Medicine (Austin & Northern Health) - Research Publications
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ItemNo Preview AvailableReview article: the pathophysiological roles of the renin-angiotensin system in the gastrointestinal tract(WILEY, 2012-02)BACKGROUND: The renin-angiotensin system (RAS) is a homeostatic pathway widely known to regulate cardiovascular and renal physiology; however, little is known about its influence in gastrointestinal tissues. AIM: To elicit the anatomical distribution and physiological significance of the components of the RAS in the gastrointestinal tract. METHODS: An extensive online literature review including Pubmed and Medline. RESULTS: There is evidence for RAS involvement in gastrointestinal physiology and pathophysiology, with all the components required for autonomous regulation identified throughout the gastrointestinal tract. The RAS is implicated in the regulation of glucose, amino acid, fluid and electrolyte absorption and secretion, motility, inflammation, blood flow and possibly malignant disease within the gastrointestinal tract. Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. Given the ready availability of drugs that modify the RAS and their excellent safety profile, an opportunity exists for investigation of their possible therapeutic role in a variety of human gastrointestinal diseases. CONCLUSIONS: The gastrointestinal renin-angiotensin system appears to be intricately involved in a number of physiological processes, and provides a possible target for novel investigative and therapeutic approaches.
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ItemBeta blocker use in subjects with type 2 diabetes mellitus and systolic heart failure does not worsen glycaemic control(BIOMED CENTRAL LTD, 2012-02-14)BACKGROUND: The prognostic benefits of beta-blockers (BB) in patients with systolic heart failure (SHF) are known but despite this, in patients with diabetes they are underutilized. The aim of this study was to assess the effect of beta-blockers (BB) on glycaemic control in patients with Type 2 Diabetes (T2DM) and systolic heart failure (SHF) stratified to beta-1 selective (Bisoprolol) vs. nonselective BB (Carvedilol). METHODS: This observational, cohort study was conducted in patients with T2DM and SHF attending an Australian tertiary teaching hospital's heart failure services. The primary endpoint was glycaemic control measured by glycosylated haemoglobin (HbA1c) at initiation and top dose of BB. Secondary endpoints included microalbuminuria, changes in lipid profile and estimated glomerular filtration rate (eGFR). RESULTS: 125 patients were assessed. Both groups were well matched for gender, NYHA class and use of guideline validated heart failure and diabetic medications. The mean treatment duration was 1.9 ± 1.1 years with carvedilol and 1.4 ± 1.0 years with bisoprolol (p = ns). The carvedilol group achieved a reduction in HbA1c (7.8 ± 0.21% to 7.3 ± 0.17%, p = 0.02) whereas the bisoprolol group showed no change in HbA1c (7.0 ± 0.20% to 6.9 ± 0.23%, p = 0.92). There was no significant difference in the change in HbA1c from baseline to peak BB dose in the carvedilol group compared to the bisoprolol group. There was a similar deterioration in eGFR, but no significant changes in lipid profile or microalbuminuria in both groups (p = ns). CONCLUSION: BB use did not worsen glycaemic control, lipid profile or albuminuria status in subjects with SHF and T2DM. Carvedilol significantly improved glycemic control in subjects with SHF and T2DM and this improvement was non significantly better than that obtained with bisoprolol. BB's should not be withheld from patients with T2DM and SHF.
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ItemThe CTGF gene-945 G/C polymorphism is not associated with cardiac or kidney complications in subjects with type 2 diabetes(BMC, 2012-04-26)BACKGROUND: Connective tissue growth factor (CTGF) has been implicated in the cardiac and kidney complications of type 2 diabetes, and the CTGF -945 G/C polymorphism is associated with susceptibility to systemic sclerosis, a disease characterised by tissue fibrosis. This study investigated the association of the CTGF -945 G/C promoter variant with cardiac complications (left ventricular (LV) hypertrophy (LVH), diastolic and systolic dysfunction) and chronic kidney disease (CKD) in type 2 diabetes. METHODS: The CTGF -945 G/C polymorphism (rs6918698) was examined in 495 Caucasian subjects with type 2 diabetes. Cardiac structure and function were assessed by transthoracic echocardiography. Kidney function was assessed using estimated glomerular filtration rate (eGFR) and albuminuria, and CKD defined as the presence of kidney damage (decreased kidney function (eGFR <60 ml/min/1.73 m2) or albuminuria). RESULTS: The mean age ± SD of the cohort was 62 ± 14 years, with a body mass index (BMI) of 31 ± 6 kg/m2 and median diabetes duration of 11 years [25th, 75th interquartile range; 5, 18]. An abnormal echocardiogram was present in 73% of subjects; of these, 8% had LVH alone, 74% had diastolic dysfunction and 18% had systolic ± diastolic dysfunction. CKD was present in 42% of subjects. There were no significant associations between the CTGF -945 G/C polymorphism and echocardiographic parameters of LV mass or cardiac function, or kidney function both before and after adjustment for covariates of age, gender, BMI, blood pressure and hypertension. CTGF -945 genotypes were not associated with the cardiac complications of LVH, diastolic or systolic dysfunction, nor with CKD. CONCLUSIONS: In Caucasians with type 2 diabetes, genetic variation in the CTGF -945 G/C polymorphism is not associated with cardiac or kidney complications.
