Objective: To determine the frequency and extent of cardiac involvement in female carriers of pathogenic variants in DMD, 53 women were examined through an observational, cross-sectional study.Methods: Genetically verified female carriers of pathogenic DMD variants were examined by cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement, echocardiography, 24-h Holter monitoring, ECG, and blood concentrations of skeletal and cardiac muscle biomarkers.Results: Fifty-three female carriers of pathogenic DMD variants  were included in the study. Sixty-two percent had cardiac dysfunction on echocardiography. On CMR, 49% had myocardial fibrosis, 35% had dilated left ventricles, and 10% had left ventricular hypertrophy. ECGs were abnormal in 72%, and abnormal Holter monitoring was found in 43%. Age did not correlate with myocardial fibrosis or cardiac dysfunction. Myocardial fibrosis was more frequent in carriers of pathogenic variants associated with DMD vs. BMD .Conclusion: This study shows that cardiac involvement, affecting both structure and function of the heart, is found in over 2/3 of women with a pathogenic DMD variant. The study supports early cardiac screening, including ECG, Holter, and cardiac imaging, in this group of carriers, so that symptoms related to pathogenic variants in DMD can be recognized, and relevant treatment can be initiated. Longitudinal studies are needed to assess morbidity and mortality related to single, pathogenic DMD variants in women. DMD). In affected males, the pathogenic variants cause progressive muscular wasting and weakness, respiratory failure, dilated cardiomyopathy, arrhythmias, and congestive heart failure (Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked recessive disorders caused by pathogenic variants in the dystrophin gene . Written informed consent was obtained for all participants, according to the Declaration of Helsinki. Participants were evaluated by medical history, transthoracic echocardiography, Holter monitoring (24 h), 12-lead ECG, and cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE). Blood concentrations of creatine kinase (CK), creatine kinase MB (CK-MB), myoglobin, pro-brain natriuretic peptide (proBNP), and troponin T (TnT) were determined. A CK-MB/CK ratio was calculated for CK-MB values above the reference range and was considered suggestive of cardiac involvement, not skeletal muscle affection, when the CK-MB/CK ratio was ≥3%. Furthermore, manual testing of muscle strength was performed with the Medical Research Council scale for muscle strength (MRC). All participants also underwent lower extremity muscle MRI and strength investigations presented in the accompanying article in Frontiers in Neurology.n = 3) or via the DMD/BMD carrier register (n = 50) at the Department of Clinical Genetics, Rigshospitalet. Inclusion criteria were as follows: confirmed pathogenic variant in the DMD gene, and a woman 18 years of age or older. Subjects were excluded if they had contraindications against CMR. One hundred and eight invitation letters were sent out, and in case of no response, they were followed up by a phone call. Fifty-three subjects who accepted the invitation fulfilled the inclusion and none of the exclusion criteria and were included in the study from December 2016 to April 2018. The remaining 58 invited subjects were either excluded on the basis of the exclusion criteria, did not wish to participate, or did not respond to neither letter nor phone call. Twenty of the 58 non-participating persons were interviewed by phone after the 53 included participants had been tested. This was done to uncover the presence of cardiac and skeletal muscle symptoms and their reasons not to participate, to assess potential bias in the selection of included subjects. The remaining 38 persons who did not participate could not be reached.Subjects were recruited from our Neuromuscular Clinic . All ECGs were analyzed by TS and HB. An ECG was defined as abnormal in the presence of atrial flutter/fibrillation (AFL/AF), atrioventricular block (AVB) grades I–III, QRS-interval >120 ms, prolonged QTc >470, or incomplete right bundle branch block (IRBBB). Additionally, ECGs were assessed with special focus on ECG abnormalities known to be observed in DMD patients and carriers, which included increased R-wave in V1–V2 (>4 mm), increased R/S ratio in V1 or V2 in the absence of incomplete or complete right bundle branch block (RBBB), pathological Q-waves (>0.2 mV) in lateral  or inferior leads , complete or incomplete left bundle branch block (LBBB/ILBBB) or complete RBBB .A 24-h Holter was performed using a three-electrode PocketECG . All holter monitor data were analyzed by TS and HB. Holter monitor was defined as abnormal in the presence of AVB grades I–III, AFL/AF, other supraventricular tachyarrhythmias (SVT) [>30 supraventricular premature contractions (SVPC) per hour or runs of ≥20 SVPC], frequent ventricular premature contractions (VPC) (≥30/h), non-sustained ventricular tachycardia (NSVT) (minimum of 3 beats at ≥100 bpm) and supraventricular or ventricular couplets and/or triplets .Echocardiography was obtained with Philips EPIQ 7C  or Vivid E95  and analyzed by an experienced cardiologist using Philips IntelliSpace Cardiovascular version 1.2/QLAB version 10.5 or GE Healthcare EchoPac version 202, respectively, in accordance with current guidelines . SystoliCMR was performed on a 3.0 Tesla MR scanner  using a body matrix coil. All CMR images were analyzed by TS and AAR. Steady-state free precession end-tidal breath hold cine images with retrospective ECG gating were obtained in two-, three-, and four-chamber views, followed by a short-axis stack and a transversal stack, both covering the entire heart . T1 mapping was performed using the modified look-locker inversion recovery technique (MOLLI) on one mid-ventricular short-axis image. LGE was assessed by using T1-weighted gradient echo sequences in two-, three-, and four-chamber views and a short-axis stack contiguously covering the left ventricle. LGE and post contrast MOLLI images were obtained 10 min after administration of an intravenous bolus of gadolinium (0.15 mmol/kg body weight) . To exclude artifacts, cross-sectional views were acquired when LGE was present on standard views. Inversion time was 250–350 ms .42 . Endocardial boarders of the left ventricle were traced on the short-axis cine images in the end-diastolic and end-systolic phase, respectively, and epicardial boarders were traced in the end-diastolic phase. The papillary muscles were incorporated as part of the cavity. End diastole and end systole were identified as the largest and smallest volume, respectively. Left ventricular (LV) mass was calculated by the software as the volume between the two borders multiplied by the myocardial density (1.05 g/cm3), excluding papillary muscles.CMR analysis was performed with CVIFor the right ventricle, the endocardial borders were traced in the end-diastolic and end-systolic phase from the transversal stack; the papillary muscles were incorporated as part of the cavity. Endocardial borders of the left atrium were manually traced in ventricular end systole from the transversal stack. Left atrial appendage was included, but pulmonary veins were excluded from the atrial volume.LGE images were first reviewed for visible LGE , and if positive, quantified. LGE was interpreted as present only if confirmed on both short-axis view and a matching location on long-axis or cross-sectional views. Quantification was performed as a signal intensity threshold of >6 SD above remote myocardium. The extent of dense replacement fibrosis was quantified as mass and as a percentage of total left ventricular mass. Manual correction was performed for obvious threshold errors.MOLLI images where analyzed to construct T1 maps, recovery curves, and DICOM maps, both pre- and post-contrast. Extracellular volume (ECV) was calculated by the Equation :2, LV mass indexed >74 g/m2, right ventricular EF <49%, right ventricular volume indexed >153 ml/m2  and data with skewed distribution as median (range). Categorical values are presented as frequency count (percentage), and differences among groups were analyzed using chi-square test and Fishers exact test. Comparison between categories was calculated with Mann–Whitney Anonymized data will be shared with any qualified investigator on reasonable request.DMD variants originated from 45 families and were on average 49.6 years old (range: 26–81 years). Cardiac risk factors and comorbidities are listed in The 53 women with pathogenic Of the 20 non-participants that were interviewed, 10 reported that they did not participate due to distance to the hospital and lack of time, six had too many hospital visits with their DMD sons or due to other diseases of their own that were unrelated to cardiac and neurologic disease. Three had not received the letter of invitation. The last wished to participate but had contraindications against MRI. None of the 20 individuals declined participation due to cardiac symptoms or muscle symptoms. There was no difference in symptoms reported by the non-participants compared with the participants: dyspnea (17 vs. 15%), fatigue (28 vs. 28%), palpitations (13 vs. 11%), lower extremity edema (8 vs. 6%), and syncope (6 vs. 6%).p = 0.02), CK-MB (p = 0.02), and CK (p = 0.01), but not with higher levels of TnT (p = 0.35) or ProBNP (p = 0.23). We found a trend toward higher levels of CK and CK-MB in women with a pathogenic variant associated with DMD vs. BMD .Over two-thirds of participants had elevated levels of skeletal muscle biomarkers of muscle damage . Half haThe majority of participants (92%) had normal muscle strength when manual testing was performed. Four participants (8%) scored four or four minus on MRC in one or more of the tested muscle groups. Of these four, none had abnormal LVEF on echocardiography, and one had myocardial fibrosis on CMR. There was no association between cardiac affection and muscle weakness.Electrocardiography section, largely due to high R waves in V1 and/or V2  participants, either as reduced longitudinal function in GLS and/or reduced LVEF. Twenty-seven participants (52%) had reduced diastolic function, of whom two (4%) showed a pattern consistent with restrictive filling (Grade 3). Structural changes in the left ventricles were found in <20%, predominantly as LV dilation . SignifiElectrocardiography section. When comparing participants older and younger than 50 years, there was no significant difference in the occurrence of EF < 54%, diastolic dysfunction, or LV dilation  but did not correlate with LVEF  or LV end diastolic volume .No association was found between an abnormal echocardiography and the cardiac measurements compared in the dilation . Age corFifty-two patients completed CMR for volumetric measurements. One participant was not examined with CMR due to claustrophobia. Forty-nine patients had post-contrast imaging performed. The remaining three participants did not wish to be injected with the gadolinium contrast.Myocardial fibrosis of the left ventricle was found in 49% of participants, with a median LGE quantity of 3.8% of total left ventricular mass (range 0.1–17.9%) . Eleven Six participants (12%) had reduced LVEF . Dilatedp = 0.02) but was not associated with any other CMR measurement. When compared with the other cardiac modalities, the presence of myocardial fibrosis was not associated with other cardiac measures