Kegg Pathway: Angiotensin antagonists

Clin Transplant. 2009 Nov 18;
Marx C, Busch M, Ott U, Gerth J, Wolf G

Background: Proteinuria is a known side effect of therapy with sirolimus. The effect of Angiotensin-converting enzyme inhibitors or Angiotensin-receptor blockers (ACEI/ARB ) on sirolimus-associated proteinuria has not yet been assessed. Patients and methods: A retrospective cohort study of renal transplant patients treated with sirolimus (n = 55) was performed. Results: Of 55 patients, 24 (44%) had no proteinuria (<0.15 g/d) prior to conversion. Of 24 patients, 11 (46%) showed de novo proteinuria >0.15 g/d after 12 months, only 2 developed proteinuria > 1 g/d. The total number of proteinuria >1 g/d after 12 months including patients with pre-existing proteinuria >1 g/d (n = 3) was seven of 55 patients (13%). Multivariate regression analysis revealed pre-existing proteinuria > 0.15 g/d and reduced glomerular filtration rate as independent predictors for the development of proteinuria after conversion to sirolimus. Conclusion: Reduced glomerular filtration rate and pre-existing proteinuria but not therapy with ACEI/ARB are independent predictors for proteinuria after conversion to sirolimus. Treatment with ACEI/ARB did not reduce pre-existing proteinuria after conversion except in single cases with severe proteinuria.

Exp Physiol. 2009 Nov 18;
Feng Y, Xia H, Santos RA, Speth RC, Lazartigues E

Overactivity of the renin-Angiotensin system (RAS) is involved in the pathogenesis of hypertension and a hyper-functioning brain RAS has been highlighted in several genetic and experimental models. Until now, Angiotensin (Ang)-II has been considered to be the main effector of this system. Inhibitors of Angiotensin converting enzyme (ACE) and AT1 Angiotensin receptor subtype antagonists are widely used antihypertensive therapies. A new member of the RAS, ACE2 (Angiotensin converting enzyme type 2) has been identified in organs and tissues related to cardiovascular function (e.g. heart, kidney, vessels) and appears to be part of a counter-regulatory pathway buffering the excessive activity of Ang-II. We recently identified the ACE2 protein in brain regions involved in the central regulation of blood pressure (BP) and showed that it regulates, and is regulated by, other components of the RAS. Here, we present evidence for brain ACE2's involvement in the central regulation of BP, autonomic and cardiac function. We show that lack of ACE2 is deleterious to the central regulation of BP and that brain ACE2 gene therapy can restore normal baroreflex and autonomic functions and prevent the development of hypertension. Additionally, and independently of reduction of Ang-II levels, we will highlight some of the mechanisms responsible for the beneficial effects of central ACE2 for cardiovascular function.

Blood Press. 2009 Oct 29; 18(5): 242-246
Rizzoni D, Muiesan ML, Porteri E, Ciuceis CD, Boari GE, Salvetti M, Paini A, Rosei EA

Abstract Macrovasculature and microvasculature are deeply interrelated, since microvascular structure is not only the site of vascular resistance but probably also the origin of most of the wave reflections generating increased central systolic blood pressure. In fact, preliminary data suggest that some index of large artery stiffness is related with the media to lumen ratio of subcutaneous small resistance arteries of hypertensive patients. Microvascular structural alterations and changes in the mechanical properties of the macrovessels represent potent predictors of prognosis. Hypertension-related damage to the micro- and macrovascular system may be corrected by pharmacological agents. Among them, beta-blocking agents and diuretics have a negligible effect on microvascular structure, while renin-Angiotensin system antagonists and calcium entry blockers have favorable actions, improving large artery mechanics and possibly reducing central wave reflections.

Rev Med Suisse. 2009 Oct 14; 5(221): 2045-8
Mottu I, Perrier A

The recently published ACCOMPLISH study concludes that the combination of a dihydropyridin calcium-antagonist (amlodipine) with an Angiotensin-converting enzyme inhibitor (ACEI) is superior to the classical ACE-hydrochlorothiazide diuretic association in terms of cardiovascular risk reduction in high-risk hypertensive patients. These results contrast with those of the older ALLHAT study in which amlodipine was not superior to another thiazide diuretic (chlortalidone). This paper presents the results of both studies and attempts to put them in the larger perspective of the management of arterial hypertension.

