Background: An electrocardiogram (ECG) is a simple and cheap non-invasive tool that shows various abnormalities and has prognostic value for patients with light-chain amyloidosis (AL). The present study aimed to explore the association between ECG characteristics and cardiac magnetic resonance (CMR)-detected amyloid burden and to investigate the prognostic value of ECG in AL amyloidosis.Methods: We prospectively enrolled 99 patients with AL amyloidosis . Detailed clinical information, 12-lead ECG, and CMR data were collected. All patients were followed up longitudinally, and the endpoint was all-cause mortality. ECG characteristics were analyzed and correlated with the degree of late gadolinium enhancement (LGE) and extracellular volume (ECV) by T1 mapping on CMR. The prognostic value of ECG characteristics was analyzed using Kaplan–Meier survival analysis and multivariate Cox regression.Results: During a median follow-up period of 33 months, 69 of the 99 patients died. Fragmented Q wave-R wave-S wave (QRS), pathological Q waves, the Sokolow index, QRS duration, and voltages were significantly associated with the extent of LGE, native T1, and ECV by CMR (p < 0.05). Fragmented QRS and Sokolow index showed independent prognostic value in AL amyloidosis . Fragmented QRS remained independent after adjusting for clinical values . However, no ECG characteristics were independent predictors for prognosis in AL amyloidosis when LGE and ECV were included in the multivariate analysis.Conclusion: ECG abnormalities showed significant association with CMR indicators of amyloid burden. Fragmented QRS has an independent prognostic value in AL amyloidosis and could be used as an alternative marker when CMR is not available. Amyloidosis is a rare systemic disease caused by tissue infiltration of misfolded, insoluble proteins, which leads to multiorgan dysfunction –4. CardiElectrocardiography, as a simple and cheap non-invasive tool, reveals various abnormalities in patients with AL cardiac amyloidosis. Amyloid infiltration in the myocardium can lead to bradycardia, conduction abnormalities, atrial fibrillation, and even sudden cardiac death , 12. OthTo date, cardiac magnetic resonance imaging has been considered an excellent non-invasive test to measure cardiac amyloid infiltration. Late gadolinium enhancement (LGE) , myocardThe present study aimed to identify simple 12-lead ECG characteristics that can stratify disease severity and prognosis in patients with AL amyloidosis.We studied prospectively patients who were diagnosed with systemic AL amyloidosis from September 2013 to December 2018 at West China Hospital. We excluded those patients who did not have any one of the following examinations: laboratory tests, ECG, and contrast-enhanced CMR. We also excluded patients with other potential causes of low-voltage QRS . Furthermore, patients with poor ECG and CMR image qualities were excluded. In total, 99 patients were enrolled into the present study. The diagnosis of AL amyloidosis was confirmed using immunohistochemistry and Congo red staining of a biopsy taken from an involved organ or tissue. Cardiac involvement was defined according to a left ventricle (LV) wall thickness of more than 12 mm with no other potential cardiac cause, as shown by echocardiography or CMR . This stA standard 12-lead ECG was obtained from each patient at the time of the first clinical evaluation after being referred to our center. We measured the Q wave to T wave (QT) interval, QT corrected (QTc) interval, QRS duration, and QRS complex voltages, and analyzed the tracings for atrial fibrillation, atrial flutter, pathological Q waves, and fQRS waves. The QTc interval was corrected by the QT interval for the heart rate based on the formula (QTc = QT/√RR). Voltages were measured in millimeters (1 mm =0.1 mV) after calibration, and the duration was measured in milliseconds (1 mm =0.04 s). A pseudo infarct pattern was defined as a pathological Q wave in at least two adjacent leads without obstructive coronary artery disease or no prior myocardial infarction history. fQRS was defined as the presence of various RSR' patterns and included a notching or additional R or S wave, or the presence of > 1 R′ in two consecutive leads corresponding to a major coronary artery region . The SokAll cardiovascular magnetic resonance imaging was performed using a 3.0-T scanner  using a 32-channel phased-array cardiac coil during breath holding. According to a standardized protocol, steady-state free-precession cine images were obtained in continuous short axes and in the long axis . The parameters were the following: repetition time ms/echo time ms, 3.4/1.3; flip angle, 50°; field of view, 320–340 mm; matrix, 256 × 144; and slice thickness, 8 mm with no gap. Gadolinium-enhanced images were obtained in the same slices of cine images at 10–15 min after injection with gadopentetate dimeglumine . LGE images were acquired using an inversion recovery sequence with phase-sensitive reconstruction. T1 mapping images of three short-axis slices  were obtained using a modified Look-Locker inversion recovery sequence and a fixed 5 (3) 3/4 (1) 3 (1) 2 scheme. Post-contrast T1 mapping was repeated using the same prescription as the pre-contrast T1 mapping at 15 min after contrast agent injection .Ventricular volumes, masses, and ejection fractions were assessed from the short-axis images with the QMass v7.6 software . Papillary muscles were included as part of the ventricular volumes and were excluded from the myocardial mass. Ventricular volumes and LV mass were standardized by the body surface area.* [(1/T1myo post-1/T1myo pre)/(1/T1 blood post-1/T1 blood pre)]. Mean ECV, myocardial native T1 (T1myo), and post T1 were acquired as the averages of the ECV and myocardial T1 values at two slices, respectively.LGE types were divided into three groups using the following criteria: (1) no or non-specific LGE; (2) sub-endocardial LGE; and (3) transmural LGE , 25. NatThe endpoint for this study was defined as all-cause mortality. Mortality was assessed by medical records or phone interviews with the patient's family. There was no loss of follow-up in the entire cohort. The patients were followed up until 6 August 2019 or censored if they were alive.n, %) for categorical variables. Differences between groups were tested using Student's t-test or one-way ANOVA for continuous variables and using Fisher's exact test or the χ2 test for categorical variables, as appropriate. The statistical comparison between groups was performed using scatter plots and histograms to describe the trend of variables. Kaplan–Meier curves and multivariate Cox proportional hazard regressions were used for the survival analyses. All variables with a p < 0.05 in the univariate Cox regression were included in the stepwise multivariate Cox regression analysis. All tests were two-sided, and p < 0.05 was considered to be statistically significant. SPSS statistical software  and GraphPad Prism  were used for all statistical analyses.Data were expressed as the mean ± standard deviation (SD) for continuous variables and number and percentage : 9,350 pg/ml vs. 4,054 pg/ml, p < 0.001] and were more likely to have fQRS  . There were no significant differences in age, sex, body surface area (BSA), heart rate, myocardial markers, creatinine, estimated glomerular filtration rate (eGFR), serum free light chains, hematocrit, and other ECG parameters, such as the QTc interval and the total limb and precordial lead voltages. Other patient clinical characteristics and CMR data are reported in Of the 99 patients  included in this study, 69 patients died, and a total of 88 patients were diagnosed with cardiac involvement. Apart from a low Sokolow index (73.7%), we found that the common ECG abnormalities were fQRS (63.3%) , followe< 0.001) . In addip < 0.01) (p = 0.004). However, there was no significant difference among the three groups with regard to atrial fibrillation, atrial flutter, and or total precordial lead voltages.In the present study, 31 (31.3%), 20 (20.2%), and 48 (48.5%) patients had no or non-specific, subendocardial, or transmural LGE patterns, respectively. There were significant differences in fQRS, pathological Q waves, QTc interval, QRS duration, total limb lead voltages, or the Sokolow index among the three LGE groups ( < 0.01) . More se < 0.01) . For ther = −0.5254, p < 0.0001; r = −0.4758, p < 0.0001) (p < 0.05)  . A simil 0.0001) . Moreove < 0.05) .2 = 13.152, hazard ration (HR) 2.471, P = 0.001] and Sokolow index  were independent predictors. The Kaplan–Meier curves for fQRS and the Sokolow index indicated that the absence of fQRS and a normal Sokolow index were associated with better outcomes among patients with AL amyloidosis , 1.190–3.234; p = 0.008] were independent prognostic factors.In the univariate Cox regression analysis of the ECG data, the variables that were associated significantly with mortality were the presence of fQRS or pathological Q waves, QRS duration, the Sokolow index, and total limb lead voltages. In the multivariate analysis , only fQloidosis . After aloidosis . When weloidosis . The finThis study investigated the ability of ECG parameters to detect the degree of cardiac involvement in AL amyloidosis and explored the prognostic value of ECG in comparison with CMR. The main study findings were as follows: (1) ECG characteristics in AL amyloidosis were associated significantly with cardiac amyloid burden, as reflected by LGE extent and T1 mapping; (2) both fQRS and a low Sokolow index were significant independent predictors for the survival of patients with AL amyloidosis; (3) fQRS was a significant independent prognostic marker and could be a simple and alternative prognostic factor, especially when CMR is not available.With recent increasing awareness and improved screening technology, the contemporary estimate of the prevalence of AL amyloidosis is 18–55 cases per 100,000 person-years, leading to ~8% of heart failure hospitalizations within the previous year . CardiacGenerally, patients with AL amyloidosis and arrhythmic manifestations might have more advanced disease and worse prognosis . AssessiFragmented QRS morphologies are believed to represent conduction block caused by myocardial necrosis or scarring in either ischemic or non-ischemic cardiomyopathy , 22, 32.The present study had several limitations. First, this was a single-center study and included a relatively small population, which is unsurprising, given the rarity of AL amyloidosis. Second, the cardiac amyloid burden was assessed using non-invasive CMR because a minority of patients underwent endomyocardial biopsy. Currently, LGE and T1 mapping are considered powerful tools to assess cardiac amyloid involvement. Third, we excluded some patients whose CMR and ECG imaging were poor, which might have induced bias. Fourth, the ECG parameters that we used were within the limits of commonly evaluated abnormalities on the ECG; however, there might be other potential values measured by ECG that should be explored.We demonstrated that 12-lead ECG is a simple tool to stratify myocardial infiltration in patients with AL and might provide useful information when CMR is not available. Fragmented QRS is an independent prognostic marker for a poor outcome, providing important risk stratification of patients with AL amyloidosis.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Institutional Ethics Committee of West China Hospital, Sichuan University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.XG, ZC, KW, RS, QZ, YH, and YC: guarantors of integrity of entire study. XG, ZC, KW, YH, and YC: literature research. XG, ZC, RS, TY, YX, QZ, and YC: clinical studies. XG, ZC, KW, and YH: statistical analysis. XG, ZC, KW, QZ, YH, KA, and YC: manuscript editing. All authors: study concepts/study design, data acquisition, data analysis/interpretation, manuscript drafting, manuscript revision for important intellectual content, approval of final version of submitted manuscript, and agreed to ensure any questions related to the work were appropriately resolved.This work was supported by a grant from the Project for Disciplines of Excellence, West China Hospital, Sichuan University [Grant No. ZYJC18013].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.