assessed in this study.The presence of myocardial fibrosis, independent of severity, was associated with increased left atrial volume  and LV end systolic volume , but did not correlate with any other CMR measurement.The amount of myocardial fibrosis correlated with the following measurements on CMR: LVEF .When comparing participants older and younger than 50 years, there was no significant difference in the incidence of myocardial fibrosis , also whn = 33) vs. BMD (n = 20) phenotype, we found that the presence of myocardial fibrosis on CMR was more frequent in carriers of DMD  (When comparing women with a pathogenic variant associated with a DMD ( = 0.02) , but on The present study demonstrates that women with dystrophin gene aberrations have a high prevalence of cardiac involvement that affects structure, as apparent from myocardial fibrosis on CMR (49%), function, as assessed by echocardiography (62%), and conduction abnormalities as demonstrated by ECG (72%) and Holter monitoring (43%).DMD variants that predict DMD (61%) and BMD (28%), agrees with findings in other studies  , but the amount of fibrosis is lower   , 26. Then males) . We alsod by DMD 7–67%, bun males) , 28.DMD variant, which is considerably higher than reported in recent carrier studies (Cardiac dysfunction on echocardiography was found in 33 (62%) of women with a pathogenic  studies . This in studies . It reve studies , 9, 30. We found a high prevalence of DMD-specific ECG changes in our cohort. Earlier studies have shown a large difference in prevalence of both specific and general ECG changes, ranging from 7 to 47% , 11. TheWhen examining the biomarkers, 49% of the cohort had elevated CK-MB levels. Both CK and CK-MB values have been seen to rise during both skeletal and heart muscle damage. A CK-MB/CK ratio <3% has been shown to predict that the rise likely relates to damaged skeletal muscle, rather than heart involvement . As we hDMD variants. This is supported by Hoogerwaard et al. (DMD variants (Troponin and pro-BNP were only mildly elevated in some carriers, and the plasma levels of these two biomarkers did not associate with myocardial fibrosis on CMR. Troponin and proBNP have been suggested as good cardiac markers in myopathic patients , 35, 36,d et al.  and Schavariants .DMD variants, including CMR, at least once to give a complete picture of cardiac status.Because of the wide range of cardiac modalities investigated in our study, we had the opportunity to compare the relationship between the different cardiac parameters. When investigating if one measurement, e.g., EF < 54%, was associated with other abnormal measurements, we found no significant association between any of the following: EF < 54%, diastolic dysfunction and dilatation on echocardiography, IRBBB and any DMD-specific change on ECG, couplets/triplets, SVT and frequent VPCs on Holter, and fibrosis on CMR. This indicates that each modality cannot, with any certainty, predict the presence of abnormalities in the other three modalities, hence, underlining the importance of a full cardiac workup for all carriers of pathogenic DMD variant carriers, the relationship between this and cardiac involvement is still unresolved.The differences in cardiac involvement among carriers can be influenced by the level of skewed X chromosome inactivation. Some studies report a good correlation between clinical symptoms and skewed X chromosome inactivation, in particular, the relationship between skewed X chromosome inactivation and cardiomyopathy , 39. HowDMD variants predicted to associate with DMD vs. BMD because the abovementioned skewed X chromosome inactivation obscures the results. In this study, we did, however, find a significantly higher frequency of cardiac fibrosis in the carriers of a pathogenic variant associated with DMD vs. BMD. However, we did not find the same difference between carriers of DMD variants predicted to give DMD vs. BMD for any of the other cardiac measurements we performed.It is inherently difficult to detect differences between women with DMD variants and other smaller cross-sectional studies of this group showing the same tendency (Our study does not provide longitudinal data, and we can therefore not predict if cardiac dysfunction progresses with time, as suggested by follow-up reports , 30. In tendency , 43. ThiDMD variants.There is a possible selection bias concerning recruitment, as information about cardiac status is missing for the group of non-responders. The possibility that these women regarded themselves as being either asymptomatic or too symptomatic to participate must be considered and might skew the results in either direction. We have, however, recruited our subjects mainly from a genetic register and not through cardiac outpatient clinics. This is at variance with some of the earlier studies that have been retrospective –6 and reDMD variants compared with the general population (Holloway et al. found that life expectancy and death from cardiac disease were not increased in a population of 94 women considered as definite carriers of pathogenic pulation . They thDMD will progress to overt cardiomyopathy and recommends treating the women with evidence of cardiac involvement similar to DMD/BMD patients (The American Academy of Pediatrics estimates that 10% of women with pathogenic variants in patients . Our stuDMD that affects both structure and function of the heart. Systolic and diastolic function as well as myocardial fibrosis is affected independent of age, making early cardiac examinations and follow-up important. The study supports systematic screening of this group, including ECG, Holter, and cardiac imaging, so that symptoms related to pathogenic variants in DMD can be recognized, and relevant treatment can be initiated early.In conclusion, the present study shows that cardiac involvement is found in over 2/3 of women with pathogenic variants in 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 Danish Data Protection Agency and the National Committee of Health Research Ethics. The patients/participants provided their written informed consent to participate in this study.Skeletal muscle investigations performed on the same cohort are presented in the simultaneously submitted article “Quantitative Muscle MRI and Clinical Findings in Women with Pathogenic Dystrophin Gene Variants” by Freja Fornander.JV was responsible for the study design. TS, FF, NP, and MD collected the data. TS, JV, HB, AR, and RM contributed to data analysis. TS drafted the manuscript. All authors provided critical feedback and helped shape the research, the data interpretation, and the manuscript.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.


Left ventricular (LV) global longitudinal strain (GLS) has established itself in the last decade as a reliable, more objective method for the evaluation of LV systolic function, able to detect subtle abnormalities in LV contraction even in the presence of preserved ejection fraction (EF). However, recent studies have demonstrated that GLS, similar to LV EF, has important load dependency. Non-invasive myocardial work (MW) quantification has emerged in the last years as an alternative tool for myocardial function assessment. This new method, incorporating measurement of strain and LV pressure, has shown to overcome GLS and LV EF limitations and provide a loading-independent evaluation of myocardial performance. The presence of a commercially available echocardiographic software for the non-invasive MW calculation has allowed the application of this new method in different settings. This review sought to provide an overview on the current knowledge of non-invasive MW estimation, showing its potential applications and possible added value in clinical practice. Left ventricular ejection fraction (LVEF) is considered the first-line tool for left ventricular (LV) systolic function description. Due to its wide diffusion, simple estimation, and extensive use in clinical trials and guideline recommendations for various diseases, LVEF is the most commonly used surrogate marker of LV function in many cardiac diseases. Despite its widespread use, LVEF has important limitations : as a voIn the recent years, myocardial work (MW) has emerged as an alternative tool for myocardial function assessment. This new parameter derives from GLS, with the advantage to incorporate information on afterload, through interpretation of strain in relation to dynamic non-invasive LV pressure. The presence of a commercially available echocardiographic software for the non-invasive MW calculation has allowed the application of this new method in different settings.This review sought to provide an overview on the current knowledge of non-invasive MW estimation, showing its potential applications in clinical practice.In physiologic conditions, myocardial contraction provides energy necessary to eject blood out of the ventricles and to circulate through the body. Actually, the ratio between the mechanical energy developed by the myocardium and imparted to the blood and the total energy consumed depends upon the loading conditions. As previously demonstrated , the anaCertainly, the estimation of pressure curve from the arterial systolic pressure, measured by a brachial cuff, holds the chance to make MW measurement easily achievable. However, an experimental study aimed at verifying the accuracy of the algorithm proposed by Russell et al. in different hemodynamic conditions, showed that the estimation of pressure curve is imperfect, since the accuracy varies along the cardiac cycle . MoreoveIn the currently available echocardiographic software, after calculating GLS in 2-, 4-chamber and long-axis apical views, values of brachial blood pressure and time of valvular events are needed to derive PSLs. Valvular event times are set by pulse-wave Doppler recordings at mitral valve and aortic valve level, and then confirmed by 2D evaluation of the apical long-axis view .The area of PSL represents approximately the MW and is calculated by computing the rate of segmental shortening, obtained by differentiating the strain curve, and multiplying this value with instantaneous LV pressure. This product is a measure of instantaneous power, which is integrated over time during the cardiac cycle to obtain MW, expressed in mmHg%. In addition to MW index , segments were analyzed for wasted work (WW) and constructive work (CW), with global values determined as the averages of all segmental values.In general, MW may allow an in-depth evaluation of myocardial systolic performance across a broad range of physiologic and pathologic conditions beyond traditional echocardiographic techniques. While MW indices, mainly GWI and GCW, have shown good correlation with EF and strain parameters , the proThe first and more promising application of segmental MW is the prediction of therapeutic effects and outcomes in heart failure (HF) patients undergoing cardiac resynchronization therapy (CRT). Currently, CRT plays a key role in the treatment of symptomatic HF patients with LVEF ≤35% and wide QRS complex . Howeverp = 0.92), a GCW <1057 mmHg% identified 85% of non-responders with a positive predictive value of 88%. Taken together, all these data have been convincing about the role of MW indices, mostly segmental but also global, in the prediction of CRT therapy response and LV remodeling. Accordingly, the evaluation of MW indices, especially wasted and constructive work, should be routinely