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ItemTo TOE or not to TOE? That is the question in patients with portal hypertension and varices(BMJ PUBLISHING GROUP, 2013-04)
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ItemEmerging markers in cardiovascular disease: Where does angiotensin-converting enzyme 2 fit in?(WILEY, 2013-08)The renin-angiotensin system plays a major role in the pathophysiology of cardiovascular disease (CVD). The enzyme angiotensin-converting enzyme (ACE) converts angiotensin (Ang) I into the vasoconstrictor AngII and was thought, until recently, to be the main effector of the system. The enzyme ACE2, discovered in 2000, can counterbalance the effects of ACE through degradation of AngII and generation of Ang-(1-7). Angiotensin-converting enzyme 2 is abundantly expressed in the heart and localized to the endothelial cells of coronary vessels and smooth muscle cells. Its catalytically active ectodomain undergoes shedding, resulting in ACE2 in the circulation. There are 10 studies to date that have measured circulating ACE2 activity in humans, including in healthy subjects and those with heart failure, Type 1 diabetes, implantable cardioverter/defibrillator, elderly subjects undergoing emergency orthopaedic surgery and kidney transplant patients. The results suggest that circulating ACE2 activity may be a marker of CVD, with low levels in healthy individuals and increased levels in those with cardiovascular risk factors or disease. Whether increased plasma ACE2 activity reflects increased synthesis from tissue ACE2 mRNA or increased shedding of tissue ACE2 remains to be determined. Angiotensin-converting enzyme 2 is located on the X-chromosome and circulating ACE2 levels are higher in men than in women. Large clinical studies in CVD are needed to more precisely clarify the role of ACE2 as a biomarker of CVD, determine the prognostic significance of circulating ACE2 activity and assess whether the measurement of ACE2 will improve CVD risk prediction.
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ItemEffect of intensive structured care on individual blood pressure targets in primary care: multicentre randomised controlled trial(BMJ PUBLISHING GROUP, 2012-11-20)OBJECTIVE: To determine the effectiveness of intensive structured care to optimise blood pressure control based on individual absolute risk targets in primary care. DESIGN: Pragmatic multicentre randomised controlled trial. SETTING: General practices throughout Australia, except Northern Territory, 2009-11. PARTICIPANTS: Of 2185 patients from 119 general practices who were eligible for drug treatment for hypertension according to national guidelines 416 (19.0%) achieved their individual blood pressure target during a 28 day run-in period of monotherapy. After exclusions, 1562 participants not at target blood pressure (systolic 150 (SD 17) mm Hg, diastolic 88 (SD 11) mm Hg) were randomised (1:2 ratio) to usual care (n=524) or the intervention (n=1038). INTERVENTION: Computer assisted clinical profiling and risk target setting (all participants) with intensified follow-up and stepwise drug titration (initial angiotensin receptor blocker monotherapy or two forms of combination therapy using angiotensin receptor blockers) for those randomised to the intervention. The control group received usual care. MAIN OUTCOME MEASURES: The primary outcome was individual blood pressure target achieved at 26 weeks. Secondary outcomes were change in mean sitting systolic and diastolic blood pressure, absolute risk for cardiovascular disease within five years based on the Framingham risk score, and proportion and rate of adverse events. RESULTS: On an intention to treat basis, there was an 8.8% absolute difference in individual blood pressure target achieved at 26 weeks in favour of the intervention group compared with usual care group (358/988 (36.2%) v 138/504 (27.4%)): adjusted relative risk 1.28 (95% confidence interval 1.10 to 1.49, P=0.0013). There was also a 9.5% absolute difference in favour of the intervention group for achieving the classic blood pressure target of ≤ 140/90 mm Hg (627/988 (63.5%) v 272/504 (54.0%)): adjusted relative risk 1.18 (1.07 to 1.29, P<0.001). The intervention group achieved a mean adjusted reduction in systolic blood pressure of 13.2 mm Hg (95% confidence interval -12.3 to -14.2 mm Hg) and diastolic blood pressure of 7.7 mm Hg (-7.1 to -8.3 mm Hg) v 10.1 mm Hg (-8.8 to 11.3 mm Hg) and 5.5 mm Hg (-4.7 to -6.2 mm Hg) in the usual care group (P<0.001). Among 1141 participants in whom five year absolute cardiovascular risk scores were calculated from baseline to the 26 week follow-up, the reduction in risk scores was greater in the intervention group than usual care group (14.7% (SD 9.3%) to 10.9% (SD 8.0%); difference -3.7% (SD 4.5%) and 15.0% (SD 10.1%) to 12.4% (SD 9.4%); -2.6% (SD 4.5%): adjusted mean difference -1.13% (95% confidence interval -0.69% to -1.63%; P<0.001). Owing to adverse events 82 (7.9%) participants in the intervention group and 10 (1.9%) in the usual care group had their drug treatment modified. CONCLUSIONS: In a primary care setting intensive structured care resulted in higher levels of blood pressure control, with clinically lower blood pressure and absolute risk of future cardiovascular events overall and with more people achieving their target blood pressure. An important gap in treatment remains though and applying intensive management and achieving currently advocated risk based blood pressure targets is challenging.