Arch Soc Esp Oftalmol. 2009 Oct; 84(10): 491-500
Muñoz-Negrete FJ, Pérez-López M, Won Kim HR, Rebolleda G

The medical treatment of glaucoma has undergone significant development in recent years. Research in this field is focused on improving pre-existing drugs and on the development of new molecules. In relation to commercial drugs, there is a trend to improve local tolerance, using less toxic preservatives as in the case of sofZIA in travoprost, and eliminating the preservatives as in tafluprost. The development of new, fixed combinations of commercial drugs could also enhance their administration and therapeutic compliance. There is also intense research activity in the search for new therapeutic groups for glaucoma treatment. Calcium channel-blockers such as lomerizine do not seem to affect systemic hypotension, while topical calcium-blockers like flunarizine and iganidipine are also under research. Endothelin 1 antagonists such as sulfisoxazole and bunazosine could be also useful in the treatment of glaucoma. In the renin Angiotensin system, Angiotensin (1-7) and olmesartan are under investigation for use in glaucoma patients. Trabecular drugs such as Rho-kinase inhibitors could be effective on the pathogenic mechanism of primary open angle glaucoma. Finally, topical mifepristone, an antagonist of glucocorticoid receptors, is under evaluation for corticosteroid-induced elevated intraocular pressure (Arch Soc Esp Oftalmol 2009; 84: 491-500).

J Am Board Fam Med. 2009 Nov-Dec; 22(6): 686-97
Ong HT

PURPOSE: This article seeks to objectively review the clinical trial evidence to determine whether Angiotensin-converting enzyme inhibitors (ACEIs) and Angiotensin-receptor blockers (ARBs) have special cardiovascular protective effects. METHODS: An objective review of the clinical trial evidence. RESULTS: Clinical trials in hypertensive patients comparing ACEI and ARB with other drugs generally showed no difference in the primary cardiovascular outcome (United Kingdom Prospective Diabetes Study Group, Captopril Prevention Project, Swedish Trial in Old Patients with Hypertension 2, Japan Multicenter Investigation for Cardiovascular Diseases-B Randomized Trial, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, Second Australian National Blood Pressure Study Group, Valsartan Antihypertensive Long-Term Use Evaluation). Where the primary, or major secondary, cardiovascular end-point favors one of the treatment arms, it was always the arm with the lower achieved blood pressure that saw the better clinical result as in Losartan Intervention For Endpoint Reduction in Hypertension Study, Captopril Prevention Project, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, and Valsartan Antihypertensive Long-Term Use Evaluation. Trials comparing ACEI or ARB against placebo in patients at high risk of cardiovascular events have not showed a consistent result; cardiovascular outcomes were reduced in Heart Outcomes Prevention Evaluation, European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease, and the Jikei Heart Study, but were not significantly reduced in Perindopril Protection Against Recurrent Stroke Study, Comparison of Arnlodipine vs Enalapril to Limit Occurrences of Thrombosis Trial, Prevention of Events with ACEIs Trial, Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease Trial, and Prevention Regimen for Effectively Avoiding Second Strokes Trial. In the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, combining ACEIs with ARBs in high-risk patients did not reduce cardiovascular or renal outcomes compared with ACEI monotherapy alone. This absence of a reduction in cardiovascular outcome from the ACEI and ARB combination arm is further evidence suggesting that these drugs do not have any special cardiovascular protective effect. This objective review thus shows that the rennin-Angiotensin antagonists do not have special cardiovascular protective properties. CONCLUSION: The key to reducing cardiovascular outcome is to appropriately control blood pressure as well as to treat all other coronary risk factors.

