Platelet Adhesion and Activation in an ECMO Thrombosis-on-a-Chip Model.

Use of extracorporeal membrane oxygenation (ECMO) for cardiorespiratory failure remains complicated by blood clot formation (thrombosis), triggered by biomaterial surfaces and flow conditions. Thrombosis may result in ECMO circuit changes, cause red blood cell hemolysis, and thromboembolic events. Medical device thrombosis is potentiated by the interplay between biomaterial properties, hemodynamic flow conditions and patient pathology, however, the contribution and importance of these factors are poorly understood because many in vitro models lack the capability to customize material and flow conditions to investigate thrombosis under clinically relevant medical device conditions. Therefore, an ECMO thrombosis-on-a-chip model is developed that enables highly customizable biomaterial and flow combinations to evaluate ECMO thrombosis in real-time with low blood volume. It is observed that low flow rates, decelerating conditions, and flow stasis significantly increased platelet adhesion, correlating with clinical thrombus formation. For the first time, it is found that tubing material, polyvinyl chloride, caused increased platelet P-selectin activation compared to connector material, polycarbonate. This ECMO thrombosis-on-a-chip model can be used to guide ECMO operation, inform medical device design, investigate embolism, occlusion and platelet activation mechanisms, and develop anti-thrombotic biomaterials to ultimately reduce medical device thrombosis, anti-thrombotic drug use and therefore bleeding complications, leading to safer blood-contacting medical devices.

Cardiogenic Shock Challenges and Priorities: A Clinician Survey.

BACKGROUND: Cardiogenic shock (CS) is common and survival outcomes have not substantially improved. Australia's geography presents unique challenges in the management of CS. The challenges and research priorities for clinicians pertaining to CS identification and management have yet to be described. METHOD: We used an exploratory sequential mixed methods design. Semi-structured interviews were conducted with 10 clinicians (medical and nursing) to identify themes for quantitative evaluation. A total of 143 clinicians undertook quantitative evaluation through online survey. The interviews and surveys addressed current understanding of CS, status of cardiogenic systems and future research priorities. RESULTS: There were 143 respondents: 16 (11%) emergency, cardiology 22 (16%), 37 (26%) intensive care, 54 (38%) nursing. In total, 107 (75%) believe CS is under-recognised. Thirteen (13; 9%) of respondents indicated their hospital had existing CS teams, all from metropolitan hospitals, and 40% thought additional access to mechanical circulatory support devices was required. Five (5; 11%) non-tertiary hospital respondents had not experienced a delay in transfer of a patient in CS. All respondents felt additional research, particularly into the management of CS, was required. CONCLUSIONS: Clinicians report that CS is under-recognised and further research into CS management is required. Access to specialised CS services is still an issue and CS protocolised pathways may be of value.

ECPR Survivor Estimates: A Simulation-Based Approach to Comparing ECPR Delivery Strategies.

Objective: The number of out-of-hospital cardiac arrest (OHCA) patients who may benefit from prehospital extracorporeal cardiopulmonary resuscitation (ECPR) is yet to be elucidated. Patient eligibility is determined both by case characteristics and physical proximity to an ECPR service. We applied accessibility principles to historical cardiac arrest data, to identify the number of patients who would have been eligible for prehospital ECPR in Sydney, Australia, and the potential survival benefit had prehospital ECPR been available.Methods: The New South Wales cardiac arrest registry between January 2017 to June 2021 included 39,387 cardiac arrests. We retrospectively defined two groups: 1) possible ECPR eligible arrests that would have triggered activation of a team, and 2) ECPR eligible arrests, those arrests that met ECPR inclusion criteria and remained refractory. Transport accessibility modeling was used to ascertain the number of arrests that would have been served by a hypothetical prehospital service and the potential survival benefit.Results: There were 699 arrests screened as possibly ECPR eligible in the Sydney metropolitan area, 488 of whom were subsequently confirmed as ECPR eligible refractory OHCA. Of these, 38% (n = 185) received intra-arrest transfer to hospital, with 37% (n = 180) arriving within 60 min. Using spatial and transport modeling, a prehospital team located at an optimal location could establish 437 (90%) patients onto ECMO within 60 min, with an estimated survival of 48% (IQR 38-57). Based on existing survival curves, compared to conventional CPR, an optimally located prehospital ECPR service has the potential to save one additional life for every 3.0 patients.Conclusions: A significant number of historical OHCA patients could have benefited from prehospital ECPR, with a potential survival benefit above conventional CPR.