performed in this setting of patients. Of course, available evidence on these echocardiographic parameters is not robust enough to allow them to guide treatment alone, but an integrating approach, which combines clinical, electrocardiographic and advanced echocardiographic parameters, may help in the right selection of CRT candidates.Some authors have supposed that the assessment of residual myocardial contractility in patients with dyssynchrony could play a role in the prediction of LV functional restoration after CRT ,46. In tIn patients with HF and reduced EF (HFrEF), the treatment with Sacubitril/Valsartan has also shown to significantly increase GCW after 6-months follow-up, while the improvement of global work efficiency (GWE) becomes evident at 12-months follow-up with respect to baseline . Thus, GNon-invasive detection of early ischemia in patients with significant coronary artery disease (CAD) and normal resting systolic function is challenging and still being investigated . In prevIn non-ST-segment acute coronary syndrome, regional MW index has shown to be superior to all other echocardiographic parameters  to identify acute coronary artery occlusion . The preMore reduced GWI, GCW, and GWE and more increased GWW, instead, have been detected in STEMI patients who developed LV ischemic remodeling at 3-months follow-up . ConsistArterial hypertension is an ideal model for assessing the changes in myocardial deformation and performance related to the pressure overload and the development of LV concentric geometry. Indeed, arterial pressure is one of the most important independent predictors of an accelerated decline in GLS during a follow-up period ,58. MoreIn patients with non-obstructive hypertrophic cardiomyopathy (HCM), GWI, GCW and GWE have shown to be significantly impaired compared to controls with similar LVEF ,30, thusAdditionally, in a subgroup of patients with dilated cardiomyopathy (DCM), Chan et al. described a significant reduction of GWI, GCW and GWE, with an increase of GWW, which reflected an important impairment of cardiomyocytes contractile performance within DCM patients, either ischemic or non-ischemic . After, The analysis of MW in endurance athletes represents an interesting application to evaluate LV myocardial deformation and contractile reserve in a less loading-dependent manner C,D. A laThe assessment of myocardial performance during exercise stress echocardiography through non-invasive MW estimation has been recently proposed as a valuable method to overcome the change in loading condition occurring during the test. In their report, Halabi et al. showed that MW is feasible during stress echocardiography , and GWIFurther and larger studies are needed to better understand the additive value and potential usefulness of the application of this new tool during stress echocardiography on the measurement of myocardial reserve and on the prediction of myocardial ischemia.In actuality, the chronic overload that characterizes aortic regurgitation is responsible for LV remodeling, starting from eccentric hypertrophy, progressive dilation, and LV systolic dysfunction. In this context, MW analysis may allow a more reliable quantification of myocardial performance corrected by overload, permitting to individuate patients with incipient LV systolic decompensation. Indeed, in a study conducted in patients with asymptomatic severe aortic regurgitation undergoing physical effort, D’Andrea et al. demonstrated that baseline GLS and MWE are significantly correlated with functional capacity, LV filling pressure, and pulmonary congestion during effort .Since MW measurement is based on the estimation of non-invasive LV pressure from SBP measured with a cuff manometer, its evaluation was not recommended in pathologic conditions such as aortic stenosis (AS), in which SBP is not representative of LV peak systolic pressure owing to the fixed obstruction of a stenotic valve. However, the study of myocardial energetics through MW would be particularly useful in this setting, since LVEF remains preserved until late stages of the aortic disease, while GLS, which is a well-known predictor of worse prognosis, has shown to have important load dependence ,64. ReceAs previously described, non-invasive MW indices are currently measured with a software validated for the measurement of LV MW. Recently, a proof-of-concept study showed the feasibility of right ventricle (RV) MW indices measurement in a small population of HFrEF . In addiSince MW calculation is a speckle-tracking–derived measurement, it has inherited technical limitations, partly inherent to echocardiography: poor image quality that does not allow correct endocardial border delineation, and difficult to scan anatomy often leading to foreshortened ventricles, which impact on longitudinal strain (and consequently MW indices) measurements in the apex. Moreover, although having incorporated LV pressure measure makes them less sensitive to LV afterload than GLS, MW indices cannot be considered load-independent, as their values are derived by strain measurements. Considering the difficulty in obtaining strain traces and MW estimation in cases of significant variability, in most of the studies patients with atrial fibrillation have been excluded. Actually, only one system currently provides software to calculate MW, limiting the applicability of this method.Validation studies have demonstrated that the non-invasive estimation of MW indices obtained from LV PSL strongly correlates with invasive measurement of stroke work and with cardiac metabolism. This has allowed a broad application of MW measurement in several clinical settings.The main advantage of this new diagnostic tool is that, integrating stain measurement with pressure, it yields a more objective evaluation of ventricular function, which incorporates loading conditions and overcomes EF and GLS limitations. Thus, MW assessment may become particularly useful in situations to elucidate if the reduced contraction is due to increased afterload  or attenuated contractility. Furthermore, the ability to provide more insight into segmental and global myocardial energetics has opened new horizons in the study of cardiomyopathies and in the prediction of response to therapy.Within the last years, a growing body of evidence has accumulated, showing the good feasibility and reproducibility of MW, and supporting its use in several clinical applications. However, multicenter well-designed studies for the validation of this technique in large populations are needed, to definitively attest its added value and in order to include MW indices in the routine echocardiographic evaluation.


Trials.gov, and The Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) of ivabradine with search terms Ivabradine (MeSH Terms), chronic heart failure and beta‐blocker. The primary endpoints of the study include the impact of Ivabradine on heart rate, left ventricle ejection fraction (LVEF), left ventricular remodeling, exercise capacity, and quality of life (QoL) in patients with chronic HFrEF. Secondary endpoints were safety analysis of Ivabradine including cardiovascular mortality, worsening HF readmission, visual disturbances, and asymptomatic bradycardia. The analysis was done by Review Manager 5.4 Analyzer, to analyze the mean differences (MD) for continuous data and risks ratio (RR) for dichotomous data. A total of six RCTs and one subgroup analysis showed add of Ivabradine to standard HF therapy was associated with greater resting heart rate reduction , improved LVEF , left ventricular reverse remodeling improvement , increased exercise capacity , and significant reduction on rehospitalization due to worsening HF . However, Ivabradine has no significant effect on the quality of life , and cardiovascular mortality . Moreover, there were some events of visual disturbances and asymptomatic bradycardia observed in the Ivabradine group compared to the placebo group . Addition of Ivabradine to standard HF therapy is associated with cardiac function improvement, reduction on worsening HF readmission, greater HR reduction, and better exercise capacity in chronic HFrEF patients, although it cannot reduce cardiovascular mortality or improve the quality of life.Elevated resting heart rate in chronic heart failure (HF) patients has been associated with higher mortality and poor prognosis. Ivabradine is a new pure bradycardic agent that has been used to treat angina or heart failure reduced ejection fraction (HFrEF) with sinus heart rate above 70 beats per minute. However, the effect of ivabradine for chronic HF patients on rehospitalization and cardiac function is still inconsistent. Thus, this meta‐analysis aimed to elucidate the effect of Ivabradine in chronic HFrEF patients. We systematically searched PubMed, Medline, Clinical  Ivabradine is selectively acted to lower the HR through specific inhibition of the I2This study was conducted per standard article publication in Medical Journals, as this article has been made in coherence with Preferred Reporting Items for Meta‐Analysis PRISMA Checklist.2.1Trials.gov, and The Cochrane Central Register of Controlled Trials for RCTs with search terms Ivabradine (MeSH terms), chronic heart failure and beta‐blocker without any specific time restriction  Non‐human studies; (2) Articles in a language other than English; (3) No follow up data; (4) Other types of HF; (5) No comparison between intervention and control groups , left ventricular end‐diastolic diameter (LVEDD), left ventricular end‐diastolic volume (LVEDV), and left ventricular end‐systolic volume (LVESV). Assessment for exercise capacity was measured with exercise duration, meanwhile, Minnesota Living with Heart Failure (MLWHF) questionnaire were used to detect an improvement in the QoL of HF patients.  