AL) and transthyretin (ATTR) cardiac amyloidosis may have prognostic implications.The relationship between structural pathology and electrophysiological substrate in cardiac amyloidosis is unclear. Differences between light‐chain (ECG imaging and cardiac magnetic resonance studies were conducted in 21 cardiac amyloidosis patients (11 AL and 10 ATTR). Healthy volunteers were included as controls. With respect to ATTR, AL patients had lower amyloid volume , lower myocardial cell volume , and higher T1  and T2 . ECG imaging revealed differences between cardiac amyloidosis and control patients in virtually all conduction‐repolarization parameters. With respect to ATTR, AL patients had lower epicardial signal amplitude , greater epicardial signal fractionation (P=0.019), and slightly higher dispersion of repolarization . No significant difference between AL and ATTR patients was found using the standard 12‐lead ECG. T1 correlated with epicardial signal amplitude (cc=−0.78), and extracellular volume with epicardial signal fractionation (cc=0.48) and repolarization time (cc=0.43). Univariate models based on single features from both cardiac magnetic resonance and ECG imaging classified AL and ATTR patients with an accuracy of 70% to 80%.AL than in ATTR. Combined ECG imaging–cardiac magnetic resonance analysis supports the hypothesis that additional mechanisms beyond infiltration may contribute to myocardial damage in AL amyloidosis. Further studies are needed to assess the clinical impact of this approach.In this exploratory study cardiac amyloidosis was associated with ventricular conduction and repolarization abnormalities, which were more pronounced in  This is the first combined assessment of the electrical and structural ventricular substrate in cardiac amyloidosis patients, integrating data from advanced cardiac magnetic resonance imaging with recently proposed ECG imaging.This study demonstrates for the first time an interaction between cardiac magnetic resonance imaging indices  and ECG imaging features , and results suggest that several structural and functional parameters are different in AL and ATTR patients and could be used to discriminate between these 2 groups.This novel approach may provide a better understanding of the underlying pathophysiology and enable more accurate prognosis in cardiac amyloidosis as well as track treatment effects, but further studies are needed to fully determine its clinical implications.Cardiac amyloidosis is a disorder characterised by the deposition of abnormal protein fibers known as amyloid fibrils that can lead to heart failure and sudden cardiac death. Electrophysiological abnormalities and their relation to structural pathology are not well characterized in this population despite the fact that amyloid infiltration can induce complete heart block and has been linked to ventricular arrhythmias.Cardiac magnetic resonance (CMR) has been proven to be able to measure the continuum of amyloid infiltration and the myocardial response, both in terms of myocyte loss/myocyte hypertrophy and myocardial edema, providing a deeper understanding of disease pathogenesis and of the differences between the 2 main types of amyloidosis.The data that support the findings of this study are available from the corresponding author on reasonable request.99mTc‐DPD  scintigraphy in the absence of a monoclonal gammopathy, or, in the presence of monoclonal gammopathy, a cardiac biopsy confirming ATTR.TTR gene. Of the 10 ATTR patients, 8 were wild type, and 2 had hereditary ATTR associated with the V122I variant. Cardiac AL amyloidosis was determined on the basis of international consensus criteriaTwenty‐one patients with cardiac amyloidosis (11 AL and 10 ATTR) were prospectively recruited and underwent ECGI and CMR studies at The Royal Free Hospital, University College London Hospitals, United Kingdom. Cardiac ATTR amyloidosis was defined as the combination of symptoms with an echocardiogram consistent with or suggestive of cardiac amyloidosis,Two groups of healthy volunteers were recruited: 1 served as control for CMR parameters (n=25 patients), and the other served as control for 12‐lead ECG and ECGI parameters (n=30 patients).min) during the QRS complex and the time of steepest signal upslope (dV/dtmax) during the T‐wave, respectively. Cardiac intervals were referenced to the earliest AT and were carefully reviewed and corrected with semiautomatic custom software as in previous studies.AT) were measured as the absolute AT difference between neighboring sites divided by their distance, averaged across all neighbors.RT) were measured similarly. Epicardial signal amplitude was measured as peak‐to‐peak amplitude, ie, the difference between the maximum and the minimum (which can be negative) values within the QRS complex of the unipolar electrogram  precontrast and postcontrast, and total myocardial amyloid volume was calculated as LV mass/g×ECV, where g is the specific gravity of myocardium (1.05 g/mL). Total myocardial cell volume was calculated as LV mass/g×(1−ECV). For T2 mapping, 3‐short‐axis matching the T1 maps was acquired and analyzed in the same way as the T1 maps.All participants underwent standard CMR on a 1.5 T scanner . A standard clinical scan protocol with late gadolinium enhancement imaging and T1 mapping (by Modified Look‐Locker Inversion recovery) before and after a bolus of gadolinium contrast (0.1 mmol/kg of gadoterate meglumine) was performed.A 12‐lead ECG was recorded, and standard parameters were derived. QRS amplitude was measured as the average of peak‐to‐peak QRS amplitude in limb, precordial, and all leads, respectively.Analyses of CMR and ECGI data were blind to cardiac amyloidosis pathology (AL and ATTR) but not to controls, as these patients were recruited at a further stage of the study.P<0.05. Given the exploratory nature of the study and the expected correlation among several variables, corrections for multiple comparisons were not performed.P<0.10 (Wilcoxon rank sum test), and the least absolute shrinkage and selection operator method was used to identify the most suitable subsets of features to be tested in multivariate models. Cross validation was performed to assess possible issues related to overfitting using the leave‐1‐out technique. Accuracies achieved by different models were compared with the McNemar test.Continuous variables are presented as median/interquartile range. The Wilcoxon rank‐sum test was used to test unpaired comparisons with statistical significance set at P=0.01, median/interquartile range).Cardiac amyloidosis patients were predominantly male (81.8% of AL and 100% of ATTR), and ATTR were older than AL patients , total myocardial amyloid volume , and myocardial cell volume  were higher in ATTR than in AL patients, whereas T1  and T2  were higher in AL than ATTR. LV ejection fraction was slightly lower in AL than in ATTR , mainly because of slightly larger end‐systolic volume in AL . Figure With respect to healthy controls, cardiac amyloidosis patients (both AL and ATTR) showed expected abnormalities, including higher ECV, T1, T2, LV mass, and diastolic impairment (Table P<0.005), longer PR interval , longer QTc , and lower QRS amplitude in all lead configurations (Table P=0.73), suggesting that QTc prolongation could be explained by a widening of the QRS complex. T‐wave inversion and poor R‐wave progression were more frequent in cardiac amyloidosis than in controls. No surface ECG parameter showed statistically significant differences between AL and ATTR patients (Table P<0.005), a secondary analysis was performed by comparing 10 cardiac amyloidosis patients (5 ATTR+5 AL) with 10 age‐matched controls. Results were in agreement with those between amyloidosis patients and younger volunteers with the exception that although median QTc was still longer in cardiac amyloidosis, this difference was no longer significant , intraventricular conduction was slower , and markers of conduction abnormality were higher . Furthermore, all repolarization parameters demonstrated a longer and more spatially dispersed repolarization process in cardiac amyloidosis than in controls . In secondary analysis, comparison between cardiac amyloidosis patients (5 ATTR+5 AL) and 10 age‐matched controls showed similar results, with all differences remaining significant despite a reduction in statistical power , a higher degree of signal fractionation , and longer (but nonsignificant) dispersion of repolarization  than ATTR patients.As shown in the example reported in Figure P=0.052) and inversely correlated with total myocardial cell volume . A very high (negative) correlation coefficient characterized the association between T1 and epicardial signal amplitude . Signal amplitude also showed a moderate correlation with total myocardial cell volume  and T2 . ECV positively correlated with signal fractionation  and showed a borderline significant correlation with repolarization time .Correlation coefficients between ECGI and CMR parameters are reported in Table P=0.50). Penalized logistic regression using the least absolute shrinkage and selection operator identified several multivariate models with similar deviance. Among these, those that used the fewest features included T2+ΔRT (accuracy=85.7%) and T2+LV mass+ΔRT (accuracy=90.5%). The difference in accuracy with respect to the best univariate model was nonsignificant (P>0.37).The univariate models showing higher accuracy in classifying AL and ATTR patients used T2 (accuracy=81.0%) followed by T1, Total Cell Volume, and LV mass (accuracy=71.4%) from CMR, and epicardial signal amplitude (accuracy=71.4%) from ECGI. There was no significant difference between the accuracy provided by the best CMR univariate model and that from the best ECGI univariate model  grant FS/18/21/33447 and Royal Society Grant IE141601. ECGI maps were processed in the Rudy laboratory under support from NIH grant R01‐HL33343. Lambiase is supported by University College London Hospital (UCLH) Biomedicine NIHR and received educational grants from Medtronic. O'Regan, de Marvao, and Cook are funded by the Medical Research Council, United Kingdom. The study was supported by the Academy of Medical Sciences (SGL015/1006) and the National Institute for Health Research Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London.Dr Rudy was a cochair of the scientific advisory board and received royalties from CardioInsight Technologies. CardioInsight Technologies does not support any research conducted in Dr Rudy's laboratory. The remaining authors have no disclosures to report.Table S1. Patients’ Age, Sex, Etiology, and MedicationTable S2. 12 Lead ECG ParametersTable S3. ECGI ParametersClick here for additional data file.