Stroke. 2009 Nov 5;
Lu GC, Cheng JW, Zhu KM, Ma XJ, Shen FM, Su DF

BACKGROUND AND PURPOSE: Angiotensin receptor blockers are widely used in patients at high risk of cardiocerebrovascular events. The aim of this meta-analysis was to investigate the effects of Angiotensin receptor blockers on the risk of stroke. METHODS: Electronic searches of MEDLINE, EMBASE, and the Cochrane central register of controlled trials were performed. A total of 20 randomized clinical trials with 108 286 patients reporting stroke were available for this clinical outcome analysis. RESULTS: Angiotensin receptor blockers were associated with a significant reduction in the risk of stroke than placebo with an OR of 0.91 (0.84 to 0.98). Angiotensin receptor blockers were associated with no significant reduction in the risk of stroke compared with Angiotensin-converting enzyme inhibitors (OR, 0.93; 0.84 to 1.03) and calcium antagonists (OR, 1.16; 0.91 to 1.48). CONCLUSIONS: Evidence of the benefit of Angiotensin receptor blockers on the risk of stroke is provided when compared with placebo. There was no evidence of the benefit when comparing Angiotensin receptor blockers with Angiotensin-converting enzyme inhibitors and with calcium antagonists.

Clin Drug Investig. 2009; 29(12): 811-9
Yajima K, Shimada A, Hirose H, Oikawa Y, Yamada S, Meguro S, Irie J, Irie S

Renin-Angiotensin system (RAS) inhibitors, such as Angiotensin-converting enzyme (ACE) inhibitors and Angiotensin II type 1 receptor antagonists (Angiotensin receptor blockers [ARBs]), are recommended by the American Diabetes Association for blood pressure control and prevention or management of cardiovascular disease in patients with diabetes mellitus. However, some investigators have suggested that ARBs may increase the risk of myocardial infarction in hypertensive patients. Activation of the RAS is associated with an increased risk of ischaemic events. Angiotensin II stimulates the production of plasminogen activator inhibitor type-1 (PAI-1), a powerful predictor of cardiovascular disease. ACE inhibitors are reported to reduce PAI-1 levels and activity, while ARBs do not reduce or may even elevate levels of this atherogenic marker. The objective of this study was to determine whether the ACE inhibitor imidapril reduces PAI-1 levels in hypertensive patients already being treated with an ARB. This was a prospective cohort study carried out in primary care with a follow-up period of 6 months. Estimating the alpha error (p-value) at 0.05, the power of the test as 80%, and the difference in PAI-1 levels as 10 +/- 15 ng/mL, the required sample size was calculated to be 40. Participants were hypertensive patients taking ARBs for more than 8 weeks, and having dyslipidaemia, obesity or abnormal glucose metabolism. Imidapril 5-10 mg/day was prescribed for 6 months to reduce blood pressure to <130/80 mmHg. The main outcome measure, PAI-1 level, was measured before and 6 months after the addition of imidapril to ARBs in 21 subjects (13 men, eight women), all with abnormal glucose metabolism, nine with dyslipidaemia, and six who were obese. Bodyweight, body mass index, blood pressure, homeostasis model assessment of insulin resistance, glycosylated haemoglobin, creatinine, potassium, high sensitivity C-reactive protein (hs-CRP), and high molecular weight adiponectin levels were measured as secondary outcomes. PAI-1 level was not significantly changed overall. Hs-CRP level was also not significantly changed; however, the high molecular weight adiponectin level was significantly increased (p = 0.044), especially in men (p = 0.026). There were no significant changes in the other outcomes measured. The current study showed that imidapril added to ARBs did not decrease PAI-1 levels in hypertensive patients with abnormal glucose metabolism; however, this combination therapy significantly increased high molecular weight adiponectin levels in men.