with 95% CIs. Effect model was used in data analysis depends on the degree of heterogeneity and 2.5The Cochrane risk of bias domains were used to analyze the bias ratings of each study. The selection of domains includes random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. Ratings of bias are divided into low risk, unclear risk, and high risk. Quality of evidence extracted by two independent investigators (Richard Bryan and Bi Huang), where the disagreement about inclusion data will be settled by a third investigator (Gang Liu) through a discussion and consensus.3In total, six RCTs and one subgroup analysis with 7074 participants  were enrolled in this meta‐analysis. The main outcomes of this study were the effect of Ivabradine therapeutic on HR, LVEF, exercise capacity, QoL, and left ventricular remodeling. The high heterogeneity presented might be attributed to a distinct measurement index, insufficient number of studies on preferred outcomes, and different baseline characteristics of represented studies, such as sample size, age, gender, and follow‐up time.3.1Six RCTs included in our study showed that Ivabradine added to the standard HF treatment was associated with a better optimization for resting HR reduction in chronic HFrEF patients  compared to the placebo group.Five RCTs  demonstrated treatment with added Ivabradine significantly increased LVEF in the chronic HFrEF patients .Three echocardiographic studies of chronic HFrEF  were enrolled to observe the possibility of Ivabradine for left ventricular remodeling. Analysis was done by dividing parameter index into four groups including LVEDD,Exercise capacity between optimal HF treatment compared to added Ivabradine treatment was measured by total exercise duration.Two studies  were enrolled to observe the improvement of QoL in chronic HFrEF patients. It indicated that added Ivabradine treatment had no significant effect on MLWHF score  , but not in the <60 years old group (I2 = 0%), thus indicating aging was one of the reasons for the high heterogeneity.High heterogeneity investigation in the resting HR was stratified into two subgroups based on age and follow‐up duration. First, included studies were grouped based on the age < 60 years old2 79%), nevertheless in ≥6 months group 2 RCTs showed no heterogeneity .Second, subgroup analysis was performed based on the duration of Ivabradine treatment for HR reduction with distinction <6 monthsIn the present study, high heterogeneity also existed in the other outcomes, such as in the left ventricular remodeling indexes, exercise capacity, and QoL. As for the LV remodeling parameters, after conducting a sensitivity analysis, low heterogeneity was displayed on LVEDV and LVESV. Meanwhile, owing to an insufficient number of studies, subgroup analyses for exercise capacity and QoL was unable to be conducted.4The present meta‐analysis demonstrated apart from several adverse events mentioned, added Ivabradine treatment was not only safe, but also effective for HR reduction, improvement of cardiac function, and better exercise tolerance in patients with chronic HFrEF. To the best of our knowledge, this meta‐analysis is among the few meta‐analyses to discuss the effect of Ivabradine in chronic HFrEF patients.In terms of the efficiency of Ivabradine, the present meta‐analysis complies with SHIFTIvabradine lead to improvement in HR and LVEF was mainly attributed to the fact that the combination with beta‐blocker produces a significant reduction in the resting HR. Tsutsui, et alAssociation between dosage of Ivabradine and LVEF improvement was also found in some studies. Tsutsui, et al.Moreover, the improvement of exercise capacity is beneficial from the combination of beta‐blocker and Ivabradine which increase the beta‐blocker non‐selective effects on the alpha‐adrenergic receptor, thus affect muscle‐skeletal dilatation during exercisep < .001). Moreover, Volterrani M, et alMost studies inferred the observed effect of Ivabradine on QoL improvement was likely to be related to exercise capacity improvement,Ivabradine was thought to have no relation with renin angiotensin aldosterone (RAA) system and the sympathetic nervous system, therefore, theoretically, Ivabradine does not affect cardiac reverse remodeling. However, our meta‐analysis included two RCTs and one subgroup analysis favors adding Ivabradine for reverse remodeling in chronic HFrEF patients.5There are several unavoidable limitations in this study. First, although we included six RCTs and one subgroup analysis associated with Ivabradine efficiency and safety in patients with chronic HFrEF, however, the high heterogeneity and the numbers of patients included to each study contributed to the statistical analysis and conclusion. Second, different parameter indices associated with LV remodeling, exercise capacity, and quality of life were used in different studies, thus limiting the analysis with the same parameters and also the final conclusion. Third, echocardiographic indexes as ventricular remodeling indicators are easily affected by afterload and preload, thus careful and repeated measurement of cardiac echocardiography is necessary. Fourth, most of the included studies only provided average doses of Ivabradine and therefore we could not get the dose‐effect relationship. Therefore, more large‐scale studies are still needed to elucidate the association of Ivabradine with the outcome in patients with chronic HFrEF.6Addition of Ivabradine to standard HF therapy is associated with cardiac function improvement, reduction on worsening HF readmission, greater HR reduction, and better exercise capacity in chronic HFrEF patients, although it cannot reduce cardiovascular mortality or improve the quality of life.6MWT6 minutes walking testACEIangiotensin converting enzyme inhibitorAECOPDacute exacerbation chronic obstructive pulmonary diseaseARBangiotensin receptor blockerBEAUTIFULeffects of ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunctionBPMbeats per minuteCHFchronic heart failureCIconfidence intervalCQMUChongQing Medical UniversityCVDcardiovascular deathFDAFood and Drug AdministrationHFheart failureHFrEFheart failure reduced ejection fractionHRheart rateKCCQKansas City Cardiomyopathy QuestionnaireLVEDDleft ventricular end‐diastolic diameterLVEDVleft ventricular end‐diastolic volumeLVEFleft ventricular ejection fractionLVESDleft ventricular end‐systolic diameterLVESVleft ventricular end‐systolic volumeLVSDleft ventricular systolic dysfunctionMDmean differencesMeSHmedical subject headingMLWFHMinnesota living with heart failurePRISMAPreferred Reporting Items for Systematic Review and Meta‐AnalysisQLMIquality of life after myocardial infarctionQoLquality of lifeRAASrenin angiotensin aldosterone systemRCTrandomized controlled trialsRevManreview managerRRrisk ratiosSHIFTeffects of ivabradine on cardiovascular events in patients with moderate to severe chronic heart failure and left ventricular systolic dysfunctionThe authors declare no competing interests.Appendix S1. Supporting informationClick here for additional data file.Appendix S2. Supporting informationClick here for additional data file.Figure S1 Ivabradine vs Placebo on Echocardiographic studies. A: Left Ventricular End‐Diastolic Diameter (LVEDD); B: Left Ventricular Systolic Diameter (LVESD); C: Left Ventricular End‐Diastolic Volume (LVEDV) limited and sensitivity analysis; D: Left Ventricular End‐Systolic Volume (LVESV) limited and senstivity analysis.Supplement Figure 2. Ivabradine vs Placebo on Exercise Capacity Improvement.Supplement Figure 3. Ivabradine versus Placebo in Minnesota Living with Heart Failure (MLWHF) questionnaireSupplement Figure 4. Risk of Bias Summary for Included StudiesClick here for additional data file.Table S1 Standard Heart Failure Treatment at RandomizationSupplement Table 2. Baseline Characteristics of Included StudiesSupplement Table 3. Post‐Follow up OutcomesClick here for additional data file.


Background: The cardiac response to endurance exercise has been studied previously, and recent reports have described the extension of this remodeling to the pulmonary vasculature. However, these reports have focused primarily on land-based sports and few data are available on exercise-induced cardio-pulmonary adaptation in swimming. Nor has the impact of sex on this exercise-induced cardio-pulmonary remodeling been studied in depth. The main aim of our study was to evaluate cardiac and pulmonary circulation remodeling in endurance swimmers. Among the secondary objectives, we evaluate the impact of sex and endurance sport discipline on this cardio-pulmonary remodeling promoted by exercise training.Methods:Resting cardiovascular magnetic resonance imaging was performed in 30 healthy well-trained endurance swimmers  and in 19 terrestrial endurance athletes  to assess biventricular dimensions and function. Pulmonary artery dimensions and flow as well as estimates of pulmonary vascular resistance (PVR) were also evaluated.Results:In relation to the reference parameters for the non-athletic population, male endurance swimmers had larger biventricular and pulmonary artery size  with lower biventricular ejection fraction (EF) (left ventricular (LV) EF: 58 ± 4.4 vs. 67 ± 4.5 %, p < 0.001; right ventricular (RV) EF: 60 ± 4 vs. 66 ± 6 %, p < 0.001), LV end-diastolic volume (EDV): 106 ± 11 vs. 80 ± 9 ml/m2, p < 0.001; RV EDV: 101 ± 14 vs. 83 ± 12 ml/m2, p < 0.001). Significantly larger LV volume and lower LV EF were also observed in female swimmers . Compared to terrestrial endurance athletes, swimmers showed increased LV indexed mass . The two groups of endurance athletes had similar pulmonary artery remodeling.Conclusions: Cardiac response to endurance swimming training implies an adaptation of both ventricular and pulmonary vasculature, as in the case of terrestrial endurance athletes. Cardio-pulmonary remodeling seems to be less extensive in female than in male swimmers. Long-lasting endurance exercise training induces structural and functional remodeling of all four cardiac chambers , 2, affeDifferent patterns of cardiac adaptation to endurance exercise have been observed between athletes of different disciplines –8. In thConsequently, this study had three aims: (1) by means of CMR imaging, to analyze cardiac and pulmonary circulation remodeling in a series of endurance open-water swimmers; (2) to evaluate the impact of the endurance sport discipline, by comparing the remodeling observed in swimmers to that observed in a cohort of terrestrial endurance athletes; and (3) to analyze the impact of sex on this exercise-induced cardio-pulmonary remodeling.Thirty non-elite endurance-trained swimmers taking part in the open water swimming race “Oceanman Palamós 9.5 Km” in Catalonia, Spain, and currently engaged in endurance open-water swimming competitions of distances between 3 and 10 km, volunteered to participate in the study. All athletes were trained primarily using the front stroke technique.Additionally, data on 19 healthy age and sex-matched non-elite endurance athletes trained in terrestrial sports (cycling and running) were obtained retrospectively from a pre-analyzed CMR data base managed by our working group.A cardiovascular evaluation including a comprehensive personal and family history, resting 12-lead electrocardiogram, treadmill stress test and transthoracic echocardiography at rest was performed prior to the study in order to rule out cardiovascular disease.All participants filled out a questionnaire providing details of their training history. Exclusion criteria included any history of cardiopulmonary disease and standard contraindications for CMR imaging. To assess training load, a standardized form based on the IPAQ questionnaire  was usedThe study protocol was approved by the ethics committee of our institution and complied with the Declaration of Helsinki.The CMR studies in the swimming group were carried out by an experienced cardiologist on a 1.5 Tesla scanner  using standard steady-state, free precession ECG-gated breath-hold cines in three long-axis planes and sequential short axis slices from the atrioventricular ring to the apex. Additional cross-sectional cine images of main pulmonary artery and ascending aorta at level of right pulmonary artery were acquired. For flow measurements, standard breath-hold velocity-encoded phase-contrast MR sequences were used with slices positioned perpendicular to the long axis of the ascending aorta where the flow is parallel to the long-axis of the body, and perpendicular to the long axis of the main pulmonary artery. The CMR studies in the group of terrestrial athletes were conducted previously using the same acquisition protocol, and the images were also analyzed beforehand by the same cardiologist.syngo.via, Siemens Healthcare, Erlangen, Germany). Global LV and RV function were assessed by manually contouring the endocardial borders of end-diastolic and end-systolic short-axis images. For the computation of LV mass, the epicardial borders were additionally contoured at end diastole. LV and RV volumes and EF and left ventricular mass were