This study sought to assess the value of myocardial deformation using strain echocardiography in patients with mitral valve prolapse (MVP) and severe ventricular arrhythmia and to evaluate its impact on rhythmic risk stratification.MVP is a common valvular affection with an overly benign course. Unpredictably, selected patients will present severe ventricular arrhythmia.Patients with MVP as the only cause of aborted SCD (MVP-aSCD: ventricular fibrillation and monomorphic and polymorphic ventricular tachycardia) with no other obvious reversible cause were identified. Nonconsecutive patients referred for the echocardiographic evaluation of MVP were enrolled as a control cohort and dichotomized according to the presence or absence of premature ventricular contractions . All patients had a comprehensive strain assessment of mechanical dispersion (MD), postsystolic shortening, and postsystolic index (PSI).p = 0.014) and a higher MD value than that in MVP-No PVC . In addition, PSI and MD increased the prediction of severe ventricular arrhythmia on top of classical risk factors in MVP. Net reclassification improvement was 61% (p = 0.008) for PSI and 71% (p = 0.001) for MD.A total of 260 patients were enrolled . Deformation pattern discrepancies were observed with a higher PSI value in MVP-aSCD than that in MVP-PVC (4.6 ± 2.0 vs. 2.9 ± 3.7, In MVP, myocardial deformation analysis with strain echocardiography identified specific contraction patterns with postsystolic shortening leading to increased values of PSI and MD, translating the importance of mitral valve–myocardial interactions in the arrhythmogenesis of severe ventricular arrhythmia. Strain echocardiography may provide important implications for rhythmic risk stratification in MVP. Mitral valve prolapse (MVP) is a common echocardiographic finding  that has an overall benign course , 2. HoweSeveral MVP phenotypes have been described and correlated to an increased risk of arrhythmias: bileaflet prolapse, female sex, ectopic ventricular activity, and ST-segment/T-wave anomalies –8. TheseMore recently, cardiac magnetic resonance (CMR) imaging has provided a new focus on fibrosis induced by recurring the stretch exerted by the prolapsing leaflet on the myocardium , 10. MorNew insights were provided in assessing the interactions between the mitral valve and the left ventricle (LV) using speckle-tracking strain echocardiography in MVP . RegionaThe aims of our study were to assess myocardial deformation using strain echocardiography in patients with MVP and a history of aborted SCD, to compare this assessment with patients with MVP presenting with and without premature ventricular contraction, and to evaluate the value of strain echocardiography on top of established risk factors for arrhythmic risk stratification.All patients who had an indication for an internal cardioverter defibrillator (ICD) between 2000 and 2018 were retrospectively selected. Patients with a prophylactic indication were discarded. Secondary indications were guideline-directed and consisted of aborted sudden cardiac death (SCD: ventricular fibrillation and monomorphic and polymorphic ventricular tachycardia) or syncope aggravating a documented cardiomyopathy. Patients underwent a comprehensive cardiac evaluation with systematic echocardiography, coronary angiography, cardiac MRI, and electrophysiological study when judged necessary.Mitral valve prolapse was implicated when a reversible cause was carefully excluded after the patient's file review and in the absence of any of the following: any obstructive coronary artery disease, structural cardiomyopathy or impaired LV function (ejection fraction <50%), active myocarditis, long QT syndrome, or channelopathy. For the purpose of the study, patients who underwent mitral valve surgery were not included in the analysis .To account for potential residual postresuscitation myocardial electromechanical discrepancies, only echocardiography during patients' follow-ups was analyzed.ad hoc postprocessing speckle-tracking analysis and mitral valve characterization was left for analysis. The clinical investigation focused on MVP-related symptoms  and functional status. The presence of premature ventricular contraction (PVC) was based on 24-h external loop recorders.A nonconsecutive control cohort of patients with MVP was retrospectively selected from our echocardiography database. Only comprehensive echocardiography that allowed The investigation was in line with the Declaration of Helsinki and good clinical practice guidelines.Echocardiography was performed using a commercially available standard ultrasound scanner  with a 2.5-MHz transducer.MVP was defined as a systolic displacement of the mitral leaflet >2 mm beyond the annular plane, and mitral regurgitation (MR) was graded according to recent guidelines . The locMitral annular disjunction (MAD) was measured in the parasternal long axis as the maximal distance between the insertion of the mitral valve leaflet and the inferolateral basal LV wall. Curling of the basal myocardium, which represents the systolic rocking motion of the inferolateral basal LV wall, was measured as the length of a perpendicular line joining the tip of the inferolateral wall to the insertion of the mitral valve leaflet, as previously described , 16. LV Speckle-tracking analysis was performed offline by investigators blinded to the arrhythmic status of the patients using automated and dedicated software  from the three apical views. Myocardial longitudinal deformation curves were obtained with measurement for each segment of (1) maximal absolute value of strain during the ejection phase before aortic valve closure  and (2) postsystolic strain (PSS) as the maximal absolute value of strain during isovolumic relaxation after the aortic valve closure with the calculation of the PSS index (PSI) . Values t-tests. Data not normally distributed were presented as median (25th–75th or interquartile range) and compared using Mann–Whitney U tests. Categorical variables were expressed as a percentage and were compared using Pearson's chi-squared tests.Normally distributed values were expressed as mean ± SD and compared using Student's Univariable logistic regression was performed to assess the association between aborted SCD as an outcome and each of the explanatory variables: age, female sex, PVC, chest pain, lipothymia/syncope, familial SCD, bileaflet prolapse, Barlow's disease, LVEF, LV end-systolic diameter, left atrial end-systolic volume, curling, MAD, MR >2, GLS, PSI, and mechanical dispersion. Odds ratios and their confidence intervals were reported.Multivariable logistic regression models were used to estimate the association between aborted SCD and each of the deformation parameters  after adjustment for the previous and significant explanatory variables from the univariable analysis. Odds ratios and their confidence intervals were reported., MR severity, and LVEF) was assessed using net reclassification improvement (NRI). For this purpose, GLS was considered as a continuous variable, PSI as a binary variable , and MD in a logarithmic scale. SAS version 9.4 was used for the statistical analysis. P values ≤ 0.05 were considered statistically significant.The incremental value of the adjunction of deformation parameters on top of classical risk factors , or equivalent, yielding a 2% incidence. Age ranged from 15.1 to 71.1 years. There were 11 female patients (55%). All data concerning MVP-aSCD patients are presented in aSCD was the inaugural event leading to the diagnosis of MVP for eight (40%) patients. MVP corresponded to an incidence of 2% of secondary indications for overall ICD implantation. Indications were based on monomorphic ventricular tachycardia , polymorphic tachycardia , and ventricular fibrillation .Fifty-five percent of patients had no mitral annular disjunction. CMR was performed in 15 patients (75%). Eleven (73%) patients had LV myocardial fibrosis, and eight (53%) patients had papillary muscle fibrosis.Following the aSCD event, an ICD was systematically suggested. Seventeen patients (85%) accepted the implantation. At least one recurrent arrhythmic event requiring appropriate ICD therapy occurred in 9out of 17 implanted patients (53%) after a mean delay of 1.6 ± 2.2 years. Seventy-eight percent of recurrence occurred within the first year after ICD implantation. No patient died during a mean follow-up of 5.1 years. Two patients (10%) underwent mitral valve surgery for symptomatic MR.The control MVP population consisted of 240 patients with no difference in regard to age and sex. The control population was dichotomized on the presence (MVP-PVC) or absence (MVP-No PVC) of PVC. PVC was documented in 54 patients (22.5%). Clinical parameters are presented in p = 0.001; presyncope or syncope, p < 0.001), while others had more frequent MR-related symptoms .Comparative clinical and echocardiographic data are listed in p = 0.005) with more frequent flail leaflet (p = 0.001), increased LV end-diastolic volume (p = 0.040), EF (p < 0.001), and global longitudinal strain (p = 0.003). There was no difference in the presence of mitral annular disjunction among the different groups of patients (p = 0.824). However, curling of the inferolateral basal wall increased significantly (p = 0.001) in MVP-aSCD vs. MVP-PVC and MVP-PVC vs. MVP-No. A linear and significant correlation was observed between MAD and curling . Significant differences in PSS (p = 0.005) and MD (p = 0.002) were noted, with higher values observed among MVP-aSCD vs. MVP-No PVC  or pre/syncope , curling , drop