Background: Association of premature ventricular complexes (PVC) with left ventricular systolic dysfunction (LVSD) and efficacy of catheter ablation treatment have been demonstrated in studies. The role of left atrial (LA) mechanics in the etiopathogenesis of PVC-induced cardiomyopathy (PVC-CMP) as well as changes in LA mechanics with catheter ablation have not been studied before. Methods: A total number of 61 patients (Mean Age 43 ± 3) with idiopathic outflow tract (OT) PVCs undergoing radiofrequency catheter ablation (RFCA) were enrolled. ECG, 24 h Holter, and echocardiographic evaluation with left ventricular (LV) diastolic functions and LA volumetric assessments were performed before and three months after RFCA. Results: Along with a marginal increase in left ventricle ejection fraction (LVEF), improvement in diastolic functions and left atrial mechanics were observed in the study  in short-term follow-up. The frequency of LV diastolic dysfunction (LVDD) decreased with catheter ablation . The overall LA function improved. Left atrium passive and overall emptying fraction (LAEF) increased significantly . Active LAEF decreased significantly . Conclusions: The results of this study are indicative of “PVC-induced atriomyopathy” which responds to RFCA in short-term follow-up. Atrial dysfunction might play a role in symptoms and etiopathogenesis of LVSD. Premature ventricular complexes (PVCs) are not uncommon in the general population and are often an incidental finding in ECG or Holter recordings of healthy individuals. Their clinical significance and consequences depend on various properties of the arrhythmia. Left ventricle systolic dysfunction, which is termed PVC-induced cardiomyopathy (PVC-CMP), is an undesirable consequence associated with frequent PVCs .Most of the patients with PVCs do not need a specific treatment. The presence of intractable symptoms clearly attributable to PVCs, underlying heart disease that would render the patient susceptible to complications of this arrhythmia, a very high PVC burden in 24 h  that would increase PVC-CMP risk significantly, or the presence of PVC-CMP at the time of diagnosis warrant a treatment with antiarrhythmics, pacing, or ablation, depending on the underlying etiopathogenesis [Radiofrequency catheter ablation (RFC) has become popular because of its potential of eliminate arrhythmias completely, which would consequently enable a physician to discontinue antiarrhythmics which are associated with several side effects and complications. Additionally, the procedure was associated with improved outcomes when performed for PVC-CMP . GuideliIn Turkey, the major cause of death in the very elderly is cardiovascular disease. In 2016, the rate of death from circulatory system diseases was 46.8% in Turkey, higher than the rate in Europe, which was 42% [Abnormalities in left atrium (LA) geometry and volumes as well as the response of these parameters to catheter ablation were studied before in a heterogeneous set of patients with PVC-CMP and demonstrated significant positive changes in diastolic functions and LA volumes . Left atSixty-one patients older than 18 years with OT-PVCs in their ECG or 24 h Holter recordings, without significant structural heart disease, who consequently underwent catheter ablation, were enrolled prospectively. Outflow tract PVC was defined as the absence of structural heart disease with a left-bundle branch block, inferior axis, relatively narrow QRS duration, and R/S transformation later than V3 in surface ECG. Patients with ischemic heart disease, more than mild-degree valvular lesion, prosthetic valve, previous history of cardiac surgery, known diagnosis of cardiomyopathy, pericarditis, myocarditis, or endocarditis and patients with non-sustained or sustained ventricular tachycardias or other types of supraventricular tachycardias in rhythm Holter recordings were excluded from the study.The study was approved by the Ethical Committee of Bursa Education and Research Hospital. Written informed consent was obtained from all patients prior to participation in the study, and this study was conducted in accordance with the Declaration of Helsinki.All patients underwent a detailed diagnostic work-up including ECG, 24 h Holter monitorization, echocardiography, radionuclide scans, coronary computerized tomographic angiography, and/or invasive coronary angiography and cardiac magnetic resonance imaging as indicated, to rule out coronary artery disease (CAD) and valvular or structural heart disease at least three months prior to the ablation procedure .Two-dimensional transthoracic echocardiography  was performed at least three months prior to the procedure and three months following the ablation procedure. A standard examination protocol was followed by a detailed assessment of the left ventricle (LV) diastolic functions and LA functions . Left veLeft ventricular diastolic functions (LVDD) were assessed by pulsed-wave Doppler analysis of the diastolic mitral inflow and Tissue Doppler imaging of the left ventricular wall at the basal segments of the lateral and septal walls. Conventional Doppler parameters along with LVDD grading according to the latest guidelines were assessed, calculated, and recorded ,9.Volumetric measurements were performed with a modified Simpson’s method, as defined in the guidelines . Left atElectrocardiography, 24 h Holter recording and 2-dimensional transthoracic echocardiography (2D-TTE) were repeated at three-month follow-up. At least 80% decrease in PVCs with the same morphology in 24 h Holter recording at three months was defined as successful sustained ablation. Antiarrhythmic medications were not started again after the ablation procedure.Patients were instructed to discontinue antiarrhythmic drugs for a period of five half-lives prior to the planned ablation procedures. The electrophysiological study was performed during a fasting state, by local anesthesia. The patients were not sedated prior to procedure to avoid the risk of suppressing the automaticity. If clinical premature ventricular complexes (PVCs) were not present at baseline, isoproterenol infusion and electrical stimulation were used to induce the arrhythmia. Intravenous isoproterenol 1–5 μg/min was infused to achieve at least 20% heart rate increment. Electrical stimulation was performed using incremental pacing and triple extra-stimuli pacing from the right ventricular apex or right ventricular outflow tract (RVOT).Electroanatomical mapping was performed with the EnsiteTM Precision  or CARTO . Using fluoroscopic guidance, a decapolar mapping catheter was inserted through the right femoral vein and positioned in the coronary sinus. The ablation catheter used for mapping and ablation was an 8F quadripolar irrigated ablation catheter Thermocool Smarttouch CF  and FlexAbility  with a 4 mm tip and a 2–5–2 mm inter-electrode spacing. Left-sided access was performed via retrograde aortic route or trans-septal puncture, and intravenous unfractionated heparin was administered to maintain an activated clotting time between 300 and 350 s.In the first step, an activation map was implemented using a mapping catheter. The PVC focus was determined as the earliest local timing and a QS-complex on unipolar electrogram in case of radial spread away from the focus. The goal of activation mapping was to find the earliest sites ≳30 ms ahead of reference surface QRS onset. Additionally, to identify the origin and optimal ablation site of PVCs, pace mapping was implemented, aiming for at least 11 of 12 leads matching with clinical PVCs. In the outflow tract ventricular zone, radiofrequency energy was delivered in a power-controlled mode at 30–35 W for the irrigated catheter, targeting for an impedance decrease of 10 Ω. Electrophysiologic study and programmed electrical stimulation (PES) were repeated with and without isoproterenol following 30 min of waiting period after ablation, and non-inducibility of tachycardia or (Ventricular premature complexes) VPCs with the same morphology was assumed as successful ablation.p-values of less than 0.05 were accepted to represent statistically significant differences. Analysis of variance for repeated measures procedure was used for assessing the significance of changes in parameters with RFCA along with the effects of various factors on changes.Statistical analysis was performed with SPSS version 22. Continuous variables were summarized as mean ± standard deviation or median  when normal distribution was not present. Analysis of variance for repeated measures was used for evaluating changes in echocardiographic parameters after ablation. Wilcoxon signed-rank test was used for comparing the changes in distribution of ordinal values after RFCA. A total number of 61 patients with a median age of 41 years  were enrolled in the study. None of the patients had a syncopal episode or documented ventricular tachycardia (VT) in their recent or past medical history. The burden of PVC localized electrocardiographically to outflow tract (OT) was 20% (9–33%) in 24 h Holter recordings. There were no patients with severe left ventricular systolic dysfunction, defined as a LVEF <30% . The chaThe procedural