Phosphoinositide 3-Kinase p110alpha Gene Therapy Rescues Diabetic Cardiomyopathy in a Type 2 Diabetic Model

Abstracts

months pre-implementation at each site were compared to 16 months post-implementation data. Results: Median total hospital LOS fell by 404 min (95% CI: 370-437 min) from 1210mins (IQR: 511-3494) to 806mins (IQR: 368-2300). ED LOS fell from 230mins (IQR: 163-352) to 213mins (IQR 150-307). There was an absolute decrease in hospital admissions of 13.1% (95% CI: 12.3-13.9%) from 70.4% to 57.3%. 5815 patients were managed on the ADP, accounting for 23.2% (95% CI; 22.7-23.8%) of possible cardiac chest pain presentations and closely matching ADAPT. Conclusion: The ADAPT ADP is applicable to routine clinical practice across a broad range of hospitals. Implementation had a profound positive impact on hospital LOS and admission rates for patients presenting with possible cardiac chest pain. http://dx.doi.org/10.1016/j.hlc.2016.06.014 14 Effectiveness of a Phone-Based Care Coordination Pilot on Reducing Hospital Utilisation and Costs for Patients with Chest Pain P. Price 1,2,4,∗ , R. Vincent 1 , M. Tacey 1,3 , J. Gilchrist 1 , D. Liew 1,3 , L. Grigg 1 , L. Naccarella 4 1 Royal

Melbourne Hospital, Parkville, Victoria, Australia 2 Merri Health, Coburg, Victoria, Australia 3 Melbourne Epicentre, Department of Medicine, University of Melbourne, Victoria, Australia 4 School of Population and Global Health, University of Melbourne, Victoria, Australia Background: Patients who present to hospital with chest pain do not always fit established pathways for acute myocardial events. They are often discharged from the Emergency Department (ED) after short lengths of stay. Following a formative evaluation that identified gaps in existing care, a phone-based care-coordination pilot was designed to meet the needs of patients with cardiac and non-cardiac chest pain. Methods: 95 patients were recruited as the intervention group; 97 patients were retrospectively matched as controls. These patients had represented with chest pain within 6 months of a cardiac event, or attended hospital within 12 months two or more times with chest pain and/or complex needs. Intervention group patients were holistically assessed then phone-coached to support self- management of chest pain over six months. Following descriptive and univariate analysis, multivariate analysis was conducted to adjust for noted differences between the intervention and control groups.

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Results: 30-day representation to ED was significantly less for the intervention group (14.1%) compared to controls (27.7%). After adjusting for baseline differences, intervention patients were more than twofold less likely to represent compared to controls (OR=0.42, 95%CI: 0.19-0.96). After adjustment for baseline differences, the savings in subsequent inpatient costs was $1588 per-person, as a result of intervention patients less likely to have inpatient readmissions (16.3%) compared to controls (20.2%), although this was not statistically significant (p=0.588). Conclusion: A phone-based care-coordination pilot with targeted interventions has the potential to reduce ED presentations and hospital readmissions among patients representing with chest pain. http://dx.doi.org/10.1016/j.hlc.2016.06.015 ISHR Student Investigator Prize Finalists - Basic Mechanisms (15–18) 15 Phosphoinositide 3-Kinase p110alpha Gene Therapy Rescues Diabetic Cardiomyopathy in a Type 2 Diabetic Model D. Prakoso 1,2,∗ , M. De Blasio 1,2 , H. Kiriazis 1 , H. Qian 1 , M. Deo 1 , E. Jap 1 , K. Weeks 2 , L. Parry 1 , X. Du 1 , P. Gregorevic 1 , J. McMullen 1,2 , R. Ritchie 1,2 1 Baker

IDI, Melbourne, Australia of Melbourne, Australia

2 University

Phosphoinositide 3-kinase (PI3K) mediates membrane trafficking, cell growth and survival. We previously demonstrated that PI3K adeno-associated viral (AAV) gene therapy limits type-1 diabetic cardiomyopathy, but its efficiency in the clinically relevant context of type-2 diabetes (T2D) is unknown. Our aim is to test the hypothesis that PI3K gene therapy rescues diabetic cardiomyopathy in a mouse model of T2D. T2D was induced in 6wks old male mice by low dose streptozotocin (55 mg/kg/day i.p for three days) combined with 24wks high fat diet. After 16wks of diabetes, diastolic dysfunction was confirmed by echocardiography (impairment isovolumic relaxation time (IVRT), peak A wave, and E/A). A single tail vein injection of rAAV6caPI3K (2x1011 vg) or null vector was then administered, and mice were followed for a further 8wks. As shown in the table, T2D-induced diastolic dysfunction and its key trigger (increase superoxide and blunted sarco/endoplasmic reticulum Ca2+ ATPase [SERCA2a]) were significantly attenuated by PI3K gene therapy. In conclusion, our data are the first to demonstrate rAAV6-caPI3K gene therapy may rescue T2D cardiomyopathy.