in GLS values , and higher MD . Additional values of GLS, PSI, and MD were independently assessed in multivariable models after adjustment for pairs of established risk factors   .p = 0.008) or MD  was associated with a significant improvement of reclassification but not of GLS . In a model containing the classical risk factors and MD, adding PSI provided further reclassification possibility   were evaluated to predict SCD using NRI. The addition to the logistic model of PSI  .Based upon the comparative evaluation of 20 patients with MVP who had presented an aborted SCD to a control cohort of MVP patients, our study shows (1) a 2% prevalence of MVP among secondary indications of ICD, (2) clinical and echocardiographic characteristics associated with a higher risk of severe ventricular arrhythmia, and (3) a specific strain deformation profile combining contraction inhomogeneity with postsystolic shortening and increased value of mechanical dispersion.Strain echocardiography conveys risk reclassification information of relative importance in the arrhythmic evaluation of MVP patients on top of established risk factors. These parameters, relaying the implication of myocardial–leaflet interactions, may be of particular interest in the identification of high-risk MVP patients.Despite a much lower incidence with regard to ischemic cardiomyopathy, MVP-related cardiac arrests account for 2.5% of overall SCD and mainly affect a younger population , 2. ThisThe mechanisms behind ventricular arrhythmia in MVP are complex. Three sites at the origin of ventricular arrhythmias were identified: (1) papillary muscles, (2) mitral annulus, and (3) LV fascicules , 22. MosVarious and heterogeneous causes of electrical disturbances may explain the difficulty in identifying a specific mechanism at the origin of cardiac arrhythmias. Understanding the underlying mechanism for better estimating the consequent rhythmic risk is critical in developing a large-scale screening strategy prior to discussing a specific therapeutic algorithm.Established risk factors include female sex, PVC, bileaflet or valvular redundancy, mitral regurgitation severity, and ST-segment or T-wave anomalies, but all, individually or combined, are not specific enough to clearly identify high-risk patients –8. IndeeThe implication of MR is also equivocal, and most of our patients had none to mild MR. Fibrosis in the setting of important MR may rather be associated with MR-induced ventricular remodeling, neurohumoral activation, and subsequent myocardial scar , 8, 23.Mitral annular disjunction was recently described as another important dynamic substrate for arrhythmogenesis , 24. MADRenewed interest in malignant MVP has been stimulated by recent works based on identifying LV myocardial fibrosis , 23. AmoFibrosis appears to be a pivotal structural damage strongly associated with the occurrence of ventricular arrhythmia but is not systematically observed in SCD survivors. In a recent meta-analysis evaluating MVP and SCD, Nalliah et al. reported that 13% of patients had fibrosis on CMR without ventricular arrhythmia and 20% had VA without fibrosis . FibrosiPrevious studies focusing on myocardial deformation in MVP have found that the mechanical interactions between the LV myocardium and the mitral valve can be achieved using strain echocardiography , 18. GLSDeformation analysis with a specific focus on postsystolic shortening and MD bore significant supplemental prognostic information in arrhythmic risk reclassification on top of all accepted classical risk factors of SCD. Fibrosis detection using strain analysis has proven reliable, especially when using PSI . HoweverThe connection between mitral valve prolapse and ventricular arrhythmia has evolved from the initially described ballerina-foot pattern to the identification of myocardial fibrosis in cardiac MRI and the description of MAD and the concept of myocardial stretch , 25, 32.As we have described, patients with aSCD showed a higher degree of myocardial dyssynchrony compared to patients with PVC and control MVP patients, suggesting the possibility of an intertwined cardiomyopathic process rather than an isolated valvular affection. Furthermore, the lack of correlation with MAD and the presence of electromechanical dyssynchrony tend to point toward the left ventricular myocardium rather than the mitral valve. Nevertheless, a larger picture must be kept in mind integrating a wider spectrum of parameters, such as (1) clinical variables , (2) valvular structural characterization (presence and severity of MAD and curling), (3) MVP-specific features , and (4) myocardial substrate .During follow-up, a majority of patients suffered from recurring arrhythmic episodes, mostly within the first year after the initial event, requiring appropriate ICD therapies. This observation points to the concept of a continual cardiomyopathic process and implies that ventricular arrhythmia in MVP has significant prognostic implications.MVP must be carefully evaluated, particularly at the initial diagnosis, with a clinical focus on syncope or presyncope, and an evaluation of the extent of the prolapse, presence of MAD, and strain analysis must be carried out. PVC has to be regularly looked for using loop recorders. Further serial testing should be performed based on these initial results and in case of new symptoms and not solely on MR grade .We believe that an analysis of myocardial deformation with strain echocardiography in MVP is valuable in routine practice and may help to identify patients in whom CMR may be pertinent. However, the association between postsystolic contraction, mechanical dyssynchrony, and myocardial fibrosis needs further evaluation.This study was limited by its retrospective design justified by the necessity of risk stratification and the rarity of the occurrence of SCD in MVP. The proportion of patients with SCD and MR grade repartition do not reflect the observed or expected proportion among the general population exposed to a potential risk of referral bias.We acknowledge that strain measurements are prone to inter- and intraobserver variability . PostsysCardiac MRI was systematically attempted in all aborted SCD patients but not always performed due to post-arrest related conditions. We also lack a complete evaluation among the otherwise normal MVP patients. At the present time, cardiac MRI is not routinely recommended for the assessment of MVP, and a specific study assessing the added value of LGE analysis on top of strain analysis in MVP should be undertaken.MVP remains an under-recognized cause of SCD, and the established risk factors appear insufficient to identify high-risk patients. Myocardial deformation and the presence of fibrosis are at the crossroads of myocardial–leaflet interactions and electrical ventricular hyperexcitability. Strain echocardiography, with identification of postsystolic shortening and increased mechanical dispersion values, conveys risk reclassification information of relative importance in the arrhythmic evaluation of MVP patients on top of established risk factors. Prognostic implications require further evaluation. Nevertheless, these parameters may be of particular interest in identifying high-risk MVP patients.


Panel C). Transthoracic echocardiography demonstrated a dilated right ventricle (RV) with flattened interventricular septum (see Video S1). Troponin-T level was 133 ng/L (reference: <14 ng/L). Despite heparin therapy, blood pressure decreased upon minor mobilization. Endovascular thrombectomy was performed using the 24Fr Flowtriever  with concomitant invasive biventricular pressure–volume (PV) loop monitoring to appraise immediate changes in cardiomechanics.2 Heart rate immediately fell from 105 to 85 beats/min. Systolic pulmonary artery pressure dropped from 42 to 19 mmHg. A prompt left-shift of the RV PV loop indicated direct RV unloading (Panel A). Biventricular PV area (PVA) decreased with higher stroke work/PVA ratio, suggesting improved cardiomechanics leading to enhanced myocardial metabolic demand . Arterial elastance (Ea) decreased for both ventricles. Right ventricle PV loop morphology transformed from notched to quadratic throughout thrombectomy (Panel A).3 Ventricular–vascular coupling (Ees/Ea ratio) improved for both ventricles in the presence of stable load-independent contractility . The patient could mobilize within hours after thrombectomy and was discharged home the next day. These observations underscore the immediate favourable effects of restored pulmonary flow on biventricular cardiomechanics in the setting of intermediate high-risk PE. The patient provided informed consent for publication.A 49-year-old female with recent intracranial bleeding was admitted after an unwitnessed syncope. On hospital admission, oxygen saturation was 97% on room air, heart rate was ≥100 beats/min, and blood pressure was 121/52 mmHg. Pulmonary embolism (PE) was confirmed by computed tomography, affecting bilateral central and subsegmental branches (European Heart Journal online.A.J.M.v.d.E. received personal fees from Abiomed and honorarium from Angiodynamics. C.L.M. declares no conflict of interest. N.M.V.M. received grant support from Abbott Vascular, Biotronik, Boston Scientific, Edwards Lifesciences, Medtronic, Daiichi Sankyo, Abiomed, PulseCath BV, FEops, and Pie Medical and received financial support from Antaris Medical and JenaValve.The data underlying this article will be shared on reasonable request to the corresponding author.ehac508_Supplementary_DataClick here for additional data file.


