Baker Heart Research Institute

Melbourne, Australia

Baker Heart Research Institute

Melbourne, Australia
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Smink P.A.,University of Groningen | Bakker S.J.L.,University of Groningen | Laverman G.D.,University of Groningen | Berl T.,University of Colorado at Denver | And 3 more authors.
Journal of Hypertension | Year: 2012

Objective: Increased levels of serum uric acid (SUA) are thought to be an independent risk marker for cardiovascular complications. Treatment with the angiotensin receptor blocker (ARB) losartan lowers SUA in contrast to other ARBs. Whether reductions in SUA during ARB therapy are associated with cardiovascular protection is unclear. We aimed to investigate this. Method: In a post-hoc analysis of the Reduction of Endpoints in Non insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) and Irbesartan Diabetic Nephropathy (IDNT) trials we determined whether the short-term effect of losartan and of irbesartan on SUA is related with long-term cardiovascular outcome by means of Cox regression. Results: Compared to placebo, losartan significantly changed SUA [-0.16 mg/dl; 95% confidence interval (CI)-0.01 to-0.30; P = 0.031], whereas irbesartan did not (-0.09 mg/dl; (95% CI 0.09 to-0.28; P = 0.30). Each 0.5 mg/dl decrement in SUA during losartan treatment in the first 6 months resulted in a reduction in the risk of cardiovascular outcomes by 5.3% (95% CI 0.9 to 9.9; P = 0.017). Losartan reduced the risk of cardiovascular outcomes by 9.2% (95% CI-7.9 to 23.6). Adjustment for the 6-month change in SUA attenuated the treatment effect to 4.6% (95% CI-16.2 to 22.0), suggesting that part of the cardiovascular protective effect of losartan is attributable to its short-term effect on SUA. Conclusion: Losartan but not irbesartan significantly lowers SUA compared to placebo in patients with type 2 diabetes and nephropathy. The degree of reduction in SUA explains part of the cardiovascular effect of losartan. This supports the hypothesis that SUA is a modifiable risk factor for cardiovascular disease, at least in type 2 diabetics with nephropathy. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Berry P.A.,Monash University | Maciewicz R.A.,Astrazeneca | Wluka A.E.,Monash University | Wluka A.E.,Baker Heart Research Institute | And 4 more authors.
Annals of the Rheumatic Diseases | Year: 2010

Background: Biomarkers of cartilage metabolism have prognostic potential. Objective: To examine whether serum cartilage biomarkers, cartilage oligomeric matrix protein (COMP), N-propeptide of type IIA procollagen (PIIANP), type II collagen breakdown product (collagen type-II cleavage (C2C)) predict cartilage volume loss and knee joint replacement. Methods: 117 subjects with knee osteoarthritis (OA) had MRI at baseline and 2 years. Cartilage biomarkers were measured at baseline. Change in knee cartilage volume over 2 years and knee joint replacement over 4 years was determined. The population was divided into subgroups with high or low cartilage biomarkers (based on biomarker levels greater than or equal to, or less than, the mean, respectively). The relationships between biomarkers and outcome measures were examined in the whole population, and separately in marker subgroups. Results: The relationship between cartilage biomarkers and cartilage volume loss was not linear across the whole population. In the low (regression coefficient B=-9.7, 95% CI -0.01 to 0.003, p=0.01), but not high (B=-0.46, 95% CI -8.9 to 8.0, p=0.92) COMP subgroup, COMP was significantly associated with a reduced rate of medial cartilage volume loss (p for difference between groups=0.05). Similarly, in the low (B=-8.2, 95% CI -12.9 to -3.5, p=0.001) but not high (B=2.6, 95% CI -3.3 to 8.5, p=0.38) PIIANP subgroup, PIIANP was associated with a significantly reduced rate of medial volume cartilage loss (p for difference=0.003). C2C was not significantly associated with rate of cartilage volume loss. PIIANP was associated with a reduced risk of joint replacement (odds ratio (OR)=0.28, 95% CI 0.10 to 0.93, p=0.04). Conclusion: Cartilage biomarkers may be used to identify subgroups among those with clinical knee OA in whom disease progresses at different rates. This may facilitate our understanding of the pathogenesis of disease and allow us to differentiate phenotypes of disease within a heterogeneous knee OA population.