characteristics of the study population are shown in The effect of RFCA on OT-PVCs was examined in three domains: effects on left ventricle systolic functions, effects on LVDD, and effects on left atrial mechanics, with VPC burden as a covariate, and antiarrhythmic use and prior history of RFCA as cofactors.p < 0.05) (p < 0.05). Mitral E-wave, A-wave, deceleration time of the E wave (DT), e’-wave, all changed significantly after ablation in directions indicative of improvement in LVDD, whereas E/A ratio did not change significantly, and E/e’ ratio improved only among patients with PVC-CMP at baseline . There w < 0.05) . Only a Left atrial mechanics revealed statistically significant responses to RFCA along with LV diastolic functions. Left atrium anteroposterior diameter (LAAPd) and LAVI decreased significantly, and left atrium conduit volume indexed to BSA (LACV-BSA) increased significantly after RF ablation compared to pre-ablation values . HoweverSubgroup analyses for LVEF and LA mechanical functions were performed in patients with PVC-CMP. There was significant improvement in LV systolic function . Left atThe main findings from the current study could be summarized as follows: Firstly, left ventricular function improved significantly during short-term follow-up of the patients following RF ablation. Secondly, the frequency of LVDD significantly decreased as a result of RF ablation. Thirdly, parallel to the improvement in left ventricle diastolic functions, significant improvement was observed in left atrial active systolic function, as assessed by left atrial volumes.The development of tachycardia-induced left ventricular systolic dysfunction (LVSD), independent of accompanying structural heart disease is a well-defined clinical condition . Left veThe efficacy of RFCA in the management of LV systolic function was questioned in several trials, and a favorable effect of this modality on LV as well as RV systolic function was demonstrated ,20. Two Premature ventricular complex-induced cardiomyopathy is well known to exert its unfavorable effects on myocardium by restricting the diastole phase of the cardiac cycle in the first place. Preclinical studies demonstrated that tachyarrhythmia causes relaxation abnormalities even when contractile functions are preserved . EvidencIn our study, unlike LV systolic functions, which improved only marginally, LV diastolic functions improved significantly during short term follow-up, so that there was no patient with LVDD at follow-up echocardiography. This is notable, because this finding is in agreement with the current knowledge that LV diastolic function is affected earlier, compared with the systolic function, particularly because of inappropriate and inadequate myocardial cellular calcium handling. Right ventricular outflow tract VTs result in a myocardial electrical activation that does not comply with the infrastructure of the conduction system, disturbing interventricular, intraventricular, and atrioventricular synchrony. Shorter cycle lengths associated with tachycardia cause truncation of the diastole at the cellular level with resultant intracellular calcium accumulation, ATP depletion, and ischemia with unfavorable short- and long-term functional and structural effects .It is suggested from studies of RV apical pacing that left atrial remodeling and decreased atrial pump function might be present even in the absence of LVSD . The intThe conventional Doppler parameters of LVDD  and deceleration time of E-wave displayed significant changes, indicating improvement of LV diastolic functions. The E/e’ ratio decreased significantly in patients with depressed LVEF in contrast to patients with normal LVEF. This finding indicates that LV diastolic functions improve more in patients with compromised baseline LV systolic functions.2) is a major criterion for the diagnosis of LVDD [Atrial mechanics are closely coupled with ventricular systolic and diastolic functions. The atrial cycle consists of mainly four phases: atrial reservoir, conduit, diastasis, and booster pump phases. The relaxation phase coincides with LV systole, while the remaining phases take place during LV diastole. As an indirect estimate of LV diastolic function and LA cycle, LAAP and LA diastolic volumes might be examined. Left atrial anteroposterior diameters and LAVI indirectly indicate LVDD in the absence of accompanying structural heart disease. Increased LAVI  or 3D echocardiography to assess left ventricle ejection fraction and left atrium volumetric measurements. However, two-dimensional echocardiography is an accepted method for the evaluation of LA and LV functions and is highly correlated to MRI and 3D echocardiography. Another limitation of our study is that patients included in the study included patients with and without normal left ventricular function. Long-term follow-up is indeed important, and we plan to examine long-term changes in atrial functions in the long run too. However, we think that the fact that the favorable changes in LA dynamics were observed even in short-term follow-up is a very significant finding and is worth being reported separately. Lastly, besides premature ventricular contractions, no other ECG variables were investigated related to cardiovascular mortality. A prospective designed study examining the relationship between the ECG variables and cardiovascular mortality should be the aim of a study in the future.Disturbance in left atrial mechanics assessed by left atrial volume measurements might be an early manifestation of PVC-CMP as well as a marker of clinical benefit from RFCA, even when LV systolic functions are preserved.


Treatment options are limited, especially in non-obstructive forms. A minority of patients (around 3.5%) can progress to an end-stage state, characterized by systolic dysfunction and restrictive ventricular filling, related to extensive fibrotic replacement and chamber remodeling. In these cases, life expectancy is significantly reduced: a mean 3-year survival time has been reported4,5. Development of severe pulmonary hypertension is common in this population and can constitute a contraindication for heart transplantation. In other populations, it could be overcome by the use of left ventricular assist devices, but these have shown to perform poorly in restrictive physiology ventricles. The bad short-term prognosis of patients with end-stage heart failure and hypertrophic cardiomyopathy together with the specific difficulties for heart transplantation and circulatory support in this population make advisable an early consideration for aggressive therapies, as the window of opportunity may be short.Heart transplantation can be a life saving therapeutic option for patients with hypertrophic cardiomyopathy in a burn-out end-stage phase. Patients showing signs or symptoms of advanced heart failure should be early considered for aggressive management. Special attention must be paid to patients with ejection fraction <50% or restrictive diastolic pattern, new-onset atrial fibrillation, increased extension of left ventricular fibrosis, elevated plasma levels of natriuretic peptides or declining oxygen consumption rates6–9.The development of pulmonary hypertension is common in left-sided cardiopathies, including valvular disease and heart failure with preserved or reduced ejection fraction. It is mainly related to the presence elevated left ventricular filling pressures due to diastolic dysfunction. In the case of hypertrophic cardiomyopathy, diastolic dysfunction, left ventricular outflow obstruction, mitral regurgitation and, in a minority of patients systolic dysfunction, can be present and cause the development of pulmonary hypertension10.Although few groups have studied pulmonary hypertension specifically in hypertrophic cardiomyopathy population, their findings are consistent throughout the studies: pulmonary hypertension is common, and its frequency increases with the severity of the cardiomyopathy, from 20% in patients with no outflow tract obstruction to 70% in patients with end-stage disease. Moreover, the presence of pulmonary hypertension, particularly when it is associated to right ventricular dysfunction is a significant prognostic factor in this population11.Irreversible pulmonary hypertension, with increased pulmonary vascular resistance can be a contraindication for heart transplantation, since it is an important cause of post-operative right ventricular failure, graft dysfunction and mortality. Pre-transplant treatment options include a pharmacological approach with pulmonary vasodilators or the implant of a left ventricular assist device12.The use of pulmonary vasodilators in type 2 pulmonary hypertension is not recommended, due to consistently deleterious results in several clinical trials with prostaglandins, phosphodiesterase-5 inhibitors or endothelin antagonists. Nevertheless, its use in a highly selected pre-transplant population, allowing patients to reach candidacy has been reported in small cohorts, with good results13.Ventricular assist devices are increasingly used to support patients with left ventricular dysfunction and advanced heart failure to transplant. In