Valvular heart disease (VHD)-related heart failure (HF) is a special subtype of HF with an increasingly concerned heterogeneity in pathophysiology, clinical phenotypes, and outcomes. The mechanism of VHD-related HF involves not only mechanical damage to the valve itself but also valve lesions caused by myocardial ischemia. The interactions between them will lead to the occurrence and development of VHD-related HF subtypes. Due to the spatial  and temporal effects  of valvular damages, it can make the patient's condition more complicated and also make the physicians deal with a dilemma when deciding on a treatment plan. This indicates that there is still lack of deep understanding on the pathogenic mechanism of VHD-related HF subtypes. On the other hand, mitochondrial dysfunction (MitD) is not only associated with the development of numerous cardiac diseases such as atherosclerosis, hypertension, diabetes, and HF but also occurs in VHD. However, the role of MitD in VHD-related HF is still not fully recognized. In this comprehensive review, we aim to discuss the current findings and challenges of different valvular damages derived from HF subtypes as well as the role of MitD in VHD-related HF subtypes. VHD becomes one of the major global health problems, showing different disease burdens in developing and developed countries . In deveMitochondria (Mit), as double-membrane-bound organelles, are found in almost all eukaryotic cells and primarily located within subsarcolemmal, perinuclear, and intrafibrillar regions of the cardiomyocyte . The majThis review provides a discussion of the current findings and challenges related to different valvular damages derived from HFrEF, HFmrEF, and HFpEF, as well as the role of mitochondrial abnormalities in VHD-related HF subtypes.2.HFrEF is defined as LVEF of less than 40% , while H2.1.Mitral valve damages increases the risk of HFrEF. A recent study on evaluating the associations of cardiac valve damages in a Lebanese population with myocardial function reported that mitral valve diseases were associated with a 6.2-fold increased risk of left ventricular (LV) SD but exhibited heterogeneity with different types of valvular damages . Mitral . . .2.2.Aortic stenosis (AS) is the most common cause of HFrEF, accounting for approximately 6.0%–35.0% of patients with HFrEF. Among AS patients with HFrEF, the clinical phenotype was presented in males, a history of myocardial infarction and diabetes mellitus, which was similar to that of HFrEF patients without valvular damages , 21. Dur2, and mean gradient of <40 mmHg  was divided into three types, namely, normal-flow LG-AS, paradoxical low-flow LG-AS, and classic low-flow LG-AS . Classic<40 mmHg . Low flo<40 mmHg . Notably<40 mmHg , which w<40 mmHg . This su<40 mmHg . Consist<40 mmHg , Ito et  mmHg  is relatively slow. Patients with mild to moderate AR may have no obvious clinical symptoms. Once progressing to severe AR, the myocardial function is impaired , and clinical symptoms of HF rapidly occur . The stu.  found thThe progression of AR to HFrEF is actually a process of compensation to decompensation of LV adaptation to regurgitated blood volume. During this process, AR patients may not exhibit any evident symptoms and/or signs of HF for an extended period. In the compensatory phase, elevated preload leads to LV concentric/eccentric remodeling, particularly the eccentric remodeling, which gradually results in extensive interstitial fibrosis and collagen composition changes. In the decompensated phase , LV compliance was reduced in AR patients, resulting in HFrEF. On the other hand, increased LV afterload reduces coronary perfusion, causing subendocardial ischemia that leads to irreversible replacement of necrotic cardiomyocytes with the fibrous tissue and resulting in LV SD and poor prognosis in AR patients , 44, 45.3.HFpEF is a cluster of clinical syndromes with symptomatic HF and LVEF of ≥50%, characterized by DD of myocardial infarction . Approxi3.1.The most prominent feature of HFpEF is DD, which can be caused by both MS and MR, suggesting that patients with MS and/or MR may suffer from HFpEF. MS significantly increases the risk of LV DD and mostly develops in elderly patients and/or in patients with hypertension, which is consistent with the etiological features of HFpEF . LAF is MR also increases the risk of HFpEF. In the Lebanese population, Nader et al.  found th3.2.2), low gradient (mean gradient of <40 mmHg), low flow (peak aortic velocity of <4 m/s), and LVEF (>50%)  . ParadoxF (>50%) . AS-induF (>50%) . AS-relaF (>50%) , 72. IndF (>50%) ..  can appear in the early stage of AR. With the development of LV eccentric remodeling, LV compliance decreased accordingly. Once the LV eccentric remodeling cannot compensate to the harmful effect of AR-induced regurgitated blood volume, the end-diastolic pressure evidently increased and then HF-related symptoms followed, which suggested that AR patients had the potential to develop HFpEF . Zhang e.  revealed. . AR incr.  previous.  included tricuspid and pulmonary valve lesions. Tricuspid stenosis, pulmonary stenosis, and pulmonary regurgitation are rare valve defects, especially the first two. Thus, in this section, we will only discuss the tricuspid regurgitation (TR)-related HF.. . It, in the narrow sense, means the LVEF, which only reflects the systolic function status of the left heart. The aforementioned types of HF  are classified according to LVEF. However, it is worth noting that cardiac function is an organic whole and the functional status of the left heart is also influenced by the right heart. Melo et al.  first pr.  and pulmonary artery systolic pressure (PASP) can also be used to evaluate the RV function. TAPSE is the total longitudinal displacement of the tricuspid annulus from tele-diastole to end-systole, which is a powerful indicator of RV function. A TAPSE measurement of less than 17 mm indicates RVD , and lesRV–PAU mainly emphasizes the influence of the interaction between right ventricular systolic function and PH status on RVD. However, the effect of the interaction between right heart valve damage and PH status on RVD is ignored, especially TR. Tricuspid valve is the core physical component of the right heart system, and its regurgitation will lead to RVD. TR can be divided into three types: primary, secondary, and isolated TR , 94. The5.VHD can lead to HF through multiple mechanisms, including both mechanical damage to the valve itself and the impact of valve lesions on the myocardium. The interactions between different valve damages and myocardium dysfunction can exacerbate these processes and lead to the development of different VHD-related HF subtypes. MitD may play an essential role in this process and also contribute to the progression and severity of the condition. MitD can lead to reduced ATP production, increased oxidative stress, impaired calcium signaling, and altered mitochondrial dynamics. Different valvular damages lead to altered blood flow , causingCardiac mitochondria are essential for contractile function, while a progressive impairment of mitochondrial morphology and function characterizes HF . DiffereMitochondrial function was disordered with its morphological changes. The changes of mitochondrial morphology and function represented early cardiac adaptation to pressure overload or volume overload of LA and/or LV. In patients with ostium secundum atrial septal defect, Macchiarelli et al.  reportedmt) played a key role of maintaining mitochondrial function. Smyrnias et al.  study (NCT05209919) is a non-interventional, prospective, international, multicenter, longitudinal study designed to characterize the pathophysiological mechanisms and clinical relevance of functional TR in HFrEF, HFmrEF, and HFpEF .Second, the current research evidence focuses on single-valve/single-lesion induced HF, ignoring the fact that clinically VHD patients often suffered from combined valve damages. A study based on etiology, clinical features, treatment, and outcomes of VHD in a Chinese population has been preliminarily completed (NCT03484806). Furthermore, the development of VHD-related HF and its prognosis depend on the spatial  and temporal effects  of valvular damages, which complicates the exploration of VHD. In particular, HFpEF is a heterogeneous syndrome. Previous studies on HFpEF mostly focused on the effect of different etiologies caused by primary and/or secondary myocardial ischemia in HFpEF development and ignored the role of valve damages and PH degree in it, making the heterogeneity of the VHD-related HFpEF phenotype more pronounced. It would be beneficial to characterize the VHD phenotype based on a three-dimensional model of valvular damage-myocardial ischemia-pulmonary pressure. Hence, a real-world study on VHD-related HF phenotypes based on artificial intelligence is one of the promising new directions.Third, the right heart acts as a separate system, independent of the left heart. RVD is almost always associated with poor prognosis of HF. However, the role of RVD which has an independent HF effect in various HF subtypes has been overlooked. RVD is the result of the combined effect of three factors, such as tricuspid valve damage, RV myocardial ischemia, and PH degree.Lastly, whether MitD is a cause or a consequence of VHD remains unclear. Evidence indicates that MitD may play an important role in various valvular damages and its related HF subtypes, but understanding of the specific molecular mechanisms of MitD in valvular damages derived from HF subtypes still faces many challenges, particularly in the processes of inflammation and oxidative stress , 108. By7.VHD often coexists with HF in clinical practice, especially in the elderly. Due to the spatial  and temporal effects  of valvular HF, this can complicate the patient's condition. In addition, physicians may deal with a dilemma when deciding on a treatment plan. Some classic prognosis-improving medications in patients with non-valvular HF are not applicable in patients with VHD due to some contraindications, or they may fail to improve clinical outcomes in patients with valvular HF. This suggests a partial lack of understanding of the mechanism of occurrence and development of VHD-related HF. Further studies are necessary to fully comprehend the complex interactions in the pathophysiology and pathogenic mechanisms of different HF subtypes with various valvular damages. This will assist in developing optimal diagnostic and therapeutic strategies for this special population.Since MitD acts an essential role in the pathogenesis of VHD and HF, further investigations are encouraged to reveal the relationship of MitD with the morbidity and mortality in VHD-related HF  through large-scale, real-world clinical studies. These studies should aim to clarify the homogeneity and heterogeneity of MitD among the various phenotypic subgroups of VHD. Based on these studies that have been planned and conducted, mitochondrial targeting may lead to the development of early and accurate diagnosis and/or treatment strategies, which could result in preferable outcomes for patients with VHD-related HF.


