The failing heart is traditionally described as metabolically inflexible and oxygen starved, causing energetic deficit and contractile dysfunction. Current metabolic modulator therapies aim to increase glucose oxidation to increase oxygen efficiency of adenosine triphosphate production, with mixed results.o2), invasive arteriovenous sampling and pressure–volume loops were performed (n=9).To investigate metabolic flexibility and oxygen delivery in the failing heart, 20 patients with nonischemic heart failure with reduced ejection fraction (left ventricular ejection fraction 34.9±9.1) underwent separate infusions of insulin+glucose infusion (I+G) or Intralipid infusion. We used cardiovascular magnetic resonance to assess cardiac function and measured energetics using phosphorus-31 magnetic resonance spectroscopy. To investigate the effects of these infusions on cardiac substrate use, function, and myocardial oxygen uptake (MVP=0.002); however, no change in cardiac function was seen relative to basal conditions. In contrast, during Intralipid infusion, cardiac long-chain fatty acid (LCFA) delivery, uptake, LCFA acylcarnitine production, and fatty acid oxidation were all increased . Myocardial energetics were better with Intralipid compared with I+G , and systolic and diastolic function were improved . During increased cardiac workload, LCFA uptake and oxidation were again increased during both infusions. There was no evidence of systolic dysfunction or lactate efflux at 65% maximal heart rate, suggesting that a metabolic switch to fat did not cause clinically meaningful ischemic metabolism.At rest, we found that the heart had considerable metabolic flexibility. During I+G, cardiac glucose uptake and oxidation were predominant (70±14% total energy substrate for adenosine triphosphate production versus 17±16% for Intralipid; Our findings show that even in nonischemic heart failure with reduced ejection fraction with severely impaired systolic function, significant cardiac metabolic flexibility is retained, including the ability to alter substrate use to match both arterial supply and changes in workload. Increasing LCFA uptake and oxidation is associated with improved myocardial energetics and contractility. Together, these findings challenge aspects of the rationale underlying existing metabolic therapies for heart failure and suggest that strategies promoting fatty acid oxidation may form the basis for future therapies. In nonischemic cardiomyopathy, the failing heart is flexible in metabolic substrate, able to increase uptake of fat depending on the prevailing metabolic conditions or when required under stress.In the failing heart in nonischemic cardiomyopathy, a switch to fat metabolism does not cause clinically overt hypoxia.Increased fatty acid metabolism in the failing, nonischemic heart improves myocardial energetics (PCr/ATP ratio) and increases contractility.Therapies that target fat metabolism may form the basis of novel treatments in cardiomyopathy.Regardless of the pathogenesis, most cardiac diseases eventually manifest in systolic dysfunction. Because delivery of adenosine triphosphate (ATP) to the myofilaments and membrane pumps is essential for normal contractile function, it follows that a reduction in ATP delivery could serve as the final common pathway that allows many different pathogeneses to manifest as the same end phenotype .1 In the resting state, the healthy heart achieves this by producing ATP from the oxidation of mainly fatty acids (60% to 90%), with a lesser contribution from glucose (10% to 40%), but exhibits remarkable flexibility to alter its substrate preference depending on prevailing metabolic and hemodynamic conditions. This allows for the natural fluctuations in substrate supply that occur with fasting, feeding, and exercise to be accommodated, and matches ATP production to demand. A pathological reduction in ATP production would necessarily lead to impaired cardiac function; as a corollary, promoting cardiac ATP production could be a potential therapy for HFrEF. In HFrEF, cardiac fatty acid oxidation (FAO) rates are lower2 across animal models of infarction,3 pacing-induced HF,4 and also in humans.6 This results from downregulated peroxisome proliferator-activated receptor α (PPARα) signaling, which reduces fatty acid transport and downregulation of fatty acid oxidizing enzymes.7 In animal models, this reduction is not accompanied by decreased fatty acid uptake,8 leading to triglyceride storage, nonoxidative metabolism, and lipotoxic species, which may contribute to HFrEF progression.9 In addition, myocardial insulin resistance reduces glucose uptake and pyruvate dehydrogenase (PDH) flux is decreased.10 As such, both glucose and FAO are decreased,15 but as FAO is reduced proportionally more, a relative “substrate switch” toward glucose metabolism is observed.1 It is believed that glucose is used initially in anaplerotic pathways for amino acid synthesis (necessary for the generation of left ventricular [LV] hypertrophy) rather than serving as a substrate for myocardial ATP production.16As the only immediate source of energy for contraction and relaxation of the heart, cardiac ATP demand is very high. To keep up with this demand, the heart needs to produce ≈20× its own weight in ATP per day.19 and oxygen-starved,21 a major therapeutic focus in HFrEF has been to identify pharmacological strategies to promote myocardial glucose oxidation, providing a more oxygen-efficient ATP synthesis pathway (glucose has higher phosphate/oxygen ratio [P/O] than fat).17 This can be achieved by either stimulating glucose uptake22 or improving the coupling of glucose uptake to oxidation by increasing PDH flux. PDH activity also can be increased by inhibition of FAO, and partial FAO inhibitors26 have been shown in small studies to produce improvements in LV function27 and energetics28 in chronic ischemic HFrEF. However, this approach is limited by the intrinsically lower yield of ATP from glucose oxidation (≈3.5× lower than FAO), which, when combined with the reduced cellular uptake from insulin resistance in HFrEF,30 is unlikely to fully compensate for the loss of FAO, which has a higher molar ATP yield per carbon. Should the human failing heart be shown to be metabolically inflexible and have sufficient oxygen to perform FAO at stress, then this therapeutic approach would be brought into question.On the premise that the failing heart appeared metabolically inflexible,The study was approved by the National Research Ethics Service (REC reference 18/SC/0170) and conformed to the principles outlined in the Declaration of Helsinki. Written informed consent was obtained from all participants. Participants with HFrEF were recruited from HF clinics, cardiac magnetic resonance imaging lists, and other studies in which the participants had consented to future contact. The original data that support the findings of this study are available from the corresponding author upon reasonable request.31P-MRS) to measure contractility, phosphocreatine (PCr)/ATP ratio (PCr/ATP), and creatine kinase (CK) flux. We recruited an additional 9 volunteers (5 of whom had undergone the CMR/31P-MRS protocol) scheduled to have cardiac resynchronization therapy pacemaker insertion to undergo additional invasive measurements of cardiac oxygen and substrate use (arteriovenous sampling) and LV function with pressure–volume loop interrogation at the time of their device implant. All participants were studied after an overnight fast.We recruited 20 volunteers with nonischemic HF and 10 healthy volunteers to undergo intravenous infusion that aimed to manipulate cardiac metabolic substrate supply. We used noninvasive cardiac magnetic resonance (CMR) and phosphorus-31 magnetic resonance spectroscopy (31 and LV ejection fraction (LVEF) <40% by echocardiography or CMR.Participants had symptomatic HF as defined by European Society of Cardiology guidelinesExclusion criteria were diabetes medications, egg or soy allergy, disturbances of normal fat metabolism , liver disease , recent fracture of pelvis or long bones, anemia , blood coagulation disorders , or metallic foreign bodies preventing CMR imaging.Exclusion criteria were ischemia as primary cause of HFrEF .Exclusion criteria were any LV dysfunction or other cardiac diagnosis.To elevate free fatty acid supply, 20% Intralipid (Fresenius Kabi) was infused intravenously at 60 mL per hour. For those not taking anticoagulant medications, unfractionated heparin  was concomitantly infused at 0.4 U/kg per hour to increase lipolysis. This was infused for 1 hour before scanning in the CMR arm, or commenced 15 minutes before measurements in the invasive arm, and then continued throughout the subsequent experiment.To increase cardiac glucose, a euglycemic hyperinsulinemic clamp was used. Insulin  was infused at 0.8 mU/kg per minute with an infusion of 20% glucose titrated to maintain blood glucose measurements at around the baseline for participants. Samples of venous blood were taken from a cannula up to every 5 minutes and tested with a point-of-care device . Patients were established on the euglycemic clamp for 1 hour in both arms before study measures were obtained.All participants underwent the after-CMR imaging protocol. All scans were performed at 3T . At the first visit, all participants were established on either an insulin+glucose (I+G) or Intralipid infusion 1 hour before CMR imaging, with the infusion type determined randomly by a computer-generated algorithm. Venous blood samples were drawn immediately before scanning. The noninvasive protocol was repeated after 7 days with the other infusion.32 In brief, all images were ECG-gated and taken during end-expiratory breath-hold. Typical steady-state free precession sequence measures were: slice thickness, 8 mm; gap, 2 mm; retrospective gating, 1.5 ms; repetition time (TR), 46 ms; flip angle 50º; field of view, 400 mm; and matrix size, 256 in frequency encode direction. When necessary, prospective gating was used in atrial fibrillation. Images were analyzed with manually drawn LV endocardial and epicardial contours in cvi42 (Circle Cardiovascular Imaging), as described previously.33 The validation of CMR-derived pressure–volume loops from CMR and blood pressure is described separately in the Expanded Methods in the Supplemental Material.A short stack of cine images was obtained using a 24-channel spine matrix coil, 6-channel body array coil (both Siemens), and steady-state free precession sequences, as described previously.1H/31P surface coil at magnet isocenter . A nongated 3D acquisition-weighted ultrashort echo time chemical shift imaging sequence was run as described previously.33 Parameters included: acquisition matrix size 16 × 8 × 8 voxels, field of view 