Extracorporeal cardiopulmonary resuscitation for refractory cardiac arrest in Australia: a narrative review.

Extracorporeal cardiopulmonary resuscitation (ECPR) in patients with prolonged or refractory out-of-hospital cardiac arrest (OHCA) is likely to be beneficial when used as part of a well developed emergency service system. ECPR is technically challenging to initiate and resource-intensive, but it has been found to be cost-effective in hospital-based ECPR programs. ECPR expansion within Australia has thus far been reactive and does not provide broad coverage or equity of access for patients. Newer delivery strategies that improve access to ECPR for patients with OHCA are being trialled, including networked hospital-based ECPR and pre-hospital ECPR programs. The efficacy, scalability, sustainability and cost-effectiveness of these programs need to be assessed. There is a need for national collaboration to determine the most cost-effective delivery strategies for ECPR provision along with its place in the OHCA survival chain.

A randomized trial of expedited intra-arrest transfer versus more extended on-scene resuscitation for refractory out of hospital cardiac arrest: Rationale and design of the EVIDENCE trial.

BACKGROUND: Refractory Out of Hospital Cardiac Arrest (r-OHCA) is common and the benefit versus harm of intra-arrest transport of patients to hospital is not clear. OBJECTIVE: To assess the rate of survival to hospital discharge in adult patients with r-OHCA, initial rhythm pulseless ventricular tachycardia (VT)/ventricular fibrillation (VF) or Pulseless Electrical Activity (PEA) treated with 1 of 2 locally accepted standards of care:1 expedited transport from scene; or2 ongoing advanced life support (ALS) resuscitation on-scene. HYPOTHESIS: We hypothesize that expedited transport from scene in r-OHCA improves survival with favorable neurological status/outcome. METHODS/DESIGN: Phase III, multi-center, partially blinded, prospective, intention-to-treat, safety and efficacy clinical trial with contemporaneous registry of patient ineligible for the clinical trial. Eligible patients for inclusion are adults with witnessed r-OHCA; estimated age 18 to 70, assumed medical cause with immediate bystander cardiopulmonary resuscitation (CPR); initial rhythm of VF/pulseless VT, or PEA; no return of spontaneous circulation following 3 shocks and/or 15 minutes of professional on-scene resuscitation; with mechanical CPR available. Two hundred patients will be randomized in a 1:1 ratio to either expedited transport from scene or ongoing ALS at the scene of cardiac arrest. SETTING: Two urban regions in NSW Australia. OUTCOMES: Primary: survival to hospital discharge with cerebral performance category (CPC) 1 or 2. Secondary: safety, survival, prognostic factors, use of ECMO supported CPR and functional assessment at hospital discharge and 4 weeks and 6 months, quality of life, healthcare use and cost-effectiveness. CONCLUSIONS: The EVIDENCE trial will determine the potential risks and benefits of an expedited transport from scene of cardiac arrest.

The effect of restrictive versus liberal selection criteria on survival in ECPR: a retrospective analysis of a multi-regional dataset.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) is an established rescue therapy for both out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA). However, there remains significant heterogeneity in populations and outcomes across different studies. The primary aim of this study was to compare commonly used selection criteria and their effect on survival and utilisation in an Australian ECPR cohort. METHODS: We performed a retrospective, observational study of three established ECPR centres in Australia, including cases from 1 January 2013 to 31 December 2020 to establish the baseline cohort. We applied five commonly used ECPR selection criteria, ranging from restrictive to liberal. RESULTS: The baseline cohort included 199 ECPR cases: 95 OHCA and 104 IHCA patients. Survival to hospital discharge was 20% for OHCA and 41.4% for IHCA. For OHCA patients, strictly applying the most restrictive criteria would have resulted in the highest survival rate 7/16 (43.8%) compared to the most liberal criteria 16/73 (21.9%). However, only 16/95 (16.8%) in our cohort strictly met the most restrictive criteria versus 73/95 (76.8%) with the most liberal criteria. Similarly, in IHCA, the most restrictive criteria would have resulted in a higher survival rate in eligible patients 10/15 (66.7%) compared to 27/59 (45.8%) with the most liberal criteria. With all criteria a large portion of survivors in IHCA would not have been eligible for ECMO if strictly applying criteria, 33/43 (77%) with restrictive and 16/43 (37%) with the most liberal criteria. CONCLUSIONS: Adherence to different selection criteria impacts both the ECPR survival rate and the total number of survivors. Commonly used selection criteria may be unsuitable to select IHCA ECPR patients.