The prevalence of mitral (MR) and tricuspid regurgitation (TR), especially in heart failure (HF) populations, is high. However, the distinct role of atrioventricular valve diseases in HF, whether they are merely indicators of disease status or rather independent contributors in a vicious disease cycle, is still not fully understood. For decades, tricuspid regurgitation (TR) was considered an innocent bystander subsequent to other heart or lung pathologies, thus, not needing dedicated treatment. Recent increasing awareness towards the role of atrioventricular valve diseases has revealed that MR and TR are, in fact, independent predictors of outcome in HF, thus, warranting attention in the HF treatment algorithm. This awareness arose, especially, with the development of minimally invasive transcatheter solutions providing new treatment options, which can also be used for patients considered as having increased surgical risk. However, outcomes of such transcatheter treatments have, in part, been sub-optimal and likely influenced by the status of the concomitant HF disease. Thus, this review aims to summarize data on the current understanding regarding the role of MR and TR in HF, how HF impacts outcomes of transcatheter MR and TR interventions, and how the understanding of this relationship might help to identify patients that benefit most from these therapies, which have proven to be lifesaving in properly selected candidates. Severe symptomatic mitral (MR) and tricuspid regurgitation (TR) have been identified as independent predictors of mortality , 2. FurtA lot of attention has been paid to outcomes after interventional treatment in patients with secondary forms of MR (SMR) or TR (STR) most often presenting in the setting of chronic HF. For mitral TEER (M-TEER) in patients with HF and reduced ejection fraction (HFrEF), two large randomized trials, namely the COAPT trial and the Mitra-FR trial, have resulted in diverging outcomes. In the COAPT trial, a significant benefit of M-TEER, when added to optimal guideline-directed medical therapy (GDMT), was evident, while in the Mitra-FR trial, the additive effect of interventional treatment was neutral , 15. TheInterventional treatment of severe TR, on the other hand, has caught up at a rapid pace in the last years, first using established M-TEER devices in the tricuspid position (T-TEER) but now also utilizing dedicated devices, including several replacement solutions –22. The Given this interplay of chronic HF with SMR and STR, this review aims to define the role of these valvular lesions in the HF disease complex and summarize the reported response to transcatheter treatment according to different HF characteristics, and based on this, tries to understand which parameters might be of use to identify those patients most likely to benefit from interventional MR and/or TR treatment.In the European population, MR represents the most common heart valve disease and is the second most common reason for heart valve surgery after aortic stenosis: MR is present in 2% of the overall population, being  ≥  moderate in 2.3% of people ≥65 years, and in 9.3% of people ≥75 years , 28. RosIn addition to established SMR definitions, atrial functional MR has been recently discussed as a distinct form of SMR –35. TypiFor any form of SMR, it is important to highlight that its severity may dynamically vary depending on loading conditions . Thus, dOver half of the patients with severe SMR and HF will not undergo surgery because their disease state has a direct impact on outcomes. This scenario represents an unmet clinical need, potentially addressable with M-TEER and other transcatheter solutions .n = 302] baseline characteristics: LVEF: 31.3 ± 9.1%, left ventricular end-diastolic dimension: 6.2 ± 0.7 cm, left ventricular end-diastolic volume [LVEDV]: 101 ± 34 ml/m2, NT-proBNP: 5,174.3 ± 6,566.6 pg/ml; see p < 0.001], and had a significantly lower rate of mortality within 24 months . This corresponds to the number needed to treat 5.9 patients (95% CI: 3.9–11.7) to prevent one death ; see Two large randomized controlled trials evaluated the role of M-TEER in addition to GDMT in the HFrEF population. In the COAPT trial, patients treated with MitraClip  when compared to patients with GDMT alone  in an SMR and HFrEF population  sitting over a still not too much dilated left ventricle (LVEDV index <96 ml/m2) as a predictor of ideal treatment response, seemed intriguing  as a significant predictor of increased 2-year mortality . Thus, wAnother important aspect when placing M-TEER intervention in the context of HF is GDMT and its optimization. As the pre-procedural optimization of GDMT has been a crucial part of the trial, when aiming to achieve COAPT-like results, it is a prerequisite to ensure optimized GDMT before discussing M-TEER or other transcatheter treatments. On the other hand, it is important to highlight that M-TEER in the COAPT trial showed a number needed to treat (NNT) that is lower than those of almost any HF medication or intervention  51). Ba. Ba51). Indeed, a recent study by Higuchi et al. based on the EuroSMR registry of SMR patients who underwent M-TEER was able to highlight the beneficial effects of maximized GDMT at the baseline of M-TEER and during subsequent follow-up . In patiTricuspid regurgitation has historically been considered a subsequent consequence of left-sided heart disease, and following this conception, no dedicated treatment was recommended, believing that TR would vanish after successful treatment of the left-heart disease . HoweverKoelling et al. in an HFrEF cohort (LVEF ≤ 35%) identified ≥ moderate TR in 34.5% of patients, with severe TR being a significant predictor of mortality in a multivariable analysis . SimilarThe limited outcomes of TV surgery paired with the high prevalence of relevant symptomatic disease historically led to large undertreatment of TR; for example, in the US, out of the 1.6 million patients with ≥ moderate TR, less than 8,000 per year undergo surgery, resulting in a large unmet clinical need , 65. In-n = 65, n = 46 at 1-year follow-up; TAPSE [cm]: 1.53 ± 0.47, SPAP [mmHg]: 68% at ≥30, LVEF [%]: 57.4 ± 7.0; other baseline HF characteristics see Evaluating the role of transcatheter TR treatment as the first prospective single-arm trial of T-TEER using TriClip , the TRILUMINATE trial presented 1-year outcomes in 85 patients  PAP was ≤30 mmHg and when the trans-pulmonary gradient (TPG) was ≤17 mmHg . If mPAPNot only the pulmonary vasculature itself is of predictive importance as the coupling between the right ventricle (RV) and the pulmonary arterial (PA) system can also bear prognostic implications. RV-PA coupling can be assessed as the ratio of TAPSE and SPAP, representing the contractile response of the RV to increased afterload, with lower ratios implying insufficient RV response. In the TriValve registry, when divided per TAPSE/SPAP ratio >0.406 vs. ≤0.406, patients with a lower rate of RV-PA coupling had a significantly higher risk of post-procedural mortality .Of note, when assessing SPAP via echocardiography, the estimated values might differ from what would be measured invasively. Lurz et al. demonstrated that patients who echocardiographically present without pulmonary hypertension but then discordantly show pulmonary hypertension when measured invasively  have a significantly worse prognosis  after T-TEER .In all of this, it is important to consider that most of these evaluations have been based on patient collectives that predominantly underwent T-TEER. Especially in the case of TV replacement, the role of the RV after intervention might substantially differ; as with abolished TR, the ventricle faces a substantial after-load increase that might lead to failure of the RV even though it may be only temporary.TR patients often present even later in their disease course than those suffering from MR; thus, apart from cardiac parameters, it is important to holistically assess the status of the patient. A chronic TR state might lead to complex hypercirculatory HF impacting hepatic, renal, and intestinal function. Even though a prognostic benefit of treatment might be possible, it may be smaller among patients with chronic right HF, who show advanced congestive hepatopathy, decreased peripheral vascular tone, and potentially lack the ability to respond with venous pressures to TR reduction .One specific additional aspect to consider in the treatment planning of MR and/or TR might arise in the case of multi-valvular disease. The EURObservational Research Programme Valvular Heart Disease II Survey found that among over 5,000 patients with valvular heart disease, over 20% suffered from more than one valvular lesion . For surIt is obvious that transcatheter MR and TR interventions are addressing a complex disease conundrum often characterized by chronic HF; thus, a simple, standardized, and straightforward treatment algorithm, for example in aortic stenosis, does not likely exist.To allow transcatheter MR and TR interventions to fully exploit the potential they bear for HF patients, a paradigm shift regarding the intended role of these procedures might be needed. Only when such interventions are considered synergistic with HF medications and, thus, are included in the discussion of treatment options along the whole course of progressing HF, they can then be applied at that exact point of the disease course when they will be most beneficial. However, if these transcatheter interventions continue to be only considered bailouts when GDMT has been fully optimized and failed to optimally control HF symptoms, they will often be likely applied after the occurrence of irreversible changes to cardiac structures and other organs that otherwise could have been prevented. An open and cooperative heart team, including sub-specialties such as HF experts, clinical cardiologists, and geriatricians, is the ideal platform for such discussion and at the same time represents the key prerequisite to establishing a future-oriented HF treatment armamentarium, including transcatheter MR and TR interventions.It has become evident that HF cannot be sufficiently characterized by only one cut-off value, namely LVEF, which itself is an often dynamic parameter and at times imprecise. A more distinct characterization of HF must include several different cardiac parameters as well as a holistic appreciation of the organic status in elderly patients. Assessing cardiac structures must incorporate a broad appreciation of the ventricular-annular unit, including assessment of LV dimensions, pressure and contractility, annular dimensions and contractility, as well as synchrony and synergy of the whole atrio-annular-ventricular valve apparatus with its impact on coaptation and tethering . Here, uAs patients with severe symptomatic SMR and STR are often suffering from chronic HF, evaluating such patients for treatment and finally performing transcatheter interventions in such a condition poses a challenge for inter-disciplinary heart teams. Following the growing experience, especially with TEER, the first markers of likely treatment response could be identified. In SMR, patients should match the COAPT trial criteria, as then an actual prognostic benefit from intervention can be drawn. However, also in COAPT-ineligible patients, intervention should be discussed as a substantial alleviation of symptoms is still achievable for them. In STR patients, an RHC should be performed when evaluating potential treatment candidates, and pre-capillary pulmonary hypertension should be excluded before interventional treatment of TR.Finally, in the future, the heart team should discuss transcatheter interventions for SMR and STR ideally as one part of a synergistic framework alongside established HF medications. In chronic HF, only a multifaceted holistic treatment approach can likely bring the potential lifesaving therapeutic effects of current medical and interventional innovations to these patients in need.


Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD). Cardiac magnetic resonance (CMR) parametric mapping sequences offer insights into disease pathophysiology. We propose a novel approach by leveraging T2 mapping in conjunction with T1 and extracellular volume (ECV) mapping to perform a virtual myocardial biopsy. While previous work has attempted to describe myocardial changes in DMD, our inclusion of T2 mapping enables comprehensive categorization of myocardial tissue characteristics of fibrosis, edema, and fat to better understand the pathological composition of the myocardium with disease progression.DMD patients  underwent CMR, including T1, T2, and ECV. Categories were defined as normal, isolated high T1 , fibrosis , edema , fat  or fibrofatty .Median left ventricular ejection fraction (LVEF) was 59% with 27% having LVEF < 55%. Those with normal LVEF and no late gadolinium enhancement (37%) were younger in age . Native T1 was elevated in at least one slice in 82% of patients. Those with high T2 at any slice (27%) were older (p = 0.005) and had lower LVEF (p = 0.005) compared with subjects with normal T2 (73%). The most common myocardial characterization was fibrosis (43%) followed by isolated high T1 (24%). Of the 13 with high T2, ten were categorized as edema, two as fibrofatty, and one as fat.CMR parametric mapping sequences offer insights into Duchenne cardiomyopathy pathophysiology, which should drive development of therapeutic interventions aimed at these targets. Myocardial fibrosis is common in DMD. Patients with elevated T2 were older and had lower LVEF. Though fat infiltration was present, the majority of subjects with elevated T2 met criteria for myocardial edema.The online version contains supplementary material available at 10.1186/s12968-023-00951-y. Duchenne muscular dystrophy (DMD), an X-linked myopathy, affects approximately 1 in 5000 live male births . The cliThe underlying pathogenesis of skeletal muscle disease is relatively well understood, with dystrophin loss leading to destabilization of the sarcolemma. The progression of disease has also been relatively well described, with recurrent muscle use leading to a cycle of cellular damage and repair that eventually leads to necrosis and fibrofatty replacement of skeletal muscle tissue. Presumably, the pathogenesis of myocardial progression is similar, but it is less well defined for a number of reasons: animal models do not completely mimic human disease and human cardiac autopsy and biopsy samples through the disease course have limited availability –11. PrioCardiac magnetic resonance (CMR) parametric mapping sequences, such as native T1, T2, and extracellular volume (ECV) mapping, allow for detailed tissue characterization and may allow for a more comprehensive assessment of DMD disease progression compared to echocardiography. Native T1 increases with fibrosis and edema and decreases with fat, while ECV increases with fibrosis and edema and remains unchanged with fat . PreviouComprehensive parametric mapping, including T2 mapping, can help answer whether edema and fat play a role in the progression of DMD cardiovascular disease. These sequences can define the pathological progression of DMD cardiomyopathy, thus providing a roadmap for the future development of therapies that can arrest myocardial progression. Understanding the natural history of myocardial changes in this population may help direct timing and choice of pharmacologic intervention. More importantly, a better understanding of disease progression could help researchers identify novel, targeted therapies. Through this virtual biopsy, we aim to characterize the myocardial composition in DMD cardiomyopathy by evaluating the pathological changes that occur globally as well as in regions of interest with LGE and focal T2 elevation. We hypothesized that myocardial tissue characterization would demonstrate a progression similar to skeletal muscle, with evidence of edema, fibrosis, and fatty infiltration.The Institutional Review Board approved this study. The majority of DMD subjects were enrolled prospectively (n = 45); additional DMD subjects who had signed consent for research CMR but were not enrolled in this specific prospective natural history study (n = 4) were also included. This natural history study was focused on collecting prospective clinical and CMR data for DMD boys to track longitudinal progression of disease. Enrollment was completed between November 2014 and November 2018. Consent was obtained for all participants; those under 18 years of age signed an age-appropriate assent form. DMD subjects able to undergo CMR without sedation or anesthesia with a clinical phenotype and confirmation with either genetic testing or muscle biopsy were included. Subjects were excluded from enrollment with a contraindication to CMR with contrast. Clinical data were collected from the electronic medical record.CMR was performed on a 1.5 Tesla Siemens Avanto  or a 1.5 Tesla Siemens Avanto Fit. CMR protocol included functional imaging performed as previously described using balanced steady-state free precession imaging . IntraveNormal values for T1 and T2 were derived from 54 prospectively enrolled healthy controls of varying ages (range 7–56 years-old (y/o)) and sex  as per the most recent parametric mapping consensus statement . Normal Individuals were first characterized by T2 values. Elevated T2 for any slice served as inclusion criteria for high T2 categorization. T1 values served as second tier characterization tool. Low T1 at any slice took precedent over T1 time at other slices categorizing the individual as low T1. If there was elevated T1 in any slice, without low T1 time at any slice, the individual was placed into the high T1 category. ECV percentage was dichotomized as normal or high based on a threshold of 28.5% , 17. FigDemographic variables were compared using Wilcoxon rank-sum test for continuous variables and Chi-square for categorical variables. Continuous variables compared between T2 groups were compared with Wilcoxon rank-sum test. Slice average tissue characterization parameters were compared to LGE and T2 ROIs within the same patient by Wilcoxon signed-rank test. Spearman’s rank correlation was used to estimate the correlation between continuous variables. Comparison of left ventricular ejection fraction (LVEF) and age between categories was completed with analysis of variance (ANOVA) followed by pairwise comparison of means with Tukey post-hoc testing. Statistical analysis was performed using Stata 16 . Statistical significance was achieved with p < 0.05. Myocardial composition category plots Figs.  were creForty-nine individuals with DMD met inclusion/exclusion criteria. The median age at first CMR was 12 years-old (interquartile range (IQR): 10.4–16.3). Full demographic characterization is available in Table Median LVEF was 59% with 13 patients having LVEF less than 55% at time of first CMR. Age was inversely related to LVEF . The most common areas of LGE are shown in Table High native T1 time was detected in at least one segment in 48 of 49 patients. Similar to the distribution of LGE, the highest areas of native T1 were the anterolateral and inferolateral segments of the basal and mid slices. Forty patients 82%) had at least one slice with elevated T1 with the base being the most common slice . Thirty-five patients (71%) had elevated T2 in at least one segment and 13 patients (27%) had elevated T2 in at least one slice at first CMR. The highest T2 values by slice and segment were seen at the apex , weighed more , and had lower LVEF  compared to those with normal T2  on initial CMR Fig. A. Of theAreas of LGE were localized on PSIR images and ROIs were placed in these areas on the native T1, T2, and ECV maps . LGE ROIs demonstrated higher native T1, T2, and ECV at base and mid, though the difference in mid T1 did not reach statistical significance . These ROIs demonstrated elevated ECV and T1, though basal T1 did not reach statistical significance  fibrosis is the most common DMD myocardial composition change, and normal myocardial tissue characterization is rare in DMD; (2) elevated T2 times occur in older patients with decreased LVEF; and (3) most areas of LGE are comprised predominately of fibrosis. The majority of patients with elevated T2 at the slice level had elevated T1 and ECV in the same location. Taken together, these data suggest that edema is a common pathway in the development of myocardial abnormalities and that fatty infiltration, while present, likely occurs in older patients with more significant myocardial disease Fig. .Fig. 8PoStudies have shown increased T2 relaxation time in thigh muscles of DMD patients in comparison to controls . With thGlobal T1 is lower in patients with elevated T2; however, in ROIs of T2 elevation at the mid slice, the T1 tended to be elevated. We hypothesize that fatty infiltration is a more diffuse process, while edema is more focal. We also suspect, based on the pathogenesis of disease, that edema is a transient finding during early myocardial inflammation and/or ischemia and thus more difficult to capture prior to fibrotic changes. Emerging pre-clinical data suggest that edema may be part of earlier pathogenesis, while fatty infiltration is a late finding . With onElevated native T1 and ECV have been demonstrated in patients with DMD previously , 26, 27.Although 98% of this cohort demonstrated elevated T1 in at least one segment, it is likely that many of these abnormalities are spurious. Indeed, previous studies from our institution have shown that even healthy controls may have segmental T1 abnormalities . It is pStrain data in this manuscript suggest a similar base to apex gradient as seen with LGE. While strain values did not correlate with parametric mapping values in this cohort, there were abnormal strain values at all three slices. Strain values remained abnormal over serial CMR; however, there was no significant change in strain values over serial CMR in this cohort. While the focus of this study was on parametric mapping values to categorize myocardial changes, it is clear that longitudinal strain values should be