Clin Sci (Lond). 2010 Feb; 118(4): 231-40
Savoia C, Volpe M, Alonzo A, Rossi C, Rubattu S

Natriuretic peptides are endogenous antagonists of vasoconstrictor and salt- and water-retaining systems in the body's defence against blood pressure elevation and plasma volume expansion, through direct vasodilator, diuretic and natriuretic properties. In addition, natriuretic peptides may play a role in the modulation of the molecular mechanisms involved in metabolic regulation and cardiovascular remodelling. The metabolic syndrome is characterized by visceral obesity, hyperlipidaemia, vascular inflammation and hypertension, which are linked by peripheral insulin resistance. Increased visceral adiposity may contribute to the reduction in the circulating levels of natriuretic peptides. The dysregulation of neurohormonal systems, including the renin-Angiotensin and the natriuretic peptide systems, may in turn contribute to the development of insulin resistance in dysmetabolic patients. In obese subjects with the metabolic syndrome, reduced levels of natriuretic peptides may be involved in the development of hypertension, vascular inflammation and cardio vascular remodelling, and this may predispose to the development of cardiovascular disease. The present review summarizes the regulation and function of the natriuretic peptide system in obese patients with the metabolic syndrome and the involvement of altered bioactive levels of natriuretic peptides in the pathophysiology of cardiovascular disease in patients with metabolic abnormalities.

Clin Exp Hypertens. 2009 Oct; 31(7): 585-94
Yamanari H, Nakamura K, Miura D, Yamanari S, Ohe T

The side effects of thiazide-type diuretics include metabolic abnormality and increased oxidative stress, which might cause endothelial dysfunction despite blood pressure reduction. In hypertensive patients with heart failure, treatment with an aldosterone antagonist resulted in improvements in endothelial function and significant blood pressure reduction. The purpose of the present study was to evaluate the differences between spironolactone and chlorthalidone in hypertensive elderly patients treated with calcium antagonists and Angiotensin II receptor blockers. Fourteen uncontrolled hypertensive patients treated with amlodipine and candesartan were included in this study. The study was an open-label randomized crossover comparison of 16 weeks treatment with spironolactone against chlorthalidone added to amlodipine and candesartan. Blood pressure significantly decreased in patients treated with both spironolactone and chlorthalidone. Chlorthalidone reduced flow mediated dilation significantly compared to the baseline condition and spironolactone. Serum high sensitively C-reactive protein and uric acid increased significantly in chlorthalidone-treated patients compared to spironolactone treated patients. We conclude that spironolactone may be a more useful add-on therapy than chlorthalidone in hypertensive patients inadequately controlled on candesartan and amlodipine, because spironolactone preserves endothelial function and reduces inflammation compared to chlorthalidone.

J Pharmacol Sci. 2009 Nov 19; 111(3): 227-234
Bhuiyan MA, Hossain M, Miura SI, Nakamura T, Ozaki M, Nagatomo T

The present study investigated the internalization behavior of the constitutively active mutant (CAM) N111G of Angiotensin II type 1 (AT(1)) receptor and correlated the result with the mechanism of the constitutive activity of the mutant. The inverse agonist activity of valsartan, losartan, candesartan, and telmisartan was also examined by inositol phosphate (IP) accumulation study as well as receptor-internalization assay. Both wild-type (WT) and N111G mutant receptors were transiently expressed in COS-7 cells and the binding affinities towards the agonist and these four AT(1) antagonists were determined. Production of total IP was measured in the presence and absence of the compounds. The agonist-induced receptor internalization of both WT and N111G mutant receptors was also investigated. Although the mutant showed similar binding characteristics with agonist and the antagonists used as WT, the internalization of the mutant was much lower (19.56 +/- 2.87%) than that of the WT receptor (74.63 +/- 1.00%). Internalization of the mutant significantly increased (63.22 +/- 0.03%) in the presence of valsartan, which also showed significant inverse agonist activity in the N111G mutant. The results indicate that internalization of CAM N111G of the AT(1) receptor is induced by the use of valsartan, which may be an important characteristic of inverse agonist activities of AT(1) antagonists in N111G.