Anti-Factor-Xa and Activated Partial Thromboplastin Time Concordance and Outcomes in Adults Undergoing Extracorporeal Membrane Oxygenation: A Secondary Analysis of the Pilot Low-Dose Heparin in Critically Ill Patients Undergoing Extracorporeal Membrane Oxygenation Randomized Trial.

OBJECTIVES: To determine the concordance between activated partial thromboplastin time (aPTT) and anti-factor-Xa (anti-Xa) in adults undergoing extracorporeal membrane oxygenation (ECMO) and to identify the factors associated with discordant paired aPTT/anti-Xa. DESIGN: Pre-planned secondary analysis of the Low-Dose Heparin in Critically Ill Patients Undergoing Extracorporeal Membrane Oxygenation pilot randomized unblinded, parallel-group controlled trial. SETTING: Two ICUs in two university hospitals. PATIENTS: Thirty-two critically ill patients who underwent ECMO and who had at least one paired aPTT and anti-Xa assay performed at the same time. INTERVENTIONS: We analyzed the concordance between aPTT and anti-Xa and identified factors associated with discordant paired aPTT/anti-Xa based on their respective therapeutic ranges. We also compared biological parameters between heparin resistance episode and no heparin resistance. MEASUREMENTS AND MAIN RESULTS: Of the 32 patients who were included in this study, 24 (75%) had at least one discordant paired aPTT/anti-Xa. Of the 581 paired aPTT/anti-Xa that were analyzed, 202 were discordant. The aPTT was relatively lower than anti-Xa in 66 cases (32.7%) or relatively higher than anti-Xa in 136 cases (67.3%). Thirty-three heparin resistance episodes were identified in six patients (19%). CONCLUSIONS: In these critically ill patients undergoing ECMO, one third of paired aPTT/anti-Xa measures was discordant. Coagulopathy and heparin resistance might be the reasons for discordance. Our results support the potential importance of routinely monitoring both tests in this setting.

Expert consensus on training and accreditation for extracorporeal cardiopulmonary resuscitation an international, multidisciplinary modified Delphi Study.

BACKGROUND: A multidisciplinary group of stakeholders were used to identify: (1) the core competencies of a training program required to perform in-hospital ECPR initiation (2) additional competencies required to perform pre-hospital ECPR initiation and; (3) the optimal training method and maintenance protocol for delivering an ECPR program. METHODS: A modified Delphi process was undertaken utilising two web based survey rounds and one virtual meeting. Experts rated the importance of different aspects of ECPR training, competency and governance on a 9-point Likert scale. A diverse, representative group was targeted. Consensus was achieved when greater than 70% respondents rated a domain as critical (> or = 7 on the 9 point Likert scale). RESULTS: 35 international ECPR experts from 9 countries formed the expert panel, with a median number of 14 years of ECMO practice (interquartile range 11-38). Participant response rates were 97% (survey round one), 63% (virtual meeting) and 100% (survey round two). After the second round of the survey, 47 consensus statements were formed outlining a core set of competencies required for ECPR provision. We identified key elements required to safely train and perform ECPR including skill pre-requisites, surrogate skill identification, the importance of competency-based assessment over volume of practice and competency requirements for successful ECPR practice and skill maintenance. CONCLUSIONS: We present a series of core competencies, training requirements and ongoing governance protocols to guide safe ECPR implementation. These findings can be used to develop training syllabus and guide minimum standards for competency as the growth of ECPR practitioners continues.

