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BACKGROUND—: Dietary intake of fruit and vegetables is associated with lower incidence of hypertension, but the mechanisms involved have not been elucidated. Here we evaluated the effect of a high fibre diet and supplementation with the short-chain fatty acid (SFCA) acetate on the gut microbiota and the prevention of cardiovascular disease. METHODS—: Gut microbiome, cardiorenal structure/function and blood pressure were examined in sham and mineralocorticoid-excess treated mice with a control diet, high fibre diet or acetate supplementation. We also determined the renal and cardiac transcriptome of mice treated with the different diets. RESULTS—: We found that high consumption of fibre modified the gut microbiota populations and increased the abundance of acetate-producing bacteria, independently of mineralocorticoid-excess. Both fibre and acetate decreased gut dysbiosis, measured by the ratio of Firmicutes to Bacteroidetes, and increased the prevalence of Bacteroides acidifaciens. Compared to mineralocorticoid-excess mice fed a control diet, both high fibre diet and acetate supplementation significantly reduced systolic and diastolic blood pressure, cardiac fibrosis and left ventricular hypertrophy. Acetate had similar effects and also markedly reduced renal fibrosis. Transcriptome analyses showed that the protective effects of high fibre and acetate were accompanied by the down-regulation of cardiac and renal Egr1, a master cardiovascular regulator involved in cardiac hypertrophy, cardiorenal fibrosis and inflammation. We also observed the up-regulation of a network of genes involved in circadian rhythm in both tissues, while down-regulated the renin-angiotensin system in the kidney and mitogen-activated protein kinases (MAPK) signalling in the heart. CONCLUSIONS—: A diet high in fibre led to changes in the gut microbiota which played a protective role in the development of cardiovascular disease. The favourable effects of fibre may be explained by the generation and distribution of one of the main metabolites of the gut microbiota, the SCFA acetate. Acetate effected several molecular changes associated with improved cardiovascular health and function. © 2017 by the American College of Cardiology Foundation and the American Heart Association, Inc.

Tan S.M.,IDI Group | Stefanovic N.,IDI Group | Tan G.,Monash University | Wilkinson-Berka J.L.,Monash University | de Haan J.B.,IDI Group
Investigative Ophthalmology and Visual Science | Year: 2013

PURPOSE. Glutathione peroxidase-1 (GPx1) is highly expressed during normal retinal maturation; however, its role in retinopathy of prematurity (ROP) is not fully understood. We postulated that GPx1 plays an important role in protecting the premature retina from oxidative injury in a mouse model of ROP. METHODS. ROP was induced in wild-type (WT) and GPx1 knockout (KO) mice by exposing neonatal mice to 75% oxygen from postnatal days 7 to 11, followed by 1 week of room air. Structural effects of ROP were evaluated by retinal histology, and gene expression of retinal pro-angiogenic factors was measured by qRT-PCR. RESULTS. Retinas from ROP GPx1 KO mice had a significantly larger central avascular area compared to those from ROP WT mice (P < 0.001), indicative of a more severe vaso-obliteration. In ROP GPx1 KO mice, retinas also displayed increased preretinal neovascularization (P = 0.05) with a concurrent increase in the expression of vascular endothelial growth factor (P < 0.05) compared to values in ROP WT mice. Elevated oxidative stress was observed in ROP GPx1 KO retinas as evidenced by increased nitrotyrosine immunolabeling (P < 0.01) and superoxide (P < 0.05) in vessels compared to ROP WT retinas. In contrast to these findings of exacerbated retinal vascular injury in GPx1 KO mice, Müller cell gliosis and microglial density were similar in ROP GPx1 KO and ROP WT mice. CONCLUSIONS. GPx1, an important antioxidant enzyme of the premature retina, afforded protection against oxidative stress and oxidative injury in ROP. Lack of GPx1 was associated with increased oxidative stress, an increase in retinal avascular area, upregulation of retinal VEGF, and increased neovascularization in a mouse model of ROP. Copyright 2013 The Association for Research in Vision and Ophthalmology, Inc.

