Animal models for myocardial injuries represent important cornerstones in cardiovascular research to monitor the pathological processes and therapeutic approaches. We investigated the association of 18F-FDG derived left ventricular metabolic volume (LVMV), defect area and cardiac function in mice after permanent or transient ligation of the left anterior descending artery (LAD).d-glucose positron emission tomography (18F-FDG PET) after permanent or transient LAD ligation enabled a longitudinal in vivo correlation of 18F-FDG derived left ventricular metabolic volume to functional parameters and myocardial defect.Serial non-invasive ECG-gated 2-deoxy-2-[18F]fluoro-The LVMV shows a more prominent drop after permanent than transient LAD ligation and recovers after 30 days. The loss of LVMV correlates with the defect area assessed by QPS software. Cardiac function parameters  by the QGS software positively correlate with LVMV after permanent and transient LAD ligation.This study provides novel insight into 18F-FDG derived LVMV after permanent and transient LAD ligation by longitudinal in 18F-FDG PET imaging and underlines the associations of the FDG derived parameter and cardiac function.The online version contains supplementary material available at 10.1007/s12149-022-01734-8. Coronary artery disease (CAD), the manifestation of pathological accumulation of atherosclerotic plaques in cardiac arteries, is a leading cause of morbidity and mortality in western society .Narrowing the coronary arteries over time and rupturing atherosclerotic plaques result in myocardial injury by the diminished heart blood supply. Loss of cardiac muscle tissue leads to decreased cardiac function and can progress to heart failure with detrimental effects on the patient’s health. Percutaneous coronary intervention (PCI), a minimally invasive procedure to recanalize the occluded artery, facilitates reperfusion of the ischemic cardiac tissue and has significantly improved the outcome of patients after myocardial infarction .To further reduce mortality and morbidity after ischemic cardiac injury, basic animal models are essential to understand the pathological processes better and transfer new therapeutics into the clinical setting. Nowadays, two surgical myocardial infarction models in mice are established to mimic cardiac injury , 4. PermBesides cardiac magnetic resonance imaging, which is another valuable tool in mice as demonstrated by several investigators –8, the sRegardless of a large amount of published data in the setting of ischemic cardiomyopathy, our study is the first to evaluate the association of LVMV and cardiac function after transient and permanent LAD ligation.n = 10) or transient (n = 9) ligation of the left anterior descending artery, as described previously [n = 8). In brief, mice were anaesthetized using intraperitoneal injection of fentanyl (0.05 mg/kg), midazolam (5.0 mg/kg), and medetomidine (0.5 mg/kg), and mechanically ventilated . After left lateral thoracotomy, the proximal LAD was either ligated permanently (inducing MI) or transiently for 60 min, inducing IR injury. Study protocols complied with the institution’s guidelines and were approved by the Government’s animal ethics committee (ROB-55.2-2532.Vet_02-19-17 and ROB-55.2-2532.Vet_02-19-1).Male C57/BL6 mice were purchased from Charles River . Animal care and all experimental procedures were performed according to the Guideline for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health . Myocardial infarction and ischemia–reperfusion injury were induced in 12–16 week-old C57BL/6 mice by surgical permanent  and water, as described previously [ECG-gated 18F-FDG-PET scans were performed on post-operation day 6 and day 30, using a dedicated small-animal PET scanner  as described previously , 14. Theeviously , 12–15. eviously . After pAnalysis of PET images was performed by the Inveon Research Workplace  described previously , 18.Inveon Research Workplace was used for assessing the percentage of the cardiac injected dose per gram (%ID/g) and left ventricular metabolic volume (LVMV) from static PET images. A cubic volume of interest (VOI) was drawn around the left ventricle, and a threshold value excluding 30% of the least hot voxels was applied. Correct VOI placement was verified in three projections  . In addi®  using a normative database, as described previously [® 2012) from static FDG PET scans by creating polar maps of the left ventricle. In this approach, the FDG uptake in a given region is quantified as the percentage of the maximum tracer uptake in the polar map. The individual polar map is then compared to the average polar map from our normative database consisting of gender, strain, and age-matched animals . The extent of the abnormally viable myocardium is calculated as a percentage of the left ventricle surface area.The defect parameter was calculated with QPSeviously . In brieFurthermore, the severity of the injured cardiac tissue is calculated in units of standard deviations below the normal tracer uptake. Extent and severity are combined into a single parameter corresponding to the infarct size expressed as a percentage of the left ventricular surface area. We used a similar approach as described by Slomka et al.  for myoc® , as described previously [Left ventricular function parameters: end-diastolic (EDV), end-systolic (ESV) and the stroke volume (SV), and the left ventricular ejection fraction (EF), were calculated from ECG-gated images using QGSeviously , 17.On day 30, mice were sacrificed, and the hearts were excised. After fixation in 4% phosphate-buffered formalin, hearts were cut into 2 mm thick slices and embedded in paraffin. Five micrometer thick sections were cut and mounted on positively charged glass slides. Standard histological procedure (Sirius Red/Fast green Staining) was performed as described previously .t tests were used where appropriate. For groups without normal distribution, the Wilcoxon signed-rank or the Mann–Whitney U test was applied. The differences were considered statistically significant at a P value of 0.05.All results were expressed as means with standard deviation. One-way ANOVA analysis with Tukey’s multiple comparisons, unpaired Student’s The mouse hearts were evaluated using 18F-FDG PET imaging at days 6 and 30 post-transient or permanent LAD ligation. The defect assessment revealed a substantial defect in both models.p <  0.001). Figure Permanent LAD ligation results in larger defect areas than transient ligation  and the MI model .Neither after permanent nor after transient LAD ligation, a relevant change in the defect could be detected from day 6 to day 30 . Figure Serial cardiac PET imaging enabled evaluating the left ventricular metabolic volume (LVMV), which is an 18F-FDG derived parameter  and the p = 0.019; control vs MI d6, p <  0.001, Fig. p = 0.004). Regarding the %ID/g change, we could not detect any significant alterations from day 6 to day 30 . No difference in LVMV in the two injury models after 30 days was observed .We observed increased LVMV in both models at day 30 . Of note, we could not detect any difference in the maximum injected dose in the heart .Comparing the defect and the change in LVMV displayed a significant correlation after permanent LAD ligation .We detected an increased EDV on day 6 after permanent LAD ligation compared to the control and the transient ligation . The EDV in the reperfusion model increased but not achieve statistically significance over time .At day 30, the EDV further increased after MI, demonstrating ongoing LV dilatation .The SV decreased after MI at day 6 , ESV , and negative correlation to EF  underlining the methods itself are displayed in the supplement.Furthermore, we could detect no improvement in the EF after 30 days of follow-up . Correlations of the cardiac function to the histological defect such as positive correlation to EDV , ESV  and SV  , ESV , and SV .After transient LAD ligation, we as well detected several positive correlations: EDV  provides new insight into this parameter. Thus, increasing cardiac volume could be related to higher LVMVs. The correlation of EDV and ESV to LVMV indicated the utility of this parameter to monitor the volume remodelling after myocardial infarction by either permanent or transient LAD ligation. While there is a negative correlation of EF in the IR group, no correlation could be observed after permanent LAD ligation. The LV dilation and therefore the cardiac remodelling after permanent LAD ligation is by far more prominent, which might result in dilated hearts with a persistent lower EF compared to the transient LAD ligation with re-established perfusion and a decent dilations and preserved EF. Therefore, the LVMV should be carefully assessed as it might be affected by the extent of myocardial damage. It remains a possible limitation of this parameter, that volumes might be correlated, while the ejection fraction might be affected by other intracellular changes in cardiomyocytes or structural alterations (e.g.: myofibrils or sarcomere composition). Estimation of the LVMV from static images and correlation towards gated images could further represent a technical limitation. Calculating the LVMV in each frame after gated reconstruction without the technical averaging in static pictures could be a future directive.If this parameter could provide the beneficial insight in rats and pigs or can also be translated into other tracers remains to be elucidated in future investigations.Our study suffers from several limitations.Both models bear the limitation of using healthy and young mice to compensate for the loss of viable tissue. Humans develop coronary artery disease while ageing and the erupting coronary plaques occur later in life.Further, we did not evaluate the metabolic shifts in substrate difference after cardiac injury , 32, whiThis study provides new insight into the 18-FDG derived parameter LVMV and cardiac function in longitudinal PET imaging in two mouse models of myocardial infarction.Supplementary file1 (DOCX 57 KB)Below is the link to the electronic supplementary material.