240 × 240 × 200 mm3, nominal voxel size 11.25 mL, 10 averages at the center of k-space, TR per subject 910–1010 ms. The PCr/ATP ratio reported is the blood and saturation–corrected PCr/average ATP ratio, averaged over the 2 most basal septal voxels. Spectral analysis was performed using OXSA toolbox, an open-source MATLAB implementation of the AMARES algorithm.34Participants were placed into a prone position over a 3-element, dual-tuned 35 In brief, participants were scanned supine, 1H localizers confirmed coil position, and a 1-dimensional phase-encoded chemical shift imaging matrix  was used to acquire 4 sets of 31P spectra: a fully relaxed acquisition , 2 acquisitions with selective γATP saturation , and 1 acquisition with control saturation mirrored around PCr . Spectral analysis was performed using custom software as described previously.35 CK kf in the ATP-generating (forward) direction was then calculated as:The pseudo-first order unidirectional rate constant (CK forward rate constant [CK kf]) was estimated using triple TR saturation transfer adapted for use with a transmit/receive 10-cm loop radiofrequency coil (PulseTeq Ltd) as described previously.f, where [PCr] is estimated by multiplying PCr/ATP by literature values36 for [ATP] in HFrEF (5.2 μmol/g).Forward CK flux was calculated by [PCr]×kf measurement was taken, dobutamine was infused to increase cardiac work (targeted to 65% of maximum predicted for age). After target heart rate was achieved, cine images were again acquired for cardiac function, and 2 further 31P spectra were acquired (selective γATP saturation and control saturation); CK kf during stress was then calculated as described previously.35After the resting CK k2 (taken from fluoroscopy)×flow. Through a femoral arterial approach, a conductance catheter  was passed across the aortic valve into the left ventricle, and pressure–volume measurements were taken. At each measurement, 60 seconds of recordings from the impedance catheter and the flow wire were taken, along with paired arterial (from the coronary artery catheter) and venous blood sampling (from the coronary sinus). This was performed during intrinsic rhythm, and again during rapid atrial pacing .All measurements were taken during scheduled cardiac resynchronization therapy pacemaker implantation. Before the procedure, all patients were established on a euglycemic hyperinsulinemic clamp as described previously. After the implantation of atrial and ventricular leads, radial and femoral arterial access was established. A guide catheter was passed to the left main coronary artery through the right radial approach, and a flow wire  was passed into the proximal segment of the left main coronary artery to measure coronary arterial flow velocity (cm/s). Coronary flow (mL/s) was then calculated as π×coronary radiusAfter these measurements were performed, the I+G infusion was stopped, and an infusion of Intralipid was started (as described above). Fifteen minutes after the beginning of the Intralipid infusion, the sampling protocol outline was repeated during intrinsic rhythm, and atria–atria–interrupt pacing  was undertaken. Blood samples were assayed for oxygen saturation, partial pressure of oxygen, and hemoglobin using a blood gas analyzer (Seca). Glucose, nonesterified free fatty acids, β-hydroxybutyrate, insulin, and lactate levels were all assessed in the clinical-grade Oxford University Hospitals Clinical Laboratories.co2) was calculated from the McHardy equation:Myocardial oxygen usage (MVo2) was determined from arteriovenous content difference (0.0225×Po2 KPa+1.4×[Hgb]×[%O2 sat])×flow rate [mL/s]), as detailed previously. Myocardial carbon dioxide production (MV2=11.02×[(Pvco2)0.396–(Paco2)0.396]–(15–Hb)×(Pvco2–Paco2)–(95–Sao2)×0.0064. Respiratory quotient (RQ) was calculated as cardiac Vco2/Vo2. Myocardial substrate uptake was determined from arteriovenous difference (glucose/lactate/ketone/nonesterified free fatty acids)×coronary flow rate. Metabolomics were run by a commercial provider (Metabolon) and analyzed as described in the Expanded Methods in the Supplemental Material.ΔCOt tests were performed for paired data sets and repeated-measures ANOVA were performed for multiple data sets. Correlations were assessed using Pearson correlation analysis. All metabolomic and lipidomic analysis was subject to false discovery rate (set at 0.05) analysis using the Benjamini-Hochberg correction. A probability of P<0.05 was considered significant (2-tailed).Statistical analysis was performed using GraphPad Prism (GraphPad Software). All data were subjected to Kolmogorov‐Smirnov tests to establish normal distribution and are presented as mean±SD unless otherwise stated. Paired Student Table S2, and the results of substrate manipulation are shown in Figure S2. Intralipid caused an elevation in circulating nonesterified fatty acids compared with the I+G infusion , accompanied by a higher LVEF . PCr/ATP ratio was not significantly different , but CK first-order rate constant was elevated , with a trend to an increased CK flux .Baseline demographics are shown in Baseline data for the cohorts are shown in the Table. When comparing the invasive and noninvasive HFrEF cohorts, there were no significant differences in any baseline measure. Median New York Heart Association classification was II, and median baseline ejection fraction was 35% in both groups. All patients were on maximum tolerated doses of goal-directed medical therapy for HF.P<0.05; Figure r=0.74; P<0.001; Figure r=0.43; P=0.06). As expected, insulin was only taken up by the heart during I+G infusion . Furthermore, cross-heart RQ was significantly lower during Intralipid than during I+G infusion , showing a change in substrate oxidized . Overall, this shows that during changes in both arterial substrate supply and cardiac workload, substrate flexibility is surprisingly retained in compensated nonischemic HF with severe LV systolic dysfunction.When left main stem arterial long-chain fatty acid (LCFA) supply was increased by Intralipid infusion Figure A and 3E,P=0.016; Figure f , this was >2-fold higher during Intralipid, with a larger percentage contribution to ATP production from LCFA . During dobutamine stress , mean heart rate was 103±9 bpm on Intralipid and 103±8 bpm on I+G, myocardial phosphocreatine was not depleted, and PCr/ATP ratio, CK kf, and CK flux were not different between infusions . Myocardial energetics during stress were again related to venous substrate concentrations, but, in contrast to the resting state, CK flux was related to glucose  and lactate  concentrations. No difference in rate pressure product was seen between infusions. This suggests that in the resting state, increased FAO is associated with improvement in myocardial energetics of the failing human heart and that during stress, ATP flux in the failing heart is also related to glucose and lactate supply.Compared with I+G, Intralipid infusion was associated with an increase in myocardial PCr/ATP ratio . A similar pattern was seen during stress , Intralipid infusion led to increases in LV contractile work on both noninvasive CMR , net cardiac lactate consumption still occurred . In addition to pyruvate and glucose uptake, which was seen during both infusions Figure Aii.P=0.052), and nonoxidative metabolism of fatty acids seen with ceramide release only during Intralipid infusion (P=0.03). Release of lysophosphatidylcholine, phosphatidylcholine, and cholesteryl ester was seen during Intralipid infusion but not during I+G infusion , no major changes in the pattern of tricarboxylic acid cycle intermediate production or use are seen. However, the excess delivery of fatty acids or glucose used here to manipulate substrate use is associated with toxic nonoxidative metabolism and ceramide and sorbitol production, respectively. Metabolic maps are shown in Figure On the basis of the hypothesis that the failing heart is metabolically inflexible, and fatty acid metabolism creates additional oxygen demand, current metabolic therapies aim to increase glucose oxidation due to its inherently greater oxygen efficiency. In this study, we have shown that the heart, in compensated nonischemic HF with severe LV systolic dysfunction, is not metabolically rigid, and retains considerable flexibility to change substrate uptake and metabolism according to changing arterial substrate supply and workload. In addition, we show that although increasing fatty acid uptake and oxidation is associated with improved myocardial energetics and positive inotropy, no change is seen with increased glucose oxidation. Furthermore, we show that even during increased FAO under stress protocols, despite increased myocardial oxygen usage, myocardial phosphocreatine pool is not depleted, and lactate is consumed, suggesting that the oxygen supply is adequate to match oxidative phosphorylation. Taken together, this challenges the existing doctrine in HF metabolism and suggests increasing FAO may be a beneficial therapeutic intervention.38 This conclusion is derived from a body of literature showing reduced fatty acid and glucose oxidation, but no previous study has altered cardiac substrate supply in HFrEF to investigate metabolic flexibility.The failing heart is traditionally described as metabolically inflexible, unable to change substrates when prevailing conditions change, unlike in the healthy heart.To demonstrate metabolic substrate flexibility, we exposed the heart to changes in workload and substrate supply. These may be considered a form of metabolic stress test. To overcome inhibition at CPT-1  and insulin resistance (for glucose), both infusions were performed to achieve supraphysiological arterial supply and uptake levels.Using these infusions, we demonstrated that considerable substrate flexibility is retained, with a change in LCFA and glucose uptake and oxidation being induced by a change in arterial substrate supply. We showed that LCFA plasma membrane uptake is associated with production of long-chain fatty acylcarnitines, revealing that LCFA substrates for oxidation are being transported into the mitochondria. The cross-heart respiratory quotient dropped to 0.78 during Intralipid infusion, confirming that the heart is increasing FAO.As expected, the heart is able to take up ketone, with both β-hydroxybutyrate and aceto-acetate uptake being observed during Intralipid infusion, and (as expected) no circulating ketone was detected during I+G infusion.31P-MRS acquisition, dobutamine infusion was used. In contrast, as sequential infusions were used during the invasive experiment, a stress modality was required that could be started and stopped, and without time residual effects (as seen with both dobutamine and exercise). This necessitated rapid atrial pacing