fact, nowadays 50% of the heart transplants performed worldwide are bridged with a VADDespite this fact, VAD implantation in hypertrophic cardiomyopathy is difficult, and these patients have not been enrolled in any major study. The opportunity to provide more hypertrophic cardiomyopathy patients mechanical support as a bridge to transplant has been limited by the challenges of VAD placement in this hearts, including small left ventricular chamber size (transverse end-diastolic dimension <55 mm), presence of left ventricular hypertrophy in the mid and distal left ventricular, as well as left ventricular muscle bundles, each of which could impede and obstruct the inflow cannula.14.Pre VAD implantation, intra-operative myomectomy, or atrial placement of the device are surgical strategies reported in isolated cases, that may help to overcome the specific difficulties in this population. Some centers have reported their experiences with VAD implantation in restrictive and hypertrophic cardiomyopathies: compared to patients with dilated cardiomyopathies, they seem to be more susceptible to right ventricular dysfunction and hypotension, long term use of inotropes and driveline infectionThat many hypertrophic cardiomyopathy patients may not qualify for VAD placement represents an impediment for irreversible pulmonary hypertension management in this population, as well as a major obstacle to achieving higher priority on the transplant list, since proposed organ allocation schemes place higher transplant priority on patients supported with VADs (over those supported with inotropic medications).15.Heart transplantation should be considered in hypertrophic cardiomyopathy patients showing refractory heart failure signs and symptoms, or considered in an end-stage state. Younger patients have a faster progression to end-stage disease in hypertrophic cardiomyopathy, so these patients with heart failure symptoms should be early recognized and carefully monitoredHeart transplant indication can be difficult in the younger population, since functional capacity is usually overestimated by clinicians. Common markers of bad prognosis are a drop in ejection fraction <50%, and the presence of a very small ventricular cavity, that is not able to fill adequately when heart rate increases.Oxygen consumption stress tests can be performed in patients with no outflow obstruction and can provide useful information on heart performance. A decrease in oxygen consumption on exercise or peak oxygen consumption <50% of expected values adjusted for age and sex should be considered indicators of heart transplantation.Traditional oxygen consumption threshold values for transplantation (12–14 ml/kg/min) may underestimate the risk of death in the young hypertrophic cardiomyopathy population; therefore, stress test need to be carefully interpreted and adjusted values should be preferred. Neither normal ejection fraction nor peak VO2 >14ml/kg/min should exclude drug refractory severely symptomatic HC patients from heart transplant consideration. The appearance of pulmonary hypertension on follow-up should also be considered as a red flag to start heart transplant evaluation, since it is the main cause for transplant contraindication and post-transplant mortality in this population.16–18.Mortality on waiting list of hypertrophic cardiomyopathy patients is 10-15% and it does not differ significantly from the ischemic or non-ischemic dilated cardiomyopathy population awaiting heart transplantation. Although novel approaches, such as new allocation systems or the use of circulatory support devices, seem to have resulted in lower overall waitlist mortality, patients with hypertrophic cardiomyopathy have not benefited to the same extent from these strategies. Use of ICD and inotrope agents seem to decrease waiting list mortality in hypertrophic cardiomyopathy populationPost-transplant mortality in the hypertrophic cardiomyopathy group has been reported to be >90% at 1 year and >80% at 5 years, and seems to be slightly better than in other transplant populations, probably related to a younger age and less comorbidities in this group.Overall, we could conclude that when implemented in a timely fashion, heart transplantation can represent an excellent option with good 10-year survival, supporting the view that it is the only option to restore longevity among hypertrophic cardiomyopathy patients with advanced HF.Operative and post-operative management of heart-transplanted patients due to hypertrophic cardiomyopathy does not differ from other etiologies, and will be reviewed briefly in the following lines.Heart transplantation is performed with either of the following techniques: •Shumway-Lower technique: the ventricles are excised, leaving the great vessels, and left atrium of the recipient. The donor heart is then sewn to these areas. This technique is associated to permanent sinus node dysfunction in up to 5% of cases (most of them requiring a permanent pacemaker). •Bicaval anastomosis: The right atrium of the donor remains intact. This is most commonly used technique today.Immunosuppression is started soon after surgery. Several regimens can be used, usually including a calcineurin inhibitor (tacrolimus or cyclosporine), micophenolate mophetil and corticoids. At the time of transplantation, initiation of tacrolimus or cyclosporine is delayed postoperatively in patients at high risk for nephrotoxicity, and induction therapy (such as antithymocyte globulin or an IL-2 receptor antagonist such as basiliximab) may be used to permit delay or minimization of nephrotoxic calcineurin inhibitors. •Right heart failure: Frequently associated to recipients with elevation of pulmonary vascular resistance. •Biventricular failure: It may be due to poor preservation of the graft or to myocardial abnormalities present before graft harvesting. •Hyperacute rejection: Catastrophic complication that may be seen in patients with preformed antibodies or in patients receiving an ABO-incompatible graft. •Cellular Rejection: The classic form of rejection is characterized by perivascular infiltration of lymphocytes with subsequent myocyte damage and necrosis if left untreated. Myocardial biopsies are performed routinely to all heart transplant recipients, at least during the first sixth months, in order to diagnose cellular rejection. •Antibody mediated rejection is less frequent and more difficult to characterize and diagnose. The antibody deposition into the myocardium results in global cardiac dysfunction.Infection is common in organ transplant recipients. The types of infections expected in cardiac transplant recipients vary, depending on the time from transplantation. This is because the intensity of immunosuppression administered varies directly with the propensity for rejection, and the propensity to reject decreases over time. Bacteria and viruses account for more than 80% of infections after transplantation.Immunosuppressive therapy with calcineurin inhibitors has improved both graft function and survival in heart transplantation. However, calcineurin inhibitor-induced-induced nephrotoxicity still remains a serious clinical challenge. Chronic calcineurin inhibitor nephrotoxicity is characterized by a decrease in glomerular filtration rate (GFR), afferent arteriolopathy, and striped tubulointerstitial fibrosis. About 10% of heart transplant recipients develop stage four-kidney disease (with a GFR <30 mL/min) and need kidney transplantation or renal replacement therapy because of the use of calcineurin inhibitors for immunosuppression . Close monitoring of tacrolimus and cyclosporine blood levels is critically important to limit progressive decline in renal function, because there is no known treatment for preventing or reversing nephrotoxicity.CAV was the largest problem when heart transplantation began and continues to be a major concern and focus of research. CAV is characterized by myointimal hyperplasia of small and medium-sized vessels. The lesions are diffuse and may appear any time from 3 months to several years after implantation. The inciting causes are unclear, though cytomegalovirus (CMV) infection and chronic rejection have been implicated. Coronary vasculopathy develops in 30% to 40% of heart transplant recipients within 5 years, and much over the years has not reduced the incidence. Currently, there is no treatment other than retransplantation.Following heart transplantation, malignancy is identified in 3% to 18% of the recipients, with an estimated risk of 1% to 2% per year. It ranks second to coronary vasculopathy as a major cause of mortality, accounting for 10% to 23% of all deaths following heart transplantation. Cutaneous malignancy is the most common type, seen in up to 17% of patients, with a predominance of squamous cell carcinoma. Post-transplantation lymphoproliferative disorder (PTLD) is a frequently fatal complication, occurring in 1.7% to 6% of cardiac transplant recipients.The 1-year survival rate after cardiac transplantation is as high as 84%, with a 5-year survival rate of 75% and 10-year survival rate of 59%. The functional status of the recipient after the procedure is generally excellent.