Innovation is fundamental in medicine because it enables researchers to overcome the hurdles related to pathologies. This Research Topic was initiated by Iacoviello et al. and published in 2022 in Frontiers in Cardiovascular Medicine. The collection aims to bring together original research or review studies on innovations in the treatment of chronic heart failure (CHF) as a principal aim or target.Novelties in heart failure drug therapy. Over the last few years, a number of new classes of drugs have been demonstrated to further improve HF patients' prognosis and are currently recommended  and evaluated the effects of SGLT2i on major cardiovascular, renal, and heart failure events. The results add new information about the SGLT2i by demonstrating the superiority of the combination of SGLT2i and inhibition of the renin angiotensin system when compared with the inhibition of the renin angiotensin system alone in reducing cardiorenal events.ommended . In partommended . The metLi et al. analyzed data from two main trials evaluating the effects of SGLT2i in patients affected by CHF with reduced ejection fraction (HFrEF), i.e., DAPA-HF and EMPEROR-reduced, and in those affected by CKD, i.e., DAPA-CKD. SGLT2i significantly reduced cardiorenal events, i.e., hospitalization for heart failure and kidney-specific composite outcome, and increased quality of life, as evaluated by Kansas City Cardiomyopathy Questionnaire, without showing any significant increase in events related to adverse effects such as the risk of volume depletion, fracture, amputation, major hypoglycemia, and diabetic ketoacidosis.The effects of SGLT2i are even more striking when the efficacy and safety of SGLT2i in diabetic and non-diabetic patients affected by CHF or chronic kidney disease (CKD) are considered. The metanalysis of Correale et al. shows new perspectives on HF therapy, mainly focusing on new therapeutic targets such as microcirculation, cardiomyocyte, and inflammation.Despite the effects of the new pharmacological therapeutic approaches, the prognosis of patients remains poor. For this reason, there is a need to identify new therapeutic targets able to personalize and further improve HF prognosis. The review by Passantino et al. reported the most recent principles of exercise prescription for CHF patients, which are to obtain meaningful clinical results, without increasing the risk of adverse events.Besides drug therapy, exercise based cardiac rehabilitation is an approved approach that aims to improve the functional capacity of HF patients. The relevance of comorbidities. Some comorbidities are common in patients with heart failure and affect clinical outcomes. With an elegant experimental design, Hong et al. demonstrated the impact of obstructive sleep apnea on heart function in patients with dilated cardiomyopathy. The suggested mechanism of injury is related to exosomes regulated autophagy .Rizzo et al. The physiopathological, clinical, and prognostic consequences of iron deficiency (ID) are summarized, along with the main results of the FAIR-HF, CONFIRM-HF, and AFFIRM AHF studies, that demonstrated significant improvements in symptoms, quality of life, and clinical outcome after intravenous iron supplementation with ferric carboxymaltose.The clinical benefit of the treatment of another prevalent comorbidity in CHF is reported by Yi et al. that analyzes the association between HF and COVID-19. A deep compression of mechanisms of heart failure in COVID-19 patients is mandatory to identify targets for future therapeutic interventions and reduce the incidence of heart failure and improve outcomes in patients with COVID-19.ID is now unanimously considered a new therapeutic target in heart failure patients. We cannot overlook the ominous association between heart failure and COVID-19 and have included a paper by What is new, from the electrophysiology standpoint. Innovation usually starts from an idea and needs to be tested in an experimental setting. For this reason, we have also included a paper by Zhao S. et al. on “Novelties in the Therapeutic Approaches for Chronic Heart Failure.” Myocardial infarction is one of the most common causes of heart failure: the transition from acute myocardial infarction to chronic heart failure is often unpredictable and is delayed by the established pharmacological and non-pharmacological treatment of heart failure. The authors of this interesting paper focused research efforts on a new non-pharmacological treatment of heart failure, left vagal nerve stimulation. They tested a low level of stimulation, i.e., a level which does not cause significant bradycardia. Routinely used in patients with refractory chronic heart failure as one of the very last therapeutic options , seems to be a promising innovative treatment for pulmonary hypertension, at least in the experimental context. Martin et al. studied the effect of relaxin on sugen related pulmonary arterial hypertension in a group of rats, with a particular focus on the incidence of ventricular arrhythmia and sinus node dysfunction. The authors demonstrated that relaxin reverses the fibrosis process associated with right ventricular hypertrophy and pulmonary arterial hypertension, which significantly reduced right ventricular remodeling and reduced the incidence of spontaneous and induced life threatening ventricular arrhythmias. The strengths of the present study are the presence of a control group and the use of two different doses of relaxin. The last option furthered understanding by indicating that the effect of relaxin is dose-dependent, since the best effects were obtained when the blood concentrations of relaxin were in the range of 15 ng/mL. Thanks to the immunochemistry results, the authors showed that relaxin favors an increase of beta-catenins at the level of the intercalated disks, favoring better connections of myocardial cells and explaining the higher conduction velocities.Another research study published in this Research Topic, on novel heart failure concerns relaxin , deployed in patients with CHF receiving an Abbott® cardiac resynchronization therapy device. This algorithm enables it to adapt dynamically to the programmed atrioventricular delay and was demonstrated in combination with biventricular pacing to significantly narrow the QRS duration. The authors sought to investigate the effect of this algorithm on left ventricular remodeling assessed with echocardiography and on NYHA class. One hundred twenty-two patients were consecutively enrolled by Wang Y. et al. and separated into two well-balanced groups according to the use of the mentioned SyncAV algorithm. The patients in whom the SyncAV algorithm was added to the biventricular pacing obtained an acute improvement of the hemodynamics calculated by aortic VTI and subsequently a better echocardiographic and clinical response at mid-term follow-up. The authors should be congratulated for having designed a very simple study with clear endpoints. The paper is an easy read and confirms once more how cardiac resynchronization therapy could be empowered through novel algorithms that allow more physiological pacing. The main limitation of the study was the lack of randomization. The authors overcame this flaw by performing a propensity score matching within the two groups and confirming the original results.The last and third paper included in the arrhythmology section of the Research Topic concerns the use of a novel pacing algorithm called “SyncAV” (Research in chronic heart failure is a continuous endeavor. We hope to have contributed to these efforts with this Research Topic, opening new treatment pathways that will potentially increase the survival rate of patients with heart failure.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Level of Difficulty: Advanced.)Acute afterload mismatch and left ventricular dysfunction after mitral valve repair are well established. The impact of transcatheter tricuspid valve repair (TTVr) on right ventricular (RV) function is less clearly defined. To our knowledge, there are no reports of acute RV dysfunction after TTVr. Here we report a case of acute afterload mismatch after successful TTVr. (  Guideline-directed medical therapy was initiated, but effective dosing was limited by hypotensive episodes. The patient reported ongoing New York Heart Association (NYHA) functional class III dyspnea, and there was clinical evidence of volume overload.The transthoracic echocardiogram (TTE) showed normal left ventricular (LV) size and systolic function. The right ventricle was severely dilated with mildly reduced systolic function . Severe functional TR caused by annular dilatation and leaflet tethering was noted. The transesophageal echocardiogram (TEE) demonstrated TR in the anteroseptal commissure extending centrally. Cardiac catheterization revealed patent coronary arteries and elevated filling pressures with mean right atrial pressure of 10 mm Hg and v waves of 20 mm Hg, postcapillary wedge pressure was 19 mm Hg, pulmonary artery pressure was 46/22 mm Hg, mean 31 mm Hg, and LV end-diastolic pressure was 18 mm Hg. The cardiac index was 2.6 L/min (Fick).The multidisciplinary heart team evaluation deemed the patient a good candidate for transcatheter tricuspid edge-to-edge valve repair. A TriClip XTW (Abbott Cardiovascular) was implanted centrally between the anterior and the septal leaflets, which abolished the TR  and 2. IHer past medical issues includes heart failure with preserved ejection fraction, atrial fibrillation, and chronic kidney disease.The following causes of acute hypotension were considered: acute occult bleeding, pericardial tamponade, acute RV failure, arrhythmia, acute coronary syndrome, and pulmonary embolism.Almost immediately after clip implantation, the TEE demonstrated sudden worsening of the RV function  and 4. IAfter cumulative administration of 200 μg of phenylephrine and intravenous saline bolus, the patient’s blood pressure recovered to baseline within 5 minutes, and the RV function improved from severe to moderate dysfunction. A well-seated clip was confirmed on TTE the following day, which demonstrated trace TR and moderately reduced RV systolic function . The patient remained normotensive and clinically improved and was discharged home without complications.The systolic performance of the heart is determined by 3 factors: preload, afterload, and contractility, as described in the Frank-Starling law. Afterload is defined as the total force that opposes sarcomere shortening minus the stretching force that existed before contraction. The stroke volume decreases as the afterload increases. Moreover, a simultaneous increase in end-systolic volume further decreases stroke volume. The implantation of a tricuspid clip leads to a rapid increase in RV afterload because the regurgitant orifice into the low-pressure right atrium is abruptly eliminated. The concept of a decline in LV function caused by afterload mismatch after transcatheter mitral valve repair is well described.,In our case, the increase in afterload resulting from TTVr led to acute, reversible RV dysfunction and hypotension. The impact of RV dysfunction in patients undergoing TTVr is still a matter of debate, and published reports are mainly focused on preinterventional RV function as a predictor of outcome.At 1-month follow-up, the patient’s symptoms have significantly improved. She is enjoying an NYHA functional class I functional capacity, and follow-up TTE demonstrated trace TR and mild RV dysfunction .TTVr may lead to an acute reduction in RV function resulting from abrupt changes in the intracavitary pressure. Operators and anesthesiologists should be aware of this potential complication and be prepared to provide timely hemodynamic support. The long-term clinical impact of afterload mismatch after TTVr remains to be determined.Dr Hagemeyer has reported financial support from the Gottfried und Julia Bangerter-Rhyner-Stiftung. Dr Fam has consulted for Abbott and Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.