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ItemAngiotensin-(1-7) reduces the perfusion pressure response to angiotensin II and methoxamine via an endothelial nitric oxide-mediated pathway in cirrhotic rat liver(AMER PHYSIOLOGICAL SOC, 2013-01)Recent studies have shown that, in cirrhosis, portal angiotensin-(1-7) [Ang-(1-7)] levels are increased and hepatic expression of angiotensin converting enzyme 2 (ACE2) and the Mas receptor are upregulated, but the effects of Ang-(1-7) on hepatic hemodynamics in cirrhosis have not been studied. This study investigated the effects of Ang-(1-7) on vasoconstrictor-induced perfusion pressure increases in cirrhotic rat livers. Ang II or the alpha 1 agonist methoxamine (MTX) were injected in the presence or absence of Ang-(1-7), and the perfusion pressure response was recorded. Denudation of vascular endothelial cells with sodium deoxycholate was used to investigate the contribution of endothelium to the effects of Ang-(1-7). Ang-(1-7) alone had no effect on perfusion pressure. However, it reduced the maximal vasoconstriction response and area under the pressure response curve to Ang II and MTX by >50% (P < 0.05). This effect of Ang-(1-7) was not blocked by Mas receptor inhibition with A779 or by Ang II type 1 and type 2 receptor and bradykinin B(2) receptor blockade and was not reproduced by the Mas receptor agonist AVE0991. D-Pro(7)-Ang-(1-7), a novel Ang-(1-7) receptor antagonist, completely abolished the vasodilatory effects of Ang-(1-7), as did inhibition of endothelial nitric oxide synthase (eNOS) with N(G)-nitro-L-arginine methyl-ester, guanylate cyclase blockade with ODQ and endothelium denudation. The functional inhibition by D-Pro(7)-Ang-(1-7) was accompanied by significant (P < 0.05) inhibition of eNOS phosphorylation. This study shows that Ang-(1-7) significantly inhibits intrahepatic vasoconstriction in response to key mediators of increased vascular and sinusoidal tone in cirrhosis via a receptor population present on the vascular endothelium that is sensitive to D-Pro(7)-Ang-(1-7) and causes activation of eNOS and guanylate cyclase-dependent NO signaling pathways.
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ItemActivation of the Mas Receptor by Angiotensin-(1-7) in the Renin-Angiotensin System Mediates Mesenteric Vasodilatation in Cirrhosis(W B SAUNDERS CO-ELSEVIER INC, 2013-10)BACKGROUND & AIMS: Splanchnic vascular hypocontractility with subsequent increased portal venous inflow leads to portal hypertension. Although the renin-angiotensin system contributes to fibrogenesis and increased hepatic resistance in patients with cirrhosis, little is known about its effects in the splanchnic vasculature, particularly those of the alternate system in which angiotensin (Ang) II is cleaved by the Ang-converting enzyme-2 (ACE2) to Ang-(1-7), which activates the G-protein-coupled Mas receptor (MasR). We investigated whether this system contributes to splanchnic vasodilatation and portal hypertension in cirrhosis. METHODS: We measured levels of renin-angiotensin system messenger RNA and proteins in splanchnic vessels from patients and rats with cirrhosis. Production of Ang-(1-7) and splanchnic vascular reactivity to Ang-(1-7) was measured in perfused mesenteric vascular beds from rats after bile-duct ligation. Ang-(1-7) and MasR were blocked in rats with cirrhosis to examine splanchnic vascular hemodynamics and portal pressure response. RESULTS: Levels of ACE2 and MasR were increased in splanchnic vessels from cirrhotic patients and rats compared with healthy controls. We also observed an ACE2-dependent increase in Ang-(1-7) production. Ang-(1-7) mediated splanchnic vascular hypocontractility in ex vivo splanchnic vessels from rats with cirrhosis (but not control rats) via MasR stimulation. Identical effects were observed in the splanchnic circulation in vivo. MasR blockade reduced portal pressure, indicating that activation of this receptor in splanchnic vasculature promotes portal inflow to contribute to development of portal hypertension. In addition, the splanchnic effects of MasR required nitric oxide. Interestingly, Ang-(1-7) also decreased hepatic resistance. CONCLUSIONS: In the splanchnic vessels of patients and rats with cirrhosis, increased levels of ACE2 appear to increase production of Ang-(1-7), which leads to activation of MasR and splanchnic vasodilatation in rats. This mechanism could cause vascular hypocontractility in patients with cirrhosis, and might be a therapeutic target for portal hypertension.