Cardiac resynchronization therapy may stabilize patients with severe heart failure awaiting heart transplant. Transvenous interventional implantation aided by intracardiac echocardiography is feasible in patients with adult congenital heart disease. We describe successful transvenous implantation in a critically ill Mustard patient awaiting heart transplant.Transvenous implantation of an ICD lead to the subpulmonary ventricle and subsequent puncture and dilatation aided by intracardiac echocardiography to facilitate placement of a pacemaker lead in the systemic ventricle was successful. QRS narrowed from 235 to 160 ms, and cardiac index improved from 1.8 to 3.2 L/min/BSA, which translated into a more stable clinical situation.Upgrade to cardiac resynchronization therapy (CRT) is indicated in symptomatic chronic heart failure patients with impaired systolic left ventricular function and right ventricular pacing dependency.2a moderate impairment of the systemic ventricular (right ventricular morphology) systolic function and the ECG a high degree AV‐block with a wide QRS escape rhythm at 40 bpm. He was referred to our department for a dual chamber pacemaker implant. Two leads were advanced through the conduit from the superior vena cava to the systemic venous atrium. The atrial lead was placed posterolaterally in the atrium, and the ventricular lead advanced to the subpulmonary ventricle (left ventricular morphology) and placed in a posterior location  performed at one year of age. Permanent atrial tachyarrhythmia since 2009 with normal ventricular rate response without any rate‐control medication. Drug history included warfarin, losartan, and spironolactone. The patient presented in September 2017 with symptoms of progressive heart failure, dizziness, and syncope. Echocardiography showed . The patient was again hospitalized in our department and accepted for a heart transplant and put on the waiting list. An upgrade of his pacemaker system with an epicardial systemic ventricular lead was discussed with the cardiac surgeons, but both epicardial leads and ventricular assist device surgery were judged to be high‐risk procedures given the patients previous cardiac surgery and very poor systemic ventricular and impaired subpulmonary ventricular function. The patient was subsequently accepted for a transvenous upgrade to a cardiac resynchronization therapy‐defibrillator (CRT‐D) system with an endocardial systemic ventricular lead in March 2018. The procedure was performed under local anesthesia and light sedation (low‐dose midazolam). Femoral venous access from the left groin  included negotiating an S‐curved collateral branch with a microcatheter and a hydrophilic wire into the inferior vena cava, subsequently exchanged to a super‐stiff Amplatz wire facilitating placement of a long sheath in the lower conduit. An intracardiac echocardiography (ICE) catheter was then advanced through the sheath to the systemic venous atrium to guide the surgeon. From the left pectoral infraclavicular region via a percutaneous puncture of the axillary vein, a guidewire was advanced through the conduit into the systemic venous atrium; a long sheath  was then advanced supporting the introduction of a single‐coil implantable cardioverter‐defibrillator (ICD) lead  to the subpulmonary ventricle. The lead was positioned in a high septal position below the atrio‐ventricular valve. Sensing and threshold were excellent. The pocket was now opened, leads were freed from the tissues, and both preexisting atrial and ventricular pacemaker leads were extracted with simple traction. Continuous pacing via the ICD lead was necessary since the patient now demonstrated total pacing dependency. A second puncture of the axillary vein followed and a guidewire was advanced to the superior vena cava “pouch” and conduit adjacent to the systemic venous atrium. A short deflectable sheath  was then advanced to the conduit and a radiofrequency guidewire  through this. Guided by ICE, the surgeon directed the deflectable sheath in an inferior‐anterior angle toward the pulmonary venous atrium, and after 2 seconds of RF energy applied, the guidewire could enter the pulmonary venous atrium followed by the sheath. The guidewire was then exchanged for a standard 0.035” wire, and the sheath advanced to the systemic ventricular apex. The sheath was now exchanged to a CRT delivery sheath , and the sheath positioned below the atrio‐ventricular valve against the basal anterolateral portion of the systemic ventricle. A pacemaker lead  was then advanced and positioned here, and the sheath was removed. Both leads were then connected to a CRT‐D device , and the pocket was closed. An antibacterial envelope  was used to reduce the risk of infection. A hemodynamic study was performed the day before the procedure and again the day after, as well as a transthoracic echo.Tracking of the chronic atrial tachycardia with 1:1 conduction and a ventricular pacing rate of 150 bpm caused hemodynamic shock, but the patient was stabilized after reprogramming the pacemaker to ventricular pacing only (VVIR mode). Although symptoms of dizziness improved, heart failure symptoms progressed rapidly and the patient remained hospitalized in the referring hospital over four months, despite treatment with inotropic agents such as milrinone and levosimendan pulses as well as continuous furosemide infusion to maintain an adequate diuresis. Echocardiography now showed severe systolic dysfunction of the systemic ventricle3Improved hemodynamic and echocardiographic measurements Table  translatThe remarkable acute hemodynamic effects of biventricular pacing did not reverse the patient's condition, but rather stabilized the patient and thus made it possible avoid an “urgent call” transplant. The patient subsequently underwent a successful heart transplant three months after CRT upgrade and is now doing well.4We describe a successful case of transvenous CRT in a critically ill Mustard patient with a failing systemic ventricle awaiting heart transplant. Mustard patients frequently have mechanical dyssynchrony in the systemic ventricle,5Upgrade to CRT may alleviate symptoms of severe heart failure and reduce the need of inotropic agents and hospitalization in selected ACHD‐patients with advanced heart failure awaiting heart transplant. Interventional techniques and perioperative imaging make transvenous CRT‐D implantation feasible in patients having had a Mustard repair.There are no relevant financial disclosures for this manuscript.DM: served as surgeon, designed the procedure, and drafted and revised the manuscript. UT: carried out the hemodynamics assessment, followed up the patients, revised the manuscript, and provided funding of publication fees. PT: carried out the clinical assessment during in‐hospital treatment, followed up the patients, and revised the manuscript. OK: served as assisting surgeon (including intracardiac echocardiography), designed the procedure, and revised the manuscript.


In children, the left ventricle (LV) wall thickness should be more than two standard deviations above the predicted population mean1. The typical anatomo-pathological findings include myocyte hypertrophy, disarray, interstitial fibrosis and small-vessel disease3. Although all the myocytes are supposed to be affected, pathological alterations are not uniformly distributed throughout the myocardium4. Asymmetrical hypertrophy of the interventricular septum is the most commonly observed phenotype, but any pattern of hypertrophy is consistent with the diagnosis5.Hypertrophic cardiomyopathy (HCM) is diagnosed in the presence of left ventricular hypertrophy of ≥15 mm in adult index cases, or ≥13 mm in relatives of known affected patients, that is not solely explained by abnormal loading conditions6. It has been estimated that up to 10% of patients with HCM present with other genetic or non-genetic phenocopies7, 8, but up to 30% of HCM cases remain unexplained6.HCM is mainly caused by mutations in genes encoding for sarcomeric proteins, which account for almost 60% of the cases9–11 and conditions such as systemic hypertension or valvular heart disease. People of sub-Saharan African ancestry may be more prone to developing myocardial hypertrophy, even in the absence of severe predisposing factors12. It is important to correctly distinguish between these phenocopies and HCM to prevent fatal outcomes, not only for the index cases, but also for affected family membersCommon diagnostic dilemmas include the differentiation of HCM from physiological hypertrophy in athletes13–17. In children, neuromuscular disorders, inborn errors of metabolism, RASopathies or malformation syndromes are more prevalent18, 19. Many of these disorders display disease-specific clinical features that, together with the age of presentation, can assist in the diagnostic work-up13. Early identification of these conditions facilitates a tailored approach to disease management, which in some cases, may lead to significant modifications of prognosis and quality of life1, 13.Rare, but important, causes of HCM include infiltrative disorders like amyloidosis, lysosome and glycogen storage diseases, and mitochondrial diseases20. Classical symptoms in HCM are usually related to left ventricular outflow tract (LVOT) obstruction, mitral regurgitation, myocardial ischemia, diastolic dysfunction, abnormal vascular responses, and supraventricular and ventricular arrhythmias20, 21.Clinical manifestations in HCM are highly variable20.Reduced functional capacity is common in HCM. Orthopnea and paroxysmal nocturnal dyspnoea are rare, but bendopnoea and postprandial breathlessness are common symptoms. LVOT obstruction is a common cause of these clinical manifestations, but exertional dyspnoea is also caused by diastolic and systolic LV impairment and atrial arrhythmia1, 2. It is important to ensure adequate ventricular filling and relaxation and to avoid vasodilators and inotropic agents20, 22. Selective beta-blocking agents are considered the gold standard therapy. Verapamil and diltiazem are considered less effective, although they can be used in patients who are intolerant or have contraindications to beta-blockers20, 22. It is important to monitor ECG changes when using disopyramide to avoid QT prolongation, and although generally tolerated, patients should be warned of cholinergic side-effects. Verapamil or diltiazem are also considered options for the treatment of LV obstruction, and can be used in conjunction with beta-blockers under close monitoring20, 22. For drug-refractory patients, septal reduction  may be considered20. In experienced centers, septal reduction shows marked symptom