Expedited transport versus continued on-scene resuscitation for refractory out-of-hospital cardiac arrest: A systematic review and meta-analysis.

Background: The benefit of rapid transport from the scene to definitive in-hospital care versus extended on-scene resuscitation in out-of-Hospital Cardiac Arrest (OHCA) is uncertain. Aim: To assess the use of expedited transport from the scene of OHCA compared with more extended on-scene resuscitation of out-of-hospital cardiac arrest in adults. Methods: A systematic search of the literature was conducted using MEDLINE, Embase, and SCOPUS. Randomised control trials (RCTs) and observational studies were included. Studies reporting transport timing for OHCA patients with outcome data on survival were identified and reviewed. Two investigators assessed studies identified by screening for relevance and assessed bias using the ROBINS-I tool. Studies with non-dichotomous timing data or an absence of comparator group(s) were excluded. Outcomes of interest included survival and favourable neurological outcome. Survival to discharge and favourable neurological outcome were meta-analysed using a random-effects model. Results: Nine studies (eight cohort studies, one RCT) met eligibility criteria and were considered suitable for meta-analysis. On pooled analysis, expedited (or earlier) transfer was not predictive of survival to discharge (odds ratio [OR] 1.16, 95% confidence interval [CI] 0.53 to 2.53, I2 = 99%, p = 0. 65) or favorable neurological outcome (OR 1.06, 95% CI 0.48 to 2.37, I2 = 99%, p = 0.85). The certainty of evidence across studies was assessed as very low with a moderate risk of bias. Region of publication was noted to be a major contributor to the significant heterogeneity observed amongst included studies. Conclusions: There is inconclusive evidence to support or refute the use of expedited transport of refractory OHCA.

Protocolised Management of Cardiogenic Shock and Shock Teams: A Narrative Review.

Despite advances in therapy, the incidence of cardiogenic shock continues to increase, with significant mortality that has improved minimally over time. Treatment options for cardiogenic shock are complex and time-, resource-, and case volume-dependent, and involve multiple medical specialties. To provide early, more equitable, and standardised access to cardiogenic shock expertise with advanced therapies, cardiogenic shock teams with a protocolised treatment approach have been proposed. These processes have been applied across hospitals into integrated cardiogenic shock networks. This narrative review evaluates the role of cardiogenic shock teams, protocolised and regionalised shock networks, and the main individual components of protocolised shock management approaches.

CD98hc is a target for brain delivery of biotherapeutics.

Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TVCD98hc). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATVCD98hc) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATVCD98hc demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties. Specific biodistribution profiles within the brain parenchyma can be modulated by introducing Fc mutations on ATVCD98hc that impact FcγR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TVCD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.

Polysarcosine-based lipid formulations for intracranial delivery of mRNA.

Messenger RNA (mRNA) is revolutionizing the future of therapeutics in a variety of diseases, including neurological disorders. Lipid formulations have shown to be an effective platform technology for mRNA delivery and are the basis for the approved mRNA vaccines. In many of these lipid formulations, polyethylene glycol (PEG)-functionalized lipid provides steric stabilization and thus plays a key role in improving the stability both ex vivo and in vivo. However, immune responses towards PEGylated lipids may compromise the use of those lipids in some applications (e.g., induction of antigen specific tolerance), or within sensitive tissues (e.g., central nervous system (CNS)). With respect to this issue, polysarcosine (pSar)-based lipopolymers were investigated as an alternative to PEG-lipid in mRNA lipoplexes for controlled intracerebral protein expression in this study. Four polysarcosine-lipids with defined sarcosine average molecular weight (Mn = 2 k, 5 k) and anchor diacyl chain length (m = 14, 18) were synthesized, and incorporated into cationic liposomes. We found that the content, pSar chain length and carbon tail lengths of pSar-lipids govern the transfection efficiency and biodistribution. Increasing carbon diacyl chain length of pSar-lipid led up to 4- and 6-fold lower protein expression in vitro. When the length of either pSar chain or lipid carbon tail increased, the transfection efficiency decreased while the circulation time was prolonged. mRNA lipoplexes containing 2.5% C14-pSar2k resulted in the highest mRNA translation in the brain of zebrafish embryos through intraventricular injection, while C18-pSar2k-liposomes showed a comparable circulation with DSPE-PEG2k-liposomes after systemic administration. To conclude, pSar-lipid enable efficient mRNA delivery, and can substitute PEG-lipids in lipid formulations for controlled protein expression within the CNS.