Behav Brain Res. 2009 Oct 29;
Cecconello AL, Raineki C, Sebben V, Lucion AB, Sanvitto GL

Stress might influence the reproductive behavior in females, and central Angiotensin II (Ang II) is a peptide that plays a role in stress response and in the modulation of sexual behavior. The medial amygdala (MeA), an important structure that regulates this behavior, is strongly involved in stress response. The aim of the present study was to evaluate the effect of acute restraint stress on the night of proestrus on sexual receptivity in female rats and the participation of Ang II and MeA in this effect. Adult female Wistar rats with regular estrous cycles were utilized. The acute stress protocol utilized was the restraint stress for 15min on the night of proestrus. The participation of Ang II was evaluated by injecting Ang II and Ang II receptor antagonists (losartan and PD12319) into the MeA. The lordosis quotient was recorded. The stress or the microinjection of Ang II into the MeA significantly reduced sexual behavior. The blockade of AT(1) or AT(2) receptors in the MeA prevented the effect of stress and the effect of Ang II microinjection into this nucleus on sexual receptivity. We concluded that acute restraint stress on the night of proestrus reduces sexual behavior in rats, and this effect is mediated by both AT(1) and AT(2) receptors in the MeA.

Paediatr Drugs. 2009; 11(6): 381-96
Höcker B, Tönshoff B

Long-term allograft survival poses a major problem in pediatric renal transplantation, with allograft nephropathy being the principal cause of graft failure after the first post-transplant year. The mechanisms of nephron loss resulting in graft dysfunction are multiple, comprising both immunologic factors such as acute and chronic antibody- or T-cell-mediated rejection and non-immunologic components. The latter include peri-transplant injuries and renovascular lesions (renal artery stenosis, thrombosis) as well as cardiovascular risk factors such as arterial hypertension and hyperlipidemia. Another relevant issue leading to progressive nephron loss and declining kidney transplant function is acute and chronic nephrotoxicity induced by the calcineurin inhibitors (CNIs) ciclosporin (cyclosporine microemulsion) and tacrolimus. Furthermore, the presence of an abnormal lower urinary tract as well as bacterial (recurrent pyelonephritis) and viral (cytomegalovirus [CMV], polyomavirus [BK virus; BKV]) infections are crucial factors involved in the incidence of chronic allograft dysfunction and graft failure. Renovascular lesions and lower urinary tract obstruction are typical indicators for surgical intervention. The aim of treatment in pediatric patients with renal failure secondary to a dysfunctional lower urinary tract is to create a sterile, continent, and nonrefluxive reservoir. Surgical techniques such as bladder augmentation and the introduction of intermittent catheterization and anticholinergic therapy have significantly improved graft outcome. Arterial hypertension, another factor responsible for graft function deterioration in pediatric renal transplant recipients, is controlled preferably by the use of Angiotensin converting enzyme (ACE) inhibitors or Angiotensin II receptor antagonists, which are known to possess nephroprotective properties in addition to their potent antihypertensive effects. Although treatment of subclinical rejection with augmented immunosuppression has been associated with better graft survival, an increase of the immunosuppressive level to avoid subclinical rejection should be weighed against the risk of infection. The majority of viral infections affecting kidney allografts are caused by CMV and BKV. Antiviral CMV prophylaxis or pre-emptive therapy with ganciclovir has been shown to have beneficial effects in the pediatric renal transplant population. Treatment of BKV-induced nephropathy is based on reduction of the immunosuppressant therapy, although specific antiviral agents such as cidofovir and leflunomide are known to inhibit BKV. However, cidofovir itself is nephrotoxic and should therefore be administered cautiously to pediatric renal transplant patients. Since CNIs are likewise known for their nephrotoxic effects, especially with long-term use, alteration of the immunosuppressant regimen is necessary in case of deteriorating graft function due to CNI-induced histopathologic changes. Complete CNI avoidance seems inappropriate because, in this situation in pediatric renal transplant recipients, other relatively potent immunosuppressant agents such as lymphocyte-depleting antibodies, which are frequently accompanied by a higher incidence of infections, are needed for rejection prophylaxis. CNI withdrawal and switching of the immunosuppressant regimen from CNI therapy to sirolimus may be an option for some pediatric renal transplant patients with less advanced graft function deterioration. Nevertheless, potential adverse events such as aggravation of proteinuria, hyperlipidemia, myelosuppression, and hypergonadotropic hypogonadism have to be considered, and controlled studies are lacking. At present, an immunosuppressant maintenance therapy composed of low-dose tacrolimus or ciclosporin (CNI minimization) and mycophenolate mofetil with low-dose corticosteroids appears to be the most promising strategy to adopt in pediatric renal transplant recipients at low or normal immunologic risk.