Kaye D.M.,IDI Group | Kaye D.M.,Monash University | Khammy O.,IDI Group | Mariani J.,IDI Group | And 2 more authors.
European Journal of Heart Failure | Year: 2013

AimsInterstitial fibrosis is a key component of myocardial remodelling in heart failure (HF). Many studies have measured peripheral blood levels of procollagens and matrix metalloproteinases (MMPs), as a surrogate for myocardial matrix metabolism, particularly to evaluate the effect of interventions and their prognostic relevance. However, the relationship between peripheral biomarker levels and actual cardiac turnover in HF is not known. We aimed to determine whether peripheral levels of relevant biomarkers reflect cardiac release in patients with advanced HF.Methods and resultsWe determined whether the failing human heart releases collagen precursors [procollagen I N-terminal peptide (PINP) and procollagen III N-terminal peptide (PIIINP)], or key matrix metalloproteinases (MMP9) and MMP inhibitors [tissue inhibitor of metalloproteinase 1 (TIMP1)] by performing transcardiac blood sampling in healthy controls (n = 9) and in patients with advanced HF (n = 18, left ventricular ejection fraction 22 ± 2%). HF patients had higher arterial levels of PIIINP compared with controls (7.0 ± 0.7 vs. 4.0 ± 0.2 μg/L, P < 0.001). PIIINP was closely correlated with the pulmonary capillary wedge pressure (r = 0.54, P = 0.01) and the estimated glomerular filtration rate (r = -0.50, P = 0.01). Transcardiac blood sampling demonstrated that there was no net release of either PINP or PIIINP in controls or HF patients. The transcardiac MMP9 gradient was significantly lower in HF patients (P < 0.05), and was negatively correlated with left ventricular mass (r = -0.51, P = 0.01).ConclusionsOur study shows that the concentration of circulating levels of PINP, PIIINP, MMP9, and TIMP1 do not accurately reflect cardiac turnover. This study highlights the importance of performing transcardiac blood sampling to validate the utility of emerging cardiac biomarkers. © 2012 Published on behalf of the European Society of Cardiology. All rights reserved.

Jaworski C.,Alfred Hospital | Mariani J.A.,Alfred Hospital | Mariani J.A.,IDI Group | Mariani J.A.,Monash University | And 5 more authors.
Journal of the American College of Cardiology | Year: 2013

Adjuvant radiation therapy in the management of early stage breast cancer, Hodgkin's disease, and to a lesser extent other thoracic malignancies has led to a significant improvement in disease-specific survival. Cardiovascular disease is now the most common nonmalignancy cause of death in radiation-treated cancer survivors, most often occurring decades after treatment. The spectrum of radiation-induced cardiac disease is broad, potentially involving any component of the heart. The relative risk of coronary artery disease, congestive heart failure, valvular heart disease, pericardial disease, conduction abnormalities, and sudden cardiac death is particularly increased. Over the years contemporary techniques have been introduced to reduce cardiac morbidity and mortality in radiation-treated cancer survivors; however, the long-term effects on the heart still remain unclear, mandating longer follow-up. Awareness and early identification of potential cardiac complications is crucial in cancer survivors, with the management often being quite complex. This review examines the epidemiology of radiation-induced cardiac disease together with its pathophysiology and explores the available treatment strategies and the potential utility of various screening strategies for affected cancer survivors. © 2013 by the American College of Cardiology Foundation.

Maeder M.T.,IDI Group | Maeder M.T.,Alfred Hospital | Thompson B.R.,Alfred Hospital | Brunner-La Rocca H.-P.,Maastricht University | And 2 more authors.
Journal of the American College of Cardiology | Year: 2010

Objectives The purpose of this study was to invasively investigate the hemodynamic response to exercise in patients with heart failure with normal ejection fraction (HFNEF) and to evaluate the ability of the peak early diastolic transmitral velocity to peak early diastolic annular velocity ratio (E/e′) to reflect exercise hemodynamics. Background There is little information regarding the hemodynamic response to exercise in HFNEF. Methods Patients with HFNEF (n = 14) and asymptomatic controls (n = 8) underwent right-side heart catheterization at rest and during supine cycle ergometer exercise and echocardiography with measurement of resting and peak exercise E/e′. Results Resting pulmonary capillary wedge pressure (PCWP) (10 ± 4 mm Hg vs. 10 ± 4 mm Hg; p = 0.94) was similar in HFNEF patients and controls, but stroke volume index (SVI) (p = 0.02) was lower, and systemic vascular resistance index (SVRI) (p = 0.01) was higher in patients. Patients stopped exercise at lower work rate (0.63 ± 0.29 W/kg vs. 1.13 ± 0.49 W/kg; p = 0.006). Although peak exercise PCWP was similar in both groups (23 ± 6 mm Hg vs. 20 ± 7 mm Hg; p = 0.31), the peak PCWP/work rate ratio was higher in patients compared with controls (46 ± 31 mm Hg/W/kg vs. 20 ± 9 mm Hg/W/kg; p = 0.03). Peak exercise SVI (p = 0.001) was lower and SVRI was higher (p = 0.01) in patients. Resting E/e′ was modestly elevated in patients (13.2 ± 4.1 vs. 9.5 ± 3.4; p = 0.04). Peak exercise E/e′ did not differ between the groups (11.1 ± 3.4 vs. 9.4 ± 3.4; p = 0.28). Conclusions The HFNEF patients achieved a similar peak exercise PCWP to that of asymptomatic controls, at a much lower workload. This occurs at a lower SVI and in the setting of higher SVRI. The E/e′ does not reflect the hemodynamic changes during exercise in HFNEF patients. © 2010 American College of Cardiology Foundation.