Secondary mitral regurgitation (MR) in patients with heart failure with reduced ejection fraction (HFrEF) portends a poor prognosis when it occurs.Mitral valve TEER for HFrEF patients has been studied in two major trials, COAPTWhile both trials required patients to be on maximally tolerated GDMT, COAPT evaluated for this measure under the review of a central committee of experts while MITRA‐FR relied on local center approval.There is overwhelming evidence that neurohormonal modulation by GDMT leads to reverse cardiac remodeling with resultant reduction in left ventricular size and volume, leading to reduction of MR severity and improvement in functional status.Angiotensin receptor‐neprilysin inhibitors (ARNI), Entresto® (Novartis), have been a significantly potent therapy in patients with HFrEF.Another breakthrough in medical therapy have been the SGLT‐2i, which have demonstrated significant benefit in both diabetic and non‐diabetic patients with HFrEF as seen in the seminal DAPA‐HF trial.p < .001), LV end systolic volume  and LV mass . Decreased LV sphericity, increased LVEF , and increase in 6‐min walk distance  were also noted, providing strong evidence for quick LV reverse remodeling and functional benefit occurring within the 6 month study period. MR was not reported but improvement can be inferred from reduction in LV size and a dramatic improvement in symptoms based on the Kansas City Cardiomyopathy Questionnaire . Finally, the effects of SGLT2i in HFrEF are conveniently achieved at the initial dosage and up‐titration is not required.First, SGLT2i provide an impressive reduction in rehospitalization and all‐cause mortality, 25% and 13% in metanalysis, which would potentiate beneficial effects of mitral valve TEER.In conclusion, the diverging results of COAPT and MITRA‐FR clearly demonstrate TEER for secondary MR was effective after optimal medical therapy for HFrEF as it stood several years ago. Now SGLT2i have emerged as the newest pillar of management in HFrEF, with a likely class effect shown by the DAPA‐HF and EMPEROR‐reduced trials. On the backbone of BB, RAAS‐I/ARNI and MRA, SGLT2i promote significant symptomatic, morbidity, mortality, and LV reverse remodeling benefits. As medical therapy for HFrEF continues to evolve, reserving mitral valve TEER for patients with persistent MR on modern regimens is logical and should be confirmed with future studies.Dr Marcella A. Calfon Press is a proctor for Mitraclip® (Abbott). Dr Ali Nsair and Dr Neal M. Dixit have nothing to disclose.


Purpose: Asymmetric cerebral representation of autonomic function could help to stratify cardiac complications in people with epilepsy, as some seizures are associated with potentially deleterious arrhythmias including bradycardia and atrioventricular (AV) conduction block. We investigated seizure-related changes in AV conduction and ascertained whether these alterations depend on the hemisphere in mesial temporal lobe epilepsy (mTLE).Methods: EEG and ECG data of people with pharmacoresistant mTLE undergoing pre-surgical video-EEG telemetry with seizures independently arising from both hippocampi, as determined by intracranial depths electrodes were reviewed. RR and PR intervals were measured using one-lead ECG. Statistics were done with paired student's t-tests and linear regression analysis. Data are given as mean ± SD.Results: Fifty-six seizures of 14 patients  were included (2 seizures per hemisphere and patient). There were no differences of absolute PR intervals and HR before and during unilateral ictal activity between left- and right-sided hippocampal seizures. Peri-ictal modulation of AV conduction, however, appeared greater with left-sided seizures, as the slope of the PR/HR correlations was significantly steeper with seizures originating in the left hippocampus. PR lengthening >200 ms or full block did not occur in any seizure.Conclusions: Our data show that on average, PR intervals shortens with mesial temporal lobe seizures with more prominent effects in seizures with left-sided onset, supporting the notion of lateralized cerebral control of cardiac function. The clinical relevance of this subtle finding is unclear but may indicate a lateralized susceptibility to seizure-related AV node dysfunction in mTLE. Given the intricate overlap of regions involved in the central autonomic nervous system (CAN) and networks that generate or maintain epileptic activity, seizures are frequently accompanied by alterations of cardiac properties and heart activity , 2. ThesPrevious studies have predominantly reported increases and decreases of sinus node activity with subsequent changes in heart rate (HR) as well as lengthening or shortening of cardiac repolarization and QT intervals in association with seizures , 5. WhilIn view of these observations, we hypothesized that seizure-related modulation of AV conduction depends on the side of ictal activity. Such an asymmetric representation of AV node control may serve as lateralizing hint during assessment of seizure-onset zone, but may also help to identify people at an elevated risk for ictal AV block and asystole. In the present study, we investigated seizure-related changes in AV conduction in patients with medically refractory bilateral mTLE who underwent intracranial video-EEG telemetry for pre-surgical diagnostics.This study is a retrospective audit of EEG and ECG data recorded during standard clinical procedures and was approved as such by the local medical ethics committee . Patient data of a 12-year period (2000–2011) collected at our tertiary epilepsy center  were reviewed. All patients suffered from pharmacoresistant mTLE and underwent pre-surgical video-EEG telemetry, with seizures arising from both hippocampi, as assessed by intracranial EEG recordings with depth electrodes. Patients with known cardiac diseases were excluded.A total of 205 patients with bilateral hippocampal electrodes was eligible. Of these, 32 patients displayed hippocampal seizures with onsets from both hemispheres and 14 patients showed at least two seizures from each hippocampus and had EEG- and ECG-recordings of sufficient quality  to be included in the final analysis , Table 1preictal: 1 min before EEG seizure-onset, early ictal: within the first seconds of seizure activity and late ictal: at the end of the unilateral course of the seizure, before spread to the contralateral side or seizure termination). The respective values of RR and PR interval were calculated as a mean of 2–3 successive ECG intervals. After calculating HR values from RR intervals, statistical analyses were performed to compare preictal and ictal data of seizures originating from the left and right hippocampus using paired student's t-tests. Furthermore, a bivariate linear regression of HR and PR intervals for right and left-sided seizures was performed. Resulting correlations were considered as a measure of peri-ictal modulation of AV conduction. Analyses and graphs were generated using GraphPad Prism 4 . The data underlying the study are available from the corresponding author on reasonable request.RR and PR intervals were manually determined at different timepoints (Recordings of 56 seizures (2 seizures per hemisphere and patient) in 14 patients with refractory mTLE  were analyzed. Hippocampal sclerosis was found in 12 patients , 2 patients had no apparent lesions .t = −7.34, df = 27, p < 0.001) and right-sided  hippocampal seizures.Changes of HR were observed during all seizures . In 64.3At the level of individual patients, PR intervals during seizures were consistently shortened  in right-hippocampal seizures of 4 patients and left-hippocampal seizures of 3 patients. Consistent lengthening of PR intervals was found in right-hippocampal seizures of 5 patients and left-hippocampal seizures of 4 patients. Consistent shortening of PR intervals of all seizures of both sides was not observed in any patients, whereas consistent lengthening of PR intervals in all 4 seizures was seen in 1 patient.t = −0.13, df = 54, p = 0.894; HR: left 84 ± 15 bpm, right 83 ± 13 bpm, t = 0.07, df = 54, p = 0.947) as well as during early  or late  unilateral seizure activity , there were no significant differences between left- and right-sided hippocampal seizures regarding absolute PR intervals and HR before (PR intervals: left 146 ± 20 ms, right 146 ± 24 ms, activity . Peri-icIn this retrospective clinical study, peri-ictal PR intervals and HR were assessed in patients with pharmacoresistant bilateral mTLE. Importantly, these patients were bilaterally implanted and at least two seizures per side were registered, allowing a comparison between left-and right-hippocampal seizure-related changes of PR intervals, and minimizing the effects of inter- and intra-individual variability. Moreover, the simultaneous iEEG-ECG recording provides optimal ECG resolution regarding time and localization of seizure onsets. While this investigation of seizure and hemisphere related changes of PR-Intervals follows an original approach, it does not come without limitations. Firstly, several other regions involved in the CAN such as the insular cortex, hypothalamus, thalamus and cingulate gyrus were not covered by intracranial EEG electrodes, so that spreading of ictal activity could not be recorded and excluded . SecondlIn-vivo experiments in rodents and neuroimaging studies in humans provide structural correlates that link the left mesial temporal lobe to the control of cardiac properties. At the brain stem level, the nucleus ambiguus and raphe nuclei are involved in the modulation of AV conduction (As expected, all seizures were associated with alterations of HR, mainly chronotropic changes with tachycardia, or mixed patterns, supporting the notion of the hippocampus as an important element within the CAN. Overall, the absolute changes of HR and PR intervals were similar in seizures originating from the left and right hippocampus. Previous studies in apparently healthy subjects revealed an inverse correlation between PR intervals and HR, i.e., PR intervals shorten with increasing HR . Intrigunduction –12 whichnduction , which mIn conclusion, left-hippocampal seizures appear to be linked to greater changes in cardiac repolarization and AV conduction . These aThe data underlying the study are available from the corresponding author on reasonable request.The studies involving human participants were reviewed and approved by Medinizische Fakultaet Bonn. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.LMB and AJ have collected and analyzed data. MP has analyzed the data and drafted the manuscript. RS has designed and supervised the study. All authors have reviewed the draft.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.