J Am Coll Cardiol. 2009 Nov 3; 54(19): 1747-62
Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J

Heart failure is a syndrome characterized initially by left ventricular dysfunction that triggers countermeasures aimed to restore cardiac output. These responses are compensatory at first but eventually become part of the disease process itself leading to further worsening cardiac function. Among these responses is the activation of the sympathetic nervous system (SNS) that provides inotropic support to the failing heart increasing stroke volume, and peripheral vasoconstriction to maintain mean arterial perfusion pressure, but eventually accelerates disease progression affecting survival. Activation of SNS has been attributed to withdrawal of normal restraining influences and enhancement of excitatory inputs including changes in: 1) peripheral baroreceptor and chemoreceptor reflexes; 2) chemical mediators that control sympathetic outflow; and 3) central integratory sites. The interface between the sympathetic fibers and the cardiovascular system is formed by the adrenergic receptors (ARs). Dysregulation of cardiac beta(1)-AR signaling and transduction are key features of heart failure progression. In contrast, cardiac beta(2)-ARs and alpha(1)-ARs may function in a compensatory fashion to maintain cardiac inotropy. Adrenergic receptor polymorphisms may have an impact on the adaptive mechanisms, susceptibilities, and pharmacological responses of SNS. The beta-AR blockers and the inhibitors of the renin-Angiotensin-aldosterone axis form the mainstay of current medical management of chronic heart failure. Conversely, central sympatholytics have proved harmful, whereas sympathomimetic inotropes are still used in selected patients with hemodynamic instability. This review summarizes the changes in SNS in heart failure and examines how modulation of SNS activity may affect morbidity and mortality from this syndrome.

J Renin Angiotensin Aldosterone Syst. 2009 Oct 27;
Balmforth AJ

Considerable progress in our understanding of the role of the Angiotensin II type 2 (AT2) receptor in the development of cardiac hypertrophy and coronary artery disease has been achieved using in vitro and in vivo animal models. Our understanding in humans, however, has been hindered by the lack of availability of specific AT2 receptor agonists and antagonists suitable for human study. Nevertheless, an alternative approach involving genotyping humans for a functional polymorphism within the AT2 receptor gene (-1332G/A) has been used in several association studies to elucidate the pathogenic role of the AT2 receptor in cardiovascular disease. Both the A allele and the G allele have independently been associated with left ventricular remodelling. However, the methods of measuring left ventricular mass, sodium balance, age and degree of remodelling appear to influence the outcome. An association of carriers of the G allele and premature coronary artery disease has also been established, particularly in males presenting with stenotic atherosclerosis requiring revascularisation. At the molecular level, it remains unclear as to whether carriers of the G allele express more or fewer AT2 receptors when compared to carriers of the A allele. Consequently, it is presently not possible to definitively interpret the role of the AT2 receptor in human cardiovascular disease from these association studies.

J Renin Angiotensin Aldosterone Syst. 2009 Oct 27;
Steckelings UM, Rompe F, Kaschina E, Namsolleck P, Grzesiak A, Funke-Kaiser H, Bader M, Unger T

Studying the Angiotensin type 2 receptor (AT2) has been problematic in the past because a pharmacological tool for direct, specific in vitro and in vivo stimulation of the receptor has been lacking. Consequently, current knowledge about AT2 receptor signalling and function had to be obtained by indirect approaches, like studying animals or cells with genetically altered AT2 receptor expression levels, inhibitory experiments using specific AT2 receptor antagonists, stimulation with Angiotensin II under concomitant Angiotensin II type 1 receptor blockade or stimulation with the peptide agonist CGP42112A, which has additional AT2 receptor antagonistic properties. The recently developed non-peptide AT2 receptor agonist Compound 21 now, for the first time, allows direct, selective and specific AT2 receptor stimulation in vitro and in vivo. This new tool will certainly revolutionise AT2 receptor research, enable many new insights into AT2 receptor function and may also have the potential to become a future medical drug. This article reviews milestone findings about AT2 receptor functional properties obtained by 'conventional' experimental approaches within the last 20 years. Moreover, it provides an overview of the first results obtained by direct AT2 receptor stimulation with Compound 21, comprising effects on alkaline secretion, neurite outgrowth, blood pressure and post-infarct cardiac function.