Heart failure (HF) is a global disease with increasing prevalence in an aging society. However, the survival rate is poor despite the patient receiving standard treatment. Early identification of patients with a high risk of HF is important but challenging. Left ventricular end-diastolic diameter (LV-D) increase was an independent risk factor of HF and adverse cardiovascular (CV) outcomes. In this study, we aimed to develop an artificial intelligence (AI) enabled electrocardiogram (ECG) system to detect LV-D increase early.We developed a deep learning model (DLM) to predict left ventricular end-diastolic and end-systolic diameter (LV-D and LV-S) with internal and external validations and investigated the relationship between ECG-LV-D and echocardiographic LV-D and explored the contributions of ECG-LV-D on future CV outcomes.Electrocardiograms and corresponding echocardiography data within 7 days were collected and paired for DLM training with 99,692 ECGs in the development set and 20,197 ECGs in the tuning set. The other 7,551 and 11,644 ECGs were collected from two different hospitals to validate the DLM performance in internal and external validation sets. We analyzed the association and prediction ability of ECG-LVD for CV outcomes, including left ventricular (LV) dysfunction, CV mortality, acute myocardial infarction (AMI), and coronary artery disease (CAD).HRs) of developing new onset LV dysfunction , CV mortality , new-onset AMI , and CAD  in the internal validation set. In addition, the ECG-LV-D presents a 1.88-fold risk (95% CI 1.47–2.39) on new-onset LV dysfunction in the external validation set.The mean absolute errors (MAE) of ECG-LV-D were 5.25/5.29, and the area under the receiver operating characteristic (ROC) curves (AUCs) were 0.8297/0.8072 and 0.9295/0.9148 for the detection of mild (56 ≦ LV-D < 65 mm) and severe (LV-D ≧ 65 mm) LV-D dilation in internal/external validation sets, respectively. Patients with normal ejection fraction (EF) who were identified as high ECHO-LV-D had the higher hazard ratios (The ECG-LV-D not only identifies high-risk patients with normal EF but also serves as an independent risk factor of long-term CV outcomes. Heart failure (HF) is a common clinical entity with increasing prevalence in an aging society, which affects 5.7 million patients and more than 870,000 new cases are diagnosed in the United States every year . In deveIn patients with HF, there were several important parameters for the assessment of cardiac functional and structural changes. As EF was the ratio of blood leaving heart each time it contracts, the left ventricular end-diastolic diameter (LV-D) and end-systolic diameter (LV-S) influenced the value of ECHO-EF. The principal ECG changes in patients with increased LV-D and LV-S in LV hypertrophy include augmented QRS amplitude, prolonged QRS conduction time, changes in instantaneous and mean QRS vectors, ST depression and/or T-wave inversion, and P-wave abnormalities, such as left atrial enlargement , 8. VF fArtificial intelligence-based ECG (AI-ECG) has expanded to multiple applications and achieved human-level performance, effectively detecting cardiac diseases with large annotated ECG datasets, including echocardiogram predictions , 21, arrHowever, the discrepancy between ECG-EF and ECHO-EF was not fully interpreted. ECHO-EF is evaluated regularly in echocardiography, similar to other cardiac structure measurements, such as LV-D, LV-S, interventricular, and posterior wall thickness. With the aid of AI-ECG, we hypothesized that AI-ECG predicting LV-D (ECG-LV-D) may provide additional information on CV outcomes in patients with initially normal ECHO-EF, who are recognized as low ECG-EF. Therefore, the aim of this study is to build a deep learning model (DLM) to predict LV-D and LV-S and verify the accuracy by echocardiography in two independent hospitals. Finally, we tried to apply ECG-LV-D in different clinical scenarios and acquire additional information on the prediction of future CV diseases.This multicenter retrospective study was ethically approved by the institutional review board of Tri-Service General Hospital, Taipei, Taiwan (IRB NO. C202105049). The electronic medical records (EMRs) of our hospital included digital ECG signals, echocardiography images, hospital courses records, and future outcomes between 1 January 2010 and 31 September 2021. We identified patients who had at least one pair of 12-lead ECG and transthoracic echocardiography (TTE) records within 7 days. Subjects with inadequate ECG or echocardiographic information were excluded, such as noise interference, leads dislodge or dislocation, data loss of heart rate, EF, LV-D, or LV-S. The remaining ECGs were annotated by TTE information collected in this study. Finally, there were 75,942 patients in NeiHu General Hospital at NeiHu District , an academic medical center in our hospital system, and 11,633 patients in Tingzhou Branch Hospital at Zhongzheng District , a community hospital .We divided ECGs into development, tuning, internal validation, and external validation sets by different dates and hospitals. For DLM training, there were 99,692 ECGs from 60,790 patients included in development set and 20,197 ECGs from 7,601 patients were included in tuning set. We only used the first records in the validation step for the patients with multiple ECG-TTE pairs, and the internal and external validation sets included 7,551 ECGs before 31 December 2015 in hospital A and 11,644 ECGs in hospital B. No repeated patients were recruited into more than one group.The ECGs were acquired at a sampling rate of 500 Hz with a 10-s period using a Philips 12-lead ECG machine . Comprehensive 2D ECG and quantitative data were recorded at the time of the acquisition in a Philips image system for all patients. The LV parameters included EF, LV-D, and LV-S, which were routinely acquired by experienced cardiologists or technicians using standardized methods. The EF was assessed using the Simpson method, M-mode, and the reported visually estimated EF. LV dimensions and wall thickness were measured by M mode under para-sternal long axis view and recorded by millimeter. The cut-off values of EF are 50 and 35% as mild and severe LV dysfunction, which are comparable criteria described in previous studies , 36, 37.The demographic characteristics were obtained in our EMRs and disease history before the index date of ECG was collected using the corresponding code of International Classification of Disease, Ninth Revision and Tenth Revision , as described previously , 32, 44.According to the promising ability of disease previvor identification by AI-ECG, we analyzed the correlation between ECG-LV-D increased and new-onset LV dysfunction, defined as ECHO-EF ≤ 35. Moreover, patients’ data were censored at the last known TTE examination to limit bias from incomplete records. In addition to LV dysfunction, we followed and analyzed other three CV outcomes, including CV mortality, new-onset acute myocardial infarction (AMI), and new-onset coronary artery disease (CAD). CV mortality included arrhythmia-related death, acute coronary syndrome-related death, stroke death, and HF-related death. These outcomes were censored at the patient’s last known hospital alive encounter without corresponding events to limit bias from incomplete records. The end of follow-up in this study was 30 September 2021 for all the above outcomes.The ECG-based EF, LV-D, and LV-S were, respectively, considered as function score and structure status of the heart, both estimated by DLMs. The ECG12Net architecture with 82 convolutional layers and an attention mechanism was used for estimation and the technology details, such as model architecture, data augmentation, and model visualization, were described previously . We usedp < 0.05. We used scatter plots to describe the predicted value by ECG voltage-time traces compared with actual EF and left ventricular diameters (LV-D/LV-S). The accuracy of DLMs was evaluated by mean difference (Diff), Pearson’s correlation coefficients (r), and mean absolute errors (MAEs), calculated in both internal and external validation sets. The diagnostic value of DLMs was measured with the receiver operating characteristic (ROC) curve and the area under the curve (AUC). The tuning set was used to decide the operating point based on the maximum of Yunden’s index, which was calculated for the corresponding sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) in both validation sets. To identify the underlying subtype of patients with no correspondence between ECG-EF and ECHO-EF, the proportion of patients with larger ECHO/ECG-LV-D were explored in diverse ECHO/ECG-EF groups for the disease previvors of future LV dysfunction.Patient characteristics are presented as numbers of patients, population percentages, means, and standard deviations (SDs), with the significance level set as p-value to enter and to remove were 0.05 and 0.15, respectively.The relationship between traditional ECG features and AI-ECG-based ECG-LV-D was also analyzed. We showed the importance rank of different traditional ECG features, including 31 diagnostic pattern classes and 8 continuous ECG measurements based on an automatic Philips analysis system. These features were used to train an eXtreme gradient boosting (XGB) model to predict ECG-LV-D. To identify the most important ECG features in this analysis, the stepwise program was used and the HRs) and 95% conference intervals (95% CIs). We assessed the risk of adverse CV outcomes in patients with different ECG-EF/ECG-LV-D using a Cox proportional hazard model after adjusting by gender and age and demonstrated the risk matrixes of different outcomes with HRs and the concordance statistic (C-index), which were used to quantify their contributions. All the statistical analyses were conducted in R software, version 3.4.4.To investigate the long-term incidence of developing new-onset LV dysfunction, we plotted Kaplan–Meier curves of patients with an initially normal EF (EF > 50%), stratified by ECG-EF, left ventricle (end-diastole) diameter (LV-D), and ECG-LV-D. Multivariable Cox proportional hazard models were used to evaluate the predictive ability of ECG-EF, ECHO-LV-D, and ECG-LV-D adjusted by gender and age on all outcomes of interested, presenting in hazard ratios  of 0.59/0.56, and MAEs of 7.95/7.91 in the internal/external validation set, respectively. Meanwhile, the similar correlation was observed in our analysis of ECG-LV-D and ECG-LV-S, with Diff of 0.03 ± 6.75/0.86 ± 6.27, r of 0.53/0.59, and MAE of 5.26/4.83 in the internal validation set, and Diff of 0.06 ± 6.81/0.78 ± 6.40, r of 0.49/0.53, and MAE of 5.29/4.93 in the external validation set.via ECG accurately.The ROC curve analysis was used to test the diagnostic value of AI-enabled ECG parameters . The AUCSubgroup analysis was stratified by the different clinical settings and comorbidities in In the previous study, we noticed patients with low ECG-EF and normal ECHO-EF had a higher incidence of future LV dysfunction. We hypothesized that the disease previvor was associated with obscure structural abnormalities, which could be detected by ECG-LV-D before actual LV dilation. Our DLM exhibited similar performance in predicting the size of