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Introduction Type 2 diabetes (T2D) is a risk factor for heart failure. T2D causes a cardiac energy deficient state with subclinical contractile dysfunction even with a normal left ventricular ejection fraction (LVEF). Impaired cardiac energetics contributes to cardiac dysfunction in T2D. Novel treatments targeting mitochondrial dysfunction may improve cardiac energetics and function in T2D. Impaired mitochondrial function is driven by oxidative stress, with increased levels of reactive oxygen species (ROS). Antioxidant depletion leads to increased ROS generation and impaired energy production. Mitoquinone is a mitochondrial-targeted antioxidant, scavenging ROS to reduce oxidative stress.Methods In this parallel arm, prospective randomized (1:1) open blinded end-point standard care controlled trial of 70 patients with T2D we examined if mitoquinone can improve energy status. To monitor treatment response we used phosphorus-magnetic resonance spectroscopy scans ( 31P-MRS) to measure cardiac phosphocreatine to ATP ratio (PCr/ATP) as an indicator of myocardial energetic status and cardiovascular magnetic resonance (CMR) to measure cardiac rest and dobutamine-stress systolic and diastolic function.The study consisted of 2 research visits over a 16-week period. Participants were randomised to either receive a 16-week course of MitoQ (mitoquinone mesylate 40 mg/day [MitoQ Limited,Auckland,NZ]) or receive no additional supplementation.Results Seventy patients were recruited and 57 patients completed the study (3 patients due to claustrophobia, three patients had evidence of myocardial infarction on CMR, two patients did not tolerate dobutamine, five patients did not return for visit 2).The groups were matched for baseline demographics. Baseline 31P-MRS and CMR characteristics were also balanced. Average baseline LVEF was 62[61,63]%.Four months mitoquinone administration led to a significant improvement in rest PCr/ATP (1.58[1.41,1.74] to 1.78[1.65,1.91];P=0.028), and stress PCr/ATP (1.25[1.13,1.36] to 1.46[1.34,1.59];P=0.0099) with no significant difference seen in the standard care group. Improvements in energetics were accompanied by significant increases in peak early diastolic strain rate (PEDSR) as a measure of diastolic function (0.84[0.75,0.93] to 0.99[0.85,1.14]s-1;P=0.0084) in the MitoQ arm with no significant change in the control group (0.85[0.76,0.94] to 0.97[0.83,1.11]s-1;P=0.10 .There were no significant changes in any of the other CMR parameters measured including perfusion or LVEF.Conclusions Four-month mitoquinone supplementation increased rest and haemodynamic stress myocardial energetics index and diastolic function in patients with T2D patients. This was independent of any significant changes in glycaemic control. In this patient focused study our findings highlight the potential therapeutic benefit of the antioxidant mitoquinone for prevention of heart failure development in patients with T2D with subclinical disease.Introduction Type 2 diabetes (T2D) directly effect the myocardium, and is an independent risk factor for heart failure, including when adjusted for coronary artery disease and other risk factors such as hypertension: a disease process termed diabetic cardiomyopathy (DiabCM). 