end-diastolic volume and LVEF were determined by echocardiography, and the plasma brain natriuretic peptide (BNP) concentration was also measured.

In patients receiving candesartan, (123)I-MIBG scintigraphic and echocardiographic parameters were significantly improved after treatment. In contrast, there were no significant changes in these parameters in patients receiving placebo. There was a significant correlation between the changes in (123)I-MIBG scintigraphic findings and the percent change in BNP from baseline to six months in patients receiving candesartan (TDS: r = 0.587, p < 0.005; H/M ratio: r = -0.509, p < 0.01; WR: r = 0.602, p < 0.005).

Adding candesartan to standard therapy can improve CSNA and LV performance in CHF patients with preserved LVEF.

Excess amount of cytokine produced by inflammatory stimuli contributes to the progression of myocardial damage in myocarditis. Some angiotensin II receptor type 1 antagonists are reported to inhibit proinflammatory cytokine production in vitro and in vivo. We tested the hypothesis that olmesartan, a novel angiotensin II receptor type 1 antagonist, ameliorated experimental autoimmune myocarditis (EAM) in rats attributing to the suppression of inflammatory cytokines in the heart. We orally administered olmesartan 1, 3, and 10 mg/kg/day to rats with EAM for 3 weeks. The results showed that olmesartan decreased blood pressure significantly compared with the untreated group, but markedly reduced the severity of myocarditis by comparing the heart weight/body weight ratio, pericardial effusion scores, macroscopic scores and microscopic scores. Myocardial interleukin (IL)- 1beta expression by western blotting and IL-1beta-positive staining cells by immunohistochemistry were significantly lower in rats with EAM given olmesartan treatment compared with those of rats given vehicle. We conclude that Olmesartan ameliorates acute EAM in rats. The cardioprotection of olmesartan may be due to suppression of inflammatory cytokines dependent of the hemodynamic modifications.

Angiotensin receptor blocker (ARB) and angiotensin-converting enzyme (ACE) inhibitor (ACEI) each act in a different manner to prevent myocardial fibrosis and left ventricular (LV) stiffness in animals with pathways in the heart for generating ANG II as well as ACE. A model of pacing-induced congestive heart failure (CHF) was used to test the central hypothesis that ARB + ACEI prevents myocardial fibrosis and decreases LV stiffness to a greater extent than ARB or ACEI alone. Thirty-five dogs were assigned to the following treatment protocols on the 8th day of a 4-wk pacing schedule: 1) rapid ventricular pacing, 2) ARB (candesartan cilexetil, 1.5 mg.kg(-1).day(-1)) with pacing, 3) ACEI (enalapril, 1.9 mg.kg(-1).day(-1)) with pacing, 4) ARB (candesartan cilexetil, 0.75 mg.kg(-1).day(-1)) + ACEI (enalapril, 0.95 mg.kg(-1).day(-1)) with pacing, and 5) sham operation. The LV stiffness coefficient was significantly increased after rapid pacing but was significantly lower with ARB + ACEI than with ARB or ACEI alone. The collagen volume fraction and mRNA levels of collagen I and III, which were increased by rapid pacing, were significantly lower with ARB + ACEI than with ARB or ACEI alone. Thus ARB + ACEI prevents myocardial fibrosis and decreases LV stiffness during the progression of CHF compared with ARB or ACEI alone.