Abstracts

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Results: mean±SE(n)

Sham Null (n=8)

Diabetic PI3K (n=10)

Null (n=10)

PI3K (n=11)

............................................. Body weight (g) HbA1c (%) IPGTT (AUC) Fat mass (%) IVRT (%sham null) A wave (%sham null) E/A (%sham null) SERCA2a expression (fold) LV Superoxide (fold) p22phox expression (fold)

35±0.8 3.6±0.2 789±153 18±1 100±7 100±10

36±1.0 3.8±0.3 1091±132 20±2 106±6 82±7

40±1.5* 5.5±0.5* 2212±152* 29±2* 125±3* 155±9*

40±1.0* , † 5.6±0.5* , † 1900±206* , † 28±2* , † 104±4# 131±8#

100±8 1.0±0.1

126±13 0.9±0.1

66±4* 0.7±0.1*

83±6# 1.2±0.4#

1.0±0.1

0.8±0.7

1.7±0.3*

0.9±0.1#

1.0±0.2

0.9±0.2

1.7±0.4*

1.1±0.4#

∗

P<0.05 vs sham-null

†

P<0.05 vs sham-PI3K

#

P<0.05 vs diabetic-null

http://dx.doi.org/10.1016/j.hlc.2016.06.016 16 A Dietary Intervention Increasing Plasmalogen Lipids in a Mouse Model of Dilated Cardiomyopathy Attenuates Cardiac Pathology Y. Tham 1,2,∗ , N. Mellett 1 , P. Meikle 1,2 , J. McMullen 1,2 1 Baker

IDI Heart and Diabetes Institute, Melbourne, Australia 2 Faculty of Medicine, Nursing and Health Sciences, Monash University, Australia Introduction: Plasmalogens belong to a class of lipids that are enriched in the heart and were previously shown to be protective in mammalian cells. A pilot study showed that gene expression of enzymes on the plasmalogen synthesis pathway were decreased in the heart of a transgenic mouse model with dilated cardiomyopathy (DCM) due to cardiac overexpression of mammalian sterile 20-like kinase 1. Aim: To determine whether restoration of plasmalogens can attenuate cardiac pathology in DCM mice. Methods: Plasmalogens were restored via dietary supplementation of 1% batyl alcohol (BA)/ kg of chow. Non-transgenic (Ntg) and DCM mice began dietary supplementation at ∼13 weeks of age with chow or 1% BA diet for 16 weeks (N=3-6 per group). Lipids were extracted using a single phase chloroform:methanol extraction and run using liquid chromatography electrospray ionisation tandem mass spectrometry. Data was analysed in Multiquant 2.1 software and specific lipid species normalised to total phosphatidylcholine levels. Results: Specific plasmalogen species were decreased in the hearts of the DCM model, and BA supplementation increased plasmalogens (C18:0) vs. chow mice (P<0.05). Chow DCM displayed an increase in atria weight/tibia length ratio (1.2±0.06 mg/mm) vs. chow Ntg (0.4±0.02 mg/mm) and this was attenuated in BA fed DCM mice (1.0±0.06 mg/mm,

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p=0.05). Expression of the pathological marker, atrial natriuretic peptide was increased 57-fold in the DCM model but was attenuated in DCM BA mice (33-fold, p<0.05). Conclusion: Restoration of plasmalogens via dietary supplementation in a DCM model is associated with attenuation of cardiac pathology. http://dx.doi.org/10.1016/j.hlc.2016.06.017 17 Non-Invasive Tracking of Bone Marrow Mononuclear Cell Engraftment in Implanted Biomaterial Scaffolds R. Tan 1,2,∗ , S. Lee 1 , K. Jin 1 , J. Hung 1 , M. Ng 1,3,4 , S. Wise 1,2,3 1 Heart

Research Institute, Sydney, Australia Medical School, University of Sydney, Australia 3 School of Molecular Bioscience, University of Sydney, Australia 4 Royal Prince Alfred Hospital, Sydney, Australia 2 Sydney

Background: Long-term engraftment and survival of transplanted bone marrow mononuclear cells (BM-MNC) within the injured myocardium remains an elusive goal, limiting the efficacy of BM-MNC therapy for the treatment of heart disease. Our model non-invasively tracks the real-time engraftment of BM-MNCs in mice, to characterise biomaterial scaffolds which aid long-term engraftment of BM-MNCs.

Methods and Results: BM-MNCs harvested from donor FVB-L2G mice, which utilise a dual bioluminescence and green-fluorescent protein (GFP) reporter system, were intravenously injected into WT mice implanted with polycaprolactone (PCL) and PCL/Collagen hybrid scaffolds, to determine differences in BM-MNC engraftment to these materials. Over 21 days, PCL/Collagen scaffolds displayed a 73±6.6% increase in max bioluminescence compared to PCL (p<0.01, Fig 1A). Histological analysis showed GFP+ BM-MNC engraftment into the body of PCL/Collagen scaffolds, compared to peripheral accumulation around PCL scaffolds (Fig 1B). Characterisation of engrafted cell phenotypes showed increased infiltration rates of macrophages, fibroblasts, and capillaries by 187±12.1% 173±11.6% and 180±14.2%, respectively, in PCL/Collagen compared to PCL