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Aims We sought to determine if myocardial energetics could distinguish obesity cardiomyopathy as a distinct entity from dilated cardiomyopathy. Methods and results Sixteen normal weight participants with dilated cardiomyopathy (DCMNW), and 27 with DCM and obesity (DCMOB), were compared to 26 normal weight controls (CTLNW). All underwent cardiac magnetic resonance imaging and 31P spectroscopy to assess function and energetics. Nineteen DCMOB underwent repeat assessment after a dietary weight loss intervention. Adenosine triphosphate (ATP) delivery through creatine kinase (CK flux) was 55% lower in DCMNW than in CTLNW (P = 0.004), correlating with left ventricular ejection fraction (LVEF, r = 0.4, P = 0.015). In contrast, despite similar LVEF (DCMOB 41 ± 7%, DCMNW 38 ± 6%, P = 0.14), CK flux was two-fold higher in DCMOB (P < 0.001), due to higher rate through CK [median kf 0.21 (0.14) vs. 0.11 (0.12) s−1, P = 0.002]. During increased workload, the CTLNW heart increased CK flux by 97% (P < 0.001). In contrast, CK flux was unchanged in DCMNW and fell in DCMOB (by >50%, P < 0.001). Intentional weight loss was associated with positive left ventricular remodelling, with reduced left ventricular end-diastolic volume (by 8%, P < 0.001) and a change in LVEF (40 ± 9% vs. 45 ± 10%, P = 0.002). This occurred alongside a fall in ATP delivery rate with weight loss (by 7%, P = 0.049). Conclusions In normal weight, DCM is associated with reduced resting ATP delivery. In obese DCM, ATP demand through CK is greater, suggesting reduced efficiency of energy utilization. Dietary weight loss is associated with significant improvement in myocardial contractility, and a fall in ATP delivery, suggesting improved metabolic efficiency. This highlights distinct energetic pathways in obesity cardiomyopathy, which are both different from dilated cardiomyopathy, and may be reversible with weight loss.

Introduction Myocardial creatine kinase (CK) activity represents an important metabolic reserve: it correlates closely with contractile reserve and post-ischaemic function, keeps cytosolic [ADP] low, and optimises the free energy for ATP hydrolysis. It may also contribute to the transition to failure in the heart hypertrophied by chronic haemodynamic overload; modest up-regulation has been shown to be cardio-protective. Total CK activity measurement requires chemical freeze-and-extract methods, which destroy tissue, precluding repeated measures. To date, non-invasive assessments of human myocardial CK flux (calculated as kf × [PCr], where kf is the pseudo-first-order forward rate constant measured by 31P-magnetic resonance spectroscopy (MRS) have not assessed creatine content or total CK activity. Thus we aimed to validate kf measurement against total CK activity and investigate predictors of CK activity. Methods 39 subjects (median age 71, range 43–84) undergoing clinically indicated cardiac surgery had CK total activity measured from LV biopsy. 31 had severe AS (10 with impaired LVEF); 2 had severe primary MR; 5 had severe mitral stenosis (2 with impaired LVEF) and 1 had an LA mass. 35 of 39 contributed triplicate datasets: CK total activity, kf (31P-MRS TRiST sequence at 3T) and LV volumes (cine-MRI, 3T Siemens). 27 had severe AS (8 with impaired LVEF); other groups were the same. Exclusion criteria were prior myocardial infarction and flow-limiting coronary disease. Flash-frozen LV biopsies obtained within 15 min of cardiopulmonary bypass were analysed for CK total activity, total creatine, and citrate synthase (CS) activity (a marker of oxidative phosphorylation capacity). Results Multiple, novel correlations were observed between CK total activity (IU/mg protein) and CS activity (r=0.87, p=9e-13), total creatine (r=0.59, p=8e-5), kf (r=0.42, p=0.013), total creatine × kf (r=0.64, p=4e-5), LVESVi (r=−0.52, p=8e-4), LVEF (r=0.48, p=0.002) and LVMi (r=−0.42, p=0.009) (Panels A-E) (LVEDVi and non-indexed counterparts were also significant correlates.) The most predictive linear regression model incorporating elements of the CK rate equation included total creatine (nmol/mg protein), kf (/s), and kf × LVESVi (ml/m2) (adjusted R2=0.56, beta=0.426, 0.618, −1.968 and p=0.001, 5e-5, 0.003 respectively, Panel F). Figure 1 Conclusions These results are the first evidence of agreement between non-invasive estimates of human cardiac CK activity (kf) and freeze-extracted chemical methods. The key original finding is that it is feasible to attempt to predict CK capacity in vivo by using a combination of techniques (creatine by 1H MRS, CK kf by 31P-MRS and LVESVi by cine imaging). The key insight is that CK capacity is best estimated not simply from what the rate equation would predict (creatine and kf), but that other factors relating to failing contractility reduce CK activity independently from creatine content and enzyme kf. Acknowledgement/Funding British Heart Foundation Clinical Research Training Fellowship (FS/15/80/31803) and Programme Grant (RG/18/12/34040).

Introduction The transition to systolic failure in severe aortic stenosis (AS) increases mortality. There are currently no reliable markers of transition, and the guideline LVEF Methods 19 patients with severe AS, LVEF ≥55% (AS-pEF, mean±SD LVEF 63±5%, mean gradient 48±14 mmHg) and 10 with severe AS, LVEF Results When compared to controls, both CK total activity and CS activity were lower in AS-pEF (by 27% and 23% respectively, both p AS-rEF was associated with further reduction in both CK and CS activities (by 32% and 22% respectively, both p When median mitochondria-sarcomere ATP diffusion distances were plotted against CK total activity a strong positive correlation was observed (r=0.86, p=0.003, Panel F). This suggests a compensatory reduction in diffusion distance develops when CK activity falls. Conclusions Transition to failure in severe AS is associated with lower oxidative capacity and maximal ATP delivery capacity through CK. Despite compensatory falls in ATP diffusion distance and altered CK isozyme expression, these changes may underlie susceptibility to EF decline in AS. Acknowledgement/Funding British Heart Foundation Clinical Research Training Fellowship (FS/15/80/31803) and Programme Grant (RG/18/12/34040).