to be used as the stress modality for the invasive studies.Although physiological exercise would have been the ideal choice to investigate the effects of increased cardiac work, to limit movement artefact during 11 Our study adds that during rapid atrial pacing and I+G infusion, cardiac extraction of fatty acid increased >5-fold despite no change in arterial supply, with glucose uptake being numerically but not significantly reduced (by 24%). This occurred without a change in arterial supply, implying that the heart in HFrEF has active substrate selection and preference to fatty acids during increased workload.It has been shown previously in HFrEF that rapid AAI pacing increases FAO in the fasted state, and in contrast that the normal heart increases glucose oxidation.31P-MRS to measure the PCr/ATP ratio, a sensitive index of the energetic status of the heart, and saturation transfer 31P-MRS to measure CK kinetics. Here, we show that myocardial PCr/ATP ratio was returning toward normal during Intralipid infusion in participants with HF. This contrasts with the healthy volunteer group, for whom it was unchanged and presumably already maximal. When put together with the numerical  37% increase in ATP delivery rate through CK, this suggests that myocardial energetics are improved during oxidation of fatty acids when compared with glucose. This is in line with a greater molar ATP yield (≈3.5×) of fatty acids than glucose. The healthy volunteer group mounted a similar increase in CK flux, driven in their cases by a rise in CK rate constant.To assess whether substrate flexibility influenced cardiac high-energy phosphate metabolism, we used f did not fall during Intralipid, strongly implying that myocardial ATP supply did not fall below mitochondrial ATP demand during a period of increased contractility. Given the increased death rate of the chronic use of inotropes such as dobutamine and adrenaline39 due to adverse remodeling and energetic mismatch,40 this is an important observation.The concentration of phosphocreatine relative to ATP rose and CK k42 and more susceptible to ATP shortage than systole,27 hence, an improvement in diastolic function was seen with both –dp/dt and tau improving during Intralipid.On both invasive and noninvasive measures of cardiac function compared with I+G, when no change from basal condition was observed, Intralipid infusion was associated with a measurable increase in contractility, with improvements in LVEF, LV strain, LV stroke work, LV +dp/dt, and LVDP all being observed. Healthy volunteers showed similar increases. LV end diastolic pressure was not different between groups, indicating that loading conditions could not have played a role in increasing contractility. As cardiac contractile function is a highly energetically demanding process, and FAO provides more ATP per mole oxidized, it is likely that increases in ATP production  are at least in part responsible for improved contractility. This is seen here, with the strong positive correlation between measured CK flux and rate pressure product. Diastole is also a highly energetically demanding process,2 molecules to produce 105 ATP [P/O 2.3], whereas glucose requires only 6 O2 molecules to produce 31 ATP [P/O ≈2.5]).44 The lower P/O ratio of FAO accompanied by higher contractility (and therefore greater ATP demand) will increase myocardial oxygen use (MVo2), whereas cardiac efficiency (cardiac work per unit oxygen consumption) will be reduced. This can be seen in this study with higher MVo2 during Intralipid infusion, and during stress, and lower cardiac oxygen efficiency. However, as inotropes such as dobutamine are associated with increased death rate,40 it is important that the increased ATP demand during increased inotropy is met by oxidative metabolism. The phosphocreatine pool was not depleted, strongly implying that myocardial ATP demand did not exceed mitochondrial ATP supply.When oxygen is limited, the disadvantage that FAO is inherently less oxygen-efficient becomes apparent . This would suggest that sufficient oxygen was available for normal mitochondrial oxidative phosphorylation, and that the mitochondrial oxygen supply was not exceeded during stress.45 and have theoretical metabolic advantages: greater reduction of complex I of the electron transport chain and increased succinate,46 increasing the redox span between electron transport chain sites I and III, and the free energy for ATP synthesis.47 In this study, a trend to higher succinate production was seen during Intralipid infusion, during which ketones were taken up by the heart. Murine6 and human studies show increased β-hydroxybutyrate uptake in HF,48 which has been linked to increased stroke volume and MVo2 without change in oxygen efficiency when compared with an I+G infusion.49 However, despite an increase in β-hydroxybutyrate uptake during Intralipid infusion  and branched-chain amino acids , although alternative energy substrates, did not show differences in uptake between infusions (data not shown), suggesting that these were not responsible for the contractile differences seen here.Recent work highlights 2 additional potential metabolic substrates: ketones and short-chain fatty acids. Despite low circulating levels (<2% of fasted substrate), ketones are readily taken up and metabolized,51 This study highlights that excessive delivery of fatty acids results in ceramide species being produced, and as a result, is unlikely to be a long-term solution to chronic HF. Likewise, increased sorbitol production during I+G infusion suggests polyol pathway activation. In general, balancing uptake and oxidation of any substrate to prevent spillover into toxic overflow pathways should be the goal of any therapy aimed at manipulating substrate supply.Although this study has shown that promoting FAO has advantages energetically and functionally in nonischemic HFrEF, this was achieved by means of increased LCFA delivery. Whereas this was necessary to overcome reduced fatty acid transport protein (CD36 [fatty acid transport protein]/FATP [fatty acid transport protein]) and CPT-1/2 transporter expression, the increasing intracellular pool of long-chain fatty acyl-CoA produces a larger pool of fatty acid substrate for nonoxidative processes, including the synthesis of triacylglycerol, diacylglycerol, and ceramides, which, in animal models, cause lipotoxicty.This is a short-term study taking place over hours aimed to demonstrate the principle of substrate flexibility in the failing heart. These techniques to manipulate metabolic substrate supply may have limitations of lipotoxicity or insulin resistance. Other strategies are likely to be required for longer-term treatments to target fat metabolism directly.31P spectroscopic techniques require homogenous myocardium.Despite a history of HFrEF, elevated NT-proBNP , and echocardiographic evidence of LVEF <40% at screening, 2 participants had an LVEF >40% at baseline. This may be related to partial recovery of LVEF between screening and baseline. Despite this, the trend in response to metabolic intervention was similar in these 2 participants. Although it is a major cause of HF, ischemic cardiomyopathy was not included in this study, as the To limit the time in which the participants underwent additional left coronary artery catheterization, flow wire, coronary sinus catheter, and LV catheter instrumentation during their cardiac resynchronization therapy implantation, and remove the potential for hypoglycemia, all participants underwent Intralipid infusion after the euglycemic clamp. Although this has the potential for systematic bias, we are confident that the primary objective of the infusion, to deliver excess substrate to the myocardium and delineate residual flexibility, was demonstrated.Whereas cross-heart arteriovenous sampling allows uptake and efflux of metabolites, endogenous substrate flux is not measured directly.This study has shown that in compensated nonischemic cardiomyopathy with severe LV systolic dysfunction, the human heart retains substantial metabolic substrate flexibility if arterial supply or workload is changed. It also provides evidence that the heart is not oxygen-limited to a level that interferes with mitochondrial oxidative phosphorylation. In addition, it has been shown that increasing fatty acid uptake and oxidation, but not glucose, is associated with positive energetic and inotropic effects, with ATP production and consumption matched. There was no evidence of increased oxygen demand causing hypoxia. These findings challenge the existing hypotheses underlying metabolic modulator therapy in HF and suggest that increasing FAO is a promising therapeutic approach.This study was supported by British Heart Foundation clinical research training fellowships awarded to Drs Watson (FS/17/48/32907) and Green (FS/18/50/33807). Dr Rodgers is supported by the National Institute for Health and Care Research Cambridge Biomedical Research Centre (BRC-1215–20014). The views expressed are those of the authors and not necessarily those of the National Institute for Health and Care Research or the Department of Health and Social Care. Dr Valkovič is funded by a Sir Henry Dale fellowship awarded jointly by the Wellcome Trust and the Royal Society (221805/Z/20/Z) and supported by the Slovak Grant Agencies VEGA (2/0003/20) and APVV (19-0032). Drs Herring and Rider are supported by British Heart Foundation senior clinical research fellowships (FS/SCRF/20/32005 and FS/SCRF/22/32014).None.Expanded MethodsFigures S1–S4Tables S1–S4References 54