LV-D and LV-S . Due to HRs (95% CI) of 5.91 (3.58–9.78) and 5.63 (3.55–8.93). The C-index analyses also show the significant prognostic value on new onset LV dysfunction of 0.774 (95% CI: 0.753–0.7950) and 0.791 (95% CI: 0.773–0.808), which emphasized the importance of ECG-EF. In the analyses of ECHO-LV-D and ECG-LV-D, the significant gender-age adjusted HRs demonstrated the contributions on new-onset LV dysfunction in both validation sets. The HRs of severe/mild ECG-LV-D increase was 7.30 (95% CI 3.61–14.77)/3.12 (95% CI 2.41–4.03) in the internal validation set and 5.51 (95% CI 2.85–10.66)/2.65 (95% CI 2.11–3.33) in the external validation set. The C-indexes were higher in ECG-LV-D  than in ECHO-LV-D  in internal validation set, which was consistent in external validation set [0.750 (95% CI: 0.730–0.769) vs. 0.737 (95% CI 0.718–0.757)]. It suggested that ECG-LV-D may be a better differential indicator than ECHO-LV-D, which supplements the ECG-EF to identify patients at the risk of LV dysfunction in future.In HRs increased to 4.60 (95% CI 3.17–6.68), 4.31 (95% CI 1.68–11.07), 4.80 (95% CI 2.78–8.28), and 2.23 (95% CI 1.65–3.31) on new-onset LV dysfunction, CV mortality, new-onset AMI, and CAD, respectively. Moreover, the ECG-LV-D independently provided the ability of risk stratification on new-onset LV dysfunction , CV mortality , new-onset AMI , and CAD  in the internal validation set, and achieved similar trends with 1.88-fold-risk (95% CI 1.47–2.39) of new-onset LV dysfunction in the external validation set. In the consideration of confounding bias, we further adjusted more potential confounding factors, such as comorbidities. Our data indicated that the trend of results was similar with results adjusted by gender, age, and comorbidities  in the internal/external validation set, respectively. The high correlation between ECHO-EF and ECG-EF suggested the latter is a potential diagnostic tool. Severe/mild ECG-LV-D increase with the AUCs of 0.9295/0.8297 and 0.9148/0.8072 in internal/external validation set, which exhibited its valuable diagnostic power in patients with normal ECHO-EF. Moreover, we found a higher prevalence of ECG-LV-D increase in patients with low ECG-EF. Of these false positive patients, gender and age-adjusted Heart failure is an increasing problem affecting more than 30 million people globally. In these patients, asymptomatic LV dysfunction  patients are difficult to diagnose, who account for 7.9–23% of population , 5. PatiThere are several ECG changes in LV-D increase. In dilated cardiomyopathy (DCM), about 80% of patients had ECG abnormalities, including LV hypertrophy, left/right atrial enlargement, left/right bundle branch block, abnormal Q wave, atrial fibrillation, first-degree atrial-ventricular block, and T-wave inversion in inferior and anterolateral leads . Merlo eThe clinical application of AI-ECG is a worldwide tendency and developed rapidly. As the AI-ECG could predict the disease development in healthy individuals without abnormal imaging findings or symptoms, the concept of previvors was proposed recently. With apparent false positive AI-ECG findings, patients with a higher risk of many diseases, such as LV dysfunction , future The importance and clinical significance of our ECG-LV-D should be emphasized. Both ECG-EF and ECG-LV-D are promising screening tools for patients who had a high risk of future LV dysfunction. The advantage of timely HF risk identification is evident to prevent adverse CV events and reduce medical costs. Moreover, from a large community-based study of sudden cardiac death (SCD), LV-D may contribute to the risk of SCD independent of the EF . The ECGThere are some limitations to this study. First, this study was a retrospective study. Although ECG/ECHO pairs were collected and the DLM was validated, the accuracy in different hospital settings and prospective studies are necessary to generalize the application of ECG-LV-D and promote treatment strategy. Second, the clinical impact of treatment is needed to verify. The actual benefit of ECG-LV-D import to clinical practice is not clear now. Investigation of clinical benefits including accidental HF detection, time reduction, prognosis management, and outcomes evaluation should be conducted. Third, the best application of AI-ECG is to screen asymptomatic patients with HF, but the relationship between abnormal ECG and HF symptoms was unclear. Future study should conduct a large-scale community screening to validate the benefit in asymptomatic patients with HF. Fourth, AI-ECG performed worse in patients with more comorbidities, especially in patients with a history of AMI. Interestingly, even after the adjustment of all the confounding factors, our models of ECG-EF and ECG-LV-D still provide significant predictive power for newly onset LV dysfunction. Finally, the DLM design is an uninterpretable set of methods, such as a black box, and full interpretability will be a focus of future work.In conclusion, our AI-ECG DLM could identify patients with high ECG-LV-D and predict future LV dysfunction. ECG-LV-D serves as an independent risk factor of long-term CV outcomes in patients with normal ECHO-EF and low ECG-EF. The combination of ECG-EF and ECG-LV-D provides significantly synergistic diagnostic power to predict patients with future LV dysfunction. Although further studies are needed, our ECG-LV-D could be used as a screening tool for patients with normal EF but with high cardiovascular risk to initiate appropriate treatment in time.The original contributions presented in the study are included in the article/CL, C-SL, and W-HF contributed to conception and design of the study. CL, C-HW, and C-CL organized the database. CL and C-SL performed the statistical analysis and wrote sections of the manuscript. H-YC and C-SL wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Nuclear imaging plays a unique role within diagnostic imaging since it focuses on cellular and molecular processes. Using different radiotracers and detection techniques such as the single photon emission scintigraphy or the positron emission tomography, specific parameters can be assessed: myocardial perfusion and viability, pulmonary perfusion, ventricular function, flow and shunt quantification, and detection of inflammatory processes. In pediatric and congenital cardiology, nuclear imaging can add complementary information compared to other imaging modalities such as echocardiography or magnetic resonance imaging. In this state-of-the-art paper, we appraise the different techniques in pediatric nuclear imaging, evaluate their advantages and disadvantages, and discuss the current clinical applications. Pediatric cardiology includes heterogeneous congenital and acquired heart diseases. Echocardiography is the key non-invasive diagnostic imaging tool that is usually sufficient to manage most children with heart disease , 2. Howein situ, with high sensitivity and specificity  two-dimensional (2D) gamma scintigraphy, (b) single-photon emission computed tomography (SPECT) and (c) positron emission tomography (PET). Scintigraphy and SPECT is to detect gamma radiation from photon emitting radiotracers, using gamma ray detectors. While planar scintigraphy is a 2D detection method, providing a projection image like a classic X-ray, SPECT allows acquisitions in the three dimensions (3D). Multiple 2D images from several angles around the patient are acquired and computed tomographic reconstruction algorithm is used to generate a 3D data set . In the Radiopharmaceuticals consists of three components: a vector molecule, a radionuclide, and a linker in between. They are administered at a nano-molar concentration and accumulate in the targeted tissue based on the specific molecular vector-target interaction. The radiotracer is most often administrated intravenously but inhalation  or ingeNuclear myocardial perfusion imaging (NMPI) provides both metabolic and functional analysis . The comMyocardial perfusion and viability can also be assessed by PET/CT. Myocardial viability is identified as a mismatch between fluorine-18 fluorodeoxyglucose (18F-FDG) uptake and rest perfusion imaging. A viable myocardial segment is defined by reduced or absent perfusion with preserved glucose metabolism . PET ageCongenital coronary abnormalities are a clinical challenge both diagnostically and therapeutically with a lot of controversies regarding the related individual risk and the management. Anomalous aortic origin of a coronary artery from the opposite sinus of Valsalva (AAOCA), associated with intramural or interarterial course, is increasingly diagnosed incidentally in children, but the related clinical risks are not well defined . A key cThe use of NMPI has been favorably reported in other rare congenital coronary disease such as left coronary artery originating from the pulmonary artery (ALCAPA) , 29, myoBoth early and late mortality after arterial switch operation (ASO) for transposition of great arteries (TGA) is predominantly related to coronary artery complications –36. ExerKawasaki disease (KD) is an acute pediatric vasculitis of unknown etiology that results in coronary artery aneurysms in up to 25% of untreated cases  and 5% oIn children with a history of KD, 99mTc SPECT provides a sensitivity of 90% and a specificity between 85 and 100% in detecting stress-induced ischemia related to significant coronary stenosis , 53 and In KD, regardless of a history of aneurysms, 12–19% of patients have an abnormal NPMI pattern with permanent and/or stress-induced perfusion defects during the follow-up –57. InteIn hypertrophic cardiomyopathy (HCM), myocardial ischemia has been suggested to contribute to the pathophysiology of the disease, and appears to be related to decreased subendocardial perfusion in the hypertrophied segments, compression of intramural small vessels and myocardial bridging . MicrovaIn pediatric dilated cardiomyopathies, NMPI can rarely be useful to non-invasively rule out underlying ischemic process, which is an uncommon etiology in children. For pediatric diseases affecting coronary microvascular perfusion such as sickle cell anemia with LV dilatation and/or dysfunction, it can help to differentiate between the possible mechanisms causing left ventricular damage . In thesOne of the long-term complications of heart transplantation (HT) is the development of cardiac allograft vasculopathy (CAV). In children, CAV is a major cause of death and retransplantation , 69. TheLung perfusion scintigraphy (LPS) performed with 99mTc labeled macroaggregated albumin (MAA) is the most widely used nuclear imaging technique to quantify lung perfusion and relative flow distribution , 73. TheThe main indication for LPS is the assessment of hemodynamic impact of pulmonary vascular abnormalities including pulmonary artery or vein stenosis, pulmonary emboli , arterioNuclear imaging and more specifically 18F-fluorodeoxyglucose (18F-FDG) PET allows visualization of inflammatory processes through the mapping of cellular glucose uptake. The 18F-FDG is a glucose analog in which the carbon-2 hydroxyl is replaced by fluorine-18, a radioisotope that decays to oxygen-18 by positron emission. The heart metabolizes both carbohydrates and free fatty acids and absorbs a large amount of 18F-FDG. A preparatory low carbohydrate diet and a fasting period are required to suppress the physiologic myocardial 18F-FDG uptake, making free fatty acids the predominant cardiac energy source and improving the contrast effect . 