Duerschmied D.,Albert Ludwigs University of Freiburg | Meissner M.,Albert Ludwigs University of Freiburg | Peter K.,Baker Heart Research Institute | Neudorfer I.,Albert Ludwigs University of Freiburg | And 5 more authors.
Investigative Radiology | Year: 2011

Objective: The final event leading to myocardial infarction is adhesion and activation of platelets after rupture of an atherosclerotic plaque, ending in thrombotic occlusion of the coronary artery. Imaging of imminent vessel occlusion may improve patient care. The feasibility of molecular magnetic resonance imaging (MRI) for the detection of coronary artery thrombosis in mice was examined. Materials and Methods: The left anterior descending coronary artery was exposed by lateral thoracotomy and incubated with ferric chloride to induce nonocclusive thrombosis in C57Bl/6 mice. A single chain antibody targeting ligand-induced binding sites (LIBS) of the activated glycoprotein IIb/IIIa or control antibody was conjugated to 1 μm-sized microparticles of iron oxide (MPIOs), resulting in LIBS-MPIO or control-MPIO MRI contrast agent, and injected intravenously. Hearts were subjected to histology and ex vivo MRI at 9.4 Tesla. Results: Thrombus size was comparable in mice injected with control-MPIO and LIBS-MPIO in histology. Significant binding of MPIOs to thrombi was observed in LIBS-MPIO-injected animals while no binding was observed in control animals (P < 0.05). In MRI, LIBS-MPIO binding to thrombi of the left anterior descending coronary artery resulted in significant MPIO-induced signal void compared with controls (P < 0.05). MRI signal void and the amount of bound contrast agent particles in histology showed a significant positive linear correlation (r = 0.939, P < 0.001). Conclusions: We established a new mouse model of nonocclusive coronary artery thrombosis. LIBS-MPIO contrast agent binds to activated platelets in this model, allowing molecular MRI of coronary thrombosis. This could have important implications on the timely noninvasive detection of arterial thrombosis, helping to initiate early therapeutic interventions. © 2011 by Lippincott Williams & Wilkins.

Lim A.K.H.,Monash Medical Center | Ma F.Y.,Monash Medical Center | Nikolic-Paterson D.J.,Monash Medical Center | Kitching A.R.,Monash University | And 2 more authors.
Diabetologia | Year: 2010

Aims/hypothesis: Diabetic nephropathy is an inflammatory disease with prominent leucocyte infiltration of the kidneys. While the importance of macrophages in diabetic renal injury has been clearly demonstrated, the role of lymphocytes is still unknown. We therefore examined the development of diabetic renal injury in lymphocyte-deficient mice. Methods: Streptozotocin was used to induce diabetes in Rag1 -/- mice, which lack mature T and B lymphocytes, and in wild-type (Rag1 +/+ ) controls. The development of renal injury was examined over 20 weeks of diabetes. Results: Both groups developed equivalent diabetes, however only Rag1 +/+ mice had kidney infiltration with CD4, CD8, CD22 and forkhead box P3-positive cells, as well as glomerular immunoglobulin deposition. At 20 weeks, Rag1 +/+ mice exhibited renal hypertrophy, increased mesangial and interstitial matrix, kidney macrophage accumulation, tubular injury, progressive albuminuria and a decline in renal function. In comparison, diabetic Rag1 -/- mice showed similar histological damage, matrix expansion, macrophage accrual and loss of renal function, but were protected from increasing albuminuria. This protection was associated with protection against loss of podocytes and glomerular podocin production, and with reduced glomerular macrophage activation. Conclusions/interpretation: These results show that lymphocytes contribute to the development of diabetic albuminuria, which may partly arise from increasing glomerular macrophage activation and podocyte damage. In contrast, lymphocytes do not appear to promote tubular injury, increased matrix deposition or decline in renal function in a mouse model of type 1 diabetes. Our findings suggest that innate immunity rather than adaptive immune responses are the major inflammatory contributor to the progression of diabetic renal injury. © 2010 Springer-Verlag.

Krum H.,Monash University | Schlaich M.,Baker Heart Research Institute | Sobotka P.,Hennepin County Medical Center | Sobotka P.,Ardian Inc. | And 3 more authors.
European Heart Journal | Year: 2011

Despite the considerable advances in the treatment of hypertension that have been made over the past few decades, adequate management and control of this condition remains poor, and efforts are ongoing to develop new strategies to improve related outcomes. Novel therapeutic approaches to the management of systemic hypertension fall into two major categories: (i) those that seek to improve blood pressure-lowering efficacy using new therapeutic strategies in addition to standard non-pharmacological and pharmacological approaches and (ii) novel ways to optimize and improve the efficacy and utility of existing therapies. Novel procedure- and device-based strategies to control hypertension include renal sympathetic denervation and baroreflex sensitization. These two techniques will be the focus of the present review. © 2010 The Author.

Hirakawa Y.,University of Sydney | Arima H.,University of Sydney | Zoungas S.,University of Sydney | Zoungas S.,Monash University | And 8 more authors.
Diabetes Care | Year: 2014