followed with patients demonstrating abnormal strain with baseline CMR. The authors believe utilizing strain to perform 3D myocardial mapping could allow for better understanding of segmental remodeling and is an area of future exploration.Parametric mapping changes are not seen uniformly throughout the myocardium; therefore, assignment to a particular characterization group may only partially describe the pathology present. The truth is likely that there is patchy progression and that multiple different pathological changes are present in some patients. Unfortunately, the parametric mapping methods reported here are unable to distinguish these more complex tissue patterns, which would be apparent in an actual myocardial biopsy. The authors acknowledge that current parametric mapping techniques cannot fully replace information obtained from an actual biopsy; however, we believe that cardiac MRI may serve as a useful non-invasive method to help understand cardiomyopathy progression in DMD that has, up to this point, been difficult to assess due to limited tissue samples. In addition, these methods are ideal for tracking longitudinal myocardial changes.Due to technical limitations, we were unable to complete fat/water separation imaging to provide additional evidence to distinguish between edema and fat infiltration, but we feel that the combination of T1, T2, and ECV provides an adequate, quantitative method for tissue characterization. Many DMD patients become uncomfortable in the scanner due to contractures, scoliosis, or claustrophobia. Those that were unable to tolerate CMR were not enrolled and this could lead to some bias in the study, though these factors are usually unrelated to cardiac disease. In addition, given the concern for discomfort, our DMD protocols are designed to limit required scan time. This comes at the expense of additional sequences. Therefore, long axis imaging  and more comprehensive short axis coverage were not performed in an effort to limit total scan time for our patients. More comprehensive coverage could not be performed without removing other sequences of interest . Therefore, there were areas of LGE without a map. However, given that LGE is usually present in contiguous slices, the “missed” areas were felt to be of minimal consequence.Of note, partial volume averaging is a possible confounder for parametric mapping, particularly at the apical slices. We were careful to not contour slices felt to be “too apical” and to contour only the mid-myocardium. Blood pool in the ventricular cavity has high native T1 signal; therefore, if partial volume averaging were occurring, we would have expected artificially elevated T1 times at the level of the apex. The T1 values at the apex were lower in this study, suggesting that partial volume averaging was successfully avoided at the apical slices. Due to the inherent challenges with mapping of the apical slice, there were five apical slices that were unable to be analyzed for native T1 and six apical slices that were unable to be analyzed for ECV. All apical slices were able to be analyzed for T2.While LGE is unable to distinguish between fibrosis, fat, and edema, parametric mapping, including T2-mapping, may allow for the differentiation of these tissue characteristics. In this cohort of DMD subjects, fibrosis was the most commonly observed myocardial change. Patients with elevated T2 were older and had decreased LVEF, and the areas of LGE predominately represented fibrosis. Longitudinal data suggest that development of edema portends persistence of myocardial pathology with subsequent normalization of tissue parameters a rare finding. Measurement of T1, ECV, and T2 may provide a virtual biopsy to define the pathological composition of DMD cardiomyopathy with the eventual goal to develop targeted therapies to mitigate these changes.Additional file 1: Table S1: Segmental T1 and T2 Measurements. Table S2: Tissue Characterization Parameters in LGE ROIs. Table S3: Tissue Characterization Parameters in T2 ROIs.


Long term survivors of haematopoietic stem cell transplantation (HSCT) for β-thalassemia major are designated “ex-thalassaemics”. Whether ex-thalassaemics continue to harbour residual myocardial dysfunction and thereby stand the risk of heart failure-related morbidity and mortality is unknown. The aim of this study was to assess the prevalence and predictors of subclinical left ventricular (LV) dysfunction in an apparently normal ex-thalassaemic population.We conducted a single centre cross-sectional study among 62 ex-thalassaemic patients, who had undergone HSCT for β-thalassaemia major at our centre. The primary outcome variable was LV systolic dysfunction, as assessed by 1) LV global longitudinal strain (GLS) derived by 2D speckle tracking echocardiography and 2) LV ejection fraction (EF) derived by 2D Simpsons Biplane method.Among the 62 patients included in the study, 7 [11.3%] were found to have LV systolic dysfunction, all of which were subclinical. Of these, 4 [6.5%] had abnormal GLS and LVEF, 2 [3.2%] had abnormal GLS with normal LVEF, and 1 [1.6%] had abnormal LVEF with low normal mean GLS. There were no statistically significant predictors of LV dysfunction in this cohort.There was a high prevalence of subclinical myocardial dysfunction in the ex-thalassaemic population reiterating the need for close follow up of these patients. 2D Speckle tracking echocardiography-derived LV global longitudinal strain is an effective tool in detecting subclinical myocardial dysfunction in this cohort. Heart disease accounts for almost three quarters of deaths in patients with β-thalassaemia major . The preAllogeneic haematopoietic stem cell transplantation [HSCT] has revolutionized the treatment of beta-thalassaemia major as a curative option . ThalassAt present, magnetic resonance imaging [MRI] scan is considered to be the investigation of choice for detection of iron overload in patients with beta thalassaemia. MRI assessment of cardiac T2* can identify and quantify cardiac iron stores, thus identifying those individuals at risk of developing cardiac complications , 7, 8. HMyocardial strain, which is the relative deformation of myocardium during cardiac cycle, as assessed by 2D speckle tracking echocardiography, has been demonstrated to be a sensitive tool in detecting subclinical left ventricular [LV] dysfunction in patients with various cardiomyopathies including chemotherapy-induced LV dysfunction and iron overload cardiomyopathy, with minimal inter- and intra-observer variability –14. In pThe aim of this study was to assess the prevalence and predictors of subclinical LV dysfunction in an apparently normal asymptomatic ex-thalassaemic population.We conducted a single centre cross-sectional prospective study on ex-thalassaemic patients. All ex-thalassaemic patients, who had undergone HSCT for β-thalassaemia major at our centre, and came for follow-up between March and September 2018, and were willing for cardiac evaluation were screened and included in the study. Exclusion criteria included history of documented congenital or acquired heart disease in the past. The study was approved by the institutional review board (IRB:11134) and the ethics committee of our institution. Informed written consent and assent were obtained from the participants or their parents. Investigators had access to information that could identify individual participants.2 body surface area per day for 3 days (from day -5 to day -3), and intravenous Fludarabine 40 mg per m2 body surface area per day for 4 days (from day -5 to day -2). Graft Versus Host Disease [GVHD] prophylaxis consisted of Cyclosporine and short course Methotrexate in all patients as previously reported  echocardiography by the same investigator, who was blinded to the haematological profile of the patients. Global longitudinal strain [GLS] was determined by 2D speckle tracking echocardiography in all these patients, using Philips Epiq 7 machine (Q lab software version 1.5.2). The primary outcome variable was LV systolic dysfunction evidenced by diminished 2D speckle tracking echocardiography-derived left ventricular global longitudinal strain [LVGLS] or LV ejection fraction [LVEF] derived by Simpson’s biplane method. The cut-off for LVGLS was accepted as -19.5% based on standard recommendations , 19, as Acquired data were summarized as mean  for continuous variables, and percentages for categorical variables. Continuous variables were compared using t-test, and categorical variables with chi-square/Fisher’s exact test. Predictors of LV dysfunction were analyzed using penalized regression analysis, and expressed as Odds Ratio (OR) with 95% confidence intervals (CI) for continuous variables and absolute risk (AR) with 95% CI for categorical variables. Statistical significance was defined as P<0.05. All analyses were done using SPSS v25 and SAS 9.4.Sixty-two patients were included in the study for analysis. The median age was 8 years [range: 2–22]. There were 40 [64.5%] males. The median age at the time of HSCT was 7 years range: 1–17]. As per the Pesaro risk stratification for HSCT for thalassaemia major , 3 were . As per The median time elapsed between HSCT and the echocardiographic study was 13 months [range: 1–72 months]. While most patients did not receive any potentially cardiotoxic drugs during HSCT, 19.3% [n = 12] of the patients had received cyclophosphamide (cumulative dose of 200 mg/kg) as a constituent of the conditioning regime. There were no cases of documented cardiac toxicity during or following HSCT. None of the patients had clinical or laboratory documented evidence of heart failure either at the time of the study or in the past.The median number of red cell transfusions till the date of echocardiographic study in the study group was 80 [range: 10–500]. The median time elapsed since the last transfusion was 13 months [range: 1–72]. The median of peak serum ferritin levels documented in the study group was 3187 ng/mL [range: 303–9811]. The median of serum ferritin levels in the study group at the time of echocardiographic evaluation was 1981 ng/mL [range: 24–9811].Iron reduction therapy was administered to 56 [90.3%] patients, with either oral [n = 46] or parenteral [n = 10] chelating agents, as per institutional protocols, with the goal of reducing serum ferritin levels to <300 ng/mL. Out of these, 10 patients were still on chelation therapy at the time of the study. The median duration of chelation therapy was 53 months in the study group [range: 6–120 months].Left ventricular systolic function was assessed by Simpsons 2D LV ejection fraction [LVEF] as well as 2D LV GLS. The mean LVEF was 59.7 +/- 5.4% in the study group. 