Med J Malaysia. 2009 Mar; 64(1): 3-11
Ong HT, Rozina G

Hypertens Res. 2009 Oct 23;
Thornton SN

J Am Coll Cardiol. 2009 Oct 27; 54(18): 1674-82
Mak GJ, Ledwidge MT, Watson CJ, Phelan DM, Dawkins IR, Murphy NF, Patle AK, Baugh JA, McDonald KM

OBJECTIVES: This study was designed to evaluate the impact of eplerenone on collagen turnover in preserved systolic function heart failure (HFPSF). BACKGROUND: Despite growing interest in abnormal collagen metabolism as a feature of HFPSF with diastolic dysfunction, the natural history of markers of collagen turnover and the impact of selective aldosterone antagonism on this natural history remains unknown. METHODS: We evaluated 44 patients with HFPSF, randomly assigned to control (n = 20) or eplerenone 25 mg daily (n = 24) for 6 months, increased to 50 mg daily from 6 to 12 months. Serum markers of collagen turnover and inflammation were analyzed at baseline and at 6 and 12 months and included pro-collagen type-I and -III aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha. Doppler-echocardiographic assessment of diastolic filling indexes and tissue Doppler analyses were also obtained. RESULTS: The mean age of the patients was 80 +/- 7.8 years; 46% were male; 64% were receiving an Angiotensin-converting enzyme inhibitor, 34% an Angiotensin-II receptor blocker, and 68% were receiving beta-blocker therapy. Pro-collagen type-III and -I aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha increased with time in the control group. Eplerenone treatment had no significant impact on any biomarker at 6 months but attenuated the increase in pro-collagen type-III aminoterminal peptide at 12 months (p = 0.006). Eplerenone therapy was associated with modest effects on diastolic function without any impact on clinical variables or brain natriuretic peptide. CONCLUSIONS: This study demonstrates progressive increases in markers of collagen turnover and inflammation in HFPSF with diastolic dysfunction. Despite high background utilization of renin-Angiotensin-aldosterone modulators, eplerenone therapy prevents a progressive increase in pro-collagen type-III aminoterminal peptide and may have a role in management of this disease. (The Effect of Eplerenone and Atorvastatin on Markers of Collagen Turnover in Diastolic Heart Failure; NCT00505336).

Ir J Med Sci. 2009 Oct 17;
Zaharan NL, Mahmud A, Bennett K, Feely J

BACKGROUND: Hypertension is the commonest medical condition in Ireland. AIMS: (1) To examine the level of awareness of blood pressure (BP) in the population and (2) to ascertain the opinion of general practitioners (GPs) in diagnosis and management of hypertension. METHODS: BP measurements and assessment of BP awareness were performed in a sub-sample of the general population (n = 1,071). The opinion of GPs (n = 1,037) on hypertension was determined in a postal survey. RESULTS: Amongst the population sampled (45 +/- 13 years, mean age +/- SD), almost half had elevated BP (>140/90 mmHg) but only half of those were already on antihypertensives. 40% had no knowledge of their BP and 54% were not aware of what constituted normal BP. While some 80% of GPs said they followed British guidelines, their practice was more in keeping with the European guidelines. Approximately, 90% of GPs required ambulatory BP recording to confirm diagnosis of hypertension. First choice antihypertensive agents were ACE inhibitors and Angiotensin receptor antagonists in younger patients and diuretics and ACE inhibitors in older patients. CONCLUSION: These results suggest that there is a need for further public education on BP and nationally agreed hypertension guidelines.