Prehospital Extracorporeal Cardiopulmonary Resuscitation for Out-of-Hospital Cardiac Arrest: A Systematic Review and Meta-Analysis.

OBJECTIVES: To evaluate the available published evidence of the effects of extracorporeal cardiopulmonary resuscitation (ECPR) in the prehospital setting on clinical outcomes in patients with out-of-hospital cardiac arrest. DESIGN: A systematic review and meta-analysis designed according to the Preferred Reporting Items for Systematic Reviews an Meta-Analyses guidelines. SETTING: In the prehospital setting. PARTICIPANTS: All randomized control trials (RCTs) and observational trials using pre-hospital ECPR in adult patients (>17 years). INTERVENTIONS: Prehospital ECPR. MEASUREMENTS AND MAIN RESULTS: The study authors searched Medline, Embase, and PUBMED for all RCTs and observational trials. The studies were assessed for clinical, methodologic, and statistical heterogeneity. The primary outcome was survival at hospital discharge. The study outcomes were aggregated using random-effects meta-analysis of means or proportions as appropriate. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence. Four studies were included, with a total of 222 patients receiving prehospital ECPR (mean age = 51 years [95% CI 44-57], 81% of patients were male (CI 74-87), and 60% patients had a cardiac cause for their arrest (95% CI 43-76). Overall survival at discharge was 23.4% (95% CI 15.5-33.7; I2 = 62%). The pooled low-flow time was 61.1 minutes (95% CI 45.2-77.0; I2 = 97%). The quality of evidence was assessed to be low, and the overall risk of bias was assessed to be serious, with confounding being the primary source of bias. CONCLUSION: No definitive conclusions can be made as to the efficacy of prehospital ECPR in refractory cardiac arrest. Higher quality evidence is required.

Extracorporeal membrane oxygenation and Extracorporeal Membrane Oxygenation Cardiopulmonary Resusciation (ECPR) research priorities in Australia: A clinician survey.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) for cardiorespiratory failure and during cardiopulmonary resuscitation has increased significantly and is resource intensive. High-quality evidence to guide management of patients on ECMO is limited. OBJECTIVES: The objective of this study was to determine the research priorities of clinicians for ECMO and Extracorporeal Membrane Oxygenation Cardiopulmonary Resusciation (ECPR) in Australia and New Zealand. METHODS: A prospective, binational survey of clinicians was conducted in May 2022. RESULTS: There were 133 respondents; 110 (84%) worked at an Australian ECMO centre; 28 (21%) were emergency, 45 (34%) were intensive care, and 41 (31%) were nursing clinicians. All aspects of ECMO care were identified by respondents as being important for further research; however, appropriate patient selection and determining long-term outcomes were ranked the highest. While most believed ECMO was efficacious, they felt that there was insufficient evidence to determine cost-effectiveness. There was uncertainty of the best model of ECPR provision. Equipoise exists for randomised studies into anticoagulation, blood product usage, and ECPR. CONCLUSIONS: This survey found strong support amongst clinicians for further research into the optimal use of ECMO and ECPR and provides a frame work for prioritising future clinical trials and research agendas.