92% of the patients [n = 57] had normal LVEF. The rest had mild LV systolic dysfunction. None had LVEF <45%.The mean LV GLS was -22.4 +/- 2.3% in the study group. 9.7% of the patients [n = 6] had LV systolic dysfunction, with abnormal LVGLS. It was noted that an additional 13% [n = 8] had abnormal LV GLS in atleast one of the three imaging planes , although the mean GLS was normal.Overall, 9.7% [n = 6] of the participants had abnormal mean LV GLS and 8.1% [n = 5] had abnormal LVEF. Among the 5 patients with reduced LVEF, 4 were found to have reduced mean LV GLS as well. The remaining one patient had low normal mean GLS but with an abnormal GLS in one of the imaging planes. Thus 11.3% [n = 7] of the study group was found to have myocardial dysfunction, all of which were subclinical.Table 1.Diastolic function was found to be normal in all the patients studied. There was no evidence of pulmonary hypertension or right ventricular systolic dysfunction in any of the patients. Apart from subclinical LV systolic dysfunction, no other abnormality was detected in the echocardiographic study. The profile of patients, who were detected to have LV dysfunction, is depicted in Table 2.Indices of iron overload such as pre-transplant serum Ferritin values, pre-transplant Pesaro class, or evidence of iron overload on MRI (cardiac T2* or hepatic T2* done prior to HSCT) did not correlate with subclinical LV dysfunction. The results of logistic regression analysis are depicted in Interestingly, none of the twelve patients who received Cyclophosphamide-based conditioning regimen prior to HSCT were found to have LV systolic dysfunction. In other words, all patients who were noted to have LV systolic dysfunction on echocardiography, had received a non-cardiotoxic conditioning regime consisting of Thiotepa, Treosulphan and Fludarabine (TTF).For the 7 patients with subclinical LV dysfunction, the median ferritin around the time of GLS testing was 4080 ng/mL (interquartile range: 867 to 4523). At the last follow up of these patients, the median ferritin was 2000 ng/mL (interquartile range: 185.3 to 3282). Four patients still had ferritin above 1000 ng/mL. However, all had normal effort tolerance for their daily activities.With increasing success of HSCT for higher risk patients with thalassemia major and their long term survival, attention needs to be focused on potential organ dysfunction related to pre-HSCT complications. Iron overload and related organ damage are the most significant of these. There is limited data on cardiac function among ex-thalassemics.This study is therefore significant as it evaluated a large number of ex-thalassaemics with no history of overt cardiac dysfunction over a wide age range (8–22 years) going into early adulthood and with long follow-up after HSCT. Given this profile, other risk factors for myocardial dysfunction were unlikely and none were identified in any of the patients studied, apart from cyclophosphamide based HSCT conditioning regimen which was found to have no correlation with the outcome. Our data shows that subclinical myocardial dysfunction exists in about 11% of ex-thalassemics. Further follow-up is needed to understand its evolution in time.Table 3.It has long been recognized that regular monitoring of myocardial function is warranted in patients with β-thalassaemia, especially in those receiving repeated blood transfusions, for early detection of subclinical myocardial dysfunction . AlthougIron reduction therapy implemented in ex-thalassaemics is often targeted at bringing serum ferritin to normal levels. Myocardial iron deposition may persist in such patients. In thalassaemia patients, this has been shown to be non-uniform in MRI-based studies, with different patterns of regional distribution , 33. PepHeterogeneity has also been reported in resorption of myocardial iron in response to chelation therapy, with apical inferoseptum showing greater improvement as compared to the other segments . LV GLS The major limitation of the study was its cross sectional design. The natural history of subclinical myocardial dysfunction in this cohort–whether it will resolve with time, or remain the same forever without manifesting clinically, or progress gradually to culminate in clinical heart failure- needs to be ascertained with long-term follow-up studies. However, it is indeed significant to find that a proportion of an apparently normal, relatively young ex-thalassaemic cohort, who have been receiving appropriate iron chelation therapy, harbour asymptomatic myocardial dysfunction.As the ex-thalassaemic population is expected to achieve a normal life span, whether the subclinical myocardial dysfunction makes them more susceptible to subsequent unrelated cardiac morbidity in the future is another area of concern which needs to be addressed. Our study underlines the fact that close monitoring and follow-up of ex-thalassaemics for progressive myocardial dysfunction and clinical heart failure is warranted.There is a high prevalence of subclinical myocardial dysfunction in the ex-thalassaemic population, reiterating the need for close follow up of these patients. 2D speckle tracking echocardiography-derived LV global longitudinal strain is an effective tool in the evaluation of these patients, which should become a part of the follow-up even in asymptomatic patients, at least till iron overload is corrected.S1 Checklist(DOCX)Click here for additional data file.S1 Data set(XLSX)Click here for additional data file.


Ventricular dyssynchrony and its relationship to clinical outcomes is not well characterized in patients following Fontan palliation.Single-center retrospective analysis of cardiac magnetic resonance (CMR) imaging of patients with a Fontan circulation and an age-matched healthy comparison cohort as controls. Feature tracking was performed on all slices of a ventricular short-axis cine stack. Circumferential and radial strain, strain rate, and displacement were measured; and multiple dyssynchrony metrics were calculated based on timing of these measurements . Primary endpoint was a composite measure including time to death, heart transplant or heart transplant listing (D/HTx).A total of 503 cases  and 42 controls  were analyzed. Compared to controls, Fontan patients had increased dyssynchrony metrics, longer QRS duration, larger ventricular volumes, and worse systolic function. Dyssynchrony metrics were higher in patients with right ventricular (RV) or mixed morphology compared to those with LV morphology. At median follow-up of 4.3 years, 11% had D/HTx. Multiple risk factors for D/HTx were identified, including RV morphology, ventricular dilation, dysfunction, QRS prolongation, and dyssynchrony. Ventricular dilation and RV morphology were independently associated with D/HTx.Compared to control LVs, single right and mixed morphology ventricles in the Fontan circulation exhibit a higher degree of mechanical dyssynchrony as evaluated by CMR-FT. Dyssynchrony indices correlate with ventricular size and function and are associated with death or need for heart transplantation. These data add to the growing understanding regarding factors that can be used to risk-stratify patients with the Fontan circulation.The online version contains supplementary material available at 10.1186/s12968-023-00984-3. Despite significant improvements in life expectancy after the Fontan operation, patients with functional single ventricles often experience progressive heart failure and increased risk of premature death or heart transplantation (D/HTx) –3. The eSynchrony plays an important role in efficient ventricular pump function and cardiac output. In a normal 2-ventricle circulation, the fast activation of electrical conduction through the heart is reflected by a narrow QRS on electrocardiogram (ECG) and a synchronous pattern of contraction. Left ventricular dyssynchrony is defined by temporal differences in activation  and contraction  of various myocardial segments of the left ventricle. In adult and pediatric patient populations with biventricular circulations, ventricular dyssynchrony has been associated with life-threatening arrhythmias , heart fThe present study uses cardiac magnetic resonance (CMR) to characterize mechanical dyssynchrony in functional single ventricles using FT. It describes novel dyssynchrony metrics and analyzes their relationship with ventricular morphology, volumetric and function data, and QRS duration. In addition, the study evaluates the association between dyssynchrony and clinical outcomes including death and need for heart transplantation.This was a single-center, retrospective cohort study. The Institutional Review Board approved the study and waived the need for informed consent.All patients with a Fontan circulation who had at least one available CMR after 7/1/05 through 9/23/21 were screened for eligibility. The study workflow is illustrated in Fig. i), indexed end-systolic volume (ESVi), indexed stroke volume (SVi), EF, indexed ventricular mass (Massi), and ascending aortic flow as a measure of cardiac output. When two ventricles contributed to the systemic circulation (i.e. mixed type ventricles), their mass and volumes were combined. For the comparison cohort, only the LV measurements were considered.Fontan imaging was conducted according to standard practice at our center, as has been previously described . BrieflyFeature tracking analysis was performed on the short-axis cine stack of images as previously described . BrieflyFrom this, the following six deformation measurements were obtained: circumferential strain (CS), circumferential strain rate (CSR), circumferential