1 T2D causes a cardiac energy deficient state with subclinical diastolic impairment and contractile dysfunction even with a normal left ventricular ejection fraction (LVEF).2 Myocardial tissue, as an aerobic organ, requires a constant supply of adenosine triphosphate (ATP). Mitochondria produce over 90% of ATP within myocytes under normal physiological conditions, via the electron transport chain, with reactive oxygen species (ROS) as a by-product. Patient’s with T2D have been shown to have impaired cardiac energy metabolism, resulting in a reduced phosphocreatine to ATP (PCr/ATP) ratio. Excessive ROS can cause oxidative stress, with animal models demonstrating that inducing oxidative stress causes LV hypertrophy and myocardial dysfunction. Therefore, antioxidants have been proposed as a therapeutic agent to treat DiabCM.3 Mitoquinone is an antioxidant that accumulates within mitochondria, scavenging ROS to reduce oxidative stress. Mitoquinone supplementation has been shown to significantly reduce mitochondrial ROS levels in patients with T2D, however there are very little data assessing potential clinical benefits of Mitoquinone supplementation in the context of DiabCM.4 The purpose of this single-centre, randomised, open-label clinical trial recruiting patients with T2D without established cardiovascular disease (CVD) was to assess potential efficacy of adding Mitoquinone supplementation to standard care in the treatment of DiabCM, by assessing markers of myocardial health derived from rest and haemodynamic stress (dobutamine-stress) cardiac magnetic resonance imaging (CMR) and phosphorus-magnetic resonance spectroscopy (31P-MRS).Methods Patients were recruited at the Leeds Teaching Hospitals NHS Trust. Key inclusion criteria included adulthood, and a diagnosis of T2D at least six months prior to recruitment. Exclusion criteria included known heart failure, known significant coronary artery disease (epicardial coronary artery stenosis >50% on imaging if performed), previous myocardial infarction and angina.The study consisted of 2 research visits over a 16-week period. Participants were randomised in a 1:1 ratio (using stratified randomisation), to either receive a 16-week course of Mitoquinone (mitoquinone mesylate 40 mg/day [MitoQ-Limited, Auckland, NZ]) or receive no additional supplementation. 31P-MRS and CMR imaging were performed on a 3.0 Tesla MR system (Prisma,Siemens). At each visit, 31P-MRS was used to measure cardiac PCr/ATP ratio (as a marker of myocardial energetics), at rest and on dobutamine-stress. CMR imaging protocol included cine imaging for cardiac rest and dobutamine-stress systolic and diastolic function (figure 1). Baseline demographic data, anthropometric measurements, and fasting blood samples were taken at each visit measuring glycated haemoglobin (HbA1c), N-terminal pro-B-type natriuretic peptide (NT-proBNP), full lipid profile, and insulin levels.Findings Between 11/06/2023–01/07/2024, 2181 potentially eligible patients were screened ( figure 2). Seventy patients were recruited and randomised in a 1:1 ratio to receive Mitoquinone supplementation or receive no additional supplementation. Eight patients were excluded during visit 1 (three patients had severe claustrophobia, three patients had evidence of prior myocardial infarction on CMR, and two patients did not tolerate dobutamine). Therefore 62 patients completing visit 1. Five patients did not return for visit 2, resulting in 57 patients completing both visits.The groups were matched for baseline demographics, anthropometrics, and biochemical characteristics (table 1). The mean age was 60 years [58,63], mean BMI was 30.5 [29.6,32.0], and mean HbA1c of 60.5 [56.0,64.9].Four months of mitoquinone administration led to a significant