It is unclear whether clinical benefits of cardiac resynchronization can be achieved by pacing only the left ventricle.We aimed to compare the effect of a novel adaptive left ventricular‐only fusion pacing (LVP) on ventricular function with conventional biventricular pacing (BVP) in cardiac resynchronization therapy (CRT) indicated patients.This prospective, randomized, multicenter study enrolled CRT‐indicated patients with PR interval ≤ 200 ms who were randomized in the adaptive LVP group  or the echocardiography‐optimized BVP group. Cardiac function and echocardiography were evaluated at baseline and follow‐ups. CRT super response was defined as two‐fold or more increase of left ventricular ejection fraction (LVEF) or final LVEF >45%, and LV end‐systolic volume (LVESV) decrease >15%, and New York Heart Association (NYHA) class improved by at least one level.Sixty‐three patients were enrolled in the study (LVP = 34 vs. BVP = 29). At 6‐month follow‐up, significant improvements in LVEF, LVESV, and NYHA class were observed in both groups. The CRT super response rate was significantly higher in patients with high‐percentage adaptive LV‐only pacing in LVP group (68.4%) than in BVP group .Adaptive LV‐only pacing was comparable to BVP in improving cardiac function and clinical condition in CRT‐indicated patients. This finding raises the possibility that an adaptive LVP algorithm with appropriate right ventricular sensing to fuse with intrinsic right ventricular activation in a two‐lead (right atrium and left ventricle) device may provide clinical benefit in a subset of CRT patients with intact atrioventricular conduction. Inclusion criteria were (1) aged between 18 and 80 years old; (2) NYHA class II or III after guideline‐directed medical treatment for at least 3 months; (3) LVEF ≤35%; and (4) sinus rhythm, LBBB pattern with QRSd ≥150 ms and intrinsic PR interval ≤200 ms. Exclusion criteria included severe hepatic or renal dysfunction, persistent atrial fibrillation, AV block, upgrade from a pacemaker or defibrillator device, valvular heart disease, pregnancy, inability to give informed consent or to perform the follow‐up assessments. The establishment of this study was approved by the Ethical Committees of Shanghai Zhongshan Hospital, Fuwai Hospital, Zhejiang Greentown Cardiovascular Hospital, The First Affiliated Hospital of Nanjing Medical University, and The First Affiliated Hospital of Xinjiang Medical University. All procedures followed the ethical standards of the Ethical Committees and in line with the 1964 Helsinki Declaration. Written informed consent of clinical information collection and follow up was acquired from each patient at admission.2.2http://www.clinicaltrials.gov under the identifier NCT03071978.This study is a prospective, multicenter, randomized, controlled clinical trial. Consented patients who fulfilled inclusion and exclusion criteria were enrolled and randomly assigned to LVP or BVP group. Randomization was performed among all patients. Centralized random sequence was generated from natural number with odd or even number standing for LVP or BVP group, then site staff would assign each patient to a corresponding group and intervention per random sequence. Ethics committee approvals were obtained in all study sites. Written informed consent was obtained from each patient. The study was registered at All enrolled patients received CRT devices featured with the AdaptivCRT™ algorithm  according to clinical demands. The AdaptivCRT algorithm2.3Assessments of cardiac function and clinical outcomes were conducted at 3‐ and 6‐month follow‐ups. The primary endpoint was the improvement in LVEF; the secondary endpoints included (1) NYHA class and 6 min walking distance (6MWD); (2) QRSd; and (3) LV end‐systolic volume (LVESV), LV end‐diastolic volume (LVEDV), LV end‐systolic dimension (LVESD), and LV end‐diastolic dimension (LVEDD) by echocardiographic assessments.Echocardiographic measurements were performed with a commercially available system . Echocardiographic data were recorded for at least three consecutive cardiac cycles. LVEF, LVESV, and LVEDV were measured by Simpson's biplane method from the apical four‐chamber view. Parameters were analyzed with a consistent protocol in a core laboratory. CRT response was defined as an absolute increase of LVEF >10% or a relative decrease of LVESV >15% or NYHA class improved by at least one level at 6‐month follow‐up compared to baseline value. In addition, CRT super response2.4t‐test or Wilcoxon signed‐rank test. For comparisons of continuous variables between the LVP and BVP groups, independent Student's t‐test or Mann–Whitney U test was applied. Categorical variables were compared using the chi‐square test or Fisher's exact test. Statistical significance was defined as a p < .05. All analyses were performed with SPSS software .Continuous variables were presented as means ± standard deviation, and categorical variables as numbers and proportions. Continuous variables were compared between baseline and 3‐/6‐month follow‐up using paired Student's 33.1n = 34) or echocardiography‐optimized BVP group (n = 29). Study follow‐ups were completed in Jan 2019. The numbers of loss of follow‐up at 6 months were three in LVP group and two in BVP group  and 6 months (p < .001). Meanwhile, comparable results were observed between two groups at both 3‐month (p = .50) and 6‐month (p = .88) follow‐ups Figure . Specifi3.3In this study, the AdaptivCRT algorithm was enabled in LVP group to avoid RV pacing. Of 31 patients in LVP group, 25 had a high percentage of adaptive LV pacing that well fused with intrinsic RV activation  within 6 months. On the contrary, the remaining six patients had an average BVP percentage = 88.5%  because AdaptivCRT algorithm could automatically switch the pacing mode to BVP when intrinsic RV conduction was failed to sense within default periodical check. Given that RV pacing output was set to the minimum for nonfunctional pacing, these six patients received LV‐only pacing without fusion with intrinsic RV activation (low‐aLVP% subgroup).Subgroup analysis revealed significant improvement of LVEF and LVESV at 6 months in both subgroups, compared to baseline, respectively. However, significant improvements in QRSd, NYHA class, and 6MWD were observed in high‐aLVP% at 6 months, but not in low‐aLVP% subgroup. Furthermore, comparing to the BVP group, the high‐aLVP% subgroup had significantly greater improvements in LVEF, NYHA (both p < .01) and QRSd (p < .05) at 6 months and a trend of better decrease in LVESV  or device detected non‐sustained ventricular/supraventricular tachycardia episodes (four out of six), letting the AdaptivCRT algorithm automatically switched to BVP mode. Heart failure related medication remains unchanged for these patients during follow‐up. As there was no functional RV pacing, these patients still had LV‐only pacing but without fusion with natural RV activation. Comparable improvements were observed in these six patients compared to the BVP group. Given the significant improvement of clinical outcomes in high‐aLVP% subgroup, the hypothesis was confirmed that LVP was at least equivalent to BVP. This was consistent with earlier studies showing no differences in major clinical outcome measures, including LVEF, NYHA class and 6MWD, between LVP and BVP.4.1This study is the first prospective randomized multicenter clinical study to assess the feasibility of LV‐only pacing fused with intrinsic RV activation in CRT‐indicated patients. The favorable clinical results by LVP are comparable to conventional BVP and even better in patients with a high percentage of adaptive LVP. This study provided clinical evidence for a novel pacing mode, that is, LVP with an adaptive algorithm to optimize the fusion by continuously adjusting LV pacing timing to leverage intrinsic RV conduction and achieve dynamic and physiologic pacing. The positive results raise the possibility that cardiac resynchronization could be achieved by a novel two‐lead pacemaker system, that is, the right atrial pacing lead and LV epicardial pacing lead. In order to create a two‐lead LV‐only pacing system with the novel LV fusion pacing approach, the pacing lead in the right atrium and/or LV epicardium would be capable of sensing the RV activation, which would require a new type of sensing configuration. Furthermore, LVP may increase device longevity due to no RV pacing compared to BVP, which is in line with prior research.4.2The present study has some limitations. First, this pacing approach is not suitable for CRT‐indicated patients without LBBB or persistent atrial fibrillation. Defibrillation is not applicable for this pacing approach. In addition, LV‐only pacing without fusion that leads to less improvement in cardiac function might be a result of prolonged intrinsic PR interval or ventricular/supraventricular tachycardia. Therefore, more research is warranted to investigate adaptive LVP in these status. Meanwhile, the sample size of patients enrolled in this feasibility study is relatively small. Longer follow‐up is warranted to better assess hospitalization and mortality of adaptive LVP compared to conventional BVP.5The present study demonstrated comparable clinical outcomes between adaptive LVP group and conventional BVP group. Moreover, our study found that high‐percentage adaptive LVP was significantly associated with better clinical outcomes and a higher CRT super response rate than BVP. This finding raises the possibility that an adaptive LVP algorithm with appropriate RV sensing to fuse with intrinsic RV activation in a two‐lead (right atrium and LV) device may provide clinical benefit in a subset of CRT patients with intact AV conduction.Yangang Su, Wei Hua, Farong Shen, Jiangang Zou, Baopeng Tang, and Keping Chen have received research grants from Medtronic. Shu Zhang has received consulting fees from Boston Scientific, Medtronic, St. Jude Medical, and Biotronik. Xiaohong Zhou, Xue Zhang and Hongyang Lu are employees of Medtronic. Yixiu Liang and Lang He have no competing interest to disclose.