displacement (CD), radial strain (RS), radial strain rate (RSR), radial displacement (RD). These deformation measurements were used to calculate quantify dyssynchrony using 4 methods: (1) standard deviation of time-to-peak (SDTTP) for circumferential and radial deformation measurements for all segments, 2) maximum opposing wall delay (MOWD) as the maximum difference in the average time-to-peak for 3 opposing wall pairs, and (3) base-to-apex delay (BAD) as the time difference between peak deformation (average of 6 segments) of the most basal slice and the most apical slice (BAD1) as well as (4) the difference between the peak deformation for the 2 most basal and apical slices, respectively (BAD2). As such, 24 dyssynchrony indices were derived from the FT data . For time-to-event analysis, follow-up was measured from the date of CMR to the composite outcomes (earliest event in case of multiple) or last known documented follow-up in the medical record. If the first occurrence of transplant listing was prior to the CMR, it was excluded as an outcome.Data are presented as a median with interquartile ranges (IQR) as appropriate for continuous variables and as a frequency (percentage) for categorical variables. Continuous variables were compared between groups using a Mann–Whitney U test while proportions were compared using a Fisher’s exact test. Correlation between continuous variables was quantified using the Pearson’s correlation coefficient (r). Using a set of 11 a priori chosen predictors, bivariate and multivariable Cox regression analyses were performed to assess relationships between predictors and time to composite outcome . Approximately 7% of patients’ CMR examinations (36 out of 503) were missing data. Schafer  found thA total of 576 patients with a Fontan circulation and CMR were screened for eligibility and the final study cohort included 503 patients with a median age of 15.2  years and 42 comparison group patients with median age of 15.7  years. A total of 73 patients were excluded from after screening due to inadequate imaging. Common reasons for inadequate imaging were lack of full short-axis image stack (51 patients), inability to obtain reliable feature tracking due to motion artifact or blurring (10 patients), metallic artifact (9 patients), imaging performed at a lower than standard 30 phases/cardiac cycle temporal resolution (3 patients). Ventricular morphology was RV in 190 (38%), LV in 157 (31%), and mixed type in 156 (31%) of the patients with a Fontan circulation. The type of Fontan operations were lateral tunnel (69%), extracardiac conduit (20%), RA-PA (10%), and RA-RV (1%). Compared to the comparison group, Fontan patients had a lower BSA and were more frequently male  and percent MHR  were independently associated with D/HTx, however, dyssynchrony metrics were not on multivariable analyses  for single RVs, 3.5%  for mixed typed ventricles, and 1.4%  for single LVs . Using the cut off point of 73 ms for SDTTP-GCS that maximizes the log rank statistic, those with a SDTTP-CS of  > 73 ms had a higher Kaplan Meier estimate of 3-year percent D/HTx  compared to those below the cut off . Patients with EDVi > 146 ml/m2 had a higher rate of the primary outcome than those with EDVi ≤ 146 ml/m2  vs. 2.8% ; p-value 0.002).With a median follow-up period of 4.3  years, 57 (11.3%) of the patients met the composite primary outcome with 46 deaths, 8 heart transplantations, and 18 heart transplant listings. In the RV group, 28 (14.7%) patients had the outcome compared to 19 (12.2%) in the mixed group, and 10 (6.4%) in the LV group. On bivariate Cox regression analysis, D/HTx was associated with RV or mixed ventricular morphology, lower blood pressure, higher heart rate, longer QRS, ventricular dilation, lower EF, and higher dyssynchrony indices (Table This retrospective analysis of a large cohort of patients with a Fontan circulation provides a comprehensive characterization and analysis of mechanical dyssynchrony in single ventricles using CMR-FT. The cohort covers a wide breadth of single ventricular morphology, including dominant right, left, and mixed type ventricles. Our data demonstrate that ventricles in the Fontan circulation have a higher degree of dyssynchrony compared to control LVs and that dyssynchrony is associated with reduced ventricular function and D/HTx. RV and mixed morphology subtypes had a higher degree of dyssynchrony compared to those with LV morphology. Conversely, in those with LV morphology, dyssynchrony indices were more similar to those in the comparison group LVs. These results contribute to the growing body of literature demonstrating adverse ventricular remodeling in the Fontan circulation and highlight new risk factors for increased morbidity and mortality, which are critical to understanding and managing a growing population surviving into adulthood.Data regarding the characterization and patterns of dyssynchrony in patients with a Fontan circulation are growing but remain to be fully elucidated. Both adult and pediatric patients with heart failure are known to have more dyssynchronous patterns of electrical and mechanical ventricular contraction, which is associated with worse LV and RV systolic function and increased morbidity , 26. Sim. The discovery of CMR markers of mechanical dyssynchrony may offer an opportunity to identify high-risk Fontan patients who may benefit from CRT and subsequently follow their response to CRT. Furthermore, segmental analysis using FT to compare the timing and peak offset for GCS may inform lead placement to achieve optimal synchronous contraction in an individual patient.In biventricular hearts with acquired heart diseases, QRS duration correlates with markers of ventricular dyssynchrony, dilation, and heart failure , 32. QRSThis study reaffirmed that impaired ventricular EF, ventricular dilation, and RV or mixed ventricular morphology are established risk factors for poor clinical outcomes in patients with a Fontan circulation , 39, 40.This study has several limitations that must be acknowledged. The generalizability of the findings to the Fontan population as a whole may be limited by a single-center retrospective design that uses availability of a CMR as an inclusion criterion. The study focused on mechanical performance of the ventricles and did not analyze markers of fibrosis such as late gadolinium enhancement or myocardial T1 measurements, as that would have resulted in a substantially smaller cohort. The relatively low temporal resolution of CMR-FT analysis must also be acknowledged. Our cohort has a selection bias as pediatric patients referred for a CMR tend to be older and those with pacemakers and defibrillators were excluded. Moreover, a referral bias for CMR testing may lead to sicker and more symptomatic patients being overrepresented in the cohort. Lastly, our cohort had a relatively small number of age-matched controls for comparison due to availability.Compared to control LVs, single right and mixed morphology ventricles in the Fontan circulation exhibit a higher degree of mechanical dyssynchrony as evaluated by CMR-FT. Dyssynchrony indices correlate with ventricular size and function and are associated with death or need for heart transplantation. These data add to the growing understanding of progressive decline in ventricular performance in the Fontan population.Additional file 1: Table S1. Dyssynchrony metrics for comparisons and patients by ventricular morphology. Table S2. Correlation between dyssynchrony metrics and measures of systolic function. Figure S1. Scatterplot matrix showing correlation between ventricular size, function, dyssynchrony, and QRS duration for the Fontan cohort and separated by ventricular morphology


In 2009, the Veterans Health Administration (VHA) released a national bulletin regarding the risk of hypoglycemia associated with the use of glyburide in elderly patients with renal dysfunction. Providers were encouraged to avoid glyburide and use glipizide in patients with a calculated creatinine clearance (CrCl) of less than 50 mL per minute. Since this initiative, many veterans were converted by their providers from glyburide to glipizide regardless of renal impairment.To (a) identify whether hemoglobin A1c remained equivalent in patients converted from glyburide to glipizide, (b) evaluate the prevalence of hypoglycemia during treatment with glyburide or glipizide, (c) com- pare change in glycemic control for renally impaired versus nonimpaired patients, and (d) analyze dosage conversion ratios selected by providers and measures of patient follow-up after conversion including time until A1c measurement and number of glipizide dose titrations.This was a single-center, retrospective analysis of veterans converted from glyburide to glipizide from January 1, 2008, through May 31, 2010, who had documented A1c values concurrent with glyburide and glipizide use. A 2-sided equivalence analysis was used for the primary outcome. Equivalence was defined as a change in mean A1c of±0.2. Hypoglycemia was defined as blood glucose of less than 70 mg per dL, symptoms of hypoglycemia, or hypoglycemia that led to a fall, loss of con- sciousness, emergency room visit, hospitalization, or death. The pre- to post-conversion change in rates of hypoglycemia was tested for significance using a McNemar’s test.In the 141  patients meeting inclusion criteria between 2008-2010, the average change in A1c (+0.34) was nonequivalent after conversion from glyburide to glipizide . Hypoglycemia occurred more frequently during treatment with glyburide than glipizide . Mean dose conversion ratios were consistent with VHA recommendations (1 mg per day glyburide=1.26- 1.55 mg per day glipizide).Conversion from glyburide to glipizide was associated with an increase in A1c, but the incidence of hypoglycemia was reduced. Results of this study are consistent with the recommendation of the American Diabetes Association and European Association for the Study of Diabetes to use second-generation sulfonylureas other than glyburide. Patients converted to glipizide should be monitored closely to adjust therapy as appropriate to maintain glycemic control.