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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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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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.
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ItemChronic kidney disease: cardiac and renal angiotensin-converting enzyme (ACE) 2 expression in rats after subtotal nephrectomy and the effect of ACE inhibition(WILEY-BLACKWELL, 2012-04)Renin-angiotensin system blockade slows but does not prevent the cardiovascular complications of chronic kidney disease (CKD). Angiotensin-converting enzyme (ACE) 2 is differentially regulated in acute kidney injury, with increased cardiac ACE2 but decreased kidney ACE2 levels. This study investigated the effect of long-term ACE inhibition on cardiac and renal ACE2 in rats with CKD induced by subtotal nephrectomy (STNx). Sprague-Dawley rats had sham (control) or STNx surgery. Control rats received vehicle (n = 9) and STNx rats ramipril (1 mg kg(-1) day(-1); n = 10) or vehicle (n = 10) for 28 days. Subtotal nephrectomy resulted in impaired creatinine clearance (P < 0.05), proteinuria (P < 0.05), renal fibrosis (P < 0.05) and reduced renal cortical ACE2 mRNA (P < 0.05) and activity (P < 0.05). In rats with CKD, ramipril improved creatinine clearance (P < 0.05) and was associated with an increase in cortical but not medullary ACE2 activity (P < 0.05). Compared with control rats, STNx rats were hypertensive (P < 0.01), with increased left ventricular end-diastolic pressure (LVEDP; P < 0.01), left ventricular hypertrophy (LVH; P < 0.05) and interstitial (P < 0.05) and perivascular fibrosis (P < 0.01). In rats with CKD, ramipril decreased blood pressure (P < 0.001) and reduced LVEDP (P < 0.01), LVH (P < 0.01) and perivascular fibrosis (P < 0.05) but did not significantly reduce interstitial fibrosis. There was no change in cardiac ACE2 in rats with CKD compared with control rats. In rats with CKD, ACE inhibition had major benefits to reduce blood pressure and cardiac hypertrophy and to improve creatinine clearance, but did not significantly impact on cardiac ACE2, cardiac interstitial fibrosis, renal fibrosis or proteinuria. Thus, in rats with CKD, renal ACE2 deficiency and lack of activation of cardiac ACE2 may contribute to the progression of cardiac and renal tissue injury. As long-term ACE inhibition only partly ameliorated the adverse cardio-renal effects of CKD, adjunctive therapies that lead to further increases in ACE2 activity may be needed to combat the cardio-renal complications of CKD.