To compare the diagnostic efficiency of the mono-exponential model and bi-exponential model deriving from intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) in differentiating the pathological grade of esophageal squamous cell carcinoma (ESCC).mono, D*mono, and fmono) and bi-exponential fit parameters  were calculated using the IVIM data for the tumors. Mean parameter values of three groups were compared using a one-way ANOVA followed by post hoc tests. The receiver operating characteristic curve was drawn for differentiating pathological grade of ESCC. Correlations between pathological grades and IVIM parameters were analyzed.Fifty-four patients with ESCC were divided into three groups of poorly-differentiated (PD), moderately-differentiated (MD), and well-differentiated (WD), and underwent the IVIM-DWI scan. Mono-exponential . The fmono were 0.32 ± 0.07, 0.23 ± 0.08, and 0.16 ± 0.05, respectively, and the fbi were 0.35 ± 0.08, 0.26 ± 0.10, and 0.18 ± 0.07, respectively. There was a significant difference in the Dmono between the WD and the PD group , but there was no significant difference between the WD and MD groups, MD and PD groups . The D*mono, Dbi, and D*bi showed no significant difference among the three groups . The area under the curve (AUC) of Dmono, fmono and fbi in differentiating WD from PD ESCC were 0.764, 0.961 and 0.932, and the sensitivity and specificity were 92.9% and 60%, 92.9% and 90%, 85.7% and 100%, respectively. The AUC of fmono and fbi in differentiating MD from PD ESCC were 0.839 and 0.757, and the sensitivity and specificity were 78.6% and 80%, 85.7% and 70%, respectively. The AUC of fmono and fbi in differentiating MD from WD ESCC were 0.746 and 0.740, and the sensitivity and specificity were 65% and 85%, 80% and 60%, respectively. The pathologically differentiated grade was correlated with all IVIM parameters .There were significant differences in fThe mono-exponential IVIM model is superior to the bi-exponential IVIM model in differentiating pathological grades of ESCC, which may be a promising imaging method to predict pathological grades of ESCC. Diffusion-weighted imaging (DWI) is a quantitative technology for evaluating the water motion of tissues without injecting contrast agents . It is aDespite these promising studies, the accuracy and reliability of IVIM parameters are still challenged by a variety of fitting methods, such as the full fitting and segmented fitting method –19. The Therefore, the purpose of the present study is to determine whether the bi-exponential or mono-exponential fit model of IVIM can be used to distinguish the pathological grade of esophageal squamous cell carcinoma (ESCC), and which fitting model is more suitable for the pathological grade of ESCC.The study was approved by the ethics committee of the Affiliated Hospital of North Sichuan Medical College. Written informed consent was obtained from each participant. From January 2016 to February 2018, 68 consecutive patients with ESCC were enrolled in the present study according to the following inclusion criteria: patients with ESCC were confirmed by endoscopic pathology; and patients have not undergone any treatment for this disease before, such as radiotherapy, chemotherapy, and surgery; and MRI scan and IVIM-DWI were performed using the same magnetic resonance instrument. Fourteen patients were excluded, and the exclusion criteria were as follows: the patients had contraindications to MRI, or patients had a greater area of internal necrosis caused by lesions, or the images had severe motion artifacts. Finally, 54 cases of ESCC were included in this study.The degree of pathological differentiation of the tumors was divided into poorly-differentiated (PD), moderately-differentiated (MD), and well-differentiated (WD) ESCC groups, and the T stage of tumors and tumor location  were determined according to the seventh edition guidelines of American Joint Committee on Cancer Stage .2, respectively. The corresponding number of excitations were 2, 2, 2, 2, 2, 2, 2, 4, 6, 8, respectively. The total scan time of IVIM-DWI was about 8 minutes.MRI was performed using a 3.0T magnetic resonance instrument  with 32-channel phased-array body coil. Before the examination, patients were asked to fast for six hours and conduct shallow slow breath training, and to remove all metal objects. The patients were in a supine position and did not swallow during the examination. Patients were placed foot first, and supine with arms extended above their heads. The shimming was adopted to reduce gas interference before IVIM-DWI scanning. The respiratory-triggered technique and saturation suppression technology were used to avoid motion artifacts and guarantee the image quality of IVIM-DWI scans. The scanning parameters of IVIM-DWI are as follows: repetition time =6315.8 ms, echo time =58.2 ms, the thickness of layer 4 mm, interlay spacing 1.0 mm, the field of view =34 cm×34 cm, and matrix = 96×128. The ten b values were 0, 30, 50, 80, 150, 200, 400, 600, 800, 1000s/mmOther sequences, such as the axial acquisition with volume acceleration-flexible T1-weighted imaging, respiratory-triggered axial propeller T2-weighted imaging (T2WI) with fat suppression, and axial single-shot fast spin-echo T2WI were also performed as routine work.2 to 55 mm2. Then, the software automatically generated the true diffusion coefficient (D) map, pseudo-diffusion coefficient (D*) map, and pseudo diffusion fraction (f) map and the corresponding parameters derived from the IVIM model. The deriving parameters of the mono-exponential model include Dmono, D*mono, and fmono, and the deriving parameters of the bi-exponential model include Dbi, D*bi, and fbi. It was measured by radiologists with 5 years of experience, and the average values of each parameter were taken.All the IVIM-DWI data were sent to GE Advantage Windows 4.5 Workstation for processing, using FuncTool software to obtain the ADC map in post-processing. IVIM-DWI and MADC maps were obtained after the images of adjacent fat, bone and gas were removed based on the definition of the diagnostic threshold. The region of interest (ROI) was drawn on the solid tumor components per MR image and three consecutive sections were selected by T2WI imaging for the measurement. Three ROIs were drawn on each section. Meanwhile, identification of a selection of the representative tumor tissue for ROI positioning was defined with the most cellularity part, and ROI was placed to cover as much of the solid part of the tumors as possible and to avoid cystic degeneration, necrosis, hemorrhage, and normal vessels to the greatest extent . The areIVIM parameters have a variety of calculation methods, including the Levenberg-Marquardt algorithm, segmentation constrained, bayesian probability, etc , 24. TheD represents the true diffusion coefficient, D* represents the pseudo-diffusion coefficient, and f represents the microvascular volume fraction.Sb is the signal intensity under a given b value, S0 is the signal intensity without diffusion weighting. The 2) and a relatively low b-value part  (–2), since D* is significantly greater than D, the effects of D* on the signal attenuation can be ignored  . When th ignored , 25, 26.The curve of the high b-value data is considered as mono-exponential decay by equation [2], and the D value can be acquired with a simple linear fitting by equation [2]. The fitted curve was then extrapolated to get the intercept at b = 0. The f value was given through equation f= (S0-Sb)/S0 by the ratio of the intercept to the DWI data point at b = 0 . After sThe bi-exponential IVIM model is a full fitting of DWI signals to the bi-exponential function , 28, 29.post hoc with the least significant difference test was used. If the data was not a normal distribution, the Kruskal–Wallis test was used. Spearman’s rank correlation was used to analyze the correlation between IVIM parameters and pathological grade. Receiver Operating Curve (ROC) was drawn to evaluate the diagnostic efficiency of each parameter and to determine the diagnostic threshold value for the grading of ESCC. If the AUC is ranged from 0.5 to 0.7, then it is regarded as a low diagnostic value. If the AUC is ranged from 0.7 to 0.9, it is regarded as a moderate diagnostic value. If the AUC is greater than 0.9, it is regarded as a high diagnostic value. The two-tailed p-value less than 0.05 is considered statistically significant.Statistical analyses were performed by SPSS22.0 software  and MedCalc software Version 18.11 . Quantitative data were expressed in terms of mean ± standard deviation (¯x ± SD). The Shapiro-Wilks test was used to test the normality of distributions. If the data was a normal distribution, analysis of variance (ANOVA) was used to test the significant difference of IVIM parameters among three groups, and then There were 54 patients with diagnosed ESCC . There were 14 PD, 20 MD, and 20 WD ESCC by pathologically differentiated grade. There were 25 cases in stage T3, and 29 in stage T4. The tumors were located in the lower esophagus in 14 cases, the middle esophagus in 35, and the upper esophagus in 5.mono, fmono, and fbi among the WD group, MD group, and PD group , whereas there was no difference in D*mono, Dbi, and D*bi . Detailed results were shown in The ANOVA tests showed that there were significant differences in Dmono among the PD, MD, and WD groups .For the mono-exponential fit parameters, there were significant differences in fbi among the PD, MD, and WD ESCC groups .For the bi-exponential fit parameters, there were significant differences in fmono, fmono, and fbi in differentiating WD from PD ESCC were 0.764, 0.961, and 0.932  values of Dnd 0.932 Figure 2mono  and D*mono , and correlated negatively with fmono values .For the mono-exponential model parameters, the pathologically differentiated grade correlated positively with the Dbi , D*bi , and correlated negatively with fbi values .For the bi-exponential model parameters, the pathologically differentiated grade correlated positively with the Din vivo water molecules movement. For reasons that capillary perfusion and the diffusion associated with microcirculation perfusion have a great effect on signal attenuation , and the Science and Technology Development Plan of North Sichuan Medical College .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.


LV pressure-volume relations were recorded. The primary end point was LV end-diastolic pressure (LVEDP). Secondary end points included indices of LV systolic and diastolic function. Intracoronary nitrite infusion induced a significant reduction in LVEDP, LV end-diastolic pressure-volume relationship (EDPVR), and the time to LV end-systole (LVEST) but had no significant effect on LV systolic function or systemic hemodynamics. Intravenous nitrite infusion induced greater effects, with significant decreases in LVEDP, EDPVR, LVEST, LV dP/dtmin, tau, and mean arterial pressure. Inorganic nitrite has modest direct effects on human LV diastolic function, independent of LV loading conditions and without affecting LV systolic properties. However, the systemic administration of nitrite has larger effects on LV diastolic function, which are related to reduction in both preload and afterload. These contractile effects of inorganic nitrite may indicate a favorable profile for conditions characterized by LV diastolic dysfunction.Inorganic nitrite is a source of nitric oxide (NO) and is considered as a potential therapy in settings where endogenous NO bioactivity is reduced and left ventricular (LV) function impaired. However, the effects of nitrite on human cardiac contractile function, and the extent to which these are direct or indirect, are unclear. We studied 40 patients undergoing diagnostic cardiac catheterization who had normal LV systolic function and were not found to have obstructive coronary disease. They received either an intracoronary sodium nitrite infusion (8.7–26 µmol/min, NEW & NOTEWORTHY This is the first study to assess the direct and indirect effects of inorganic nitrite on invasive measures of left ventricular function in humans in vivo. Inorganic nitrite has a modest direct myocardial effect, improving diastolic function. Systemic administration