18F-FDGOverall IE incidence in CHD patients is 1.33 per 1,000 person-years with a high proportion of right-sided IE , 93. ProThe addition of the PET/CT to the Duke criteria substantially increases the diagnostic yield of this score (sensitivity from 70 to 97%)  with a sAmongst the nuclear imaging techniques used in diagnosis of infectious diseases, radiolabeled leukocyte scintigraphy (RLS) is technically more demanding but also more specific for bacterial infection than 18-F FDG PET/CT , 111. AlAlthough nuclear imaging is widely used in pediatric oncology, its use in the field of pediatric cardiac tumors is still very limited. Pediatric cardiac tumors are benign in 90% of cases and the diagnosis is largely based on echocardiography and/or MRI , 117. Inin vivo or in vitro. The cardiac chambers are then visualized based on the radioactive emission and the LV volume is measured over the cardiac cycle to assess the ejection fraction. This technique was first validated in adults in the early 1970s (Multigated acquisition (MUGA) of the cardiac blood pool, also called equilibrium radionuclide ventriculography, is the traditional nuclear imaging modality to assess ventricular systolic function to quantify ventricular ejection fraction. This method requires the labeling of the patient’s red blood cells with a radionuclide , which can be done ly 1970s  but alsoly 1970s –124. Sysly 1970s , 66.Finally, even though radionuclide ventriculography is available and reliable in children, there is no relevant indication given the existence of non-irradiating techniques such as echocardiography and MRI which also allow a more precise study of the cardiac function.The aortic (Qs) to pulmonary (Qp) flow ratio (Qp/Qs) is a key parameter in the management of patients with intracardiac shunts in pediatric cardiology. Nuclear imaging can be useful to directly measure shunt flow and provide a non-invasive Qp/Qs assessment. The technique involves the rapid injection of a compact bolus of radionuclide  while monitoring the transit through the heart and lungs with the gamma camera. Planar acquisitions are performed with a high sampling rate and dedicated collimator to magnify the images. For quantification, the time-radioactivity curves are generated from regions of interest: superior vena cava to assess the quality of the bolus and periphery of the right, left or both lungs (pulmonary curve) for shunt detection and quantification . The norWhile it remains a simple and reliable way to non-invasively quantify the Qp/Qs, its use has become obsolete in current clinical practice as non-radiation based techniques have largely replaced nuclear methods for shunt assessment , 128.Using the same principle as described above, right-to-left shunts can be detected by first-pass method, which reveals a premature appearance of radioactivity in the left chambers. The time-radioactivity curves are generated from regions of interest over the carotid artery to quantify the shunt impact . The mosPostoperative alteration of the cardiac autonomic innervation is frequently described after cardiac surgery and is likely due to direct damage of the cardiac nervous system. This can also be caused by prolonged aortic cross-clamp and coronary manipulations leading to autonomic fiber ischemia , 130. HeCardiac autonomic imaging has also been used in vasovagal syncope work-up as exaggerated MIBG LV uptake is considered as a good marker of sympathetic hyperactivity in children with suspected neurocardiogenic syncope . AlthougEach nuclear imaging technique has its advantages and limitations, in technique or application, as detailed in previous sections. The main common limitation is the risk related to ionizing radiation and its long-term impact. The underlying neoplastic risk appears particularly important in children due to the increased radiosensitivity of this population with higher mitotic activity and longer potential for exposure over the life span . This riTo quantify and compare the doses of ionizing radiation induced by nuclear imaging, it is necessary to express them in equivalent dose. This parameter, expressed in mSv, depends on the nature of the radiation and the absorbed dose (the energy received per unit of mass). Finally, the effective dose is the equivalent dose corrected by a tissue weighting factor to consider the specific sensitivities of the different irradiated organs. This effective dose is calculated for the whole body and used to assess the biological risk related to the radiation exposure. Effective doses therefore vary widely depending on the nuclear imaging techniques, the radiopharmaceutical used and the patient’s characteristics.There are continuing efforts to determine, standardize, and reduce ionizing radiation exposure and dosage in pediatric nuclear imaging protocols –142. ForOver the last decade, significant decreases in radiation exposure has been made possible by the technological advances in camera sensitivity and image processing , 145 andAn additional limitation of nuclear imaging in pediatrics is its accessibility. Depending on the radiotracers used, the availability of a cyclotron in the hospital or the hospital’s proximity to a nuclear reactor can be essential and makes certain techniques available in only a few centers.Following technical improvements in ultrasound and the emergence of additional imaging techniques such as 4D flow MRI or stress MRI, nuclear imaging is now a second- or third-line modality for many indications in pediatric cardiology. According to the literature review, the main current indications for nuclear imaging in children are : 1/myocaThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.MV made substantial contributions to the conception and design of the work, drafted the work, and substantively revised it. MF, LM, JB, ZJ, and GT drafted the work. OV made substantial contributions to the conception and design of the work, has drafted the work, and substantively revised it. All authors have approved the submitted version and have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer LS declared a shared affiliation with the authors MV, LM, JB, and OV to the handling editor at the time of review.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The ANTHEM-HF, INOVATE-HF, and NECTAR-HF clinical studies of autonomic regulation therapy (ART) using vagus nerve stimulation (VNS) systems have collectively provided dose-ranging information enabling the development of several working hypotheses on how stimulation frequency can be utilized during VNS for tolerability and improving cardiovascular outcomes in patients living with heart failure (HF) and reduced ejection fraction (HFrEF). Changes in heart rate dynamics, comprising reduced heart rate (HR) and increased HR variability, are a biomarker of autonomic nerve system engagement and cardiac control, and appear to be sensitive to VNS that is delivered using a stimulation frequency that is similar to the natural operating frequency of the vagus nerve. Among prior studies, the ANTHEM-HF Pilot Study has provided the clearest evidence of autonomic engagement with VNS that was delivered using a stimulation frequency that was within the operating range of the vagus nerve. Achieving autonomic engagement was accompanied by improvement from baseline in six-minute walk duration (6MWD), health-related quality of life, and left ventricular EF (LVEF), over and above those achieved by concomitant guideline-directed medical therapy (GDMT) administered to counteract harmful neurohormonal activation, with relative freedom from deleterious effects. Autonomic engagement and positive directional changes have persisted over time, and an exploratory analysis suggests that improvement in autonomic tone, symptoms, and physical capacity may be independent of baseline NT-proBNP values. Based upon these encouraging observations, prospective, randomized controlled trials examining the effects on symptoms and cardiac function as well as natural history have been warranted. A multi-national, large-scale, randomized, controlled trial is well underway to determine the outcomes associated with ART using autonomic nervous system engagement as a guide for VNS delivery. Heart failure (HF) causes a progressive decline in health and physical capacity, and is the leading cause of hospitalization in the elderly . When syThe autonomic nervous system reacts reflexively to HF by stimulating the cardiovascular system in attempt to maintain cardiac output and blood pressure. This reflexive stimulation is maladaptive to a failing heart, however, and ultimately causes HF to progress. While drugs, devices, and cardiac rehabilitation have improved symptoms and survival rates by the progression of HF, HF hospitalization rates and mortality remain high. Although survival from ischemic heart disease has improved, HF prevalence has continued to rise, mainly due to an increase in the prevalence of cardiovascular (CV) risk factors and an increasingly aging population.In a recently published population-based cohort study of over 300,000 patients, HF was listed on 42% of death certificates and considered to be the cause of 7% of all deaths . The lifExisting medical treatment for heart failure and reduced LVEF (HFrEF) using guideline directed medical therapy (GDMT) is directed toward counteracting harmful neurohormonal activation using a combination of beta-blockade, angiotensin-converting enzyme inhibition, angiotensin-receptor blockade in combination with neprilysin inhibition, and mineralocorticoid receptor antagonism.HF markedly affects patients’ quality of life. Fear, anxiety, and depression are common, and work, travel, social, and leisure activities are affected. Despite the establishment of new prognosis-improving strategies for treatment, patients who continue to have reduced physical capacity, deteriorated quality of life, and hospitalizations for worsening HF desire additional remedies . The emoIn patients with persistent symptoms of advanced HF despite GDMT, electrical stimulation to modulate biological targets within the autonomic nervous system to achieve more physiologic balance between sympathetic and parasympathetic activity has the potential to delay HF progression. Neuromodulation can be achieved with the delivery of autonomic regulation therapy (ART) by stimulating the cervical vagus nerve, which is readily accessible in the neck and provides access to the appropriate central and peripheral nervous system targets for neuromodulation .We will describe the pathophysiology of the autonomic nervous system in heart failure, the progress that has been made in our approach to optimizing VNS delivery for maximal benefit, and a pathway toward clarifying the role of vagus nerve stimulation (VNS) in managing patients with heart failure and reduced left ventricular ejection fraction (LVEF (HFrEF).In health, homeostasis is maintained through afferent and efferent sympathetic and parasympathetic interactions that occur throughout the neurocardiac reflex hierarchy comprising the