improvement in rest PCr/ATP (1.58[1.41,1.74] to 1.78[1.65,1.91];P=0.028), and stress PCr/ATP (1.25[1.13,1.36] to 1.46[1.34,1.59];P=0.0099) with no significant difference seen in the standard care group (table 2).On CMR assessment, diastolic function (as measured by PEDSR) significantly increased in the MitoQ cohort (0.84[0.75,0.93] to 0.99[0.85,1.14]/second;P=0.0084), with no significant change seen in the control group (0.85[0.76,0.94] to 0.97[0.83,1.11]/second/P=0.10) (table 2). There was no significant change in E/A ratio in either cohort between visit one and two (MitoQ cohort: 1.51[1.27,1.75] to 1.73[1.44,2.01];P=0.23. Control cohort: 1.66[1.42,1.90] to 1.72[1.45,1.99];P=0.55).There were no significant changes in any of the other CMR parameters measured including perfusion parameters. No significant change in weight or other anthropometric measurements were seen at visit two in either of the cohorts. Similarly there was no significant difference in HbA1c or NTpro-BNP in either group at visit 2.Discussion This single-centre, randomised, open-label trial suggests that Mitoquinone is associated with a significant improvement in cardiac energetics, both at rest and on dobutamine stress. MitoQ administration was also associated with a significant increase in PEDSR, a marker of diastolic function, and was well tolerated by all participants with no adverse events associated with its use.This is one of the first studies assessing cardiac effects of Mitoquinone, outside of pre-clinical trials, and showed that four-month of Mitoquinone supplementation increased rest and haemodynamic stress myocardial energetics index and diastolic function in patients with T2D patients. This was independent of any significant changes in glycaemic control.In this patient focused study our findings highlight the potential therapeutic benefit of the antioxidant Mitoquinone for prevention of heart failure development in patients with T2D with subclinical disease. Further work is required in this area to further assess the role of antioxidants in the treatment of DiabCM.Abstract C Table 1Baseline demographic, anthropometric and biochemical characteristics of participants. NT-proBNP:N-terminal pro-B-type natriuretic peptide; TIA:Transient ischaemic attack; ACEi:angiotensin-converting enzyme inhibitor; ARB:Angiotensin receptor blockers; CCB:Calcium channel blockers; GLP1-RA:Glucagon-like peptide-1 receptor agonists; SGLT2i:Sodium-glucose cotransporter-2 inhibitors; T2D:Type 2 diabetes Variable T2D – Standard care and MitoQ (n=30) T2D – Standard care (n=32) P value: Visit 1 Age, y 59 [55, 63]62 [59, 64]0.37 Male, n (%) 15 (50%)17 (53%)>0.99 Weight, kg 88.0 [82.7, 93.2]88.2 [81.8, 94.6] 0.96 Body mass index, kg/m2 30.9 [29.1, 32.6]30.7 [28.9, 32.4]0.96 Waist circumference 102 [98, 106]103 [99, 107]0.75 Hip circumference 106 [102, 110]107 [103, 111]0.71 Systolic blood pressure, mmHg 126 [120, 131]130 [124.136]0.29 Diastolic blood pressure, mmHg 77 [74, 80]78 [75, 81]0.59 Resting heart rate, beats/minute 70 [66, 74]71 [68, 74]0.71 Biochemical characteristics Glycated haemoglobin, mmol/mol 60.0 (48.8, 66.3)54.5 (48.0, 64.0)0.42 Cholesterol, mmol/L 4.6 (3.6, 5.6)4.4 (3.6, 5.2)0.56 Triglycerides, mmol/L 3.21 [2.19, 4.23]3.08 [1.10, 5.06]0.91 Insulin 9.1 (4.4, 15.4)8.0 (5.3, 17.1)0.25 NT- proBNP, ng/l 44 (35, 63)53 (35, 106)0.17 Co-morbidities and medications Duration of diabetes (y) 6.0 (2.8, 13.0)5.0 (2.0, 10.8)0.61 Hypertension, n (%) 17 (57%)15 (47%)0.46 Hyperlipidemia, n (%) 14 (47%)15 (47%)>0.99 Asthma or