of nitrite has larger effects related to alterations in cardiac preload and afterload. The changes induced by nitrite appear favorable for potential use in conditions characterized by LV diastolic dysfunction. Acconitrates , 4. Inornitrates –7 and venitrates . In the nitrates . When ginitrates , 10 and nitrates . Previounitrates , 13, pulnitrates , cerebranitrates , and impnitrates , 17.Endogenously generated NO induces direct acute effects on the onset of myocardial relaxation and on diastolic distensibility, independent of changes in systolic function or systemic loading. A selective NO- and cGMP/protein kinase G (PKG)-dependent earlier onset of relaxation without change in systolic function was found in isolated mammalian cardiomyocytes and isolated hearts , 19. NO n = 40) with suspected coronary artery disease who were referred for diagnostic coronary angiography. All subjects were known to have normal left ventricular systolic function on echocardiography. Written informed consent was obtained before cardiac catheterization, and the research study was performed at the end of the diagnostic procedure if there was an absence of significant epicardial coronary artery disease . Patients were also excluded if they had heart failure , clinically significant valve disease, or had a history of glucose-6-phosphate dehydrogenase deficiency. Patients were required to be in sinus rhythm at the time of assessment, with atrial fibrillation and ventricular bigeminy/trigeminy being considered excluding factors. The study complied with the Declaration of Helsinki and was approved by the Institutional Ethics Committee (Reference: 12/LO/1067).Invasive LV pressure-volume (PV) studies were performed on patients (n = 20) or intravenous nitrite infusion (n = 20). Radial or femoral arterial access was used for diagnostic coronary angiography at the discretion of the operator. A second arterial puncture was required for patients receiving intracoronary infusion. All patients received unfractionated heparin , with additional doses as required to maintain an activated clotting time (ACT) of >250 s.We studied either intracoronary nitrite infusion  at 8.7 µmol/min for 5 min, followed by 26 µmol/min for 5 min. The higher dose is estimated to achieve a maximal intracoronary concentration of ∼1,000 µM, using average resting coronary blood flow estimates, as described previously , which represents the proportion of blood ejected from the LV from the onset of systole to the time of the first peak of LV pressure. EF1 has been suggested as an index that assesses systolic function early during contraction and reflects systolic-diastolic coupling , 27.Previous work reported that a bicoronary infusion of sodium nitroprusside induced a decrease in LV end-diastolic pressure (LVEDP) from 18 ± 5 to 12 ± 3 mmHg , equatinn, number of participants. Intracoronary data were compared by repeated measures of ANOVA with Tukey’s posttest for multiple comparisons . Student’s t test was used to compare the intravenous data and the effect of intracoronary versus intravenous nitrite on PV parameters (change from baseline). Linear regression analysis was used to test for correlation between measures of LV structure and changes in the primary end point. P < 0.05 was considered statistically significant.Analyses were performed using GraphPad Prism 8 (GraphPad Software Inc). The Shapiro-Wilk test was used to assess normality. Data are expressed as means ± SD for parametric data and median [IQR] for nonparametric data; The baseline characteristics of the patients included in the study are shown in tmax were unaltered by intracoronary nitrite (P = 0.004)  was decreased by 11 ms  (P = 0.002) at the higher dose of nitrite , consistent with a lack of systemic effect A and B.  nitrite E–G. Howe= 0.004) I. When c nitrite J and K.  volumes C–D, H, LP < 0.001, but had no effect on heart rate (P = 0.002). There was no change in the total peripheral resistance: mean change −0.7  (mean [95% CI]), P = 0.3. Intravenous nitrite also induced a significant reduction in LVEDV {−8.3 mL  (mean [95% CI]), P = 0.03}, consistent with a decrease in preload (tmax while stroke work decreased significantly: −829 centijoules (cJ)  (mean [95% CI]), P = 0.003 .Intravenous nitrite resulted in a significant decrease in MAP of 6.9 mmHg  (mean [95% CI]), art rate A and B.  preload C. No cha preload E or dP/d = 0.003 E–G. Intr < 0.001 I. Intrav and tau H, J–L. TRepresentative PV loops showing the effect of intracoronary and intravenous nitrite infusion are shown in P = 0.5 by one-way ANOVA) (Intracoronary nitrite had no significant effect on EF1 (y ANOVA) A but inty ANOVA) B–C. FromR2 = 0.33, P = 0.008)   C and the= 0.004) D. It shoIn this study, we have examined in detail that the direct and indirect acute effects of inorganic nitrite on contractile function of the human heart in patients undergoing diagnostic cardiac catheterization who did not have coronary disease or heart failure. We demonstrate several important findings that may have relevance to the potential therapeutic use of nitrite.tmin is observed following intracoronary nitrite, suggesting that while nitrite improves LV distensibility (a passive property), there is a lack of effect on active (ATP-dependent) myocardial relaxation. This pattern of effect on LV contractile function is entirely consistent with prior studies reporting similar direct myocardial effects of NO donors and NO-cGMP signaling on the onset of relaxation and diastolic stiffness, both in isolated preparations and in humans in vivo . These effects are not accompanied by any change in blood pressure or heart rate, consistent with a local action on the heart. They occur without any alteration in indices of LV systolic function, indicating a selective effect on diastolic properties of the heart. No change in tau or LV dP/d in vivo , 28, 29. in vivo , 30–32,  in vivo , 34 or a in vivo , 36 may tmin. The effects of intravenous nitrite on LV function are likely to be due to the reduced loading of the heart rather than a direct myocardial action, as the local intracoronary concentration of nitrite achieved with systemic infusion is estimated to be substantially lower than with intracoronary infusion (see methods). Therefore, intravenous nitrite-induced effects on LV diastolic function appear to be driven mainly by its actions to reduce afterload and preload rather than a direct myocardial action in this patient group. The effect of nitrite to reduce afterload and preload is well established and the underlying mechanism is NO-mediated direct (endothelium-independent) vasodilation  and afterload (MAP and Ea) and is associated with more marked effects on LV diastolic function than observed after intracoronary infusion. In addition to decreases in LVEDP, EDPVR, and LVEST, intravenous nitrite significantly accelerates tau and reduces LV dP/ddilation –7.Third, intravenous nitrite infusion significantly increases EF1, a hemodynamic index that describes the proportion of LV ejection that occurs up to the time of maximal rate of ventricular contraction . EF1 hasA careful assessment of the systemic versus direct myocardial actions of either NO donors such as sodium nitroprusside or of inorganic nitrite on cardiac contractile function has not previously been undertaken. It was reported that intracoronary infusion of the NO donor sodium nitroprusside reduced LVEDP and LVEST (similar to the current study) in patients with normal LV function but that investigation did not involve measurement of PV relations nor the assessment of the effects of systemic administration . RecentlThe pattern of effect of nitrite on LV contractile function raises the possibility that it could be of value in heart failure. Both Heart Failure with Reduced Ejection Fraction (HFrEF) and Heart Failure with Preserved Ejection Fraction (HFpEF) are characterized by significant LV diastolic dysfunction. In HFrEF, it is already well established that a reduction in the loading of the heart is beneficial and previous clinical trials in selected patient groups showed benefit from a combination of organic nitrates and hydralazine . HFpEF mWe studied a relatively small number of subjects, many of whom had risk factors for cardiovascular disease and were on medications. Some of the patients also had increased LV mass or raised LV filling pressures at baseline. As such, the study population is not comparable to healthy subjects. The possibility that the effects of nitrite may vary depending on risk factor cannot be excluded. The intracoronary group had a higher median LVMI than the intravenous group but the values were within the normal range in both groups. We looked for any correlation between LV mass and the magnitude of effect on LVEDP but found no significant relationship. The study design did not include a placebo group but all patients received an initial saline infusion (placebo) during which period the stability of LV function parameters was confirmed. It was not practical for logistic reasons to randomize allocation to intracoronary or intravenous nitrite, as the two procedures were technically different. Due to ethical and logistical considerations, it was also not feasible to perform both intracoronary and intravenous nitrite in the same patients as doing this would have made the study prohibitively long. The current study only looked at the acute effects of a single nitrite infusion at rest. It is possible that the effects may be larger upon exercise and the results also cannot necessarily be extrapolated to the effects of chronic administration. It is not known how much bioactive NO is released within the myocardium from a given dose of nitrite in this study and therefore the results are not generalizable to other NO donor drugs. This could be addressed in future studies by assessment of blood plasma sampled from both the coronary artery and the coronary sinus. EDPVR was assessed using the single beat method, rather than through vena cava occlusion to induce a loading change, but the single beat method is known to reliably detect the acute effects of interventions. As common in such clinical studies, our data set contained a number of outlier data points. However, repeating the analyses without inclusion of such outliers did not materially alter the overall pattern of results.We have undertaken a comprehensive characterization of the acute effects of intracoronary and intravenous nitrite on human cardiac contractile function, using doses designed to achieve solely local myocardial or solely peripheral vascular effects, respectively. Our findings demonstrate that nitrite has modest direct effects on LV diastolic distensibility and the onset of LV relaxation in subjects without heart failure. The effects of systemic infusion on diastolic function in this patient group are, however, much greater and involve altered cardiac loading. The overall profile of effect of nitrite may be beneficial in conditions characterized by LV diastolic dysfunction and merits further study.The data that support the findings of this study are available from the corresponding author upon reasonable request.This work was supported by a UK Medical Research Council Clinical Research Training Fellowship (MR/R017751/1 to K.’O.G.), the British Heart Foundation (RE/18/2/34213), and the Department of Health via a National Institute for Health Research (NIHR) Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London (IS-BRC-1215-20006) and King’s College Hospital NHS Foundation Trust.The authors confirm that the PI for this paper is Prof. A. M. Shah and that he had direct clinical responsibility for patients. None of the other authors has any conflicts of interest, financial or otherwise, to disclose.K.’O.G., P.J.C., A.M.S. conceived and designed research; K.’O.G., A.R.C., M.R., A.R., L.D., N.M., and A.M.S. performed experiments; K.’O.G., A.R.C., M.R., H.G., and A.M.S. analyzed data; K.’O.G., P.J.C., A.J.W., and A.M.S. interpreted results of experiments; K.’O.G. prepared figures; K.’O.G. and A.M.S. drafted manuscript; K.’O.G., P.J.C., A.J.W., and A.M.S. edited and revised manuscript; K.’O.G., A.R.C., M.R., A.R., H.G., L.D., N.M., P.J.C., A.J.W., and A.M.S. approved final version of manuscript.