To compare cardiac function indicators between mild and moderate to severe COVID-19 patients and to try to identify the sequence and directivity in cardiac muscle injury of COVID-19 patients.From December 2022 to January 2023, all patients with laboratory-confirmed SARS-CoV-2 infection in Shanghai General Hospital Jiading Branch were enrolled. The clinical classification was stratified into mild, moderate, or severe groups. We collected the clinical and laboratory information, transthoracic echocardiographic and speckle-tracking echocardiographic parameters of patients and compared the differences among different groups.P < 0.05) except LVEF. The values of LVEF of mild and moderate group were higher than severe group (P < 0.05). There were no significant differences between moderate and severe group. Positive correlations were observed between left ventricular global longitudinal strain (LVGLS) and myoglobin (r = 0.72), E/e' and age (r = 0.79), E/e' and BNP (r = 0.67). The multivariate analysis shows that SpO2 , LVGLS  and E/e'  were the independent risk factors for mild cases progressing to moderate or severe. According to the receiver operating characteristic (ROC) curves, when all the COVID-19 patients was taken as the sample size, the area under the curve (AUC) of the LVGLS was the highest (AUC = 0.861). The AUC of the LVGLS was higher than LVGCS .The values of echocardiographic parameters in mild group were lower than that in moderate or severe group (When mild COVID-19 progresses to moderate or severe, both systolic and diastolic functions of the heart are impaired. LVGLS was the independent risk factor for mild cases progressing to moderate or severe cases. Longitudinal changes may manifest earlier than circumferential changes as myocardial disease progresses in COVID-19. While primarily recognized for its respiratory impact, it is increasingly evident that COVID-19 can exert a significant influence on the cardiovascular system. This impact encompasses a spectrum of cardiovascular diseases, including but not limited to myocarditis, acute coronary syndrome, arrhythmias, and heart failure . Underst2.2.1.This study was an observational study. All patients with laboratory-confirmed SARS-CoV-2 infection at Shanghai General Hospital Jiading Branch from December 2022 to January 2023 were included in this study. The inclusion criteria were: (1) age >18 years and (2) COVID-19 diagnosis by RT-PCR swab test and comprehensive analysis of epidemiological history and clinical presentation. Patients who were <18-years-old and with end-stage renal failure, active malignancy, previous or current autoimmune diseases, coronary atherosclerotic heart disease, or congenital heart disease were excluded. This study got the permission of the Ethics Committee of Shanghai General Hospital (2019KY009-4) and complied with the Declaration of Helsinki. Every patient signed informed consent.2.2.Clinical classification followed the Diagnosis and Treatment Protocol of Novel Coronavirus (Version 10) by the National Health Commission of the People's Republic of China , which sMild: The main symptoms are upper respiratory tract infections, such as dry throat, sore throat, cough, and fever.Moderate: Persistent high fever for more than 3 days (and/or) coughing, shortness of breath, etc., but respiratory rate (RR) is <30 breaths/min and oxygen saturation is >93% when air is inhaled at rest. The imaging features of COVID-19 pneumonia were observed.1.Shortness of breath, RR is ≥30 breaths/min;2.Oxygen saturation is ≤93% when inhaling air at rest;3.2)/oxygen uptake concentration (FiO2) is ≤300 mmHg (1 mmHg = 0.133 kPa);Arterial oxygen partial pressure . Medical histories of diabetes, hypertension, and use of antihypertensive medications were recorded. The BMI was calculated as weight/height2 (kg/m2). Laboratory parameters included C-reactive protein (CRP), B-type Natriuretic Peptide (BNP), cardiac troponin I (cTnI), creatine kinase isoenzyme (CKMB), and myoglobin.The following information was collected: age, sex, height, body mass index (BMI), heart rate, arterial systolic and diastolic blood pressure, and saturation of peripheral oxygen (SpO2.3.2.A Philips EPIQ7 echocardiograph equipped with an S5-1 probe (frequency 1–5 MHz) and frame rate ≥60 beats/min was used. When performing echocardiography, patients should remain in the left lateral position and maintain calm breathing. A synchronized electrocardiogram was connected to an ultrasound machine. The left ventricular end diastolic diameter (LVDd), left ventricular end systolic diameter (LVDs), interventricular septum diameter (IVSd) and left ventricular posterior wall diameter (LVPWd) were measured in each patient, representing the end-diastolic/systolic anteroposterior diameter of left ventricular, left ventricular end-diastolic septal thickness, and left ventricular end-diastolic posterior wall thickness, respectively. The ratio of E/A and E/e' were used to estimate LV diastolic function, where E and A are early and late transmitral flow velocities, and e' is early diastolic septal tissue velocity. Left ventricular ejection fraction (LVEF) was measured using the modified Simpson biplane method.2.3.3.Two-dimensional videos of three consecutive cardiac cycles were collected at the end of breathing for post-offline analysis. In addition, the images of apical 4-chamber, 2-chamber, 3-chamber, and short-axis views were saved at the level of the parasternal papillary muscle. As shown in 2.3.4.Two physicians independently assessed LVGLS and LVGCS values for a cohort of 20 randomly selected participants to evaluate the reproducibility of the measurements. The assessment of inter-observer agreements between the two physicians was conducted using Bland–Altman plots.2.4.Enumeration data were expressed as numbers and percentages, measurement data were presented as mean and standard deviation, or expressed as median (interquartile range) for quantitative variables. Data analysis was performed using SPSS 23.0 . One-way ANOVA and Bonferroni correction were used for intergroup and intragroup comparison of continuous data, respectively. Non-normally distributed data were analyzed by the Wilcoxon signed-rank test, and categorical variables between the two groups were compared by chi-square tests. A linear correlation analysis and Bland–Altman plots were adopted for repeatability evaluation. The correlation between different parameters was analyzed by Spearman's method.2, cTnI, Myoglobin, E/A ratio, E/e' ratio, LVGLS, and LVGCS.To analyze the risk factors associated with moderate/severe COVID-19, a backward stepwise regression method was employed. The variables included in the analysis were clinical data such as age, sex, HR, SBP, SpOP < 0.05 indicated that the difference was statistically significant.The receiver operating characteristic (ROC) curve best reflected the sensitivity and specificity of the echocardiographic parameters in diagnosing moderate and severe COVID-19 at the upper leftmost value, and the area under the ROC curve (AUC) of each parameter was obtained. The value of 3.3.1.Ultimately, a total of 219 COVID-19 patients were comprehensively enrolled in the study of which 101 (46%) were males and 118 (54%) were females. The demographic details of the COVID-19 patients are shown in 3.2.P < 0.05). The values of LVEF of mild and moderate group were higher than severe group (P < 0.05). There were no significant differences between the moderate and severe groups. Moderate and severe COVID-19 patients presented with impaired LVGLS compared to mild . Out of 219 patients, 31 (14%) had reduced LVGLS values of ≤18%.3.3.The reproducibility of the LVGLS and LVGCS was assessed in 20 randomly selected participants (patients or controls), and these values were measured independently by two physicians. There was favorable agreement between the quantitative variables measured by them for LVGLS and LVGCS scores. The mean (±SD) difference was 0.22 (±0.80) for repeated measurements of LVGLS by the two observers. The mean (±SD) difference was 1.34 (±2.43) for repeated measurements of LVGCS by them .3.4.CRP, BNP, cTnI, CK-MB, and myoglobin levels differed significantly among the different groups . The sev3.5.P < 0.05). E/e' was correlated with age and BNP   .3.6.2, LVGLS, and E/e' were independently associated with the progression from mild to moderate/severe cases, with ORs of 0.360, 3.196, and 1.307, respectively . This indicates that the LVGLS is an excellent diagnostic tool for identifying moderate/severe diseases.ROC curves were depicted to evaluate the capacity of the echocardiographic parameters to diagnose moderate/severe COVID-19 cases . Accordi4.2, LVGLS, and E/e' were the independent risk factors for mild cases progressing to moderate or severe cases. In predicting moderate/severe disease, LVGLS exhibited a higher AUC compared to LVGCS, implying an earlier onset of systolic dysfunction in the long-axis direction vs. the short-axis direction.In this study, we have observed that the progression of mild cases to either moderate or severe manifestations was associated with an impairment in both systolic and diastolic cardiac functions. These changes may be related to myoglobin levels, age, BNP levels, and heart rate. The AUC of the LVGLS was higher than that of the LVGCS, indicating that the systolic function in the long-axis direction was damaged drastically. SpOCardiovascular disease remains the main cause of mortality worldwide , 13. FewEchocardiography along with LVGLS imaging is a handy and effective tool to ascertain early left ventricular dysfunction which is often seen in myocardial injury. Some studies have shown that left ventricular systolic and diastolic functions are impaired in COVID-19 patients, including increased left ventricular internal dimension diastole, reduced LVEF, increased left atrial volume, increased peak tricuspid regurgitation velocity (Vmax), and changes in mitral E/e' ratio –23.Our study found that the reduction of systolic and diastolic functions has correlation with the severity of the illness. The parameters of left ventricular structure or systolic/diastolic functions in the mild group were lower than those in the moderate or severe groups. One study showed that conventional echocardiographic parameters of the left ventricular structure or systolic/diastolic functions did not differ between the moderate and severe groups . The res2, E/e' and LVGLS were the independent risk factors for mild patients progressing to moderate/severe group, and LVGLS played the most important part. The classification criteria included oxygen saturation, so SpO2 could influence the degree of disease. In our study, E/e’ ratio was higher in moderate and severe patients compared with milder ones which was similar to previous studies (Speckle-tracking echocardiography is good at assessing myocardial deformation because it is not affected by angle , 27. Lon studies , 33. Lup studies  found thMyocardial longitudinal strain mainly reflects cardiac contractile function, while myocardial circumferential strain is more closely related to cardiac preload . In thisA limitation of our study was that it was a single-center study and recruited a small number of patients. Second, the patients in the mild group were younger than those in the moderate/severe groups. Age differences may also affect cardiac function. However, we conducted logistic regression analysis to identify age as a risk factor for heart disease. Besides, we did not set normal control patients group. In addition, we did not observe the normalization of echocardiographic data after recovery. We intend to continue this research in the future.5.When mild COVID-19 progresses to moderate or severe, both systolic and diastolic functions of the heart are impaired. LVGLS was the independent risk factor for mild cases progressing to moderate or severe cases. Longitudinal changes may manifest earlier than circumferential changes as myocardial disease progresses in COVID-19.