OBJECTIVE: There is no consensus on the importance of visit-to-visit glycemic variability in diabetes. Therefore, we assessed the effects of visit-to-visit variability (VVV) in HbA1c and fasting glucose on major outcomes in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial. RESEARCH DESIGN AND METHODS: ADVANCE was a factorial randomized controlled trial of intensive glucose control and blood pressure lowering in patients with type 2 diabetes. VVV in the intensive glucose treatment group was defined using the SD of five measurements of HbA1c and glucose taken 3-24 months after randomization. Outcomes were combined macro- and microvascular events and all-cause mortality occurring post 24 months. Sensitivity analyses were performed using other indices of variability and in the standard glucose treatment group. RESULTS: Among 4,399 patients in the intensive group, an increase in VVV of HbA1c was associated with an increased risk of vascular events (P = 0.01) and with mortality (P < 0.001): highest versus lowest tenth hazard ratio (95% CI) 1.64 (1.05-2.55) and 3.31 (1.57-6.98), respectively, after multivariable adjustment. A clear association was also observed between VVV of fasting glucose and increased risk of vascular events (P < 0.001; 2.70 [1.65-4.42]). HbA 1c variability was positively associated with the risk of macrovascular events (P = 0.02 for trend), whereas glucose variability was associated with both macro- and microvascular events (P = 0.005 and P < 0.001 for trend, respectively). Sensitivity analyses using other indices, and patients in the standard glucose treatment group, were broadly consistent with these results. CONCLUSIONS: Consistency of glycemic control is important to reduce the risks of vascular events and death in type 2 diabetes. © 2014 by the American Diabetes Association.

Rosso R.,Royal Melbourne Hospital | Kistler P.M.,University of Melbourne | Kistler P.M.,Baker Heart Research Institute | Kistler P.M.,Alfred Hospital
Heart | Year: 2010

Focal atrial tachycardia is a relatively uncommon arrhythmia. Nevertheless, the management of highly symptomatic patients with focal atrial tachycardia can be problematic owing to the poor response to medical treatment. Moreover, focal atrial tachycardia can trigger other atrial arrhythmias like atrial fibrillation and flutter. Radiofrequency ablation of focal atrial tachycardia is extremely successful and this approach is becoming the preferred treatment for symptomatic patients.In this review, we describe the pathophysiology, anatomical localisation, clinical features, diagnosis and therapeutic options for the management of focal atrial tachycardia.

Davies S.J.C.,University of Bristol | Esler M.,Baker Heart Research Institute | Nutt D.J.,University of Bristol
Journal of Psychopharmacology | Year: 2010

Although the complimentary roles of heart and brain in anxiety have been recognised for centuries, the precise contribution of each and more importantly perhaps their interplay has proved difficult to describe. Recent data from human brain imaging and cardiovascular physiology studies are beginning to delineate the mechanistic pathways of anxiety disorders in general and panic in particular. Evidence for a dysfunction of brain gamma-amino butyric acid-A and serotonin (5HT) systems in both panic and cardiovascular regulation is reviewed along with new evidence for altered sympathetic nervous system activity in the heart and periphery. Testable hypotheses and research ideas are suggested. © 2010 The Author(s).

Ott C.,Friedrich - Alexander - University, Erlangen - Nuremberg | Schneider M.P.,Friedrich - Alexander - University, Erlangen - Nuremberg | Delles C.,University of Glasgow | Schlaich M.P.,Baker Heart Research Institute | Schmieder R.E.,Friedrich - Alexander - University, Erlangen - Nuremberg
Diabetes | Year: 2011

OBJECTIVE - The barrier function of the glomerular filter has been studied for decades. Albuminuria reflects a malfunction of this barrier, and in animals dysfunctional endothelial nitric-oxide (NO) synthase results in albuminuria. We aimed to analyze the importance of NO for the glomerular barrier function in humans. RESEARCH DESIGN AND METHODS - To assess the effect of endothelial dysfunction on albuminuria, we measured the urine albumin-to-creatinine ratio (UACR) both before and after the blockade of NO synthases (NOSs) with systemic infusion of N G-monomethyl-L-arginine (L-NMMA) in two distinct study populations. In population A, 62 hypertensive patients with type 2 diabetes and, in population B, 22 patients with hypercholesterolemia but without hypertension or type 2 diabetes were examined. All subjects had normal renal function. RESULTS - There was a significant increase in the UACR in response to NOS inhibition with L-NMMA in hypertensive patients with type 2 diabetes (study population A) and in patients with hypercholesterolemia (study population B). Linear regression analyses revealed that the change in mean arterial presssure in response to L-NMMA was not related to the increase in the UACR in response to L-NMMA in either population, even after adjusting for filtration fraction. CONCLUSIONS - NOS inhibition provokes albuminuria that is unrelated to changes in blood pressure. It is noteworthy that this finding was evident in patient groups prone to endothelial dysfunction and albuminuria. Thus, acute deterioration of endothelial function by reducing NO activity causes an increase in albuminuria. © 2011 by the American Diabetes Association.

Baker Heart Research Institute and University of Queensland | Date: 2011-11-10

The present invention discloses proteinaceous compounds that comprise at least a biologically active portion of a taipan natriuretic peptide (TNP) or a variant or derivative thereof. The invention also relates to the use of these compounds in methods for stimulating vasodilation, natriuresis, diuresis, renin-suppression, bactericidal activity, weight-loss or bone growth in a mammalian host. In specific embodiments, the compounds are useful in the treatment of congestive heart failure.

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