Myocardial infarction remains the principal cause of death in Europe. In patients with ST-segment-elevation myocardial infarction (STEMI), a promptly revascularization with primary percutaneous intervention (PCI) has transformed prognosis in the last decades. However, despite increasing successful PCI procedures, mortality has remained unchanged in recent years. Also, due to an unsatisfactory reperfusion, some patients have significant myocardial damage and suffer left ventricular adverse remodeling with reduced function—all that resulting in the onset of heart failure with all its inherent clinical and socioeconomic burden. As a consequence of longer ischemic times, distal thrombotic embolization, ischemia-reperfusion injury and microvascular dysfunction, the resultant myocardial infarct size is the major prognostic determinant in STEMI patients. The improved understanding of all the pathophysiology underlying these events has derived to the development of several novel therapies aiming to reduce infarct size and to improve clinical outcomes in these patients. In this article, based on the mechanisms involved in myocardial infarction prognosis, we review the new interventional strategies beyond stenting that may solve the suboptimal results that STEMI patients still experience. Myocardial infarction is the leading cause of death and disability in Europe. Primary percutaneous coronary intervention (PCI) has dramatically improved prognosis of patients with ST-segment-elevation myocardial infarction (STEMI) over the last decades  and it iThe principal factor related to long-term clinical outcomes in STEMI patients is the infarct size, which has been strongly associated with both all-cause mortality and HF hospitalization . At the To address this unmet therapeutic need, multiple pharmacological and interventional strategies have been developed in recent years. These novel techniques aim to reduce infarct size, to preserve ventricular function and to change prognosis of STEMI patients. In this review, we provide an overview of different innovative interventional therapies—beyond primary PCI—for potentially improving outcomes in STEMI patients.Among various factors that define prognosis in STEMI patients, infarct size after reperfusion is perhaps the most important. Infarct size is related to the extent of necrotic areas upon which an adverse myocardial remodeling is generated—and thus ventricular dysfunction leading to subsequent HF is the main outcome. HF is a prevalent entity after STEMI—13% of patients at 30 days and 20% at 1 year after discharge. It has an increasing clinical and socioeconomic impact due to the large number of hospitalizations ,8. As itThe magnitude of the cardioprotective therapies efficacy has been assessed by measuring the infarct size with different means—ECG changes, biomarkers, single-photon emission computed tomography (SPECT), and more recently, cardiac magnetic resonance (CMR). The infarct size depends on the area at risk (AAR), which is the perfusion territory of the occluded artery. The only way to quantify the myocardial salvage obtained with these therapies is comparing the infarct size to the AAR. However, we have no available and generally validated in vivo measure of the AAR in the STEMI patients. In fact, the myocardial salvage assessment remains controversial, even with new proposals such as the T2-weighted CMR hyperintensity to delineate the AAR . NowadayMajor surrogate determinants of STEMI prognosis  are discussed below.Currently, one of the fundamental dogmas in STEMI treatment is that “time is cardiac muscle”. A prompt PCI is clearly associated with a reduction in mortality risk —every miCoronary distal embolization derived from the rupture or erosion of an atherosclerotic vulnerable plaque may occur in STEMI either spontaneously or iatrogenically during PCI. This phenomenon occurs frequently—11% of patients with STEMI treated with PCI—and it is also associated with increased risk of HF development . The thrA rapid and effective reperfusion is the main goal in STEMI treatment. However, paradoxically, flow restoration may produce myocardial damage by itself—a phenomenon called ‘myocardial reperfusion injury’. The pathophysiology underlying myocardial reperfusion injury includes many cellular events  that lead to edema, hemorrhage, microvascular obstruction, and finally cardiomyocyte death . ReperfuMicrovascular obstruction is present when there is a persistent perfusion defect despite a normal coronary flow in epicardial arteries. This ‘no-reflow’ phenomenon affects coronary microcirculation (<200 μm diameter) and it is recognized in angiography in a considerable number of patients—1 out of 5 STEMI patients treated with PCI . BesidesThe knowledge of these pathophysiological mechanisms has led to the development of new therapies focused on reducing infarct size and improve clinical care of STEMI patients .Many pharmacological therapies (antiplatelet and antithrombotic drugs) are used in order to reduce distal embolization and optimize stenting techniques in STEMI . Also, sThrombectomy aimed to reduce the extent of thrombotic burden by removing the thrombus before stent deployment. Thrombus aspiration has been widely discussed in recent years following encouraging initial results .p = 0.042) compared with the PCI alone group ..75].Therefore, PICSO therapy has been proposed as an additional tool for acute myocardial infarction treatment. PICSO is intended to reduce both ischemia and reperfusion injury—and ultimately infarct size—via different mechanisms:During occlusion period (5–15 s) venous flow is redistributed from normally perfused areas towards the ischemic zones through heterocoronary and homocoronary collaterals activation. Also, there is a ‘plasma skimming phenomenon’ in the venous microcirculation of the occluded territory—the systolic pressure increase pushes the blood plasma from the larger veins to venules—leading to a better perfusion in this area with plasma rich in oxygen and metabolites.In the balloon release period (3–4 s) the sudden drop in venous pressure creates a gradient that allows wash out of thrombotic debris, toxic metabolites, and myocardial edema from the microcirculation .Additionally, it is hypothesized that the cyclical change in coronary sinus pressure may activate endogenous pathways of cardiac repair. These temporary pressures elevations are believed to induce mechanotransduction and activation of vascular cells with regional release of growth factors, vasodilator substances, and miRNAs into microcirculation . Furtherp < 0.001) [n = 25), PICSO improved microvascular function 24–48 h post-PCI and reduced infarct size at six months compared with the control group  [p = 0.023) [The effect of PICSO on infarct size has been consistently positive in various animal models with a significant reduction in infarct size related to coronary sinus occlusion compared with the control group—as a meta-analysis of seven studies revealed  . The Pre< 0.001) . Later, < 0.001) . The OxA= 0.006) . In the = 0.023) .n = 144) with TIMI 0–1 to assess reduction in infarct size at 5 days.These promising studies have resulted in the setup of the first randomized clinical studies with PICSO therapy. Currently, the multicenter randomized PICSO AMI I trial (NCT03625869) is recruiting anterior STEMI patients (In the current treatment of STEMI, there is no discussion about the “time is muscle” paradigm. Thus, in the most recent studies, PICSO therapy is implemented after restoration of coronary blood flow but before stenting—preparing the injured myocardium for the following damage caused by stent implantation without delay in door-to-balloon time. However, timing of PICSO treatment—and other cardioprotective therapies—remains unclear; specially if we attend to reperfusion injury pathophysiology, which is rapidly harmful in the first minutes after flow restoration .Although primary PCI has greatly improved outcomes in patients with myocardial infarction and it is considered essential in STEMI treatment, a remarkable group of patients still suffer significant myocardial damage with substantial mortality and morbidity in the context of the later development of heart failure due to ventricular dysfunction. This poorer prognosis is mainly related to the extent of infarct size. Many factors contribute directly to infarct size magnitude: not only a promptly PCI to open the artery and achieve myocardium reperfusion is important, but also some of the pathophysiological phenomena implied in the myocardial infarction process—such as distal embolization, reperfusion injury and microvascular dysfunction—can be very harmful and cause myocardial injury.As a result, given a better knowledge of all the mechanisms involved in the infarct size determinants; novel therapeutic strategies have been identified for potentially increase myocardial salvage and thus improve clinical results. In this review, we focus on different mechanical therapeutic techniques beyond stenting in the interventional area. Encouraging data in animal models generated high expectations; however, transferring these findings to the clinical scene has been challenging with mixed results for infarct size reduction or improved clinical endpoints (summarized in


The three-dimensional strain changes after T6 and T8 had no advantages compared with GLS. Body mass index (BMI), the GLS change rate after the second cycle of chemotherapy (G2v) and the 3D-GCS change rate after the second cycle of chemotherapy (C2v) were independent factors that could predict the occurrence of CTRCD during follow-up, among which BMI was the best predictor . In conclusion, the current study determined that GLS was superior to GWI in predicting cardiac function in patients with tumors with little variation in blood pressure. BMI, G2v and C2v can be used to predict the occurrence of CTRCD.No study has examined myocardial work in subjects with cancer therapy-related cardiac dysfunction (CTRCD). Myocardial work, as a new ultrasonic indicator, reflects the metabolism and oxygen consumption of the left ventricle. The aim of this study was to test the relative value of new indices of myocardial work and global longitudinal strain (GLS) in detecting changes in myocardial function during the treatment of breast cancer by two-dimensional and three-dimensional echocardiography. We enrolled 79 breast cancer patients undergoing different tumor treatment regimens. Follow-up observation was conducted before and after chemotherapy. The effects of breast cancer chemotherapy and targeted therapy on the development of CTRCD [defined as an absolute reduction in left ventricular ejection fraction (LVEF) of >5% to <53%] were detected by two-dimensional and three-dimensional speckle tracking echocardiography. Our findings further indicate that LVEF, myocardial work index (GWI) and myocardial work efficiency (GWE) showed significant changes after the T6 cycle, and GLS showed significant changes after the T4 cycle ( Cardiovascular disease complicated by chemotherapy has become one of the important causes of posttreatment death in tumor patients , among wThe left ventricular myocardial work index (GWI) is the area of the left ventricular pressure-strain ring (LV-PSL), which represents the work done by the myocardium from mitral valve closure to mitral valve opening and reflects the metabolism and oxygen consumption of the left ventricle. Its advantage lies in the correction of afterload, which overcomes the dependence of the left ventricular ejection fraction and left ventricular strain on the load . At presA total of 79 female patients admitted to Qilu Hospital of Shandong University were enrolled in this study and were divided into three groups according to their treatment plans. Patients in G1 group who received anthracycline-free and non-targeted regimens ; G2 included patients treated