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ItemNo Preview AvailableAngiotensin-converting enzyme 2 activity in patients with chronic kidney disease(OXFORD UNIV PRESS, 2013-09)BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is a novel regulator of the renin-angiotensin system that counteracts the adverse effects of angiotensin II. In heart failure patients, elevated plasma ACE2 activity predicted adverse events and greater myocardial dysfunction. We aimed to describe plasma ACE2 activity and its clinical associations in patients with kidney disease. METHODS: Patients recruited from a single centre comprised of chronic kidney disease Stage III/IV (CKD), haemodialysis patients and kidney transplant recipients (KTRs). Plasma ACE2 enzyme activity was measured using a fluorescent substrate assay in plasma, collected at baseline and stored at -80°C. Linear regression was performed in both males and females separately to determine the covariates associated with log-transformed ACE2. RESULTS: The median (interquartile range) plasma ACE2 activity in pmol/mL/min was 15.9 (8.4-26.1) in CKD (n = 59), 9.2 (3.9-18.2) in haemodialysis (n = 100) and 13.1 (5.7-21.9) in KTR (n = 80; P < 0.01). In male haemodialysis patients, ACE2 activity was 12.1 (6.8-19.6) compared with 4.4 (2.5-10.3) in females (P < 0.01). Log-transformed ACE2 plasma activity was associated with post-haemodialysis systolic blood pressure in females [β-coefficient 0.04, 95% confidence interval (95% CI) 0.01-0.06, P = 0.006]. In males, log-transformed ACE2 plasma activity was associated with B-type natriuretic peptide (β-coefficient 0.39, 95% CI 0.19-0.60, P < 0.001). Plasma ACE2 activity was not associated with mortality. CONCLUSIONS: Plasma ACE2 activity is reduced in haemodialysis patients compared with CKD patients, and in female haemodialysis patients compared with male. The different associations of plasma ACE2 activity between male and female haemodialysis patients indicate that the role of ACE2 in cardiovascular disease may differ by gender.
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ItemNo Preview AvailableUpdate on new aspects of the renin-angiotensin system in liver disease: clinical implications and new therapeutic options(PORTLAND PRESS LTD, 2012-08)The RAS (renin-angiotensin system) is now recognized as an important regulator of liver fibrosis and portal pressure. Liver injury stimulates the hepatic expression of components of the RAS, such as ACE (angiotensin-converting enzyme) and the AT(1) receptor [AngII (angiotensin II) type 1 receptor], which play an active role in promoting inflammation and deposition of extracellular matrix. In addition, the more recently recognized structural homologue of ACE, ACE2, is also up-regulated. ACE2 catalyses the conversion of AngII into Ang-(1-7) [angiotensin-(1-7)], and there is accumulating evidence that this 'alternative axis' of the RAS has anti-fibrotic, vasodilatory and anti-proliferative effects, thus counterbalancing the effects of AngII in the liver. The RAS is also emerging as an important contributor to the pathophysiology of portal hypertension in cirrhosis. Although the intrahepatic circulation in cirrhosis is hypercontractile in response to AngII, resulting in increased hepatic resistance, the splanchnic vasculature is hyporesponsive, promoting the development of the hyperdynamic circulation that characterizes portal hypertension. Both liver fibrosis and portal hypertension represent important therapeutic challenges for the clinician, and there is accumulating evidence that RAS blockade may be beneficial in these circumstances. The present review outlines new aspects of the RAS and explores its role in the pathogenesis and treatment of liver fibrosis and portal hypertension.