brain, peripheral neural circuits, and the intrinsic cardiac network in the cardiac fat pads . NervousWith progressive HF, there is a generalized increase in sympathetic activity and a concurrent decrease in parasympathetic tone throughout the neurocardiac network . The bioIn-vitro and in vivo investigations of HF during this time have included explorations of right versus left versus bilateral stimulation, electrode and waveform configuration, efferent versus afferent versus bidirectional stimulation, continuous versus cyclic stimulation, duration of stimulation on/off cycles and number of pulses delivered per cycle, stimulation frequency, open-loop stimulation independent of any trigger, closed-loop stimulation with a physiologic trigger such as ventricular depolarization, current amplitude, effects of VNS intensity on heart rate (HR), and safety and tolerance of VNS titration , pulse frequency, pulse duration (width), and duty cycle. The duty cycle consists of a period of vagus nerve stimulation (“on-time”) alternating with a period of no stimulation (“off-time”), is quantified as the ratio of duration of the on-time to duty cycle duration , and is repetitive over time .The electrical lead of the VNS system that is in current investigational use for HF has a bipolar silicone helical design with platinum-iridium conductors, is self-sizing and atraumatic, and is identical in design to the electrical lead that has been utilized in more than 31,000 VNS system implantations for epilepsy or depression and has had 72,100 device-years of patient exposure since 2009 . Cumulative lead survival has exceeded design requirements and there have been a low rate of complications, with common causes being infection (0.87%) and vocal cord dysfunction (0.68%), and a low rate of lead failure. Feasibility studies of chronic utilization of this VNS system for HF have had no device or therapy-related serious adverse events, device malfunctions, or therapy discontinuations .The axons that comprise the cervical vagus nerve include approximately 80% afferent and 20% parasympathetic preganglionic efferent projections . The effThe functional biological effects of VNS for HF are achieved through a combination of efferent and afferent stimulation. Efferent effects occur through cathode stimulation in a caudal direction at the interface of the electrical lead with the various axons that traverse the vagus nerve interface. An acute decrease in heart rate detected at the time of stimulation of the vagus nerve during the duty cycle is indicative of autonomic engagement at the time of stimulation .Afferent activation affects efferent sympathetic and parasympathetic function centrally by modulating continuous sympathetic and parasympathetic activity (tonic effect) and activity at rest . The actions result peripherally in vasorelaxation through activation of the nitric oxide pathway . Vagus nAt the myocyte level, increases in acetylcholine signaling through muscarinic receptors reduce oxidative stress, decrease contractile force, improve calcium signaling, and restore gene expression. At the same time, cholinergic trans-differentiation of sympathetic neurons occurs, playing a normalizing role against sympathetically mediated pathogenesis .As a consequence of augmenting parasympathetic tone and reducing sympathetic hyperactivity, there is a medium-to long-term reduction of endothelial dysfunction, mitigation of cardiac remodeling, improved left ventricular function with restoration of physiologic sympathetic myocyte responsiveness, improved myocardial oxygen supply-demand ratio, and a reduced risk for arrhythmias that compromise cardiovascular function and/or longevity. These effects are complementary to those of pharmacotherapy for HFrEF , Ardell and imprThe designs and the clinical outcomes of the ANTHEM-HF, INOVATE-HF, and NECTAR-HF studies have been published previously . Each asIn ANTHEM-HF, VNS was delivered at 10 Hz to mimic the natural operating frequency of the vagus nerve. VNS titration was well-tolerated and completed with confirmation of autonomic engagement using changes in heart rate (HR) dynamics that occurred during the on-time of the duty cycle as a biomarker. Evidence of this engagement was associated with long term improvements from baseline in mean HR and mean HR variability (SDNN) as measured using 24 h ambulatory ECG monitoring, LVEF, 6-min walk duration (6MWD), Minnesota Living with Heart failure (MLWHF) questionnaire mean score, and NYHA Gold et .In INOVATE-HF, VNS administered at a lower frequency of 1–2 Hz was not associated with any long-term improvements in mean HR or mean HR variability. The primary efficacy endpoint of a composite of death or HF hospitalization showed no significant between-group difference, though improvements occurred in the secondary endpoint outcomes of NYHA class, KCCQ mean score, and 6-min walk distance .VNS titration in NECTAR-HF could not be completed in the majority of patients due to side effects  that occurred with VNS even at low current amplitudes when using a stimulation frequency of 20 Hz. There were no significant long-term improvements in mean HR or mean HR variability. At 6 months of follow up, VNS did not reduce the primary efficacy endpoint, LV end-systolic diameter, or other secondary echocardiographic measures. There were significant improvements in the secondary outcomes of MLWHF mean score and NYHA . A subsePost-hoc comparisons of the stimulation frequencies that were used for VNS, and the associated symptomatic and functional outcomes that were observed in the treatment arms in these three studies have been published and are summarized in There was no difference in efficacy, tolerability, and safety in patients who were randomized to either right VNS system implantation or left VNS system implantation in the ANTHEM-HF study. Comparable efficacy, tolerability, and safety using bilateral cervical VNS has not been studied .The background treatment with GDMT in ANTHEM-HF compared favorably with the background therapy administered during two contemporary pivotal studies that supported the approval of new categories of HF therapy . Premch For entrSimilar and statistically significant improvements in symptoms and function with ART were observed in a post-hoc analysis of patients categorized by the percentage of target beta-blocker dose administered at baseline. One hundred % of participating patients received a beta-blocker in dose that was either ≥50% of the maximum target  or less than 50% of the maximum target . Heart rate, systolic blood pressure, LVEF, use of ACE/ARB, and use of MRA at baseline were similar for the two groups at baseline. Six months after VNS titration, VNS reduced HR and significantly improved HR variability (SDNN), LVEF, 6MWD, and MLWHFS, compared with baseline, equally in both groups .Long term effects of administering ART using VNS are summarized elsewhere in this issue of the journal. Evaluation of 15 patients with HFrEF after 4.7 ± 0.3 years (range: 4.0–5.0 years) of VNS in the ANTHEM-HF study showed that the majority manifested long term engagement of the autonomic nervous system without apparent deleterious effects of ART upon patient safety, symptoms, or function.Persistent autonomic nervous system response to long term VNS provides physiologic underpinning for the sustained symptomatic and functional effects observed in association with chronic VNS in larger subsets of the ANTHEM-HF patient population. For patients with available data, statistically significant improvements from baseline in symptoms and function have been reported at 12 months  and at 42 months (33 [55%]). At 12 months, there were persistent improvements from baseline in HR variability, LVEF, 6MWD, NYHA class, and MLWHFS Cleland .At 42 months, there have been no device-related SAEs and no device malfunctions, and there have been statistically significant improvements from baseline in HR variability, LVEF, 6MWD, MLWHFS, and NYHA Class . UnderstA favorable long-term safety profile has also been reported in 91 patients receiving VNS at 18 months in the NECTAR-HF Study, whose first phase was a 6-month randomized controlled evaluation of patients receiving active VNS versus an implanted but inactive VNS system, and second phase was a safety evaluation after activation of the VNS system in all patients at 6 months .Recent heart failure studies have associated lower baseline natriuretic peptide levels with improved morbidity/mortality outcomes during pharmaceutical treatment for HFrEF,  and bettThe median NT-proBNP value at baseline was 868 pg/ml (Q1-Q3 322 -1875 pg/ml). There was a net 16% decrease from baseline in median NT-proBNP value that during VNS that was modest and non-significant in the study cohort (N = 60).While LVEF improved overall, there was a statistical interaction between baseline NT-proBNP value above or below 1,600 pg/ml and better LVEF improvement during VNS. Other symptomatic and functional improvement during chronic VNS was independent of baseline NTproBNP value above or below 1,600 pg/ml.These are preliminary and hypothesis-generating findings, and the ongoing ANTHEM-HFrEF Pivotal Study of VNS may provide additional insights.A large-scale, multi-national randomized controlled trial (ANTHEM-HFrEF) is now underway in order to fully test the hypotheses raised by results of ANTHEM-HF, and to further assess the impact of ART on morbidity and mortality. The key inclusion criteria are stable GDMT for at least 4 weeks, NYHA class III or class II if hospitalized for HF within the previous 12 months, LVEF ≤35%, LV end diastolic diameter <8.0 cm, NT-proBNP ≥800 pg/ml, and 6MWD of 150–450 m, limited by HF symptoms.A Bayesian adaptive sample size selection is being utilized in determining the impact of VNS on morbidity and mortality. The effects of ART on symptoms and function are also being evaluated. Patients are randomized 2:1 to VNS plus GDMT or GDMT alone. Evaluation of morbidity and mortality utilizes a conventional frequentist approach for analysis of the primary outcome end point—reduction in the composite of cardiovascular death or first HF hospitalization.A second study is embedded within the ANTHEM-HFrEF Pivotal Study to evaluate improvement in symptoms and function in the study population. Successful demonstration of improvement in symptoms and function will require meeting two risk-related conditions—a 60% or greater probability of a reduction in the combination of cardiovascular death/HF hospitalization at the end of the study  and sufficient freedom from device-related serious adverse events—and demonstrating statistically significant improvements in three efficacy endpoints: LVEF, 6MWD, and KCCQ overall score  Zaeem e.Progress has continued during the past decade in our understanding of how ART may be delivered using VNS in a safe and tolerable manner to alleviate symptoms, increase functional capacity, and improve the quality of life in patients with HFrEF. Findings to date, derived from pilot investigation of VNS delivered at the natural operating frequency of the vagus nerve, have provided hypotheses that are now being tested in a large multicenter randomized investigation of VNS effects on symptoms, functional status, quality of life, morbidity and mortality.