To evaluate the feasibility of retrospectively detecting and correcting periodical (cardiac and respiratory motion) and non-periodical shifts of the myocardial position  using only the acquired Rubidium-82 positron emission tomography raw (listmode) data.Recon). For the volunteers, we report test-retest repeatability using standard error of measurements (SEM). For the patient cohort, we evaluated the area under the receiver operating curve (AUC) for both stress and ischemic total perfusion deficits  using myocardial ischemia defined as fractional flow reserve values < 0.8 in the relevant coronary segment as the gold standard.This study comprised 25 healthy participants (median age = 23 years) who underwent repeat rest/adenosine stress Rubidium-82 myocardial perfusion imaging (MPI) and 53 patients (median age = 64 years) considered for revascularization who underwent a single MPI session. All subjects were evaluated for myocardial creep during MPI by assessing the myocardial position every 200 ms. A proposed motion correction protocol, including corrections for cardiorespiratory and creep motion (3xMC), was compared to a guideline-recommended protocol . AUC analysis of the ROC curves revealed significant improvements for iTPD measurements following 3xMC .Test-retest repeatability was significantly improved following corrections for myocardial creep (SEM; sTPD: Standard3xMC has the potential to improve the diagnostic accuracy of myocardial MPI obtained from positron emission tomography. Therefore, its use should be considered both in clinical routine and large-scale multicenter studies.The online version contains supplementary material available at 10.1007/s12350-023-03360-x. Intravenous administration of adenosine is used to achieve conditions of stable hyperemia in the heart; unfortunately, the hyperemia elevates the already high risks of patient motion, and non-periodical repositioning of the heart in the mediastinum, also known as myocardial creep.3 Although myocardial creep occurs frequently in cardiac MPI, only a few correction techniques have been proposed.5 Common for the proposed correction techniques is that they apply to dynamic reconstructions employed for myocardial blood flow assessments and only permit corrections for inter-frame motion.5 While introducing an averaged image of the later frames in the motion-corrected, dynamic image series may offer a solution, the resulting images may have increased noise and residual blur introduced by the missing intra-frame motion correction. Therefore, this study aimed to evaluate (a) the feasibility of retrospectively extracting information on myocardial creep using only 82Rb-PET raw data (listmode data) and (b) the impact of motion correction of the myocardial creep events. To correct the myocardial creep, we performed triple-gated reconstructions, employing a dual-gated cardiorespiratory (cardiac contraction and respiratory motion) reconstruction protocol for each detected myocardial creep event, followed by image co-registration; thus, obtaining a triple-motion-corrected image series (3xMC).7 The results of 82Rb-PET MPI were compared to fractional flow reserve (FFR) as a gold standard reference for coronary intervention.Rubidium-82  (n = 30) or known CAD (n = 23) referred for both 82Rb rest/adenosine stress MPI within 2 weeks  within 3 months before study participation, and no caffeine intake . Exclusion criteria were pregnancy, allergy or intolerance to theophylline or adenosine, any prior medical history of asthma, and inability to adhere to the study protocol.The volunteer cohort comprised 25 healthy young persons who underwent repeat ks Table .8,9 InclThe patient cohort included 53 patients Table .Inclusion criteria were age > 50 years, while exclusion criteria were claustrophobia, severe asthma, or renal failure (plasma creatinine > 140 µM). Coronary stenoses > 50% identified by invasive angiography were, in all cases, assessed for hemodynamic significance by measuring FFR during continuous adenosine infusion (140 μg/kg/min) for 2 minutes. A FFR< 80% was considered significant and led to subsequent percutaneous coronary intervention (PCI) where technically possible.82Rb. Pharmacological stressing was obtained using adenosine infused intravenously at a rate of 140 mg/kg/min for 6 minutes, with PET emission acquisition starting 2.5 minutes into the infusion. Each imaging session started with a low-dose CT for attenuation correction purposes acquired using a free-breathing protocol,10 followed by the PET emission scans. All participants were instructed to abstain from caffeine at least 16 hours before each of the imaging sessions.All study participants underwent rest/adenosine stress MPI in a 128 slice Siemens Biograph mCT PET system using targeted injection doses of 1,100 MBq (30 mCi) 82Rb-PET acquisitions,11 using the following reconstruction parameters: 2 iterations, 21 subsets, corrections for Time-of-Flight and point spread, and a 5 mm Gaussian filtration. The first reconstruction protocol provided a conventional static reconstruction (StandardRecon), as used in routine assessments. The second reconstruction protocol provided a triple-motion-corrected image series (3xMC), including corrections for myocardial creep and cardiorespiratory motion correction (described in detail below).Two PET reconstruction protocols were evaluated. Both reconstruction protocols employed data obtained between 150 and 360 seconds into the 12 employing a temporal resolution of 200 ms to facilitate the detection of myocardial creep events with a high temporal resolution. This proposed motion detection technique differed from previous attempts at detecting patient repositioning events7 as 82Rb MPI scans are affected by tracer-kinetics during the acquisitions. To this end, we hypothesize that the myocardial creep events may be detected by comparing radiotracer kinetic uptake in tissues with and without specific uptake. For the myocardium, 82Rb is being trapped via Na-K-ATPase, while healthy lung tissue, on the other hand, tends to have a non-specific uptake pattern. Given both tissues follow the same respiratory repositioning events, any significant change in the center-of-mass for the two tissues indicates a myocardial creep event. In this study, we tested this assumption by convolving the center-of-mass signals obtained in the myocardium and surrounding tissues  using a center-of-mass-based analysis,6 All gated reconstructions were co-registered using a local-registration matrix surrounding the segmented heart ± 15 slices (slice thickness = 2.07 mm) in all directions). The co-registration was obtained using a non-rigid registration protocol (demons) in MatLab.3xMC was obtained by introducing a cardiorespiratory  reconstruction protocol for each myocardial creep event, as based on a previous proposal.13 Of note, rTPD, sTPD, and iTPD are given in % of the left ventricular wall volume. In this study, an iTPD ≥ 10% was considered abnormal.14We report the average translation observed in the myocardium during the scans, the total perfusion deficits for all reconstructed datasets [rest and stress total perfusion deficits ], and the ischemic total perfusion deficit (iTPD) calculated as the respective sTPD minus rTPD for the individual MPI sessions.Recon and 3xMC assessments.We also report the test-retest repeatability using the standard error of measurement (SEM) of the motion-induced perfusion deficits observed for the healthy volunteers. For the patient cohort, we report the crosstab assessments, including the prevalence of disease, the sensitivities, and specificities, in addition to the positive and negative predictive values obtained for the Standard13In addition, two experienced readers (combined experience of > 30 years) were asked to visually evaluate the images concerning the potential of motion-induced artifacts in the images while being blinded to the used reconstruction protocol. All assessments were performed in the clinical software toolbox . The images were scored on a scale from 1 to 5, with 1 being scored when the readers were certain of motion-induced artifacts in the automatic assessments; conversely, 5 was given when the images did not show any signs of motion artifacts. Finally, we report the TPD values and the area under the receiver operating curve (AUC) for the patient cohort as the primary end-point for this study.15 using the area under the curve (AUC) as the primary end-point for this study. Test-retest repeatability was calculated as the standard error of measurement (SEM) and the 95% confidence intervals of the SEM. Differences in bias were evaluated using the Pitman-Morgan test, with P-values < .05 being considered statistically significant. Finally, the number of creep events and patient motion across the different cohorts were evaluated using a two-way ANOVA.The data were tested for normality using Shapiro-Wilk test. Continuous data were presented as mean ± SD or median and interquartile ranges, and categorical data as percentages. Employing the FFR findings for the patient population, the impact of the myocardial creep motion correction was evaluated using receiver operating characteristic curves. All receiver operating characteristic curves were compared using the DeLong and DeLong method,Recon (82Rb-PET iTPD > 10%)], whereas 25 patients had FFR < 0.8 in at least 1 coronary artery and underwent subsequent PCI (n = 22) or CABG (n = 3) intervention.Baseline characteristics for the volunteer and patient groups are shown in Table z-direction . Including cardiorespiratory motion correction, the heart moved up to 33.9 mm , of which motion in z-direction accounted for > 52% of the motion   myocardial creep events detected in the volunteer group and 2 (range: 1-5) observed in the patient cohort ; iTPD: Standardrecon = 0.883, 3xMC = 0.946 (P = .039)) , Specificity: StandardRecon = 96.4%, 3xMC = 96.4%, P = .151)  when employing the 3xMC. Likewise, a correlation trend was observed between motion during the MPI sessions and the relative change in the sTPD/iTPD assessments  motion in two cohorts, one comprising young, healthy volunteers with repeat 6 Despite the translatory impact of respiratory motion and myocardial creep, the clinical routine has a mainstay of motion-limiting ECG-gated reconstructions, which are used for assessments of the left ventricular ejection fraction.17 However, studies employing dual-correction protocols (cardiorespiratory) have been proposed with great success.18 In terms of myocardial creep corrections during MPI sessions, the primary solutions revolve around passive detections of myocardial creep during assessments of dynamic frames employed for myocardial blood flow analysis. Here, the passive correction only permits inter-frame motion correction and does not consider within-frame myocardial creep events, which might limit the effect of the myocardial creep correction technique.5 Further, this correction technique does not permit myocardial creep correction of perfusion assessments which often endures several minutes' data. Finally, this technique does not permit corrections for cardiorespiratory motion, which is known to affect quantitative accuracy.18 The proposed myocardial creep detection technique permits the detection of myocardial creep events dynamically during the acquisition and, at the same time, extracts information on the respiratory motion, which can be used for 3xMC corrections. The myocardial creep detection employed in this study expands on previous attempts at detecting patient repositioning events as tracer-kinetics influence the count rate-based assessments during the scans. In brief, the influence of tracer-kinetic on the count rate-based assessment was corrected by evaluating how the uptake pattern in the myocardium changed compared to the count rates observed in the surrounding lung tissues. This analysis permitted detection of the myocardial creep events, that occurs frequently (up to seven times) during the scans , highlighting the detrimental effect of motion during the MPI acquisitions  in the MPI sessions. We report improved test-retest repeatability in the healthy volunteers and significantly improved AUC for both sTPD and iTPD analyses in the patients. Combined, these results highlight the need for 3xMC in routine 82Rb MPI assessments.Myocardial creep is common during 82Rb MPI sessions following 3xMC, compared to the StandardRecon protocol. Further, the 3xMC improved the test-retest repeatability obtained in a cohort of healthy volunteers. Therefore, we propose to employ 3xMC in the clinical routine to strengthen the outcome measures obtained for patients undergoing routine 82Rb MPI sessions.We report significantly improved AUC for the iTPD assessments for Supplementary file1 (DOCX 14 kb)Supplementary file2 (PPTX 248 kb)Below is the link to the electronic supplementary material.