Maeder M.T.,IDI Group | Maeder M.T.,Alfred Hospital | Mariani J.A.,IDI Group | Mariani J.A.,Alfred Hospital | And 2 more authors.
Hypertension | Year: 2010

Although B-type natriuretic peptide (BNP) is widely used as a biomarker for heart failure, the in vivo mechanical stimulus for its cardiac release remains poorly defined. We aimed to characterize the hemodynamic determinants of the transcardiac BNP gradient as a measure of myocardial BNP release by performing a detailed hemodynamic assessment in subjects with a broad spectrum of systolic and diastolic left ventricular dysfunction. Forty-two subjects underwent a detailed transthoracic echocardiographic study, right heart catheterization, and simultaneous BNP measurement in arterial and coronary sinus plasma. The transcardiac BNP gradient was lowest in subjects with normal left ventricular ejection fraction/high peak early diastolic annular velocity (n=11), intermediate in those with normal left ventricular ejection fraction/low peak early diastolic annular velocity (n=13), and highest in those with low left ventricular ejection fraction/low peak early diastolic annular velocity (n=18; 29 ng/L (range: 15 to 78 ng/L) versus 88 ng/L (range: 34 to 172 ng/L) versus 1566 ng/L (range: 624 to 2349 ng/L; P<0.001). Across the range of patients, left ventricular end-systolic wall stress (r=0.51) and peak systolic mitral annular velocity (r=0.47) showed the strongest correlation with higher transcardiac BNP gradient. In contrast, the transcardiac BNP gradient was weakly related to indices of diastolic load, including pulmonary capillary wedge pressure (r=0.27) and left ventricular end-diastolic wall stress (r=0.21). Across this spectrum of pathophysiology, left ventricular end-systolic wall stress appears to be the key mechanical stimulus influencing cardiac BNP release. © 2010 American Heart Association, Inc.

Maeder M.T.,IDI Group | Maeder M.T.,Alfred Hospital | Khammy O.,IDI Group | Dos Remedios C.,University of Sydney | And 2 more authors.
Journal of the American College of Cardiology | Year: 2011

Objectives: This study sought to determine the potential pathophysiological link between anemia and disease severity, and adverse outcome in heart failure (HF). Background: Anemia frequently accompanies advanced HF; however, the pathophysiological mechanism responsible for the association between anemia and more severe HF remains uncertain. We hypothesized that a depletion of myocardial iron content may provide the biological link. Methods: Complementary clinical and basic studies were performed. Hemodynamic, biochemical, and echocardiographic investigations were performed in 9 healthy controls and 25 patients with advanced HF (left ventricular ejection fraction: 23 ± 10%). Tissue iron content and type 1 transferrin receptor (Tfr1) expression were assessed in human myocardial tissue, and the regulation of Tfr1 expression was studied in isolated cardiomyocytes. Results: HF patients displayed evidence of iron deficiency as measured by lower serum iron (p < 0.05) and transferrin saturation (TFS) (p < 0.05). When subclassified according to the presence of anemia, TFS was lower in anemic compared with nonanemic HF patients, whereas TFS in nonanemic HF patients was intermediate. In association, myocardial iron content was reduced in HF versus non-HF samples (0.49 ± 0.07 μg/g vs. 0.58 ± 0.09 μg/g, p < 0.05), and there was a significant reduction (p < 0.05) in the myocardial mRNA expression of Tfr1, which plays a key role in cellular iron transport. In the context of HF, catecholamines and aldosterone both down-regulated Tfr1 expression in isolated cardiomyocytes. Conclusions: This study suggests the presence of iron depletion in the failing human heart, providing a potential link for the association between anemia and adverse prognosis in HF. © 2011 American College of Cardiology Foundation.