Improving access to extracorporeal membrane oxygenation for out of hospital cardiac arrest: pre-hospital ECPR and alternate delivery strategies.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECPR) in refractory out-of-hospital cardiac arrest (OHCA) patients is usually implemented in-hospital. As survival in ECPR patients is critically time-dependent, alternative models in ECPR delivery could improve equity of access. OBJECTIVES: To identify the best strategy of ECPR delivery to provide optimal patient access, to examine the time-sensitivity of ECPR on predicted survival and to model potential survival benefits from different delivery strategies of ECPR. METHODS: We used transport accessibility frameworks supported by comprehensive travel time data, population density data and empirical cardiac arrest time points to quantify the patient catchment areas of the existing in-hospital ECPR service and two alternative ECPR strategies: rendezvous strategy and pre-hospital ECPR in Sydney, Australia. Published survival rates at different time points to ECMO flow were applied to predict the potential survival benefit. RESULTS: With an in-hospital ECPR strategy for refractory OHCA, five hospitals in Sydney (Australia) had an effective catchment of 811,091 potential patients. This increases to 2,175,096 under a rendezvous strategy and 3,851,727 under the optimal pre-hospital strategy. Assuming earlier provision of ECMO flow, expected survival for eligible arrests will increase by nearly 6% with the rendezvous strategy and approximately 26% with pre-hospital ECPR when compared to the existing in-hospital strategy. CONCLUSION: In-hospital ECPR provides the least equitable access to ECPR. Rendezvous and pre-hospital ECPR models substantially increased the catchment of eligible OHCA patients. Traffic and spatial modelling may provide a mechanism to design appropriate ECPR service delivery strategies and should be tested through clinical trials.

Cost-effectiveness of extracorporeal cardiopulmonary resuscitation for adult out-of-hospital cardiac arrest: A systematic review.

OBJECTIVE: The use of extracorporeal cardiopulmonary resuscitation (ECPR) for out-of-hospital cardiac arrests (OHCA) has increased dramatically over the past decade. ECPR is resource intensive and costly, presenting challenges for policymakers. We sought to review the cost-effectiveness of ECPR compared with conventional cardiopulmonary resuscitation (CCPR) in OHCA. METHODS: We searched Medline, Embase, Tufts CEA registry and NHS EED databases from database inception to 2021 or 2015 for NHS EED. Cochrane Covidence was used to screen and assess studies. Data on costs, effects and cost-effectiveness of included studies were extracted by two independent reviewers. Costs were converted to USD using purchasing power parities (OECD, 2022).1 The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist (Husereau et al., 2022)2 was used for reporting quality and completeness of cost-effectiveness studies; the review was registered on PROSPERO, and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Four studies met the inclusion criteria; three cost-effectiveness studies reported an incremental cost-effectiveness ratio (ICER) for OHCA compared with conventional care, and one reported the mean operating cost of ECPR. ECPR was more costly, accrued more life years (LY) and quality-adjusted life years (QALYs) than CCPR and was more cost-effective when compared with CCPR and other standard therapies. Overall study quality was rated as moderate. CONCLUSION: Few studies have examined the cost-effectiveness of ECPR for OHCA. Of those, ECPR for OHCA was cost-effective. Further studies are required to validate findings and assess the cost-effectiveness of establishing a new ECPR service or alternate ECPR delivery models.

Myocardial fibrosis in Type 2 Diabetes is associated with functional and metabolomic parameters.

AIMS: To identify biomarkers of cardiomyopathy in patients with type 2 diabetes mellitus (T2DM) using cardiovascular magnetic resonance (CMR) and to identify associations between functional status, metabolomic profile and myocardial fibrosis. METHODS: In this prospective case control study, patients (n = 49) with T2DM without significant coronary artery disease, and matched controls (n = 18) underwent CMR, cardiopulmonary exercise testing, and plasma metabolomic analyses. RESULTS: Patients with T2DM (n = 49, median [interquartile range] age 61 [56-63] years, 61% male, diabetes duration 11 [7-20] years), historical HbA1c 7.6% (60 mmol/mol) (6.9-8.6) and matched controls (n = 18) were examined. Study patients had increased myocardial extracellular volume (ECV) (26.9 [23.8-30.0] vs 23.4 [22.4-25.5) %, p < 0.001). Increased ECV was associated with male sex (p = 0.04), time with T2DM (p = 0.02), reduced peak VO2 (R2 = 0.48, p = 0.01), increased circulating choline (p = 0.002) and cysteamine (p = 0.002) both of which were also associated with reduced peak VO2 (p < 0.025 and 0.014 respectively). CONCLUSIONS: Patients with well-controlled T2DM without significant coronary disease exhibit focal and diffuse myocardial fibrosis and diffuse myocardial fibrosis is associated with reduced exercise tolerance and metabolites. Plasma metabolites may provide mechanistic insights into diffuse myocardial fibrosis, and cardiopulmonary fitness.