Two-dimensional speckle-tracking echocardiography (2DSTE) detects myocardial dysfunction despite a preserved left ventricular ejection fraction. Fibroblast growth factor 23 (FGF23) has become a promising biomarker of cardiovascular risk. This study aimed to determine whether FGF23 may be used as a marker of myocardial damage among patients with diabetes mellitus type 2 (T2DM) and no previous history of myocardial infarction. The study enrolled 71 patients with a median age of 70 years. Laboratory data were analyzed retrospectively. Serum FGF23 levels were determined using a sandwich enzyme-linked immunosorbent assay. All patients underwent conventional echocardiography and 2DSTE. Baseline characteristics indicated that the median time elapsed since diagnosis with T2DM was 19 years. All subjects were divided into two groups according to left ventricular diastolic function. Individuals with confirmed left ventricular diastolic dysfunction had significantly lower levels of estimated glomerular filtration rate and higher values of hemoglobin A1c. Global circumferential strain (GCS) was reduced in the majority of patients. Only an epicardial GCS correlated significantly with the FGF23 concentration in all patients. The study indicates that a cardiac strain is a reliable tool for a subtle myocardial damage assessment. It is possible that FGF23 may become an early diagnostic marker of myocardial damage in patients with T2DM. Diabetes mellitus (DM) poses a serious challenge to the world’s health. Despite global efforts to tackle the diabetes pandemic, the number of adults living with DM is on the rise. The International Diabetes Federation reported that the number of adults with DM has already surpassed 537 million and is predicted to rise to 643 million by 2030 . Even moCardiovascular disease (CVD) is the most prevalent cause of morbidity and mortality in a diabetic population . DM is aNearly 50 years ago, Rubler et al. introduced the concept of diabetic cardiomyopathy (DCM), which is considered a primary myocardial disease in diabetic patients ,8. DCM wDM claims lives and triggers disability. Patients with DM have unfavorable prognoses due to multiple diabetic complications and frequent comorbidities, worse cardiovascular (CV) outcomes, and higher rates of hospitalization compared to their healthy counterparts ,6,11. NuTransthoracic echocardiography (TTE) is the most fundamental method for a cardiac function evaluation of patients with DM. Although reduced left ventricular ejection fraction (LVEF) indicates HF among symptomatic patients, a considerable proportion of patients with HF still have preserved LVEF . The latIn 1973, Mirsky and Parmley described the concept of evaluating myocardial stiffness by using a measure of deformation  . MyocardIn recent years, fibroblast growth factor 23 (FGF23) has gained wide attention in many fields of medicine and has become a promising biomarker linking chronic kidney disease (CKD) with CV morbidity and mortality ,19. FGF2For the present analysis, we included 71 consecutive patients. Data of all individuals were obtained from a Diabetes Outpatient Clinic  database between 2019 and 2021. Patients had the following inclusion criteria: (1) T2DM duration of >10 years; (2) regular follow-up care by a mutual diabetologist; and (3) hemoglobin A1c (HbA1c) ≤ 8% were enrolled in the study, whereas subjects with any of the following conditions were excluded: (1) age < 18 years; (2) previous history of MI; (3) active infection; (4) malignant tumor; (5) no electronic TTE data available for retrospective analysis; or (6) missing key clinical data. Afterwards, participants were divided into two groups according to a diagnosis of left ventricular diastolic dysfunction (LVDD): Group 1  or Group 2 . A flowchart of the study is shown in 2), total cholesterol (TC) (mg/dL), high-density lipoprotein cholesterol (HDL-C) (mg/dL), low-density lipoprotein cholesterol (LDL-C) (mg/dL), non-high-density lipoprotein cholesterol (non-HDL-C) (mg/dL), and triglycerides (TG) (mg/dL), were analyzed retrospectively. Demographic and clinical characteristics were collected during a structured interview, and included, among others: sex, age, height, body weight, body mass index (BMI), T2DM duration, and smoking history. Data related to comorbidities , cardiovascular hospitalization, and family history of heart disease or DM were obtained from all participants as well. Diaries of self-control were used to verify home blood pressure monitoring. Laboratory examination data, such as HbA1c (%), creatinine , estimated glomerular filtration rate (eGFR) . Written informed consent was obtained for inclusion of the patients.Serum levels of intact FGF23 (iFGF23) were measured using a sandwich enzyme-linked immunosorbent assay (ELISA) with a FGF23 ELISA kit . All blood samples were collected in the morning after an overnight fast (minimum 10 h), during previously scheduled appointments at the Diabetes Outpatient Clinic, and stored at −80 °C before analysis. The reference range for serum iFGF23 level in healthy adults is 8.2–54.3 pg/mL .All patients underwent two-dimensional (2D) TTE using a commercially available ultrasound system  equipped with a 3.5-Mhz transducer. Participants were evaluated with 2D, M-mode, color Doppler, pulse Doppler, and continue Doppler echocardiographic examinations in the left lateral decubitus position. To achieve optimal image quality, we adjusted gain, compression, depth, and sector width. The images were acquired in the apical  and parasternal views (long- and short-axis views) at the basal, papillary, and apical LV levels at high frame rates of 70–90 frames/s.2. If more than two parameters met the above-mentioned cutoff values, LVDD was diagnosed, as shown in LV volumes were measured from the apical four- and two-chamber views. LVEF was calculated in the apical four-chamber view using the modified Simpson’s rule. LVDD was defined in accordance with the most recent guidelines . To deteLV function was further evaluated with 2DSTE using a software package  by two experienced and independent observers. In each plane, three consecutive cardiac cycles were captured during a breath hold at the end-expiration and stored in a cine-loop format for offline analysis. 2DSTE is a relatively new technique of cardiac imaging based on frame-by-frame tracking of ultrasonic speckles in gray scale. It allows accurate assessment of myocardial deformation in two dimensions. Two different patterns  may be evaluated using the apical and parasternal short-axis views. LS shows systolic shortening in the long-axis plane, while CS represents systolic shortening but in a short-axis plane. During systole, LS and CS are anticipated to be negative values. Moreover, we analyzed CS in three myocardial layers: epicardium, mid-wall, and endocardium, under the assumption that the alterations among diabetic population may appear layer-specific. The software automatically divided the region of interest (ROI) into six equal segments and provided the time–strain curves for each myocardial segment. If necessary, ROI was manually adjusted using a point-and-click approach to enhance tracking quality. Curves of regional and global peak systolic strain, previously calculated by segmental averaging, were obtained. The reference range for GLS and GCS strain values are based on Nagata et al. .p-value of 0.05 was used as the threshold of statistical significance. The normality assumption was verified using the Shapiro–Wilk test. Categorical variables are expressed as the number of observations (N) with the corresponding percentages (%), whereas quantitative variables as median and IQR. Pearson’s χ2 test was used to determine differences between categorical variables. If the number of cases were less than 5, Yates’s correction for continuity was used. Continuous variables were analyzed with a nonparametric test. The Mann–Whitney U test was used to compare two independent trials. Spearman’s rank correlation coefficient was used for assessment of correlation strength.All statistical analyses were performed using STATISTICA v. 14 software . A 2. Patients were diagnosed with various diseases, among others: arterial hypertension (83%), atrial fibrillation (AF) (5%), and stroke (7%). Furthermore, we assessed the frequency of chronic complications of DM, such as retinopathy (17%), neuropathy (10%), and diabetic foot syndrome (4%). Nearly two-thirds (66%) of the patients were either current or former smokers. As many as 15% of the patients were hospitalized due to CVD at least once in their lifetime. Family history of heart disease and DM were, respectively, reported in 49% and 66% patients. A total of 71 individuals with T2DM and no prior history of MI were enrolled in the study. There were 36 women (51%) and 35 men (49%) with a median age of 70 years (IQR 66–74). Baseline characteristics indicated that the median time elapsed since diagnosis with T2DM was 19 years (IQR 13–24). According to the results, the median BMI of the study population was 29.7 kg/mp = 0.918), as shown in 2, IQR 64–101) compared to subjects with normal diastolic function . Furthermore, none of the lipid parameters correlated with either normal or abnormal LV diastolic function. A lipid profile included measurements of TC , HDL-C , LDL-C , non-HDL-C , and TG .FGF23 was elevated in all patients . Interestingly, there was no significant difference in its levels between patients with LVDD and normal LV diastolic function , IVSs , and IVSd . However, no correlation was found between either normal or abnormal LV diastolic function and the following variables: LVEF, LVESV (left ventricular end systolic volume), LVEDV (left ventricular end diastolic volume), left atrial volume, LAVI , TAPSE (tricuspid annular plane systolic excursion), and RVOT (right ventricular outflow tract) proximal diameter.All patients underwent TTE evaluation. The echocardiographic findings are summarized in The parameters derived from 2DSTE are listed in p = 0.041), as shown in This study also assessed the utility of FGF23 with reference to cardiac strain. It revealed that an epicardial GCS correlated with FGF23 level regardless of LV diastolic function status  is an urgent health and social problem. It is estimated that HFpEF accounts for nearly 50% of all HF cases . It is pLVEF assessed in TTE is a cornerstone of cardiac function evaluation. Nonetheless, we must bear in mind that LVEF may remain preserved in the early stages of many heart diseases, despite actual impaired myocardial contractility. Many scientists suggest that the prognosis of patients with reduced and preserved LVEF is similar ,41. MyocInterestingly, there are a few articles presenting the relationship between myocardial strain and DM; however, the great majority of them concern LV LS, while CS was not explored or did not show any difference in a diabetic population. Flores-Ramírez et al. conducted a study of 121 diabetic patients including: 14 individuals with mildly reduced LVEF, 76 diabetics with preserved LVEF, and 31 controls . They shSeveral publications indicate that the underlying pathophysiology of systolic and diastolic dysfunction is aberrant calcium homeostasis ,52. AdenOne of the questions that interested us concerned a relationship between FGF23 and myocardial strain in a diabetic population. Our results revealed that epicardial GCS correlated significantly with elevated FGF23 level in a T2DM population, with a preserved LVEF, but confirmed LVDD. It is noteworthy that patients enrolled in our study had relatively good glycemic control, despite long-standing T2DM, preserved kidney function, and no previous history of MI. To our knowledge, no studies have so far explored this issue. Patel et al. evaluated the relationships of baseline serum FGF23 with cardiac magnetic resonance (CMR) measurements at a 10-year follow-up . They deAccording to the current state of the art findings and our findings, the incorporation of a new technique, such as 2DSTE in combination with FGF23, would increase the diagnostic sensitivity of subclinical myocardial dysfunction in asymptomatic patients with T2DM. The question arises whether GLS or GCS has better predictive value of adverse CV outcome in this population. Undoubtedly, GLS has become the most widely used strain parameter and has been considered a better risk predictor than LVEF. In the literature, one may find rather poor information about GCS as a tool for CV risk stratification, particularly in a diabetic population. FGF23 is another potent predictor of CV risk. Our results revealed that GLS and GCS were both diminished in all patients. However, only epicardial GCS correlated significantly with an elevated level of FGF23 in T2DM patients. Data from clinical trials are highly awaited in order to evaluate the role of GCS and FGF23 in patients with T2DM.The present investigation has certain limitations. Our study was limited by its sample size. Furthermore, FGF23 level might have been affected by numerous conditions. Moreover, its measurement might have been affected by technical problems. Finally, the normal range of FGF23 and GCS has not been established yet; therefore, their practical usefulness is limited. Diabetes mellitus is a global epidemic, frequently associated with an increased CV risk, resulting in significant cardiac morbidity and mortality. Early detection of HF is of paramount importance to a preventive approach aimed at enhancing outcomes in this population. Our study indicates that a cardiac strain is a reliable tool for a subtle myocardial damage assessment. Interestingly, the myocardial injury in patients with T2DM was found to be layer-specific and started from the epicardium. Furthermore, we showed that an elevated level of FGF23 was significantly associated with a reduced value of epicardial GCS among patients with long-standing T2DM. It is possible that FGF23 may become an early diagnostic marker of myocardial damage in patients with long-standing T2DM. Further larger investigations are essential to validate our findings. Estimation of calcium concentration would be a worthwhile subject of future research.