Marques F.Z.,IDI Group | Vizi D.,Heart Center Alfred Hospital Melbourne | Khammy O.,IDI Group | Mariani J.A.,IDI Group | Kaye D.M.,IDI Group
European Journal of Heart Failure | Year: 2016

Aims: Differential microRNA expression in peripheral blood has been observed in patients with heart failure, suggesting their value as potential biomarkers and likely contributors to disease mechanisms. In the present study, we aimed to evaluate the transcardiac gradient of 84 cardio-microRNAs in healthy and failing hearts to determine which microRNAs are released or absorbed by the myocardium in heart failure. Methods and results: Eight healthy volunteers and nine patients with congestive heart failure were included. Arterial and coronary sinus blood samples were collected, and microRNAs were extracted. The expression of microRNAs was analysed using real-time PCR by the miScript miRNA PCR Array Human Cardiovascular Disease. In coronary sinus samples, the microRNAs miR-16-5p, miR-27a-3p, miR-27b-3p, miR-29b-3p, miR-29c-3p, miR-30e-5p, miR-92a-3p, miR-125b-5p, miR-140-5p, miR-195-5p, miR-424-5p, and miR-451a were significantly down-regulated, and let-7a-5p, let-7c-5p, let-7e-5p, miR-23b-3p, miR-107, miR-155-5p, miR-181a-5p, miR-181b-5p and miR-320a were up-regulated in heart failure. Left ventricular filling pressure was negatively correlated with miR-195, miR-16, miR-29b-3p, miR-29c-3p, miR-451a, and miR-92a-3p. The failing heart released let-7b-5p, let-7c-5p, let-7e-5p, miR-122-5p, and miR-21-5p, and absorbed miR-16-5p, miR-17-5p, miR-27a-3p, miR-30a-5p, miR-30d-5p, miR-30e-5p, miR-130a-3p, miR-140-5p, miR-199a-5p, and miR-451a. In silico analyses suggest that the transcardiac gradient of microRNAs in heart failure may target pathways related to heart disease. Conclusion: We determined the transcardiac gradient of cardio-microRNAs in failing hearts, which supports the use of these microRNAs as potential biomarkers. The microRNAs described here may have a role in the pathophysiology of heart failure as they might be involved in pathways related to disease progression, including fibrosis. © 2016 European Society of Cardiology.

Mariani J.A.,IDI Group | Kaye D.M.,IDI Group
Journal of Cardiovascular Translational Research | Year: 2010

Although there has been considerable interest in the utilization of gene and cellular therapy for heart disease in recent years, there remain critical questions prior to widespread promotion of therapy, and key among these issues is the delivery method used for both gene therapy and cellular therapy. Much of the failure of gene and cellular therapy can be explained by the biological therapy itself; however, certainly there is a critical role played by the delivery technique, in particular, those that have been adapted from routine clinical use such as intravenous and intracoronary injection. Development of novel techniques to deliver gene and cellular therapy has ensued with some preclinical and even clinical success, though questions regarding safety, invasiveness, and repeatability remain. Here, we review techniques for gene and cellular therapy delivery, both existing and adapted techniques, and novel techniques that have emerged recently at promoting improved efficacy of therapy without the cost of systemic distribution. We also highlight key issues that need to be addressed to improve the chances of success of delivery techniques to enhance therapeutic benefit. © 2010 Springer Science+Business Media, LLC.

Mariani J.A.,IDI Group | Smolic A.,IDI Group | Preovolos A.,IDI Group | Byrne M.J.,IDI Group | And 2 more authors.
European Journal of Heart Failure | Year: 2011

AimsDown-regulation of sarcoplasmic reticulum calcium ATPase (SERCA2a) is a key molecular abnormality in heart failure (HF), which is not currently addressed by specific pharmacotherapy. We sought to evaluate, in detail, the impact of augmented SERCA2a expression on left ventricular (LV) mechanics in a large animal model of HF.Methods and resultsHeart failure was induced in adult sheep by rapid pacing (180 b.p.m.) for 1 month, followed by delivery of adeno-associated virus (AAV) 2/1SERCA, using a percutaneous, recirculating system for gene delivery over a 10 min period. Left ventricular mechanics was investigated by echocardiography and conductance catheter measurements in sheep receiving AAV2/1SERCA2a after a further 4 weeks of pacing in comparison with untreated HF controls. Left ventricular function was significantly improved in the AAV2/1SERCA2a-treated group, despite continued pacing, as measured by fractional shortening (delta absolute FS, control -4.2 ± 1.5 vs. treatment 4.4 ± 1.5; P < 0.01) and conductance catheterization (delta Ees, control -1.22 ± 0.60 vs. treatment 0.65 ± 0.51; P < 0.05). Western blots showed an increase in SERCA protein in AAV2/1SERCA2a-treated animals, and an analysis of gene delivery showed no evidence of regional myocardial heterogeneity in the distribution of AAV2/1SERCA.ConclusionIn a large animal model, AAV2/1-mediated SERCA2a gene delivery using percutaneous, recirculating cardiac delivery leads to improved LV function. © 2010 The Author.

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