automatically calculated by the software. Measurements were indexed for body surface area. For the assessment of ascending aorta and pulmonary artery flow, the cross-sectional area of these vessels was defined and manually corrected, and flow parameters were then automatically provided by the software  . All continuous variables were analyzed for normality of distribution using the Kolmogorov-Smirnov test. Subsequently, the Student's t test was used to compare baseline data. If normality was not confirmed, the Mann–Whitney-U test was applied. Bivariate correlational analysis was used for RV EF, indexed RV EDV, and RVP to determine any possible relationship. The intraclass correlation coefficient (ICC) for the two-way mixed effect models and for absolute agreement ICC  was calculated to assess the inter-rater reliability of the CMR parameters. The alpha value was set at 0.003 to account for Bonferroni correction.Statistical analysis was carried out using the SPSS Software version 22.0 p = 0.706). No significant differences were found between male and female swimmers, except for BSA, which was higher in men.Clinical and functional characteristics of both groups and according to sex are shown in CMR results in endurance swimmers are summarized in Similar to the men, female swimmers showed significantly lower values of LV EF with larger LV volumes. Conversely, RV dimensions and EF, as well as pulmonary artery size and estimated PVR, were within reference values for the healthy non-athletic population.Compared to male swimmers, females had higher biventricular EF, smaller LV mass and RV end-diastolic volume (RV EDV) and lower estimated PVR.The comparison of CMR parameters between swimmers and controls is shown in The current study presents a comprehensive CMR evaluation of the impact of endurance swimming on ventricular and pulmonary circulation structure and function. To our knowledge, the effects of endurance swimming training on cardiac and pulmonary vasculature remodeling have not been previously evaluated in CMR studies.The key findings of our study were: (1) endurance swimming promoted a significant remodeling of both ventricles, characterized by greater biventricular volumes and lower biventricular function as well as significant remodeling of the pulmonary vasculature (PV) with greater pulmonary artery size and increased PVR; (2) sex has a strong impact on the RV and PV remodeling induced by endurance swimming, with female athletes exhibiting smaller RV cavities, higher RV function and lower PVR; (3) endurance sport discipline did not influence the PV remodeling promoted by long-lasting exercise training, as similar pulmonary artery size, and equivalent estimated PVR were observed in swimmers and terrestrial endurance athletes. However, a trend toward lower exercise-induced RV remodeling was shown in swimmers.Previous studies have evaluated cardiac adaptation to endurance exercise using CMR imaging, showing enlarged LV and RV dimensions with no differences in biventricular EF between endurance athletes and non-athletic populations , 23, 24.We have recently reported that the response to endurance chronic training involves not only the four cardiac chambers but also the pulmonary circulation, since endurance athletes showed greater pulmonary artery dimensions with reduced pulmonary artery flow velocity and a higher estimated PVR than non-athletes . In the However, the cardiopulmonary adaptation differed slightly in female and male swimmers. In females, with respect to the reference population, only enlarged LV and reduced LV EF were observed. Compared to male swimmers, women had smaller LV and RV volumes, higher LV and RV EF, and lower pulmonary artery size and estimated PVR. Thus, the results of the present study show that male swimmers present more extensive biventricular and pulmonary circulation remodeling than their female counterparts. The reason for this difference is not entirely clear, but the finding is in agreement with previous studies performed in idiopathic pulmonary arterial hypertension patients, which have demonstrated a poorer adaptation of RV to increased overload in male subjects , 27. ThiUsing CMR parameters established for the general population as a reference may have induced errors in the athletes' heart evaluations, given that exercise-induced increases in ventricular dimensions may overlap with those observed in patients with pathological conditions, such as dilated cardiomyopathy and RV arrhythmogenic cardiomyopathy. In this connection, a recent meta-analysis defined the normal limits of biventricular size and function in competitive male athletes, which represent a useful tool for athletes' heart evaluations . Our resIt has been established that functional and structural cardiac remodeling induced by exercise is influenced by the specific sport discipline; cardiac response to endurance training differs according to the muscle group predominantly involved during exercise (upper- vs. lower-body) , 18. TheFinally, the beneficial effect of exercise in terms of cardiovascular health is well established, and greater benefits are obtained with moderate exercise. The athlete's heart is a result of a series of adaptive mechanisms of the heart to cope with the overload involved in intense long-lasting athletic training. However, the amount of this remodeling can make it difficult to distinguish between physiological and pathological cardiac changes. Additionally, emerging data suggest the existence of a syndrome of exercise-induced arrhythmogenic RV cardiomyopathy  which maThe small sample size of this exploratory observational study limits the statistical power and generalizability of the results. Given the low number of women in both groups of endurance athletes, the conclusions drawn from the sex comparison should be considered exploratory. Further studies with larger athlete populations including women are needed to better understand the influence of sex on cardiac remodeling. PVR values were not obtained invasively with right heart catheterization, and the method used to estimate PVR has not been validated in healthy population. However, a previous study by our group  found a As peak oxygen consumption (VO2) was not measured, we cannot rule out a possible effect of VO2 on cardiac remodeling and, therefore, on the results obtained.We did not perform delayed gadolinium enhancement sequences, thus limiting the analysis of fibrosis induced by chronic endurance swimming.Endurance chronic swimming training induces biventricular and pulmonary vascular adaptation which is more pronounced in males. As compared to other endurance athletes, swimmers seem to present a less extensive remodeling of the RV. These findings may be due to a differential hemodynamic impact of swimming on the pulmonary circulation and the right heart.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 Fundació Catalana Hospitals, approval number CEIC 15/28. The patients/participants provided their written informed consent to participate in this study.VM conceived and designed the study, analyzed the data, and interpreted the results. VM, CF, and CY performed the cardiac magnetic resonance studies. MSG, BD-X, AG-A, SP-G, and MS contributed to the interpretation of the results. VM wrote the manuscript and MS supervised the study. All authors contributed to manuscript revision, read and approved the final manuscript.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.


Introduction: Low cardiac output syndrome is one of the postoperative complications that are associated with significant morbidity and mortality after surgical closure of atrial septal defect (ASD) with small-sized left ventricle (LV). This study investigated whether preoperative left ventricular end-diastolic volume index (LVEDVi) could accurately predict low cardiac output syndrome (LCOS) after surgical closure of ASD with small-sized LV.Method: This retrospective cohort study involved adult ASD patients with small-sized LV from January 2018 to December 2019 in National Cardiovascular Center Harapan Kita. Preoperative MRI data to assess the left and right ventricle volume were collected. A bivariate analysis using independent Student's t-test was done. Diagnostic test using receiver operating characteristic (ROC) curve was also done to obtain the area under the curve (AUC) value. The best cutoff point was determined by Youden's index.Result: Fifty-seven subjects were involved in this study . Subjects who had post-operative LCOS (n = 30) have significantly lower LVEDVi , LVEDV , LVSV , and LVSVi  compared to subjects who did not have post-operative LCOS (n = 27). ROC analysis showed that the best AUC was found on LVEDVi . The best cutoff value for LVEDVi to predict the occurrence of LCOS after surgical closure of ASD was 53.3 ml/m2 with a sensitivity of 86.7% and a specificity of 85.2%.Conclusion: This study showed that preoperative LVEDVi could predict LCOS after surgical closure of ASD with small-sized LV with a well-defined cutoff. The best cutoff value of LVEDVi to predict the occurrence of LCOS after surgical ASD closure was 53.5 ml/m2. Secundum Atrial Septal Defect (ASD) is one of the most common congenital heart defects in children and adults , 2. KrumASD allows a left-to-right shunt leading to a volume overload in the right ventricle, which further causes pulmonary hypertension . As the After the closure of ASD, the left-to-right shunt from the left atrium to the right atrium will stop and the blood will start to flow from the left atrium to the left ventricle. Due to volume underload prior to the ASD closure, a sudden increase of blood volume to the previously small-sized left ventricle after the surgical closure will cause a diastolic dysfunction leading to a circulatory failure . Hence, It is important to assess the left ventricle volume to avoid circulatory failure caused by a sudden increase in left ventricle volume load after surgical closure . SeveralThe objectives of this study were to evaluate whether LVEDVi could be used as a predictor of LCOS after surgical closure of ASD with small-sized LV and to determine the cutoff value of LVEDVi that could still tolerate sudden blood flow increase after surgical closure of ASD with small-sized LV.This study was a retrospective cohort study conducted at National Cardiovascular Center Harapan Kita (NCCHK) from January 2018 until December 2019. The study was approved by the ethical research committee (IRB). The inclusion criteria were patients diagnosed with ASD who underwent surgical ASD closure and the preoperative echocardiography result showed a small-sized LV (the size of the LV is <50% of the size of right ventricle). These criteria were related to our institutional policy where the preoprative MRI is only obtained in patients based on the small-sized LV criterion. Preoperative MRI data such as right ventricle ejection fraction (RVEF), right venricle stroke volume (RVSV), right ventricle stroke volume index (RVSVi), right ventricle end systolic volume (RVESV), right ventricle end systolic volume index (RVESVi), right ventricle end diastolic volume (RVEDV), right ventricle end diastolic volume index (RVEDVi), left ventricle ejection fraction (LVEF), left venricle stroke volume (LVSV), left ventricle stroke volume index (LVSVi), left ventricle end systolic volume (LVESV), left ventricle end systolic volume index (LVESVi), left ventricle end diastolic volume (LVEDV), and LVEDVi were measured. The