The mainstay of assessment of the fetal lungs in clinical practice is via evaluation of pulmonary size, primarily using 2D ultrasound and more recently with anatomical magnetic resonance imaging. The emergence of advanced magnetic resonance techniques such as T2* relaxometry in combination with the latest motion correction post-processing tools now facilitates assessment of the metabolic activity or perfusion of fetal pulmonary tissue in vivo.This study aimed to characterize normal pulmonary development using T2* relaxometry, accounting for fetal motion across gestation.Datasets from women with uncomplicated pregnancies that delivered at term, were analyzed. All subjects had undergone T2-weighted imaging and T2* relaxometry on a Phillips 3T magnetic resonance imaging system antenatally. T2* relaxometry of the fetal thorax was performed using a gradient echo single-shot echo planar imaging sequence. Following correction for fetal motion using slice-to-volume reconstruction, T2* maps were generated using in-house pipelines. Lungs were manually segmented and mean T2* values calculated for the right and left lungs individually, and for both lungs combined. Lung volumes were generated from the segmented images, and the right and left lungs, as well as both lungs combined were assessed.P=.003; P=.04; P=.003, respectively). Right, left, and total lung volumes were also strongly correlated with increasing gestational age .Eighty-seven datasets were suitable for analysis. The mean gestation at scan was 29.9±4.3 weeks (range: 20.6–38.3) and mean gestation at delivery was 40±1.2 weeks (range: 37.1–42.4). Mean T2* values of the lungs increased over gestation for right and left lungs individually and for both lungs assessed together (This large study assessed developing lungs using T2* imaging across a wide gestational age range. Mean T2* values increased with gestational age, which may reflect increasing perfusion and metabolic requirements and alterations in tissue composition as gestation advances. In the future, evaluation of findings in fetuses with conditions known to be associated with pulmonary morbidity may lead to enhanced prognostication antenatally, consequently improving counseling and perinatal care planning. This study was conducted to assess normal fetal pulmonary development across gestation using an advanced functional magnetic resonance imaging technique, T2*, potentially reflective of oxygenation and alterations in pulmonary tissue composition across gestational age.We demonstrated that mean T2* values increased between 20 and 38 weeks gestation.This study provides original motion-corrected morphologic and functional assessment of the antenatal fetal lung during normal development. This will form the basis for reference ranges to assess fetuses who may have compromised pulmonary growth and function.Normal lung development encompasses 5 principal stages and disruption at any of these time points can result in mortality or significant long-term pulmonary morbidity. Lung growth commences during the embryonic stage (3–7 weeks of development). This initial stage is characterized by vascularization and formation of smooth muscle within the airways, tracheal cartilage, and pleura. The second, pseudoglandular stage encompasses the 7 to 16-week period. During this time, formation of the conducting airways to the level of the terminal bronchioles is complete and 75% of bronchial branching has occurred.Current assessment of the fetal lungs in clinical practice is limited to the evaluation of size, most commonly using 2-dimensional ultrasound measures but also via 3-dimensional volumes derived either from ultrasound or magnetic resonance imaging (MRI).,,Fetal MRI is a rapidly evolving field and recent advances include bespoke techniques for both acquisition and analysis. These include the application of functional acquisition techniques, such as T2* relaxometry, as well as the emergence of sophisticated motion correction pipelines, including deformable slice-to-volume reconstruction (DSVR).This project aims to comprehensively assess fetal mean pulmonary T2* values across gestation in a large cohort of uncomplicated pregnancies to assess normal pulmonary development.A retrospective study was performed by selecting a control cohort from 3 studies , undertaken at St Thomas’ Hospital over a 4-year period from 2018 to 2022. Inclusion criteria included the following: women with singleton, uncomplicated pregnancies with no preexisting medical conditions who subsequently delivered their babies after 37 weeks’ gestation with no neonatal complications. Exclusion criteria for MRI included women who had claustrophobia or a recently sited metallic implant. Cases with a birthweight centile <3rd or >97th centile ,All women underwent imaging on a clinical 3T Philips MRI scanner using a 32-channel cardiac coil in a supine position.o. The field of view was set to 360 mm × (320–400) mm × (60–120) mm using a coronal imaging plane aligned to the scanner coordinates, to encompass the whole thorax and minimize artifacts from parallel imaging reconstruction techniques. The imaging protocol, including additional techniques such as diffusion MRI, dynamic imaging, and perfusion imaging, was completed within 1 hour in all cases and women were offered a break midway through.Anatomic imaging of the fetal thorax was performed using a T2-weighted single-shot turbo spin echo sequence acquired in 3 orthogonal planes focused on the fetal body and an additional whole uterus coronal plane.As previously described, an in-house Python script was used to generate T2* maps using mono-exponential decay fitting.Raw stacks used for reconstruction with satisfactory quality (where motion artifact was evident or the imaging of the thoracic region was incomplete were discarded) and where data for both lungs was available, were inspected and selected. The motion patterns obtained from the DSVR were applied to the spatially matched T2* maps. The resulting reconstructed images , which can be converted to centiles using normal distribution. Centiles were derived from converting lung T2* values to z-scores and yielded the following for the mean: 1.488884*+21.997645 and SD: 1.488884*−18.451005.Intraobserver and interobserver variability assessment of pulmonary T2* values, volumes, and their 95% confident intervals, were calculated using an absolute-agreement 2-way mixed-effects model in SPSS statistical package version 28.0.1 (SPSS IBM). Further statistical analysis was performed using Scipy in Python 3. Linear regression analysis was performed for lung volumes and T2* values in both lungs, as well as right and left lungs separately, to assess the relationship between gestational age and pulmonary parameters. In addition, parameters for the right and left lungs were compared. Ten of the women had a maximum of 2 scans during their pregnancies. We therefore accounted for serial measures by adjusting the standard errors and for clustering. The results remained significant, all demonstrating that both mean and standard deviation (SD) increase with gestation. In addition, we conducted an analysis, which led to a method for converting lung T2* to a Eighty-seven datasets were suitable for analysis. Eighteen were excluded as follows: 3 owing to incomplete clinical outcome data; 7 owing to significant motion corruption, for which the motion correction pipelines could not compensate; and 3 owing to incomplete imaging of the fetal thorax  . MaternaP=.0001; slope=1.61; intercept=19.61; R2=.13), right lung  and left lung  (P<.001), right lung (P<.001) and left lung (P<.001).). Visual inspection of the maps reveals increasing heterogeneity with gestation )   and 5. S R2=.11)  ) .Figure 4Intraobserver and interobserver variability was good for both volume and mean T2* values. Intraobserver variability had an intraclass correlation coefficient of 0.989 for volume and 0.998 for mean T2* and interobserver variability had an interclass correlation coefficient of 0.951 for volume and 0.997 for mean T2*.In 87 healthy pregnancies, we have demonstrated that antenatal mean pulmonary T2* values increase with increasing gestational age between 20 and 38 weeks gestation in right and left lungs separately, and both lungs combined. Pulmonary volumes were also found to increase with gestation with lower volumes in the left lung compared with the right .These findings are in contrast with the only previously published study assessing pulmonary T2* values in the antenatal period.Unlike previous studies which utilized T2* to assess fetal lungs; and other structures, such as the brain,T2* values are obtained from the combined effects of spin-spin relaxation (T2) and magnetic field inhomogeneity,As gestation progresses, an increasing proportion of cardiac output is directed to the fetal lungs,A diverse range of processes are known to alter the MR properties of pulmonary parenchyma across gestation. Developmental processes include angiogenesis, development of the alveoli and bronchioles, and alterations of pulmonary tissue content. These require cellular proliferation and differentiation associated with an increased metabolic demand and tissue perfusion. In addition, the fluid composition of the lungs also alters with gestation, lung fluid secretion decreases, and sodium transport dependent resorption increases, which facilitates gaseous exchange after birth.The pulmonary volumes obtained in our study were lower than previously reported;This study characterizes pulmonary development across gestation using mean T2* encompassing 87 healthy pregnancies between 20.6 and 38.3 weeks gestation. Utilizing DSVR post-processing pipelines facilitated correction for motion and distortion deterioration. We have demonstrated excellent reliability scores, making this technique reproducible and valuable for future applications. However, assessment of pulmonary T2* values, provides an indirect assessment of tissue perfusion only and the application of DSVR may also alter the mean values of T2* owing to interpolation effects applied during the super resolution as it attempts to reconstruct the original scene image with high resolution. Although a large gestational age range has been encompassed within this study, no datasets were included before 20 weeks or after 39 weeks gestation. Further work focusing on these periods should be conducted to provide a complete assessment of in utero pulmonary development. It should also be noted that most women who participated in this study are White. It is therefore imperative that further work should assess a diverse population to ensure that findings are applicable to all ethnic groups.Our results have given functional insight into pulmonary development potentially reflecting increased perfusion and metabolic activity of tissue as gestation advances. Investigation of fetuses at high risk of pulmonary morbidity using these techniques will be required to assess if alterations in pulmonary T2* values are associated with pathology. If this is found to be the case, the role of T2* as a prognostic marker can then be assessed.