Adverse ventricular structure and function is a key pathogenic mechanism of heart failure. Observational studies have shown that both insulin resistance (IR) and glycemic level are associated with adverse ventricular structure and function. However, whether IR and glycemic level are causally associated with cardiac structure and function remains unclear.Genetic variants for IR, fasting insulin, HbA1c, and fasting glucose were selected based on published genome-wide association studies, which included 188,577, 108,557, 123,665, and 133,010 individuals of European ancestry, respectively. Outcome datasets for left ventricular (LV) parameters were obtained from UK Biobank Cardiovascular Magnetic Resonance sub-study . Mendelian randomization (MR) analyses with the inverse-variance weighted (IVW) method were used for the primary analyses, while weighted median, MR-Egger, and MR-PRESSO were used for sensitivity analyses. Multivariable MR analyses were also conducted to examine the independent effects of glycemic traits on LV parameters.P = 4.20 × 10−4), lower LV end-systolic volume , and higher LV mass to end-diastolic volume ratio  after Bonferroni adjustment. However, no associations of HbA1c and fasting glucose were observed with any LV parameters. Results from sensitivity analyses were consistent with the main findings, but with a slightly attenuated estimate. Multivariable MR analyses provided further evidence for an independent effect of IR on the adverse changes in LV parameters after controlling for HbA1c.In the primary IVW MR analyses, per 1-standard deviation (SD) higher IR was significantly associated with lower LV end-diastolic volume (β = − 0.31 ml, 95% confidence interval [CI] − 0.48 to − 0.14 ml; Our study suggests that genetic liability to IR rather than those of glycemic levels are associated with adverse changes in LV structure and function, which may strengthen our understanding of IR as a risk factor for heart failure by providing evidence of direct impact on cardiac morphology.The online version contains supplementary material available at 10.1186/s12933-022-01540-6. Heart failure is a leading cause of mortality worldwide . DespiteMendelian randomization (MR), using genetic variants as instrumental variables for exposure, can be used to provide less confounded results . GeneticIn view of the key pathogenic role of ventricular structure and function on heart failure , the preThis two-sample MR study was conducted based on publicly available summary data from genome-wide association studies (GWASs) consortia –13. TablP < 0.005 for each trait) in up to 188,577 European individuals. Each of 53 SNPs was the lead insulin-associated SNP at each 1 Mb region, all of the SNPs were located in distinct genomic regions ), and fasting glucose (0.65 mmol/l) and per 1% increase in HbA1c levels. To account for multiple testing, we used a Bonferroni correction threshold of P = 4.20 × 10−4), lower LV end-systolic volume , and higher LV mass to end-diastolic volume ratio  after Bonferroni adjustment. Genetic liability to IR was also associated with higher LV ejection fraction by suggestive evidence . In addition, per 1-SD increase in genetic liability to fasting insulin levels was marginally significantly associated with higher LV mass  and LV mass-to-end-diastolic volume ratio . We observed neither genetic liability to HbA1c nor genetic liability to fasting glucose to be associated with any LV parameters.For all analyses, there were no palindromic SNPs, so no extra SNPs were excluded from this analysis. Figure P values of Egger-intercept . No significant outlier SNPs were identified through the MR-PRESSO method. In the leave-one-out analysis, the main results were similar after removing each SNP in turn, indicating that no single SNP had an undue influence on the overall causal effect estimate , 46-SNPs (after LD clumping), 43-SNPs (excluding genetic variants associated with BMI), 28-SNPs (excluding genetic variants associated with TGs or HDL-C) and 20-SNPs  instruments , lower LV end-systolic volume , and higher LV mass to end-diastolic volume ratio . When using 46-SNPs instruments, genetic liability to IR was still significantly associated with lower LV end-diastolic volume , lower LV end-systolic volume , and higher LV mass to end-diastolic volume ratio , although the magnitude of the effect was reduced. When using 43-SNPs and 28-SNPs instruments, genetic liability to IR was still significantly associated with LV mass-to-end-diastolic volume ratio. Using 20-SNPs instruments, genetic liability to IR was also marginally significantly associated with higher LV mass to end-diastolic volume ratio. Similar estimates were derived using additional MR methods although most estimates were attenuated , whereas genetic liability to HbA1c did not result in significant alterations in IR , lower LV end-systolic volume , higher LV ejection fraction by suggestive evidence  and higher LV mass to end-diastolic volume ratio . No evidence supported that genetic liability to HbA1c was associated with LV structure and function (Table P = 0.031)  and ventricular structure and function , 48. TheIn this study, genetic liability to IR was associated with higher LV ejection fraction, but limited LV expansion during diastole and systolic, indicating that systolic function was preserved and that diastolic function was reduced. This finding is in concert with previous cross-sectional studies, which suggested that IR is associated with diastolic dysfunction, even prior to diabetes development , 49. In Numerous experimental studies have proven that metabolic disturbances mediate the adverse effects of IR on LV –55. UndeAlthough IR and hyperglycosemia are highly correlated with each other, our study has disentangled the complex relationship of IR and hyperglycosemia with changes in LV structure and function and has several clinical implications. First, our findings suggest that adverse changes in LV structure and function are the potential underlying pathophysiology on the effect of IR on heart failure as found by other studies . Second,There are several limitations to our study. First, due to a lack of large-scale GWAS data of insulin sensitivity, we only used 53 SNPs from a multi-trait GWAS as instrumental variables of IR trait . This GWIn conclusion, our results suggest that genetic liability to IR is associated with adverse changes in LV parameters and heart failure risk. However, no evidence supporting the direct impact of genetic liability to glycemic level on LV structure and function was found. Our findings may strengthen our understanding of IR as a risk factor for heart failure by providing evidence of direct impact on cardiac morphology.Additional file 1: Method S1. The detailed procedure and sensitive analyses of the Multivariable MR analysis. Table S1. Insulin resistance-related SNPs associated with potential confounders. Table S6. Sensitivity MR analysis of the association between glycemic traits and left ventricular parameters. Table S7. Heterogeneity and horizontal pleiotropy test of the associations between glycemic traits and left ventricular parameters. Table S8. Additional MR analysis of the association between insulin resistance and left ventricular parameters. Table S9. Heterogeneity and horizontal pleiotropy test of the associations between insulin resistance and left ventricular parameters. Table S10. The bidirectional associations between insulin resistance and hemoglobin A1c. Table S11. Heterogeneity and horizontal pleiotropy text of the associations between insulin resistance and hemoglobin A1c. Table S12. Heterogeneity and horizontal pleiotropy text of the associations between insulin resistance, hemoglobin A1c and left ventricular parameters in multivariate MR Analyses. Table S13. Effects of insulin resistance and hemoglobin A1c on heart failure in univariable and multivariate MR Analyses. Table S14. Heterogeneity and horizontal pleiotropy text of the associations between insulin resistance, hemoglobin A1c and heart failure in univariable and multivariate MR Analyses. Figure S1. Scatterplots of the causal estimates of glycemic traits and left ventricular end-diastolic volume. Figure S2. Scatterplots of the causal estimates of glycemic traits and left ventricular end-systolic volume. Figure S3. Scatterplots of the causal estimates of glycemic traits and left ventricular ejection fraction. Figure S4. Scatterplots of the causal estimates of glycemic traits and left ventricular mass. Figure S5. Scatterplots of the causal estimates of glycemic traits and left ventricular mass to end-diastolic volume ratio. Figure S6. Leave-one-out analyses of the association between glycemic traits and left ventricular end-diastolic volume. Figure S7. Leave-one-out analyses of the association between glycemic traits and left ventricular end-systolic volume. Figure S8. Leave-one-out analyses of the association between glycemic traits and left ventricular ejection fraction. Figure S9. Leave-one-out analyses of the association between glycemic traits and left ventricular mass. Figure S10. Leave-one-out analyses of the association between glycemic traits and left ventricular mass to end-diastolic volume ratio. Figure S11. Scatterplots of the bidirectional association of IR and HbA1c. Figure S12. Leave-one-out analyses of the bidirectional association of IR and HbA1c. Figure S13. A brief schematic diagram of possible assumption of the association of IR and HbA1c with cardiac morphology.Additional file 2: Table S2. Characteristics of the single-nucleotide polymorphisms associated with insulin resistance and their associations with left ventricular parameters. Table S3. Characteristics of the single-nucleotide polymorphisms associated with fasting insulin and their associations with left ventricular parameters. Table S4. Characteristics of the single-nucleotide polymorphisms associated with glycated hemoglobin and their associations with left ventricular parameters. Table S5. Characteristics of the single-nucleotide polymorphisms associated with fasting glucose and their associations with left ventricular parameters.