with anthracycline-containing regimens without targeted therapy ; G3 included patients treated with anthracyclines combined with targeted drugs . All patients underwent echocardiography before chemotherapy (T0) and after the end of chemotherapy cycle 2 (T2), cycle 4 (T4), cycle 6 (T6), and cycle 8 (T8).The patients who met the following inclusion criteria were enrolled: 1) those aged less than 70 years old; 2) patients diagnosed with breast cancer by histology or cytopathology; 3) patients set to receive adjuvant chemotherapy combined with trastuzumab combined with or without pertuzumab; 4) those with no previous history of chemotherapy or radiotherapy. The major exclusion criteria included poor echocardiography image quality that did not allow complete analysis of the ultrasonic data; patients with heart failure, history of coronary heart disease, acute coronary syndrome or myocarditis, myocardial infarction, severe valvular disease, cardiomyopathy and other serious heart disease; and patients with persistent atrial fibrillation and severe arrhythmia. The study protocol was approved by the Ethics Committee of Shandong University Qilu Hospital , and written informed consent was obtained from all participants.Data on age, body mass index, current or previous smoking, diabetes mellitus, coronary artery disease, systolic blood pressure (SBP), diastolic blood pressure (DBP), and administration of antihypertensive drugs and statins were collected at enrollment. Serum levels of fasting blood glucose (GLU), serum triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured in the clinical laboratory departments of Qilu hospitals.All subjects were examined by a GE Vivid E95 or GE Vivid E9 color Doppler ultrasound with an M5S-D probe (probe frequency 1.4–4.6 Hz) and a 4V-D probe (probe frequency 1.5–4.0 Hz). Ultrasound images were collected, and bilateral brachial artery blood pressure was measured. In addition to standard echocardiography, the study included 3–5 cardiac cycles at frame rates of 50–70 frames per second on apical sections of four-, three- and two-chamber views that were stored digitally in original format for analysis. All strain analyses were performed using semiautomatic speckle tracking technology  using the entire left ventricular model . Parts that were inadequately tracked were excluded. Three-dimensional full volume left ventricular acquisition using a maximum volume ratio matrix array sensor was attempted in all patients. The biplanar Simpson method was used to measure LVEF, while the measurement of GLS and myocardial work was based on automated function imaging (AFI). When the myocardial tracking was not accurate, the myocardium could be manually adjusted.CTRCD  is definp < 0.05 indicated that the difference was statistically significant.Statistical analysis involved the use of SPSS version 26.0  and GraphPad Prism 9.0 . All measurement data were tested for normality and homogeneity of variance. Measurement data meeting the normal distribution were measured as the mean ± SD (p > 0.05) . There were no significant differences in age, weight, height, BMI, body surface area (BSA), blood pressure, blood glucose or blood lipids among the different treatment groups ( > 0.05) .p < 0.05). With the progression of chemotherapy, the values of LVEF, GLS, GWI and GWE gradually decreased; GLS significantly decreased at T2; and LVEF, GWI and GWE significantly decreased at T4 . The decrease in 3D-GLS and 3D-GCS in G2 and G3 was more obvious than that in G1, the changes were statistically significant in T6, and 3D-GAS and 3D-GRS were significantly changed in T8 . The degree of decrease in 3D-GCS was G3 > G2 > G1. Note: 3D-GLS, left ventricular three-dimensional longitudinal peak strain; 3D-GCS, left ventricular three-dimensional peripheral peak strain; 3D-GAS, left ventricular three-dimensional area peak strain; 3D-GRS, left ventricular three-dimensional radial peak strain. *p < 0.01 compared with G1.3D-GLS, 3D-GCS, 3D-GAS and 3D-GRS all showed a downward trend during chemotherapy. The changes in 3D-GLS, 3D-GAS and 3D-GRS in the G3 group were significantly higher than those in the G1 and G2 groups  and the nonevent group (n = 70) is shown in p > 0.05), while BMI, BSA, LDL-C and TG in the event group were significantly increased (p < 0.05)  . L2v is p < 0.05)  .The BMI level and G2v and C2v as parameters for predicting the occurrence of CTRCD in breast cancer patients after tumor treatment showed good predictive value, with AUCs of 0.922 (95% CI: 0.858–0.987), 0.776 (95% CI: 0.600–0.952) and 0.703 (95% CI: 0.488–0.918), respectively. At the 95th percentile risk threshold, the sensitivities were 88.9, 55.6, and 66.7%, and the specificities were 88.6, 94.3, and 81.4%, respectively. Among them, BMI is the optimal parameter. When BMI is higher than 27.03, the probability of CTRCD is 1.301 times that with a BMI less than 27.03. .The ROC curves of BMI, G2v and C2v for predicting the occurrence of cardiotoxicity are shown. The area under the curve of BMI (0.922) was better than that of G2v (0.776) and C2v (0.703), and its predictive value for the occurrence of cardiotoxicity was the highest.There were several important findings in the present study. First, the GWI and GWE decreased with chemotherapy, but their sensitivity was lower than that of GLS. Second, 3D strain parameters such as 3D-GLS, 3D-GCS, 3D-GAS and 3D-GRS changed significantly in the course of chemotherapy but did not show obvious advantages over GLS. Third, BMI can be used as an independent factor to predict the occurrence of CTRCD.In this cohort study, we analyzed the changes in GLS parameters and myocardial work parameters from echocardiography over the duration of tumor therapy and the role of these changes in predicting the occurrence of CTRCD. The results showed that GLS had statistically significant changes earlier than GWI. Theoretically, myocardial work is calculated based on the left ventricle pressure applied to the strain, under normal circumstances, the changes in myocardial work and ventricular strain will show better consistency. However, in this study, some patients developed hypertension after receiving chemotherapy treatment, which can balance the reduction of strain, so that the change in myocardial work index occurred after the reduction of strain. We plan to further explore these hypotheses in a follow-up study of hypertensive patients with tumors.Evidence that 3D-STE can predict subsequent changes in 2D LVEF was first presented by A recent meta-study on the cardiotoxicity of anthracyclines  showed tOf the three groups, the results showed that the G3 group, which received anthracyclines in combination with targeted drugs, had the most significant changes in cardiac function. At present, anthracyclines are still essential in the treatment of breast cancer, but a small number of patients have been treated with targeted drugs alone. This study was limited by the patients’ economic burden and medical insurance status, and only a few patients were treated with double-targeted therapy alone (trastuzumab combined with pertuzumab). Therefore, patients who were treated with single-targeted therapy alone and double-targeted therapy alone were not compared and analyzed. We will conduct a comparative study of these two treatment regimens in the following study, aiming to explore whether pertuzumab can improve the treatment effect of patients while worsening their heart function.In tumor patients with little change in blood pressure, the predictive value of GLS on cardiac function is better than that of myocardial work parameters and 3D echocardiographic parameters. BMI, G2v and C2v were independent predictors of cardiac function impairment in breast cancer patients receiving chemotherapy, among which BMI was the best predictor. Further prospective studies in hypertensive patients are needed to evaluate the value of myocardial work parameters in predicting CTRCD.


Apesar do racional e desenho elegantes do estudo, a galectina-3 não foi capaz de predizer MSC como variável contínua ou estratificada em quartis. Seu quartil mais elevado, no entanto, esteve associado a maior risco de morte por todas as causas.        A predição de risco de MSC nos pacientes com IC não isquêmica segue um desafio e novos estudos são necessários para identificar o paciente com maior probabilidade de se beneficiar do emprego do CDI.                 –Sudden cardiac death (SCD) accounts for approximately 50% of deaths in patients with ischemic and nonischemic heart disease in the presence of severe left ventricular systolic dysfunction.            ,,–The Multicenter Automatic Defibrillator Implantation Trial II (MADIT II)            The SCD-HeFT            ,A meta-analysis            ,,In this issue of the Arquivos Brasileiros de Cardiologia, Kochi et al.            Despite the elegant study rational and design, galectin-3 could not predict SCD neither as a continuous variable nor when stratified in quartiles. However, the highest quartile was associated with higher all-cause mortality.            The prediction of risk of SCD in nonischemic heart failure patients is still a challenge, and studies determining which patients would benefit most from the use of ICD are still needed.


IHD is a significant cause of mortality and morbidity worldwide. In the acute phase, it's demonstrated as myocardial infarction and ischemia-reperfusion injury, while in the chronic stage, the ischemic heart is mainly characterised by adverse myocardial remodelling. Although interventions such as thrombolysis and percutaneous coronary intervention could reduce the death risk of these patients, the underlying cellular and molecular mechanisms need more exploration. Mitochondria are crucial to maintain the physiological function of the heart. During IHD, mitochondrial dysfunction results in the pathogenesis of ischemic heart disease. Ischemia drives mitochondrial damage not only due to energy deprivation, but also to other aspects such as mitochondrial dynamics, mitochondria-related inflammation, etc. Given the critical roles of mitochondrial quality control in the pathological process of ischemic heart disease, in this review, we will summarise the efforts in targeting mitochondria  on IHD. In addition, we will briefly revisit the emerging therapeutic targets in this field. AMI is myocardial necrosis due to acute obstruction of a coronary artery or induced hypoperfusion of myocardial tissue, which is attributed to millions of deaths worldwide every year. The longer duration of ischemia usually leads to much more severe myocardial damage. Therefore, timely reestablishment of blood flow is the critical factor for rescuing the ischemic tissue. However, another form of strike, called IRI is also responsible for local damage , 2 Figu. AccordiAdverse myocardial remodelling is a significant feature of acute myocardial infarction, characterised by various gradual changes of left ventricular morphology, such as infarcted zone expansion and chamber dilatation. HF is the end stage of myocardial remodelling after AMI. It's diagnosed in ~13% of patients at 30 days and 20–30% at 1 year after discharge for MI , 5 Figu. In addiMitochondria is the energy house of cardiomyocytes, generating ATP to maintain normal heart contractile function . MitochoMitochondrial remodelling in ischemic heart disease includes structural and metabolic changes, both of which are identified to play key roles through each stage of the pathogenesis of ischemic heart disease. In cardiomyocytes, mitochondria are highly dynamic organelles, in response to environmental or metabolic changes, they underwent continuous fission, fusion and cristae remodelling . Fusion 1F0 ATP synthase is known to form dimers in the inner mitochondrial membrane ; Natural Science Foundation of Liao Ning Province (2019-MS-386).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.