improvement without significant intraoperative morbidity and mortality23–26. The use of atrio-ventricular sequential pacing can also be considered but is generally less effective27, 28.The first approach to LVOT obstruction is based on medical treatment optimization©  is a small molecule that reduces the steady-state ATPase activity by inhibiting the rate of phosphate release of β-cardiac myosin52. This results in diminished hypercontractility in the sarcomere and a consistent reduction in LV obstruction and symptoms, which is expected to persist in mid-term follow-up53. The phase 2 PIONEER-HCM (A Phase 2 study of Mavacamten (formerly MYK-461) in Symptomatic Obstructive Hypertrophic Cardiomyopathy Patients) clinical trial has completed without significant safety concerns. The PIONEER-HCM, the EXPLORER-HCM and the MAVERIK-HF trials, will evaluate the effect in different phenotypes and larger cohorts.Mavacamten29. Exercise echocardiography should be considered in such patients to rule out provocable LVOT obstruction, mitral regurgitation or diastolic impairment with pulmonary hypertension20. The principle mechanism of symptoms in non-obstructive patients is diastolic dysfunction and much less commonly mitral regurgitation caused by intrinsic mitral valve abnormalities. It is important to perform a comprehensive study to determine the exact mechanisms of symptoms and define the best treatment strategy. Left atrial enlargement and pulmonary hypertension are usually related to the degree of diastolic impairment in HCM patients29. In the absence of concomitant obstructive haemodynamics, the addition of diuretics can help in some situations20. To date, several trials have tried to modify the disease course via blockade of the renin-angiotensin-aldosterone axis with little effect.Many patients can have severe symptoms in the absence of significant LV outflow tract obstruction30. Nonetheless, it is important to rule out significant epicardial coronary artery disease, particularly in older populations and patients with cardiovascular risk factors1, 2 using coronary angiography (either by CT coronary angiography or cardiac catheterization)20. In addition, cardiac catheterization can provide relevant information on coronary artery bridging and the anatomy of the septal arteries that can be useful in refractory patients who are candidates for alcohol septal ablation. Verapamil and diltiazem are the preferred drugs to treat chest pain, in the absence of systolic dysfunction, as they are thought to improve microvascular blood flow20. Nitrates can be used with caution in the absence of an LVOTO1.Angina in HCM is most commonly caused by obstruction and microvascular coronary abnormalities31. Perhexiline, a carnitine palmitoyltransferase (CPT)-1 inhibitor that improves myocardial performance by creating a switch from fatty acid to glucose metabolism32, has been shown to improve HCM symptoms by improving myocardial energetics, but safety issues regarding hepatitis and neuropathy has limited its widespread use33.A number of drugs that alter myocardial energy metabolism have been evaluated in HCM. The RESTYLE-HCM (ranolazine in patients with symptomatic hypertrophic cardiomyopathy) trial, failed to demonstrate benefit in exercise performance or quality of life despite showing a reduction in ventricular premature complexes34. Typical mechanisms include left ventricular outflow tract obstruction, abnormal vascular responses and arrhythmias34.Symptoms related to brief loss of consciousness may appear in one of every five HCM patients, but it is hard to identify the precise mechanisms in most of cases, in spite of a detailed comprehensive study35. AF is most commonly paroxysmal and the life-long prevalence is estimated to be around 30%36. The incidence increases in the presence of other concomitant risk factors like hypertension, dyslipidemia, diabetes mellitus or sleep apnoea35, 37. The development of AF is related to atrial electrical and structural remodeling, which in turn relates to the severity of ventricular hypertrophy and left atrial size38. AF in HCM is often accompanied by clinical deterioration and is related to adverse cardiovascular events35. The hemodynamic deterioration is presumed to be due to rapid ventricular rate and loss of atrial contribution, causing inadequate filling and exacerbating LVOT obstruction. The implementation of early and aggressive rhythm control strategies using antiarrhythmic drugs and in selected cases radiofrequency AF ablation is essential39. Long-term anticoagulation is recommended for all patients with HCM patients who present with AF, irrespective of predictive risk scores such as CHA2DS2-VASc score35, 40. Vitamin-K antagonists are considered the first choice in this setting35, although direct anticoagulants are suitable alternatives for thromboembolic prevention, and might be preferred in selected individuals41.The incidence of atrial fibrillation (AF) is estimated to be around 3% in HCM, and is considered the most common sustained arrhythmia in HCM42, 43. The intrinsic mechanisms involved in the development of arrhythmias include hypertrophy, ischemia, fibrosis, myocyte disarray and electric uncoupling43, 44. Certain mutations may be associated with SCD43, and consequently, genotyping may be considered as part of the risk stratification in some specific cases43.Non-sustained ventricular tachycardia occurs in almost one third of patients during the follow-up and is considered a major risk factor for adverse events, particularly sudden cardiac death (SCD)44. ICDs should be considered in all patients with symptomatic VT20, 45.Antiarrhythmic drugs have no role in the primary prevention of SCD but are useful in the rare patient with symptomatic ventricular tachycardia. Catheter ablation for VT is also feasible in drug-refractory patients, although the best results are achieved by using a combined endo and epicardial approach46, 47  of the mitral valve 20. The m48. Although some of these less typical phenotypes have been related to mutations in the thin-filaments, casual mutations may involve any the sarcomere genes6.Hypertrophy may involve any location of the ventricular wall54, but is particularly important as a cause of symptoms55. Mid-cavity obstruction may correlate with end-stage disease progression and development of an apical aneurysm. Stroke from thrombus formation and ventricular arrhythmias can occur in these patients, and the phenotype may be associated with cardiovascular death20. (Mid-ventricular hypertrophy in conjunction with abnormal distribution of the papillary muscles and hypercontractility of the lateral ventricular wall generating a mid-cavity obstructive gradient occurs in less than 10 % of casesdeath20. 56. It is often overlooked because of poor apical visualization on standard echocardiographt and may require echo contrast agents or CMR for identification48. Patients with apical hypertrophy have been considered to have a benevolent course, but the evidence is contradictory57. Indeed diastolic impairment, left atrial enlargement and impaired excercise capacity, might be frequent on apical forms58, 59. (The apical hypertrophic phenotype is associated with deep negative T waves in precordial leads, and the “ace of spades” appearance on ventriculographys58, 59. 60. Minor abnormalities seen in relatives include low end-systolic volumes, mild contractile and diastolic alterations, increased myocardial trabeculation, limited late gadolinium enhancement and an increase in the extracellular volume fraction20.Next generation sequencing and family screening have resulted in the identification of a large number of relatives with mild or subclinical disease. Electrocardiographic markers and minor echocardiographic changes may be helpful in diagnosing such individuals when they are relatives of clearly affected HCM patients61. Current recommendations are to perform screening at yearly intervals in children and adolescents until their mid twenties and at 3–5 year intervals in older individuals20.In a recent study, 30% of evaluated relatives were identified as having HCM at first screening. Moreover, 16% developed HCM during 7 years of repeated evaluation. Therefore, genotype positive patients need prolonged surveillance although adverse events were extremely infrequent in relatives without a clinically evident phenotype in the presence of a positive genotype62. End-stage HCM with LV dilation and systolic dysfunction is the most common clinical profile of patients undergoing heart transplantation63. In these advanced stages of the disease, patients usually present with mixed phenotypes displaying different degrees of remodelling, restrictive filling patterns and systolic dysfunction20. Furthermore, left ventricular trabeculae and non-compaction is not rare, further complicating the clinical diagnosis (62. Many factors have been proposed to account for end-stage disease including gene mutation, environmental and epigenetic factors20.Progressive systolic dysfunction, often accompanied by ventricular dilatation and left ventricular wall thinning occurs in 2.5% to 15% of patientsiagnosis  and 6. Riagnosis . Severe 64. Patients should be referred early for ICD implantation for SCD prevention because the rate of ventricular arrhythmias has been shown to be consistently higher in this population62. Cardiac resynchronization therapy has not consistently shown to improve left ventricular systolic function or survival in these patients65. Long-term mechanical circulatory support in selected cases with refractory heart failure as a bridge to transplant strategy is feasible1. In this regard, the use of continuous flow devices might be restricted to severely dilated ventricles to allow satisfactory support and avoid device complications.Treatment of HCM patients who develop LV systolic dysfunction should be according to the standard heart failure guidelines with a few provisosFinally, patients with cardiomyopathies tend to be younger than common HF patients, and are able to tolerate advanced stages of the disease with apparent good exercise performance. Accordingly, it is important to routinely refer these patients to experienced centres, in order to perform a comprehensive heart failure risk stratification.In the last 50 years, the knowledge of HCM pathophysiological features and its clinical perspective has increased enormously. It is possible to make an aetiological diagnosis in more than two-thirds of patients, with implications for clinical management, familial screening and preclinical investigation. Early disease detection facilitates early implementation of treatment strategies to prevent disease complications.