valvular disease was evaluated by echocardiography. Sign of pulmonary arterial (PA) hypertension was evaluated by the presence of pruning sign from x-ray examination, low flow of pulmonary vein, bidirectional/right-to-left ASD shunt, and D-shaped left ventricle from echocardiography. Only patients with estimated PA pressure higher than 40 mmHg underwent cardiac catheterization prior to surgery based on institution protocol. The exclusion criteria used in this study were ASD patients with severe pulmonary hypertension  with high pulmonary artery resistance index (>4 Woods unit) after being given the lung vasodilator test, those who had other organ malformations, or those who had a re-operation after ASD closure.Surgical ASD closure was done either by pericardial patch or by direct closure. Tricuspid valve repair was done with ring annuloplasty/Kay procedure on the patient who develops moderate/severe tricuspid valve regurgitation. Mitral repair was done on a patient with severe mitral regurgitation. Aortic cross-clamp time and cardiopulmonary bypass machine time were measured. The postoperative LCOS was assessed by a combination of clinical parameters and laboratory findings, such as the presence of a minimum of two clinical findings  and/or a central venous saturation <60% (oxygen extraction ratio higher than 40%), with or without metabolic acidosis or increased lactate levels, resulting in an escalation of therapy. This syndrome was evaluated and confirmed by our cardiac intensivist.All data were collected retrospectively in February 2020. Demographic and pre-operative MRI data of the patient were obtained through the medical record. Post-operative clinical patient data were collected through medical and nursing patient record review.t-test was used for bivariate analysis with normal data distribution; otherwise, Mann–Whitney test was used as a non-parametric test. The receiver operating characteristic (ROC) curve was used as a diagnostic test analysis to get the cutoff point between the LVEDVi value and the LCOS cases. Thus, we obtained the cutoff points and area under the curve (AUC). The Youden index was used to identify the best cutoff point (J = Sensitivity + Specificity – 1).Data were collected and then analyzed using SPSS software Version 20.0. The data normality was assessed using Kolmogorov–Smirnov. Independent Student's Fifty-seven subjects were included in this study. Fifty (83.9%) out of 57 subjects were females. The mean age of the subjects was 32.5 years, with the youngest being 13 years old and the oldest being 65 years old. Most subjects were NYHA II and NYHA III . Almost all (94.7%) subjects had tricuspid valve regurgitation and some were accompanied with either mild (21%) or moderate (14.5%) mitral valve regurgitation .Seventy-six percent of the subjects underwent surgical ASD closure using a pericardial patch, while only few used only polypropylene suture. Nine (14%) subjects with mild and moderate mitral valve regurgitation had surgical ASD closure complemented by mitral valve repair using ring annuloplasty .p < 0.001) (There was no significant difference between the mean duration of cardiopulmonary bypass (CPB) machine and the mean duration of aortic cross-clamp (AoX) in patients with and without postoperative LCOS. The subjects were transferred to the intensive care unit (ICU) right after the surgery had been completed, and ventilator support was used to improve their postoperative conditions. The median duration of ventilator usage and the median length of stay in the ICU were significantly higher in patients with postoperative LCOS (< 0.001) . Thirteep < 0.05)  . However2; sensitivity of 86.7%, specificity of 85.2%) followed by LVSV  , LVEDV , LVSVi , and LVSV  . Meanwhif 81.5%) .2 with higher sensitivity (88.0%) and specificity (87.0%). However, the optimal cutoff point of LVSV showed lower with lower sensitivity (88.0%) and specificity (78.3%), given the same optimal cutoff (48.7 ml/m2).ROC analyses of LVEDVi, LVEDV, LVSV, and LVSVi value with the exclusion of moderate to severe mitral valve regurgitation subjects were done  and optiLCOS occurs when there is a decrease in cardiac output caused by temporary myocardium dysfunction. LCOS may occur several hours after using a cardiac bypass machine, causing a decreased myocardium function due to increased cardiac output demand . If LCOSOut of 57 ASD patients in this study, more than half of the population (52.6%) had LCOS. However, Chandler et al.  reportedp < 0.001) and LVESVi  were significantly lower compared to the healthy subjects at rest  leaving/creating a small ASD after complete closure of ASD intraoperatively , (2) utilizing left atrial pressure monitoring line during and after the operation to avoid left venticular failure, (3) placement of a temporary atrial pacemaker to increase the heart rate in order to avoid distention of the left venticle postoperatively, and/or (4) aggressive systemic afterload reduction with phosphodiesterase III inhibitors to improve LV function postoperatively.The limitation of this study was that our subjects only focused on the ASD patient with small-sized LV, so the data implementation will be less representative of the overall population admitted for ASD closure. Regardless, this study provided a new insight related to management of patients with late-presenting ASD particularly with the small-sized LV condition. Some of our subjects had already achieved LCOS treatment on the small-sized LV through ACE inhibitor as the afterload reduction, which then becomes the confounding variable. Other confounding variables in our study were valvular regurgitations and post-surgical pulmonary hypertension. In this study, we only assessed one morbidity, which was LCOS. There are lots of morbidities that may occur after heart surgery such as arryhythmia, stroke, prolonged ventilator use, pulmonary hypertension, pulmonary edema, and death. Further studies with larger sample, multi-center and preferably the cohort are needed to evaluate and validate the LVEDVI cutoff value of this study.2, with a sensitivity of 86.7% and a specificity of 85.2%. Validation of the achieved LVEDVi cutoff value is needed to assess LCOS after surgical closure of ASD at larger samples, and it is necessary to determine the LVEDVi cutoff value against other morbidities after surgical closure of ASD such as arryhthmia, stroke, duration of ventilator use, sepsis, pulmonary hypertension, pulmonary edema, and death.This study showed that LVEDVi could be used to predict the occurrence of LCOS after surgical closure of ASD with a well-defined cutoff . The best LVEDVi cutoff value to predict LCOS after surgical closure of ASD was ≤53.3 ml/mThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.BR, ND, and OL contributed to conception and design of the study. ND and PA organized the database. PA performed the statistical analysis. BR and PA wrote the first draft of the manuscript. BR, ND, PA, and OL wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Pulmonary vascular resistance (PVR) is a marker of pulmonary vascular remodeling. A non-invasive model assessed by cardiovascular magnetic resonance (CMR) has been proposed to estimate PVR. However, its accuracy has not yet been evaluated in patients with heart failure. We prospectively included 108 patients admitted with acute heart failure (AHF), in whom a right heart catheterization (RHC) and CMR were performed at the same day. PVR was estimated by CMR applying the model: PVR = 19.38 − [4.62 × Ln pulmonary artery average velocity (in cm/s)] − [0.08 × right ventricle ejection fraction (in %)], and by RHC using standard formulae. The median age of the cohort was 67 years (interquartile range 58–73), and 34% were females. The median of PVR assessed by RHC and CMR were 2.2 WU (1.5–4) and 5 WU (3.4–7), respectively. We found a weak correlation between invasive PVR and PVR assessed by CMR . The area under the ROC curve for PVR assessed by CMR to detect PVR ≥ 3 WU was 0.57, 95% confidence interval (CI): 0.47–0.68. In patients with AHF, the non-invasive estimation of PVR using CMR shows poor accuracy, as well as a limited capacity to discriminate increased PVR values. The development of PH overshadows the prognosis of these patients, leading to right ventricular dysfunction and an increased risk of mortality3. The backward transmission of elevated left-sided filling pressures into the pulmonary circulation is the hallmark of isolated post-capillary PH (IpcPH). However, in many cases venous congestion is followed by vasoconstriction and arterial remodeling, leading to an increased pulmonary vascular resistance (PVR), superimposing a pre-capillary component, which has been defined as combined PH (Cpc-PH). In this regard, PVR has become a useful marker of pulmonary arterial remodeling with crucial diagnostic and prognostic value, involving important therapeutic implications4.Pulmonary hypertension (PH) is a common finding in patients with heart failure (HF), regardless of left ventricular ejection fraction (LVEF) status5. García-Alvarez et al. showed a strong correlation with invasive PVR and PVR derived from a model based on right ventricular ejection fraction (RVEF) and the natural log of average pulmonary arterial velocity in an heterogenous PH population6. However, its performance in a specific and larger group of PH due to left heart disease (PH-LHD) is still unknown. Accordingly, we sought to evaluate the diagnostic accuracy of a noninvasive CMR model for the estimation of PVR in a cohort of patients admitted with acute HF (AHF).Currently, the gold-standard technique for quantifying PVR is invasively, through right heart catheterization (RHC). Cardiovascular magnetic resonance (CMR), which also provides us with an excellent study of the right ventricle (RV) and pulmonary circulation, has recently been postulated as a useful technique for estimating non-invasively the PVRWe conducted a prospective, observational study that included 154 consecutive patients admitted with AHF, between February 2015 and May 2019, who were referred to the catheterization laboratory of our hospital in order to perform a RHC and in whom a CMR was realized during hospitalization. Both techniques were performed after initiating optimal medical treatment and when hemodynamic stability and congestion improvement were achieved, without inotropic agents requirements and always to the discretion of the attending physician.7. Both, a first occurrence and an acute decompensation of chronic HF were included. Patients with congenital heart disease (n = 12) and those with organic valvular disease (n = 14) were excluded from this study. In addition, we excluded patients in which RHC and CMR were performed with an interval of time of more than 6 h of difference between both (n = 20) in order to avoid discrepancies in hemodynamic status. A total of 108 patients were finally enrolled.AHF was defined according to European Society of Cardiology guidelines as rapid onset or worsening of symptoms and/or signs of HFIn order to evaluate differences in the diagnostic accuracy, subgroup analysis was performed classifying our study population according to (1) the median of LVEF, and (2) the presence of preserved (≥ 45%) or reduced (< 45%) RVEF.All participants provided written informed consent and the local ethics committee  approved the study. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki (revised in 1983) as reflected by an a priori approval by the institution´s human research committee.8.CMR was performed with a 1.5 T Siemens system . For cine imaging, breath-holding ECG-gated steady-state free precession (SSFP) sequences were used as normally to acquire long and short axis slices, and hence evaluate ventricular volumes and function. 2D flow imaging was performed perpendicular to the pulmonary artery (PA) trunk with a velocity encoded phase-contrast sequence using an upper-velocity limit of 150 cm/s . Two double-oblique orthogonal views oriented along the main PA were acquired with SSFP cine sequence and used as the reference to prescribe the plane perpendicular to the PA trunk for the acquisition of phase-contrast images. These parameters were applied as usually: field of view 300 × 400 mm, acquisition matrix 256/192, slice thickness 6 mm, time/echo time 5.9–7.5/3.1–6.5 ms, in-plane resolution 1.5–3 mm, 30 reconstructed cardiac phases, and temporal resolution 55–105 ms. 2D flow CMR acquisitions were performed during free breathing and retrospective ECG-gating was used9.Images were analyzed by a single expert cardiologist in cardiac imaging using specific software . Short axis slices were used to calculate ejection fractions and ventricular volumes using Simpson's method. PA cross-section was outlined in each cardiac phase to estimate PA area and flow, and calculate peak and average velocities during the complete cardiac cycle, minimum and maximum areas, and PA net forward volume. Ventricular volumes, ejection fractions, and PA area were adjusted to body surface area6: PVR (WU) = 19.38 − [4.62 × ln PA average velocity (cm/s)] − [0.08 × RVEF (%)].PVR were calculated using the following model proposed by García-Alvarez et al.10. Increased PVR was defined as ≥ 3 WU.RHC was performed using a 7F Swan–Ganz catheter via a femoral or brachial vein approach after optimizing diuretic treatment, and heart rate control in patients with atrial fibrillation. The following hemodynamic measurements were always recorded during end-expiration: mean right atrial pressure; systolic, diastolic and mean pulmonary artery pressure (mPAP); systolic, mean, and diastolic right ventricle pressure and mean pulmonary arterial wedge pressure (PAWP). PAWP was measured 130–160 ms after the onset of QRS and before the v-wave in patients with atrial fibrillation. Cardiac output was determined as the mean of three measurements using the thermodilution method. Fick method was used when a significant tricuspid regurgitation was present. Transpulmonary gradient (TPG) was calculated by subtracting PAWP from mean PAP, and PVR as TPG divided by RV cardiac output and expressed in WU. The diagnosis of PH-LHD was established when mPAP was > 20 mmHg and PAWP > 15 mmHg, according to recent PH diagnostic criteriaContinuous variables were expressed as median with interquartile range. Discrete variables were summarized as frequency and percentages.RHC) with CMR (PVRCMR) and different other CMR parameters  were evaluated by Spearman correlation analysis. Bland–Altman analysis was performed to assess the degree of agreement between PVRCMR and PVRRHC. The bias, standard deviation, and the 95% limits of agreement were reported. Receiver operating characteristics (ROC) curves were constructed to determine the diagnostic accuracy of non-invasive model for the detection of increased values of PVR (≥ 3 WU). Area under the ROC curve ≤ 0.5 indicates no value. The closer the area is to 1.0, the greater the diagnostic utility and significance of the test. A p-value < 0.05 was considered statistically significant. STATA 14.1 software was used to perform and display the statistical analysis .The correlations between RHC , and for right ventricle cardiac output was 3.7 l/min (3–5), using the thermodilution technique in 101 (93.5%) patients. The number of patients with PH-LHD was 84 patients (77.8%), and 45 patients (42%) exhibited CpcPH at diagnosis.The median (interquartile range) of mPAP and PAWP was 30 mmHg (21–38) and 19 mmHg (14–25), respectively. The median (interquartile range) of PVRCMR was 5 WU (3.4–7) and 71 patients (65.7%) exhibited PVR values ≥ 3 WU.The median (interquartile range) of LVEF and RVEF were 30% (20–41) and 43% (30–53), respectively. Fourteen patients (13%) showed preserved LVEF (≥ 50%), and 59 patients (55%) presented RVEF < 45%. The median (interquartile range) of PVRCMR to detect PVR ≥ 3 WU was 0.57, 95% confidence interval (CI): 0.47–0.68,  as is shown in Fig. RHC are summarized in Table RHC and RVEF .Several correlations between CMR parameters and PVRCMR and PVRRHC in patients with LVEF < 30% (n = 54) ,  and LVEF ≥ 30% 0.62, 95% CI (0.40–0.83), , we observed no correlation between PVR0), Fig. A. On the0), Fig. B. Regard0), Fig. C,D. A loTo the best of our knowledge, this is the first study designed to evaluate the diagnostic accuracy of a non-invasive PVR method in a specific population of AHF patients. Our results suggest that the CMR method fails to estimate with accuracy PVR. Furthermore, the present findings confirm its lack of ability to discriminate with precision increased values of PVR in a specific group of HF patients.1. PH-LHD is the most common form of PH, with a prevalence that ranges between 36–83%12. Currently, PVR is a well-established prognostic marker in HF patients2. Several studies suggest that HF patients with increased values of PVR, are associated with worse survival and an increase in HF hospitalizations12. In this sense, an accurate and reproductible non-invasive method capable of estimating PVR remains an unmet need in HF patients. Different studies have reported promising results with different models based in CMR imaging metrics, but all of them have several limitations, either due to a small sample size, retrospective cohorts, or because results were validated predominantly in pulmonary arterial hypertension (PAH) patients18.The development of PH is a common complication in the progression of HF, regardless of LVEF6 developed a non-invasive model assessed by CMR based on RVEF and mean PA velocity to predict PVR. They analyzed a suspected PH cohort of 100 patients divided in a homogeneous derivation and validation cohort of 80 and 20 patients, respectively. It is important to highlight, that this study included different etiologies of PH, although PAH patients were the vast majority. Only 20 patients (20%) in the derivation cohort and 3 patients (15%) in the validation cohort exhibited PH-LHD. The overall population showed a median LVEF within normal ranges (58.7%), in contrast to our HF population that showed a severely depressed LVEF, with only fourteen patients (13%) displaying LVEF ≥ 50%. Nevertheless, the median RVEF was depressed, quite similar in both studies (43% versus 40.5%). Regarding on RHC measurements, the study population showed a mPAP of 39 mmHg, slightly superior when compared to our group, but with a low value of PAWP (9 mmHg) and right atrial pressure (7 mmHg), reflecting a clear prevalence of precapilar PH phenotypes. It is noteworthy, that these patients showed a great pulmonary vascular remodeling with median RVPRHC of 4.7 WU and 66% exhibited PVR ≥ 3 WU. By contrast, our HF population had a median PVR below normal value and a less percentage of patients had PVR above normal value, maybe translating initial stages of PH-LHD or the hemodynamic pattern of different PH groups.García-Alvarez et al.RHC in their precapillary PH cohort . On Bland–Altman analysis the mean bias was − 0.54 ± 2.80 with wide limits of agreement − 6.02 to 4.94 WU. Our study, performed in a specific group of HF patients, observed by contrast a weak correlation with an important mean bias and broad range limits of agreement on Bland–Altman analysis, that translate an inadequate diagnostic accuracy in this specific HF population. In our subgroup analysis, where we searched differences in diagnostic accuracy according to the median of LVEF, we did neither find an important agreement between both methods. Similar results were observed when RVEF was evaluated.García-Alvarez et al. showed a strong correlation between the non-invasive model and PVRRHC. Pulmonary artery velocity and RVEF were the parameters that exhibited the strongest univariate correlation. In our current study, a scarce negative agreement was observed between PVRRHC and average PA velocity. This negative correlation has just been widely reported in patients with PAH20, and has been postulated as a surrogate of PH. However, the evidence describing how PA average velocity decreases assessed by CMR in the specific group of PH-LHD patients is scarce. We hypothesized that the decline of PA velocity could differ in patients with PH-LHD, especially in early stages when no component of the PH is derived from abnormalities intrinsic to the pulmonary arterial bed. This factor can be related with the lack of agreement of this method. On the other hand, no correlation with RVEF was found. Therefore, we speculate that RV dysfunction in our HF population is mainly due to the presence of a cardiomyopathic RV and does not translate solely an end-stage uncoupling of the RV and its load. We should underline, that another potential factor that can contribute to the inaccuracy of the method in this specific population is the lack of any variable that reflects left chamber pressures, essential in the pathophysiology of PH-LHD and maybe imperative in a non-invasive PVR evaluation in HF patients.The CMR-method was created using CMR variables which displayed the strongest correlation with PVRGarcía-Alvarez et al. also explored the capability to differentiate increased values of PVR, observing an excellent discrimination ability of the model in the study population, obtaining an area under the ROC curve of 0.96, 95% CI: 0.92–0.99, which was reassured in the validation cohort. Nevertheless, our results showed a lack of discrimination power of this method to detect elevated PVR in our HF cohort. It must be noted that the agreement was worse in patients with PVR values above the normal limit.These results may translate that this non-invasive method should only be recommended for the evaluation of PVR in patients with pre-capillary forms of PH, and therefore, it may warn us that this model should be used with caution when evaluating PVR non-invasively in patients with AHF.Some limitations should be acknowledged when interpreting the study results. First, this was a single center, non-blinded study. Therefore, a center-specific bias cannot be excluded. Second, CMR non-invasive method was validated with the currently gold standard technique to estimate PVR, RHC. Although, RHC were performed by three expertise interventional cardiologists, several technical inaccuracies can also be reported, including imprecise wedge pressure quantification, or inadequate measurement of cardiac output. Our study population displayed a median PVR value in the range of normality (< 3 UW), representative of HF patients in initial stages of PH-LHD. Finally, the patients here evaluated were all of them hospitalized with acute HF syndromes. Thus, we cannot directly extrapolate these findings to stable phases of the disease.In patients with AHF, a non-invasive estimation of PVR using CMR shows lack of accuracy and reliability, as well as a limited capacity to discriminate increased PVR values. Further studies are needed to confirm our findings and continue searching for non-invasive formulas for an accurate estimation of PVR in patients with HF.