The diagnosis of heart failure (HF) primarily relies on signs and symptoms that are neither sensitive nor specific. This impedes timely diagnosis and delays effective therapies or interventions, despite the availability of several evidence‐based treatments for HF. Through monumental collaborative efforts from representatives of HF societies worldwide, the universal definition of HF was published in 2021, to provide the necessary standardized framework required for clinical management, clinical trials, and research. This review elaborates the key concepts of the new universal definition of HF, highlighting the key merits and potential avenues, which can be nuanced further in future iterations. We also discuss the key implications of the universal definition document from the perspectives of various stakeholders within the healthcare framework, including patients, care providers, system/payers and policymakers. With more than 64 million people afflicted worldwide, the prevalence of HF is increasing rapidly within the aging populations of high‐income countries.Unfortunately, there is global ambiguity and subjectivity in the interpretation and definition of what constitutes HF. Such variability has impeded the implementation of therapeutics in clinical practice, communication with patients to facilitate a shared decision‐making approach, and further understanding of the pathology from a research standpoint. In response, leaders from the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and the Chinese Heart Failure Association took the monumental step of proposing a universal definition of HF in 2021.1.1As highlighted in Figure 1.2Current definitions of HF fall short in several ways. First, the hemodynamic component of the definition  is subjective, making it difficult to implement in the public healthcare setting. Despite elevated N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP) levels receiving the highest class recommendations to support the diagnosis of HF1.3HF is defined as a clinical syndrome with symptoms and/or signs caused by structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptides and/or objective evidence of pulmonary or systemic congestion.As described above, a new universal definition of HF (see text box) was recently proposed as part of the consensus document. The universal definition of HF, introduced in 2021, elegantly described HF as above. A new HF staging approach was also proposed Namely, at risk for HF, pre‐HF, HF, and advanced HF in place of the previous stages A–D articulated by the American Heart Association. “At risk for HF” refers to individuals at risk for HF, but without current or prior symptoms or signs of HF and without structural or biomarkers evidence of heart disease; “pre‐HF,” individuals present without current or prior symptoms or signs of HF, but have evidence of structural heart disease or abnormal cardiac function, or elevated natriuretic peptide levels; whilst “HF” patients are defined as those with current or prior symptoms and/or signs of HF caused by a structural and/or functional cardiac abnormality; finally, “advanced HF” patients present with severe symptoms and/or signs of HF at rest, recurrent hospitalizations despite GDMTs, and refractory or intolerant to GDMTs, requiring advanced therapies. Importantly, presymptomatic individuals  are no longer grouped together with those considered to have developed the syndrome of HF , LVEF of 41%–to 49%; “mildly reduced” replacing “mid‐range”;III.HFpEF, LVEF ≥ 50%; andIV.HF with improved ejection fraction (HFimpEF): baseline LVEF ≤ 40% with ≥10‐pt increase from baseline and second LVEF > 40%.The universal definition also proposes a categorical grouping of LVEF based on treatment differences Figure  as folloOne of the key changes includes categorizing LVEF of 40% and below as HFrEF (previous classification: LVEF < 40% as HFrEF), in recognition of trials evaluating important therapeutic targets that have included those with LVEF of 40% as HFrEF and showed therapeutic benefit . To some extent, this bodes well in recognizing patients with HFrEF who may otherwise be missed from the practice of rounding up LVEF to the nearest 5% in echocardiographic lab reports.2The universal definition serves as a necessary consensus definition of HF to standardize the recognition of HF across clinical care and clinical trials. Key merits associated with the universal definition and the new staging are elaborated further in this section.2.1Biomarker‐based diagnosis is becoming increasingly common for disease diagnostic and definition purposes, including the universal diagnosis of MI.Contention remains over the utility of NT‐proBNP as an HF diagnosis “rule‐in” marker because other clinical conditions, besides HF, also affect NT‐proBNP levels. Increased NT‐proBNP levels are also observed in chronic kidney disease, atrial fibrillation, pericardial disease, pulmonary embolism, and, broadly, within the context of the aging heart.2.2There are various noncardiovascular entities that mimic HF, as standalone or coexisting pathology with HF. Renal failure, liver failure, anemia, severe obesity with peripheral edema, and chronic respiratory failure hypoventilation syndrome are some of these competing diagnoses of HF. In acute care settings, patients presenting with congestion and acute dyspnea are often misclassified as HF when often confounded or caused by anemia or iron deficiency.2.3The consensus document formally recognizes those at risk for HF and pre‐HF as “no HF” to avoid the stigma of HF before symptom onsets. Critically, this encourages targeted HF prevention strategies. Asymptomatic stages of HF with patients at risk of HF (formerly referred to as Stage A) and patients with cardiac structural disease or abnormal cardiac function or elevated NPs (former Stage B) are no longer categorized as having HF. Interestingly, the relabeling of HF staging shares several common elements with the TNM staging system (0–IV) for cancer.n = 2029) from Olmsted County, Minnesota, showed that 32% were healthy without HF, 22% in Stage A, 34% in Stage B, 12% in Stage C, and 0.2% in Stage D HF.N = 4470) demonstrated that Stage A HF is poorly recognized and inadequately managed despite one in three American adults  having Stage A HF.Approximately 1.1 million individuals are hospitalized for HF annually, while 6.2 million are diagnosed with HF and 573 million are at risk of HF or pre‐HF.2.4One of the most important aspects of the new staging definition is the recognition of LVEF and clinical trajectory. LVEF is a dynamic measure of cardiac pump function, as is glomerular filtration rate to renal function. Longitudinal changes in LVEF hold important prognostic implications in HF.Clinical status‐based assessments also inform the risk of HF hospitalization or mortality. The Expert Consensus provides a detailed course of action toward optimal therapy based on clinical trajectory during admission for HF, that is, for improved versus stalled after initial response versus not improved/worsened clinical status.2.5The universal definition now allows early detection of patients with high risk for HF as candidates for primary prevention. This is important given that recent longitudinal cohort studies with extensive clinical and cardiac function phenotyping have shed more light on which individuals are most at risk of developing the syndrome.3The consensus document has excellent clinical utility potential with diagnostic, prognostic, and therapeutic validity. As the writing committee plans to refine the universal definition periodically, this offers opportunities to refine the definition of HF further to best guide management strategies. Here, we highlight a few areas that we will be anticipating further guidance on. Particularly, with regard to a more detailed classification of HFpEF, appropriation of congestion values based on clinical characteristics, LVEF in different populations and evolving automated diagnostic capabilities.3.1The universal definition of HF requires the presence of structural and/or functional abnormalities. Typically, the echocardiographic abnormalities that underpin an HFpEF diagnosis, whilst of potential prognostic significance,3.2Contemporary guidelines already recommend using natriuretic peptides in initial screening to diagnose HF. However, they do not recommend using them as a primary confirmatory diagnostic tool.3.3pinteraction = 0.02). As supported by a large cohort study of sex‐specific thresholds of mortality,Several studies have reported on the bimodal distribution of LVEF among patients with incident HF. Contemporary American and European echocardiography guidelines recognize that the normal LVEF range is shifted to (54%–74% in women vs. 52%–74% in men).3.4The clinical and epidemiological utility of LVEF is well‐established but the accuracy of LVEF measurement in clinical practice is debatable. Echocardiography, the most widely used imaging modality of LVEF, incurs an 18%–21% intraobserver and 6%–13% interobserver variability.4This proposed universal definition provides a new platform for understanding, detection, assessment, treatment, and management of patients with HF. As demonstrated in Figure 4.1Any healthcare discussion with an individual at high risk of, or presenting with the syndrome should be focused on heart function, particularly in the early stages of the HF spectrum, that is, at‐risk and pre‐HF. The consensus document provides the opportunity for patient education and advocacy to clarify the stage at which an individual resides based on their actual clinical status. With a better understanding of the clinical progression of HF, patients/care providers may be more inquisitive about management approaches, facilitating shared decision‐making.4.2Individuals with undetected HF exist and continue to grow within our communities. This is largely attributable to a high level of misdiagnosis, missed diagnoses, disparities in access to healthcare, and late presentations to healthcare providers .4.3Most patients presenting with acute HF are first evaluated and managed in emergency departments (EDs). Approximately one million annual ED visits in the United States are for acute HF, incurring nearly $39.2 billion in healthcare expenditure.4.4Cardiologists and HF specialists are instrumental in championing the implementation of this universal definition. Although the ESC guidelines have emphasized the need for a multidisciplinary care to be provided for all patients, throughout the HF trajectory, from acute hospital admission to long‐term follow‐up, the level of adherence/adoption is still low, even in developed countries.4.5Standardized HF definitions allow clinical research data to be captured more accurately and extended beyond their current utility. Specific endpoint detection, such as HF hospitalization, will be feasible from electronic records if data are coded accurately. Harmonization of electronic medical records between regions will also be feasible and machine learning approaches can be utilized to identify cases of HF.4.6Greater resource allocation for primary care and active annual screening for cardiovascular disease should be subsidized and supported. In the United States, the economic burden of the direct and indirect costs of HF in 2012 was US$30.7 billion, with nearly 80% of the cost associated with HF‐related hospitalization.4.7Despite strong evidence and clinical recommendations, the proportion of individuals receiving optimal GDMT is still low. Among 5000 chronic systolic HF patients enrolled in CHAMP‐HF (Change the Management of Patients With Heart Failure) registry, nearly two‐thirds discontinued GDMT or had no changes in dosage despite suboptimal therapy.5The concept of a universal definition of HF is a momentous leap forward in establishing an HF definition that is accepted worldwide, with the goal of early detection, and improving diagnosis and treatment globally. We applaud the Expert Committee of the Universal Definition and Classification of HF for this initiative. Specifically, the inclusion of raised natriuretic peptide levels in the diagnosis of HF elevates the diagnostic standards of HF to be more comprehensive, reliable, and objective. Recognition of patients' clinical trajectory changes in determining optimal therapies also holds critical clinical implications. The standardization of HF nomenclatures is not just a nicety, but a necessity, to avoid therapeutic complacency and promote aggressive management approaches. If implemented effectively, these changes will collectively influence the design of future clinical trials, interpretations of research data, clinician–patient conversations, patient care, and revamp HF management in the years to come.Chanchal Chandramouli reports philanthropic research support from Lee Foundation Singapore and has received consultancy or speaker fees from Us2.ai, Boehringer Ingelheim, and Sanofi Aventis. Simon Stewart is supported by the NHMRC of Australia (GNT 1135894); has received speaking fees or honoraria from Edwards Lifesciences and Novartis; has received consultancy fees from Edwards Lifesciences  and Novartis Australia; reports participation on a data safety monitoring board or advisory board at Edwards Lifesciences. Carolyn Su Ping Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from AstraZeneca, Bayer, Boston Scientific and Roche Diagnostics; has served as a consultant or on the Advisory Board/Steering Committee/Executive Committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc., Us2.ai, Janssen Research & Development LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd., Roche Diagnostics, Sanofi, and WebMD Global LLC; and serves as cofounder and nonexecutive director of Us2.ai. Wael Almahmeed has nothing to declare.