The association of a Classical left bundle branch block (LBBB) contraction pattern and better outcome after cardiac resynchronization therapy (CRT) has only been studied using vendor-specific software for echocardiographic speckle-tracked longitudinal strain analysis. The purpose of this study was to assess whether a Classical LBBB contraction pattern on longitudinal strain analysis using vendor-independent software is associated with clinical outcome in CRT recipients with LBBB.This was a retrospective cohort study including CRT recipients with LBBB, heart failure, and left ventricular (LV) ejection fraction ≤35%. Speckle-tracked echocardiographic longitudinal strain analysis was performed retrospectively on echocardiograms using vendor-independent software. The presence of a Classical LBBB contraction pattern was determined by consensus of two readers. The primary end point was a composite of time to death, heart transplantation or LV assist device implantation. Secondary outcome was ≥15% reduction in LV end-systolic volume. Intra- and inter-reader agreement of the longitudinal strain contraction pattern was assessed by calculating Cohen’s κ.p < 0.001) when comparing patients without to patients with a Classical LBBB contraction pattern. Adjusted for ischemic heart disease and QRS duration < 150 milliseconds the hazard ratio was 1.65 . Of the 123 (43%) patients with a follow-up echocardiogram, 64 of 85 (75%) of patients with a Classical LBBB contraction pattern compared to 13 of 38 (34%) without, had ≥15% reduction in LV end-systolic volume (p < 0.001). Cohen’s κ were 0.86  and 0.42  for intra- and inter-reader agreement, respectively.Of 283 included patients, 113 (40%) were women, mean age was 66 ± 11 years, and 136 (48%) had ischemic heart disease. A Classical LBBB contraction pattern was present in 196 (69%). The unadjusted hazard ratio for reaching the primary end point was 1.93 (95% confidence interval, 1.36–2.76, Using vendor-independent strain software, a Classical LBBB contraction pattern is associated with better outcome in CRT recipients with LBBB, but inter-reader agreement for the classification of contraction pattern is only moderate. Cardiac resynchronization therapy (CRT) is an effective treatment for patients with heart failure with reduced ejection fraction and left bundle branch block (LBBB). , 2 UnforThe aim of this study was to assess whether the presence of a Classical LBBB contraction pattern on speckle-tracked longitudinal strain analysis using vendor-independent strain software was associated with better survival and echocardiographic response in CRT recipients with LBBB.This was a retrospective cohort study performed at Duke University Hospital, a high-volume tertiary medical center.All patients who received a CRT with defibrillator from April 2006 to September 2015 were identified using an institutional dataset prepared for the National Cardiovascular Data Registry. Patients were eligible for inclusion if they had symptomatic heart failure with LV ejection fraction ≤35%, an adequate baseline echocardiogram within 365 days and an available electrocardiogram (ECG) within 180 days before CRT implantation, QRS duration ≥120 milliseconds, and LBBB morphology. Patients were excluded if they had a prior CRT device, failed LV lead implantation, 2nd or 3rd degree atrioventricular block at baseline, or cardiac surgery or percutaneous coronary intervention between the baseline echocardiogram and CRT implantation. A subset of patients with a follow-up echocardiogram  performed within 60–365 days after CRT implantation were included in secondary analyses.Clinical data were obtained from the institutional dataset and through chart review. Patients were categorized as having a history of atrial fibrillation if they had a previous diagnosis of atrial fibrillation or they had atrial fibrillation on the baseline 12-lead ECG. Two authors (D.F. and K.E.), who were blinded to outcomes, reviewed all baseline ECGs and designated QRS morphologies. LBBB morphology was further classified as either strict or non-strict LBBB. The most recent echocardiogram prior to CRT implantation was analyzed. Measurements of LV end-diastolic and -systolic volumes and two-dimensional speckle-tracked longitudinal strain analyses were performed in the vendor-independent software system ImageArena version 4.6  using apical 2-, 3-, and 4-chamber views stored in DICOM format. LV volumes were calculated using a modified Simpson’s triplane method included in the software. The apical 4-chamber view and at least one of the two other views were required for analysis.For the analysis of longitudinal strain contraction pattern, QRS onset was set as the starting point when possible; when QRS onset was not available in the beginning of the loop, the earliest point available in the cardiac cycle was used. Endocardial borders were traced manually at end-systole, and tracking was assessed visually. If the tracking was considered inadequate, retracing was performed until tracking was deemed correct. The software itself did not provide any information about its assessment of tracking quality.Risum et al. [Longitudinal strain contraction patterns were classified as a “Classical LBBB contraction pattern” when the septal peak shortening occurred within the initial 70% of the ejection phase, and the lateral wall was initially stretched and had peak shortening after aortic valve closure Fig.  as descrm et al.  Time froThe primary end point was time from CRT implantation to the first event of either death of all causes, heart transplantation or LV assist device implantation. End points were assessed on May 24, 2017 through a query of Duke Enterprise Data Unified Content Explorer (DEDUCE) by incorporating data from hospital billing claims, hospital records, and the United States Social Security Death Index. Secondary analyses on the subgroup of patients with an eligible follow-up echocardiogram included echocardiographic response defined as a reduction in LV end-systolic volume ≥ 15%, along with relative changes in LV end-diastolic and end-systolic volumes and absolute changes in LV ejection fraction and global longitudinal strain from the baseline to the follow-up echocardiogram.t test. Non-normally distributed continuous variables are presented as median (25th–75th percentile) and differences were tested using the Wilcoxon rank-sum test. Categorical variables are presented as n (%) and differences were tested using Fisher’s exact test.Normally distributed continuous variables are presented as mean ± standard deviation and differences were tested using the Student Survival free from heart transplantation or LV assist device implantation are presented using Kaplan-Meier curves and differences were tested using the log-rank test. Cox proportional hazards regression was used to estimate hazard ratios in uni- and multivariable analysis of the primary end point. The primary multivariable model included the prespecified covariates QRS duration < 150 milliseconds and ischemic heart disease in accordance with previous literature.  A secondSensitivity and specificity of a Classical LBBB contraction pattern for echocardiographic response were calculated for the secondary analyses. Intra-reader agreement on longitudinal strain contraction pattern was assessed for one reader (K.E.) by reanalysis of 50 randomly selected patients at least 90 days after the initial read. Inter-reader agreement was assessed using all included patients. For intra- and inter-reader variability and agreement between vendor-independent and vendor-specific software, overall agreement and Cohen’s κ was calculated.Sensitivity analyses excluding patients without sinus rhythm on the baseline echocardiogram and excluding patients < 25 frames per cardiac cycle were performed.p-value < 0.05 was considered statistically significant.All statistical analyses were performed in RStudio version 1.1.453  running R version 3.5.0 . The R package “survival” was used for Cox proportional hazards models and to create Kaplan-Meier curves.  