Phase-contrast cine cardiovascular magnetic resonance (CMR) of the coronary sinus has emerged as a non-invasive method to measure coronary sinus blood flow (CSBF) and coronary flow reserve (CFR). We aimed to compare the prognostic value of resting CSBF and CFR for predicting major adverse cardiac events (MACE) in patients with known or suspected coronary artery disease (CAD) who underwent vasodilator stress CMR.We studied 693 patients with known CAD and 519 patients with suspected CAD admitted to our hospital between 2009 and 2019. The CFR was calculated as the CSBF during adenosine triphosphate infusion divided by CSBF at rest. MACE was defined as composite of cardiovascular death, acute coronary syndrome, heart failure hospitalization, and sustained ventricular tachyarrhythmia.During a median follow-up of 4.6 years, 92 patients (8%) experienced MACE. The resting CSBF was significantly higher in patients with MACE than in patients without MACE . The resting CSBF remained a significant predictor for MACE after adjusting clinical and CMR variables . The area under the curve for predicting MACE was 0.73 for resting CSBF, 0.72 for CFR (p = 0.78) in patients with known CAD, and 0.82 for resting CSBF, 0.83 (p = 0.58) for CFR in patients with suspected CAD.The resting CSBF may be a useful non-invasive method for the risk stratification of patients with known or suspected CAD without any radiation exposure, contrast media, or pharmacological vasodilator agents. Accurate assessment of myocardial ischemia is crucial for improving revascularization in patients with coronary artery disease (CAD). Fractional flow reserve (FFR) has been established to identify physiological ischemia during hyperemia provoked by adenosine triphosphate (ATP); research has revealed that FFR-guided revascularization substantially improves the prognosis of CAD patients –3. RecenBlood flow of the coronary sinus can be assessed by phase-contrast (PC) cine cardiovascular magnetic resonance (CMR). The accuracy of coronary sinus blood flow (CSBF) measurements have been validated using myocardial positron emission tomography (PET),  which isThe purposes of this study were to investigate if the resting CSBF is elevated in CAD patients who experienced adverse events and to compare the prognostic values of the resting CSBF and CFR for patients with known or suspected CAD.This retrospective observational study included 1290 patients with known or suspected CAD who underwent vasodilator stress CMR between 2009 and 2019. Known CAD was defined as history of myocardial infarction, previous PCI or coronary artery bypass graft, or angiographically significant coronary artery stenosis . Suspected CAD was defined as having symptoms suspicious of myocardial ischemia (including chest pain and dyspnea on exertion) or ischemic changes on electrocardiogram . Figure Using a 1.5T CMR scanner equipped with 32-channel cardiac coils , data from cine CMR, PC cine of the coronary sinus, stress perfusion CMR, and late gadolinium enhancement (LGE) CMR were acquired. Cine CMR of the left ventricle was acquired using a balanced steady-state free-precession sequence . First-pass perfusion CMR images were obtained by a turbo field echo sequence to evaluate the presence and severity of myocardial ischemia . Immediately after beginning the scan for perfusion, 0.05 mmol/kg of gadolinium contrast  was injected into the antecubital vein at a flow rate of 4 mL/s. Pharmacological stress was induced by continuous injection of ATP (140 μg/kg/min). The time between the acquisition of stress and resting perfusion CMR was at least 10 min. We evaluated the presence and severity of myocardial infarction or scarring by acquiring LGE images in the same planes as the cine images using inversion recovery-prepared gradient-echo sequences . All patients refrained from consuming caffeinated beverages for at least 24 h before the CMR.Figure We analyzed cine, perfusion, PC cine, and LGE images using Extended MR WorkSpace workstation . To measure the left ventricular (LV) volume, mass, and ejection fraction (LVEF), we performed manual tracing of the LV epicardial and endocardial borders on short-axis cine images. LV mass was calculated as the sum of the myocardial volume areas multiplied by the assumed specific gravity (1.05 g/mL) of the myocardial tissue , To calcWe calculated the ΔCSBF and CFR using the following equations:As resting CSBF could be influenced by LV mass and rate pressure product (RPP), we calculated the corrected myocardial blood flow (cMBF) and compare its prognostic value with that of resting CSBF:The average rate pressure product at rest was 7500 from healthy controls with mean age of 50.1 years reported in a previous study .Myocardial ischemia was defined as hypointensity for ≥ 3 frames after peak myocardial enhancement; it was located within the viable myocardium and distributed along the coronary artery territory –15. We uPrognostic data were obtained via electronic medical records. Major adverse cardiovascular events (MACE) were defined as a composite of cardiovascular death, acute coronary syndrome, hospitalization for heart failure, and sustained ventricular tachyarrhythmia. The time to event was defined as the length of time from the CMR scan to the first event. Patients without MACE were censored at the time of the last-follow-up. Adverse events were investigated by medical personnel who were blinded to all CMR findings.All statistical analyses were performed using SPSS , MedCalc for Windows , or R version 3.6.3 . Continuous data were presented as means ± standard deviation, while categorical values were presented as numbers (%). The Shapiro–Wilk test was used to determine normality for each variable. Data were compared using the unpaired t-test for normally distributed values, and the Mann–Whitney U test for non-normally distributed values. The chi-squared test was used to test for significance of categorical variables. Patients were allocated into two groups based on the median resting CSBF value of 80.4 mL/min. Multivariable associations with MACE were determined using Cox proportional hazards regression analysis, and event-free survival stratified by the median resting CSBF were estimated using Kaplan–Meier survival curves. Receiver operating characteristics curve of rest CSBF, CFR, > 10% ischemia on perfusion CMR, cMBF at rest were generated to compare their prognostic value. Significance of differences of area under the curve (AUC) was tested using a Delong’s method. In addition, prognosis of patients with cMBF more than median (0.89 mL/min/g) was compared with that of patients with equal or less than median using a Kaplan Meier analysis. Multivariable Cox regression analysis was performed using two models. In model 1, continuous variables were used for LGE, ischemia, and resting CSBF; categorical variables were used in model 2. The intra- and interobserver reliabilities of the resting CSBF measurements were assessed in 20 patients using Bland–Altman plots. A p-value < 0.05 was considered statistically significant.Table Table Ninety-two (8%) patients experienced MACE over a median follow-up period of 4.6 years . In our cohort, 201 of 258 (78%) patients with > 10% ischemia underwent revascularization by the CMR results. Fifty late revascularization (> 90 days after CMR) were observed including 38 patients with acute coronary syndrome. According to Kaplan–Meier analysis, patients with a resting CSBF higher than the median showed a significantly higher rate of MACE, in both suspected and known CAD ; Table The main findings of the present study include; (1) resting CSBF is significantly higher in patients with MACE compared with those without MACE both in known and suspected CAD cohorts; (2) the annualized event rate is higher in patients with resting CSBF higher than the median value, irrespective of LGE or perfusion findings; (3) the AUC of resting CSBF is similar to that of CFR for predicting future MACE both in known and suspected CAD. These results suggested that the resting CSBF may be useful as a novel imaging marker for risk stratification for patients with known or suspected CAD without any radiation exposure, contrast media, and pharmacological agents.In clinical practice, various modalities are used to evaluate myocardial ischemia for patients with CAD; non-invasive methods, such as stress-echocardiography, single-photon emission computed tomography, perfusion CMR, and FFR-computed tomography, and invasive FFR as a gold standard invasive method, have been used to evaluate physiological ischemia . FFR is Due to its non-invasiveness, measuring the resting CSBF can be useful for young patients or can help prevent side effects of vasodilator agents (such as chest discomfort and hypotension). In addition, measuring the CSBF is a simple and rapid method; therefore, it can be applied in busy clinical laboratories. For this reason, our study findings may impact the screening of CAD using CMR. For instance, the combination of cine CMR (LV volumes and LVEF) and resting CSBF may be useful as simple and non-invasive screening CMR method for CAD. In addition, similar to CFR, resting CSBF was more suitable for predicting MACE in patients with suspected CAD than those with known CAD; this was reflected by a higher AUC for MACE (0.82 vs. 0.73) Fig. . These rPerfusion at rest is mainly determined by the LV demand of oxygen supply. Blood pressure and heart rate are the two main determinants of blood supply demand. Therefore, we calculated corrected cMBF and compared with CSBF in terms of risk stratification. In known CAD, AUC of cMBF was significantly lower compared to resting CSBF . In suspected CAD, AUC of cMBF was similar to resting CSBF   and a mCMR-derived resting CSBF is significantly higher in patients with MACE compared to those without MACE in both known and suspected CAD. The AUC of resting CSBF is high for predicting future MACE both in known and suspected CAD. These results suggested that the resting CSBF may be a useful novel non-invasive resting index that does not involve any radiation exposure, contrast media, and pharmacological stress agents for patients with known or suspected CAD.