Background: Implantable cardioverter-defibrillator (ICD) therapy is associated with several deleterious effects, which can be reduced by antiarrhythmic drugs or catheter ablation. However, it is largely unknown which patients might benefit from these therapies. Therefore, this study aimed to investigate whether myocardial scar characterization improves risk stratification for ventricular arrhythmia (VA) occurrence in patients with ischemic cardiomyopathy and an ICD.Methods: In this study, 82 patients with ischemic cardiomyopathy who received an ICD were enrolled retrospectively. Late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) images were analyzed using an investigational software tool to obtain quantitative data regarding the total scar, core, and border zone (BZ). Data regarding the QRS complex was obtained from electrocardiography (ECG). The primary endpoint was appropriate ICD therapy.Results: During a median follow-up duration of 3.98 years [interquartile range (IQR) 2.89–5.14 years], appropriate therapy occurred in 24 (29.3%) patients. Patients with appropriate ICD therapy had a significantly larger total scar mass  and BZ mass  than those without appropriate therapy. In multivariable Cox regression analyses, total scar mass [hazard ratio (HR) 1.02 [95% confidence interval (CI) 1.00–1.04]; P = 0.014] and BZ mass  independently predicted appropriate ICD therapy. Core mass and the QRS complex, however, were not significantly associated with the primary endpoint.Conclusion: LGE-CMR-based, but not ECG-based myocardial scar characterization improves risk stratification for VA occurrence in patients with ischemic cardiomyopathy who received an ICD. Sudden cardiac death (SCD), which is defined as an unexpected and non-traumatic death from a cardiovascular cause, is a leading cause of mortality, being responsible for a fifth of all deaths worldwide , 2. The Several predictors of appropriate ICD shock have been found, including male gender, non-sustained VT, and a history of atrial fibrillation . Wide QRThere is a need for more studies investigating the value of myocardial scar characterization for the prediction of the occurrence of VAs. Similarly, it is largely unknown which patients are at high risk of VAs and therefore might benefit from antiarrhythmic drugs or VT ablation. Since the prevention of the occurrence of VAs by these therapeutic methods can limit the deleterious effects of ICD therapy and improve the quality of life of ICD recipients, the identification of patients at high risk of arrhythmias, and thus ICD therapy is important. By improving risk stratification for VA occurrence, myocardial scar characterization could facilitate appropriate clinical decision making.To determine which patients have an increased risk of arrhythmias and therefore might benefit from antiarrhythmic drugs or catheter ablation, we investigated whether myocardial scar characterization improves risk stratification for VA occurrence in patients with ischemic cardiomyopathy and an ICD.de novo ICD implantation or upgrade from pacemaker to ICD, the fact that LGE-CMR imaging was performed, the presence of a myocardial scar as detected by LGE-CMR, the presence of an ECG, and age ≥18 years. Patients with an ICD replacement or an upgrade of their ICD to another type and patients with an underlying pathology other than ischemic cardiomyopathy were excluded from further analysis. Patients were also excluded if follow-up data was lacking for any of the following reasons: ICD extraction soon after its implantation due to infection, non-cardiac death within a week after ICD implantation, or unavailability of follow-up data. Finally, patients whose LGE-CMR images were unsuitable for further analysis (n = 14) were excluded as well  in the period between January 1, 2013 and December 31, 2018. All patients had a previous history of myocardial infarction. Patients were included if they met all of the following criteria: a  as well .At the time of this study, the use of anonymous data was allowed by the Dutch Central Committee on Research Involving Human Subjects (CCMO) without the requirement of obtaining prior approval of an Institutional Review Board, with the provision that the data are acquired for routine patient care. All data used were handled anonymously. This study was conducted in compliance with the Declaration of Helsinki.Primary prevention was defined as an ICD implantation for symptomatic heart failure (HF) and a left ventricular ejection fraction (LVEF) ≤ 35%. A documented VF or sustained VT with hemodynamic compromise prior to the implantation of an ICD defined secondary prevention . ElectroIn general, ICDs implanted for primary prevention were programmed with a monitor zone from 150 bpm and a therapy zone from 200 bpm with long detection with a single shot ATP followed by maximal output shock therapy. In general, detection was programmed to 30 intervals for Medtronic, Abbott, or Biotronik devices. For Boston Scientific devices detection was set to 8/10 number of intervals to detect (NID) with a duration of 5 s leading to a total detection time of about 7 s (8 × 300 ms = 2.4 s and 2.4 s + 5 s = 7.4 s). Implantable cardioverter-defibrillators for secondary prevention were programmed with an additional VT therapy zone starting with a cycle length 20 ms less than the slowest documented VT and 2 burst ATPs followed by maximal output shock therapy. If available, morphology discrimination was used in the VT zone to reduce inappropriate shocks for SVT.All ICD follow-up data, as well as the ECG data, were analyzed and validated by two cardiologists.LGE-CMR images were obtained from all patients. Myocardial scar characterization was performed using 2D phase-sensitive inversion recovery (PSIR) images. An investigational software tool  was used to create a 3-dimensional (3D) model of the left ventricle (LV). After first placing several cardiac landmarks, a manual delineation of the endocardial and epicardial borders of the LV was performed in all short-axis slices with the use of a semiautomatic segmentation algorithm. The myocardial scar tissue was subdivided into two parts, namely core and BZ. The thresholds differentiating between core and BZ and between BZ and normal, healthy myocardium were determined for each patient separately on the basis of maximum pixel signal intensity (MPSI) with normal, healthy myocardium and infarct core serving as reference . BZ was In case of severe slice shifting, which refers to the displacement of slices with respect to each other, or if the contours of the heart were unclear, or if slices of a portion of the heart were absent, thus hindering the construction of a good 3D model of the LV, the LGE-CMR images were considered unsuitable for further analysis, which led to the exclusion of the patient concerned.The primary endpoint of this study was the occurrence of appropriate ICD therapy, which included shock and ATP and represents VA occurrence. Appropriate ICD shock was defined as a secondary endpoint. The composite of appropriate device therapy and cardiac mortality was equivalent to the primary endpoint.t-test for independent groups, Mann-Whitney test, and chi-square or Fisher's exact test were performed to compare patients with and without appropriate ICD therapy.A P < 0.05 in univariable analysis  and those clinically relevant (QRS fragmentation and indication for ICD placement) were selected for the multivariable analyses. Schoenfeld residuals were used to assess proportionality of hazards. Multivariable analyses were performed separately for all myocardial scar variables, because a strong correlation existed between them . Variables that demonstrated multicollinearity (Spearman's correlation coefficient >0.7) with myocardial scar variables were excluded from the multivariable models. For the multivariable Cox regression analyses, missing data  was dealt with by applying multiple imputation under the missing at random assumption. Forty imputed datasets were created using the predictive mean matching approach. Harrell's C-index was obtained for all Cox regression models to assess their goodness of fit. Kaplan-Meier curves were also constructed for the primary and secondary endpoints and were stratified by total scar mass and BZ mass. For this, the study population was split into two groups, the cut-off point being the median of the respective myocardial scar characteristics. The log-rank test was used to assess differences in cumulative event-free survival.Cox proportional hazard regression analyses were performed to determine which myocardial scar characteristics, as obtained from LGE-CMR and ECG, are associated with the occurrence of appropriate ICD therapy and therefore also VA occurrence, after correcting for potential confounders. This was also done for the secondary endpoint. Univariable Cox regression analyses were performed for all variables stated in P < 0.05. SPSS, version 23.0  and Stata 16 were used for statistical analyses.Statistical significance was defined by a P = 0.034]. The QRS complex was normal in 15 (18.3%) patients, broad in 31 (37.8%) patients, notched in 24 (29.3%) patients and fragmented in 12 (14.6%) patients (The study population consisted of 82 patients. Median age was 64 years (IQR 57–70 years). Seventy-four (90.2%) patients were men. The median time since the first myocardial infarction was 2.94 years (IQR 0.52–13.56 years). Patients with appropriate ICD therapy had a significantly larger time since the first myocardial infarction than those without appropriate ICD therapy . Similarly, a significantly larger BZ mass was seen in patients with appropriate ICD therapy than in patients without appropriate ICD therapy . No significant difference in core mass was found between the two groups  . The median BZ mass and core mass were 28.1 g (IQR 20.3–34.5 g) and 19.5 g (IQR 9.9–28.3 g), respectively. Patients who received appropriate ICD therapy had a significantly larger total scar mass than those who did not receive appropriate ICD therapy  .P = 0.014] (P = 0.040), although a considerable number of events took place also in the latter group  1.02 [95% confidence interval (CI) 1.00–1.04]; = 0.014] . Patienter group .P = 0.009) (P = 0.039), although a considerable number of events took place also in the latter group  . It was er group .P = 0.212 ] ] .P = 0.037 (multivariable model containing core mass)]. In five out of six multivariable models, digoxin usage at baseline was significantly associated with appropriate ICD therapy ; P = 0.015 (multivariable model containing BZ mass)] ] .The median Harrell's C-index of the multivariable models was 0.768 for total scar mass and 0.759 for BZ mass .P = 0.016)  .P = 0.054)  .The median Harrell's C-index of the multivariable models was 0.810 for total scar mass and 0.817 for BZ mass .This retrospective study aimed to investigate whether myocardial scar characterization improves risk stratification for VA occurrence in patients with ischemic cardiomyopathy who received an ICD. Total scar mass and BZ mass were associated with both appropriate ICD therapy and shock, although these myocardial scar characteristics seemed to be better at predicting appropriate shock than appropriate therapy. Core mass and the QRS complex, on the other hand, were not significantly associated with either endpoint. However, the time since the first myocardial infarction was significantly associated with appropriate device therapy in the majority of the Cox regression models.Total scar mass and BZ mass were significantly associated with both appropriate ICD therapy and shock. This is consistent with previous findings –14. AccoCore mass was not significantly associated with either endpoint, which is in line with findings from previous studies –14. SincThe QRS complex was not significantly associated with either endpoint. This is in contrast with the findings of a previous study, in which a fragmented QRS complex was found to be a predictor of arrhythmic events . FurtherThe time since the first myocardial infarction was significantly associated with appropriate therapy in the majority of the Cox regression models, with older scars being more likely to lead to appropriate ICD therapy. This is in agreement with the findings of Piccini et al., who found a higher frequency of appropriate shocks when the time after myocardial infarction increased, although such a difference in frequency was not found for all-cause mortality or SCD . A potenDigoxin usage at baseline was found to have predictive value in the majority of the multivariable models. This is in agreement with previous findings that digoxin usage is associated with a higher risk of appropriate shocks .Based on Harrell's C-index, the myocardial scar characteristics of predictive significance seemed to be better at predicting appropriate ICD shock than appropriate therapy, the latter including both shock and ATP. This has beneficial clinical implications for several reasons. First, ATP usually occurs in the presence of relatively slow and hemodynamically stable VTs, whereas shocks are given under more severe circumstances, namely VF and relatively fast and hemodynamically unstable VTs . Second,Our findings may have clinical implications for patients. For instance, the use of total scar mass and BZ mass as risk stratification tools may help physicians to better select candidates for ICD implantation, since high-risk patients are in greater need of an ICD. However, there is a substantial burden associated with appropriate ICD therapies , 6. AntiOur study investigated the anatomical substrate of VAs by LGE-CMR. However, it is worth mentioning that LGE-CMR cannot detect the neuronal changes that arise after the occurrence of a myocardial infarction. Innervation abnormalities are associated with a higher risk of VAs and are thus of clinical importance. However, the scar as defined by areas of reduced voltage does not adequately reflect the size of denervated areas, which has been shown to be 2.5 times larger . KnowledTo our knowledge, this study had one of the longest follow-up periods when compared to similar studies. However, there are several limitations that should be acknowledged. For instance, the relatively small sample size constitutes an important limitation. Furthermore, thresholds for the differentiation between normal myocardium, BZ, and core were not uniform for all patients, since this led to erroneous estimations of myocardial scar characteristics. Potential confounders were corrected for in the multivariable Cox regression models.In conclusion, LGE-CMR-based, but not ECG-based myocardial scar characterization improves risk stratification for VA occurrence in patients with ischemic cardiomyopathy who received an ICD. More specifically, total scar mass and BZ mass were independent predictors of appropriate ICD therapy and shock, whereas core mass was not.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.AN collected the data, performed the statistical analysis, and drafted the manuscript. AM collected data and drafted the manuscript. HG and BM provided critical review of the manuscript. MR performed statistical analysis and provided critical review of the manuscript and YB drafted the manuscript. All authors contributed to the article 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.