Of the existing non-invasive diastolic indices, none consider arterial load. This article reveals points of caution for determining the diastolic prognostic index using a novel index of vascular resistance-integrated diastolic function in old, real-world patients with heart failure with preserved ejection fraction (HFpEF) in Japan. This index represents the ratio of left ventricular diastolic elastance (Ed) to arterial elastance (Ea), where Ed/Ea = (E/e′)/(0.9 × systolic blood pressure), showing a relative ratio of left atrial filling pressure to left ventricular end-systolic pressure. The role of hemodynamic prognostic factors related to diastolic function, such as Ed/Ea, may differ according to the clinical endpoint, follow-up duration, and sex. In HFpEF patients with heterogenous cardiac structure and function, an assessment using a serial echocardiographic diastolic index in clinical care can provide an accurate prognosis.  The circadian pattern of blood pressure is mainly affected by autonomic nerve activity. Changes that occur throughout the day affect the cardiovascular system, possibly leading to various alterations in cardiac function, including diastolic function, based on the time and circumstances. Doppler echocardiography is the most useful tool for routinely measuring diastolic function noninvasively. According to the recommendations for left ventricular (LV) diastolic evaluation using echocardiography, the severity of diastolic dysfunction is assessed using a combination of several indices for the left and right sides of the heart, including E/A, deceleration time, E/e′, tricuspid regurgitation velocity, left atrial (LA) strain pattern, and LA volume ,2,3. TheHistorically, HFpEF has been thought to be driven by increased afterload in arterial stiffness and hypertension, with consequential LV diastolic dysfunction as one of the hallmarks of the syndrome. Early studies suggested that, in the clinical setting, E/e′ is a marker of reduced LV long-axis early diastolic expansion, that is, one of the markers of LV diastolic function, resulting in an estimated LA filling pressure ,10. The Increased LV filling pressure owing to exercise correlates with changes in the diastolic relaxation rate and arterial afterload ,21. The We recently reported that the LA volume index and Ed/Ea are high in patients with HFpEF . Ed/Ea rThe pathophysiology of HFpEF is complex and includes alterations in cardiac structure and function, systemic and pulmonary vascular abnormalities, and comorbidities . HFpEF iThe prognostic factors related to LA overload may differ according to the clinical endpoint in older patients with HFpEF . Ed/Ea aThe prognostic significance of Ed/Ea may only be valid over a short-term period in older patients. Ed/Ea assessed before discharge was a significant prognostic factor for all-cause mortality during the first, but not the second, year after discharge . In landArterial stiffness may preferentially contribute to abnormal diastolic function during exercise in women with HFpEF compared with men . OriginaThe significance of Ed/Ea as a prognostic risk factor may be reduced in HFpEF patients with AF because the calculation of Ed/Ea is based on the correct measurement of E/e′, which should be carefully and precisely measured. The incidence of AF did not differ significantly in our patients (38%)  comparedBecause all of the study populations using our proposed index for prognostication included those with hospitalization only, this limits the generalizability of our findings to HFpEF outpatients with no history of hospitalization. The possible clinical utility of this unique index is expected to reveal older, symptomatic outpatients with HFpEF and “pre-HFpEF” outpatients without symptoms ,52. The The assessment of arterial load and ventricular–vascular coupling provides important physiological information and is increasingly used in clinical and epidemiological human research. However, the limitations of this study must be considered. The currently available data are limited, which limits our conclusions. Aside from sex differences found in non-HF patients showing natural differences between sexes in the Ed/Ea index , the scaOur novel index of vascular resistance-integrated diastolic function, Ed/Ea = (E/e′)/(0.9 × systolic blood pressure), was valid and useful for evaluating the prognosis of elderly patients with HFpEF. However, factors such as the clinical endpoint, the follow-up duration, and sex may influence the prognostic significance of Ed/Ea. In clinical care, a serial noninvasive index such as Ed/Ea can provide an accurate assessment of the occasional prognosis of patients with HFpEF.Prognostic findings were obtained from the PURSUIT HFpEF  registry . The PUR


Al Rifai 1 In patients with recurrent symptoms after revascularization, stress imaging can reveal myocardial ischaemia as the underlying cause of symptoms and provides prognostic information. In a meta-analysis including a total of 12 874 symptomatic or asymptomatic patients with a history of revascularization, abnormal results at nuclear myocardial perfusion imaging (MPI) or stress echocardiography were associated with an average of two-fold risk of cardiac events.2 More recently, the presence of inducible ischaemia on stress perfusion cardiac magnetic resonance was found an independent predictor of cardiovascular events after CABG.3Patients remain at risk of cardiovascular events after coronary artery bypass graft surgery (CABG) that is partly related to the progression of coronary artery disease (CAD) in native coronary arteries and bypass grafts.4 Furthermore, impaired MBF and myocardial flow reserve (MFR) in response to vasodilator stress is a strong prognostic marker.5 In patients with prior CABG, the ischaemic burden on PET provides prognostic information in predicting all-cause mortality and cardiac deaths.6 However, the prognostic value of MFR assessed by PET is unclear in this population.Positron emission tomography (PET) myocardial perfusion imaging accurately detects obstructive CAD. Measurement of myocardial blood flow (MBF) in absolute units  using PET can improve the diagnostic evaluation of CAD over relative perfusion differences.et al.7 report the prognostic value of MFR in a cohort of 836 patients with a history of CABG who underwent rest-stress 82Rb PET MPI due to a clinical indication for evaluation of ischaemia. Up to 66% of patients had MFR <2, a pre-defined cut-off value for abnormal MFR.4 Patients with abnormal MFR were older and more often men, hypertensive and diabetic, had lower left ventricular ejection fraction (LVEF), and were more likely to have scar or regional inducible ischaemia. Over a median follow-up time of 12 months, 122 patients suffered an adverse event, including 46 heart failure admissions, 28 all-cause deaths, 23 myocardial infarctions, and 25 unplanned late revascularizations. Reduced MFR was a predictor of outcome in adjusted analyses on top of early revascularization, clinical variables, and other PET parameters, including LVEF, LVEF reserve, regional perfusion defects, and transient ischaemic dilatation. Patients with abnormal MFR had a higher rate of the composite outcome  than those with normal MFR; the cumulative incidence of events being 18.4 vs. 7.1%.Al Rifai 8 In the study of Al Rifai et al., both regional ischaemia and abnormal MFR were common findings in patients with a history of CABG.7 However, there was no interaction between ischaemia and MFR in predicting the outcome, and MFR was prognostic irrespective of the presence of scar. Thus, regional perfusion abnormalities and MFR may identify different prognostic phenotypes and have implications for the selection of therapy. Observational studies have found that the reduced MFR may identify patients with survival benefit from early revascularization when compared with medical therapy.9 Such a study requires a large patient cohort and remains to be studied in patients with a history of CABG in whom the decision to proceed with repeat revascularization requires careful weighing of the risks and potential benefits. The use of evidence-based medical therapy is strongly associated with favourable outcomes after myocardial revascularization,10 and there is also an interest in reduced MFR as a potential target for novel therapies.8Impaired MFR may be due to obstructive epicardial CAD, diffuse CAD, or microvascular dysfunction.11 Hybrid imaging with coronary CTA and stress MPI has been shown to provide useful complementary information in patients with a history of CABG enabling the integration of myocardial perfusion abnormalities with the anatomy of subtending coronary arteries or bypass grafts.13In patients with a history of CABG, incomplete revascularization, occlusion of bypass grafts, and progression of CAD in the native coronary arteries can contribute to the presence of residual ischaemia. Coronary computed tomography angiography (CTA) has been shown to accurately identify stenosis in both venous and arterial bypass grafts. The presence of coronary artery territories supplied by an obstructed native coronary artery in the absence of patent bypass graft, or obstruction of a coronary artery distal to the graft insertion, predicts adverse cardiac events in patients with a history of CABG.14 A study found that impaired MFR is independently associated with diastolic dysfunction and risk of heart failure hospitalization in patients with preserved LVEF.15 Notably, in the study of Al Rifai et al., reduced MFR showed a particularly strong association with heart failure admissions (hazard ratio 2.92).7 Furthermore, both LVEF and MFR were significant predictors of the primary outcome in the adjusted model.Coronary microvascular dysfunction often co-exists with epicardial CAD, but is also common in the absence of CAD in patients with various forms of cardiomyopathy and heart failure with either reduced or preserved LVEF.et al. extends the evidence regarding the prognostic value of reduced MFR in CAD to patients with a history of CABG, suggesting that MFR may provide incremental risk prediction beyond regional myocardial ischaemia and LVEF. The study encourages further evaluation of the value of MFR in optimizing therapies to improve outcomes after myocardial revascularization.The study of Al Rifai