Chronic Obstructive Pulmonary Disease, n (%) 3 (10%)8 (25%)0.19 Previous TIA or stroke 2 (7%)3 (9%)>0.99 Smoking history Current 2 (7%)3 (9%)>0.99 Ex-Smoker 13 (43%)8 (25%)0.18 Never smoked 15 (50%)21 (66%)0.30 ACEi/ARB 13 (43%)14 (44%)>0.99 Beta blocker 3 (10%)7 (22%)0.30 CCB 5 (17%)4 (13%)0.73 Diuretic 5 (17%)6 (19%)>0.99 Statin 23 (77%)25 (78%)>0.99 Biguanide 20 (67%)26 (81%)0.25 Sulphonylurea 1 (3%)1 (3%)>0.99 GLP1-RA 1 (3%)2 (6%)>0.99 Gliptin 5 (17%)4 (13%)0.73 SGLT2i 9 (30%)11 (34%)0.79 Insulin 5 (17%)2 (6%)0.25 Diet controlled T2D 6 (20%)5 (16%)0.75Abstract C Table 2Comparisons of cardiovascular magnetic resonance findings at visit 1 and visit 2 between the two cohorts. LV:Left ventricle; EDVi:Indexed end-diastolic volume; ESVi:Indexed end-systolic volume; SVi:Indexed stroke volume; RV:right ventricle; LA:left atrium; GLS:global longitudinal shortening; RPP:rate-pressure product; MBF:Myocardial blood-flow; MPR:Myocardial perfusion reserve; ECV:Extracellular volume; LGE:Late gadolinium enhancement; PCr/ATP: Phosphocreatine to adenosine triphosphate ratio Variable T2D Standard care and Mito-q Visit 1 (n=30) T2D Standard care Visit 1 (n=32) T2D Standard care and Mito-q Visit 2 (n= 30) T2D Standard care Visit 2 (n= 27) P value: MitoQ vs Control Visit 2 P value: MitoQ group V1 vs V2 P value: Control group V1 vs V2 Anthropometric characteristics Weight, kg 88.0 [82.7, 93.2]88.2 [81.8, 94.6] 87.9 [82.2, 93.5]87.8 [80.8, 94.8]0.830.830.61 Body mass index, kg/m2 30.9 [29.1, 32.6]30.7 [28.9, 32.4]30.6 [28.8, 32.4]\30.8 [28.8, 32.9]0.770.280.49 Waist circumference 102 [98, 106]103 [99, 107]103 [99, 107]103 [98, 108]0.430.640.80 Hip circumference 106 [102, 110]107 [103, 111]106 [102, 111]108 [103, 113]0.510.510.49 Biochemical characteristics Glycated haemoglobin, mmol/mol 60.0 (48.8, 66.3)54.5 (48.0, 64.0)59.0 [54.0, 63.9]58.2 [52.5, 64.0]0.950.550.51 Cholesterol, mmol/L 4.6 (3.6, 5.6)4.4 (3.6, 5.2)4.7 [4.1, 5.2]4.7 [4.3, 5.1]0.750.810.43 Triglycerides, mmol/L 3.21 [2.19, 4.23]3.08 [1.10, 5.06]2.87 [1.79, 3.96]2.19 [1.49, 2.90]0.630.620.36 Insulin 9.1 (4.4, 15.4)8.0 (5.3, 17.1)15.9 (8.4, 22.9)9.4 (5.8, 17.1)0.22 0.018 0.73 NT- proBNP, ng/l 44 (35, 63)53 (35, 106)38 (35, 73)36 (35, 111)0.430.130.38 CMR and MRS characteristics LV EDVi, mL/m2 70 [66, 74]68 [65, 71]72 [69, 76]69 [65, 72]0.180.410.94 LV ESVi, ml/m2 27 [24, 29]26 [24, 28]28 [26, 31]26 [24, 28]0.150.220.91 LV SVi, ml/m2 43 [40, 45]42 [40, 44]44 [41, 46]41 [39, 44]0.150.120.50 LV EF,% 62 [60, 64]62 [60, 64]61 [59, 63]62 [60, 63]0.470.330.88 LV mass, g 70 [65, 75]67 [61, 72]68 [63, 72]66 [59, 73]0.370.100.94 LV mass indexed, g/m2 35 [33, 37]33 [30, 35]33 [31, 35]32 [30, 35]0.310.0860.76 LV mass to LV end-diastolic volume ratio, g/mL 0.51 [0.47, 0.54]0.48 [0.45, 0.51]0.46 [0.44, 0.49]0.47 [0.44, 0.50]0.860.0740.65 LV maximal wall thickness, mm 10.6 [10.0, 11.1]10.6 [10.0, 11.1]10.8 [10.2, 11.4]10.7 [10.0, 11.3]0.430.0810.71 RV EDV, mL 132 [122, 142]131 [121, 141]133 [125, 141]130 [119, 140]0.460.680.80 RV EDVi, mL/m2 65 [60, 69]64 [61, 68]66 [62, 69]65 [61, 69]0.630.440.74 RV SV, ml 80 [75, 86]82 [77, 87]84 [79, 88]82 [76, 88]0.540.360.76 RV EF,% 61 [59, 64]63 [61, 65]63 [61, 65]63 [61, 65]0.670.260.70 LA maximal volume, ml 66 [59, 72]68 [62, 75]63 [57, 70]66 [60, 72]0.520.440.48 LA EF,% 49 [46, 52]52 [49, 55]50 [47, 52]50 [48, 53]0.510.600.23 E/A ratio 1.51 [1.27, 1.75]1.66 [1.42, 1.90]1.73 [1.44, 2.01]1.72 [1.45, 1.99]0.980.230.55 Deceleration time, ms 134 (105, 169)138 (121, 152)141 (122, 164)142 (124, 160)0.960.790.88 Rest GLS (-%) 17.1 [16.3, 18.0]17.2 [16.3, 18.0]17.0 [16.2, 17.8]17.1 [16.0, 18.2]0.760.630.68 Peak early diastolic strain rate – circumferential,/sec 0.84 [0.75, 0.93]0.85 [0.76, 0.94]0.99 [0.85, 1.14]0.97 [0.83, 1.11]0.60 0.0084 0.10 Rest RPP, bpm*mmHg 8852 [8162, 9542]9277 [8577, 9977]8511 [7940, 9081]8741 [7994, 9487]0.540.140.72 Stress RPP, bpm*mmHg 16415 [15501, 17329]17159 [16141, 18176]16166 [15418, 16914]16935 [15584, 18286]0.360.500.92 Increase in RPP,% 90.4 [77.5, 103.2]88.9 [76.3, 101.4]95.1 [81.0, 109.2]97.2 [82.4, 112.0]0.860.370.74 Dobutamine stress GLS (-%) 19.9 [18.9, 21.0]20.5 [19.7, 21.4]19.9 [18.9, 20.9]20.1 [19.3, 20.9]0.980.870.43 Stress-MBF, ml/min/g 1.48 (1.27, 1.85)1.50 (1.36, 2.02)1.61 (1.31, 1.97)1.64 (1.40, 2.15)0.440.990.11 Stress-MBF Endo/Epi ratio 1.01 (0.97, 1.06)1.06 (0.98, 1.14)1.02 (0.95, 1.10)1.01 (0.97, 1.09)0.810.550.11 Rest-MBF, ml/min/g 0.70 (0.62, 0.77)0.76 (0.68, 0.88)0.66 (0.59, 0.75)0.72 (0.60, 0.87)0.280.460.22 MPR 2.37 (1.83, 2.61)2.05 (1.73, 2.59)2.41 (1.79, 3.32)2.36 (1.98, 2.88)0.430.160.19 Mean native T1, (ms) 1288 [1276, 1300]1306 [1297, 1316]1298 [1284, 1313]1305 [1290, 1319]0.600.180.67 ECV, (%) 27 [26, 28]29 [26, 31]27 [26, 28]27 [26, 27]0.470.730.13 Non-ischemic focal fibrosis present, n(%) 5 (17%)5 (16%)5 (17%)4 (15%)>0.99>0.99>0.99 Scar percentage on LGE, (%) 0.43 [0.01, 0.85]0.20 [0.00, 0.45]0.38 [0.00, 0.78]0.29 [0.00, 0.64]0.960.120.22 Rest PCr/ATP ratio 1.58 [1.41, 1.74]1.72 [1.62, 1.82]1.78 [1.65, 1.91]1.64 [1.51, 1.78]0.16 0.028 0.25 Stress PCr/ATP ratio 1.25 [1.13, 1.36]1.42 [1.29, 1.54]1.46 [1.34, 1.59]1.48 [1.37, 1.59]0.45 0.0099 0.31Abstract C Figure 1Cardiac magnetic resonance (CMR) protocol consisted of localiser HASTE imaging, followed by cardiac cine imaging, pre- and post-contrast T1 mapping, perfusion imaging, velocity-encoded mitral inflow imaging, and late gadolinium enhancement imaging. HASTE:Half fourier Single-shot Turbo spin-Echo; LV:left ventricularAbstract C Figure 2CONSORT diagram showing recruitment pathway with numbers of study patients screened and randomized, in addition to numbers of patients who completed follow-upReferences Hsuan CF, Teng SIF, Hsu CN, et al. Emerging therapy for diabetic cardiomyopathy: from molecular mechanism to clinical practice. Biomedicines Feb 22 2023;11(3). doi:10.3390/biomedicines11030662Levelt E, Rodgers CT, Clarke WT, et al. Cardiac energetics, oxygenation, and perfusion during increased workload in patients with type 2 diabetes mellitus. Eur Heart J. Dec 7 2016;37(46):3461–3469. doi:10.1093/eurheartj/ehv442Faria A, Persaud SJ. Cardiac oxidative stress in diabetes: mechanisms and therapeutic potential. Pharmacol Ther. Apr 2017;172:50–62. doi:10.1016/j.pharmthera.2016.11.013Escribano-Lopez I, Diaz-Morales N, Rovira-Llopis S, et al. The mitochondria-targeted antioxidant MitoQ modulates oxidative stress, inflammation and leukocyte-endothelium interactions in leukocytes isolated from type 2 diabetic patients. Redox Biol. Dec 2016;10:200–205. doi:10.1016/j.redox.2016.10.017Statement of Contribution I confirm that I assisted Prof Eylem Levelt with the study design and ethical approval of this project. I assessed eligibility of around 50% of the initial cohort (Temar Habtezghi, Sara Khalid, Rebecca Osborne assisted with the remainder of the eligibility assessments). I recruited and consented all the subjects in this study. I performed all the 31P-MRS scans, and supervised all of the CMR scans. I analysed all of the 31P-MRS and CMR scans. I performed all the statistics for this paper.