A two-si). The mean age of included patients was 66 ± 11 years, 113 (40%) were women and 136 (48%) had ischemic heart disease. All but 10 (4%) patients had all three apical views available; 9 (3%) were missing the apical 3-chamber view, while 1 (< 1%) was missing the apical 2-chamber view. The median frame rate on analyzed images was 30 frames/second (30–46 frames/second) and the median number of frames per cardiac cycle was 27 (24–37).A total of 1001 patients received a CRT device at Duke University Hospital during the period April 2006–September 2015, and 302 of the 1001 met the inclusion criteria. Of these, 283 did not meet any exclusion criteria and were thus included in the study cohort  were classified as having a Classical LBBB contraction pattern. Patients without a classical LBBB contraction pattern were more likely to be male, have ischemic heart disease, have diabetes mellitus, had shorter QRS duration and higher creatinine level . In patients without a Classical LBBB contraction pattern, 51 of 87 (59%) reached the end point compared to 80 of 196 (41%) of patients with a Classical LBBB contraction pattern  for patients without compared to patients with a Classical LBBB contraction pattern. Adjusted for ischemic heart disease and QRS duration < 150 milliseconds, the hazard ratio was 1.65 . Additional adjustment for age, gender, history of atrial fibrillation, New York Heart Association functional class, creatinine > 1.2 mg/dL, end-systolic global longitudinal strain and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use yielded a hazard ratio of 1.54 .A total of 131 (46%) patients reached the composite end point over a median follow-up of 2.8 years (1.8–5.3 years), with death being the most common cause for reaching the end point  yielded an adjusted hazard ratio of 1.80 . Excluding patients with < 25 frames per cardiac cycle  resulted in an adjusted hazard ratio of 1.87 . Excluding both patients without sinus rhythm and with < 25 frames per cardiac cycle on the baseline echocardiogram yielded an adjusted hazard ratio of 1.91 .Sensitivity analysis excluding patients without sinus rhythm on the baseline echocardiogram (p = 0.55). Relative reductions in LV end-diastolic and -systolic volumes, and improvements in LV ejection fraction and end-systolic global longitudinal strain were larger in patients with than in patients without a Classical LBBB contraction pattern (Table p < 0.001). Sensitivity and specificity of a Classical LBBB contraction pattern to predict echocardiographic response were 83 and 54%, respectively.A follow-up echocardiogram between 60 and 365 days after CRT implantation was available for 123 (43%) of the patients. Median time from CRT implantation to the follow up echocardiogram was 182 days (122–250 days) in patients with a Classical LBBB contraction pattern and 164 days (101–245 days) in patients without .In the randomly selected 50 patients, the intra-reader agreement was 94%, with a Cohen’s κ of 0.86 . The inter-reader agreement for the entire cohort was 75% with a Cohen’s κ of 0.42 . Thirty-three (12%) patients had an echocardiogram available for analysis of longitudinal strain contraction pattern by vendor-specific software. Of these, 24 (73%) had a Classical LBBB contraction pattern both by vendor-independent and vendor-specific strain analysis. Overall agreement between vendor-independent and vendor-specific software was 88%, with a Cohen’s κ of 0.69 .Using vendor-independent software analysis of standard echocardiographic images, it was found that the presence of a Classical LBBB contraction pattern was associated with better long-term outcome and echocardiographic response after CRT. Furthermore, intra-reader agreement was very good, whereas inter-reader agreement was only moderate. In this study, the association between a Classical LBBB contraction pattern and outcome after CRT was not as strong as in prior studies using vendor-specific software. , 6 FurthA recent study found that at least 25–30 frames per cardiac cycle is necessary for accurate measurement of peak global longitudinal strain.  It wouldThe spatial compression of DICOM images means that fewer data points are available for the software, decreasing the ability to discriminate and increasing the susceptibility to noise. The combination of blunted strain curves and a higher susceptibility to noise can produce contraction patterns that are difficult to interpret and may explain the lower inter-reader agreement in this study compared to studies using vendor-specific software. , 6Evidence suggests that a substantial proportion of CRT recipients do not improve their clinical or echocardiographic status. , 4 The rIt is recognized that differences between the software used for speckle-tracked strain, is a major limitation of the clinical use of strain analyses, and therefore a task force was made in a cooperation between the European Association of Cardiovascular Imaging, American Society of Echocardiography, and industry representatives with the mission of standardizing speckle-tracked deformation analysis.  So far, This was a retrospective cohort study with no control group of patients that did not receive CRT. Thus, it is not possible to assess the effect of CRT in patients with or without a Classical LBBB contraction pattern. Furthermore, the retrospective design limited the study to include only patients who had a baseline echocardiogram performed at Duke University Hospital. Selection bias in this subgroup of CRT recipients is very probable, however it is unlikely to affect the associations between contraction pattern and outcome after CRT. In addition, echocardiographic follow-up data were only available for those who had an echocardiogram ordered for clinical reasons, and the time from CRT implantation to the follow-up echocardiogram was therefore inconsistent. This means that echocardiographic response rate and magnitudes of volume reductions may not be generalizable. Furthermore, the analyses were performed retrospectively on the available echocardiographic images, which were not always optimized for speckle-tracked strain analysis, and it is not possible to determine if the modest performance of vendor-independent strain software analysis is due to image compression, image acquisition, or the software itself. Finally, a comparison between the performance of vendor-independent and vendor-specific software regarding the Classical LBBB contraction pattern and its association with CRT outcome was not possible, due to the limited number of patients with a baseline echocardiogram allowing for strain analysis using vendor-specific software.A classical LBBB contraction pattern derived from two-dimensional speckle-tracked longitudinal strain by vendor-independent software is associated with improved survival free from heart transplantation and LV assist device implantation and with higher probability of echocardiographic response. However, inter-reader agreement was only moderate, which diminishes the clinical utility of vendor-independent software for decision making in potential CRT candidates.


In the multiple regression analysis adjusted by age, sex, body mass index, and eGFR, whole blood thiamine concentration was a significant negative contributor  to plasma brain natriuretic peptide. In the logistic regression analysis adjusted by the same variables, whole blood thiamine concentration significantly contributed to plasma brain natriuretic peptide concentration higher than over 40 pg/ml . Whole blood thiamine concentration in subjects with diuretics was significantly lower than those without it (p = 0.023). Thiamine insufficiency was related to increased plasma brain natriuretic peptide concentration and may increase the risk of heart failure.Heart failure is a major manifestation of thiamine deficiency; beriberi. Even thiamine insufficiency, milder than deficiency, may be associated with increased heart failure risk. In this cross-sectional study, the relationship between thiamine insufficiency and heart failure was investigated in the Japanese institutionalized elderly from April to November 2017. Fifty-five subjects in four care facilities were evaluated for their whole blood thiamine and plasma brain natriuretic peptide concentrations. Mean whole blood thiamine concentration was 88.7 ± 22.3 nmol/L in men and 92.0 ± 16.5 nmol/L in women, and significantly and negatively correlated with plasma brain natriuretic peptide concentrations (r = −0.378,  Previously, beriberi was quite prevalent in Japan, and its severe form was lethal. Since thiamine is an essential cofactor in energy metabolism, it is quite natural that thiamine deficiency causes impaired myocardial function and heart failure. With the discovery of thiamine as well as the nutritional improvement of the society, the number of beriberi patients has dramatically decreased. Today, it seems to be generally considered that beriberi is a historical disorder and thiamine deficiency is no longer a serious health problem in Japan.Thiamine deficiency causes beriberi, which consists of neurologic manifestation (dry beriberi) and cardiovascular manifestation (wet beriberi).Vitamin deficiency causes classical deficiency diseases with typical phenotypic changes such as beriberi due to thiamine deficiency. In contrast, vitamin insufficiency, which is milder than vitamin deficiency, does not cause classical deficiency disease, but is associated with increased disease risk. For example, vitamin D deficiency causes rickets and vitamin D insufficiency is a serious risk factor for osteoporotic fracture.–9 Since thiamine does not have specific binding proteins, it is easily filtered in glomeruli and excreted in the urine, and the use of diuretics further leads to excessive loss of thiamine. Moreover, bodily storage of thiamine is quite limited. Then, a vicious circle is likely to occur, in which diuretics use causes thiamine deficiency and thiamine deficiency in turn impairs cardiac energy metabolism and further worsens heart failure.Compared to studies on the increased fracture risk by vitamin D insufficiency, reports have been scarce on the significance of thiamine insufficiency. Recently, however, papers from abroad have been published concerning the relationship between thiamine and diuretic therapy in patients with heart failure. Then, identifying modifiable risk factors for elderly heart failure would be of great clinical and societal significance. Based on the above considerations, we have made a hypothesis that thiamine insufficiency is prevalent in the elderly and it is a risk factor for heart failure. As far as we have searched, there have been no reports investigating thiamine insufficiency in heart failure patients in Japan. Then, in this paper, we have studied the thiamine status and its possible association with heart failure in the institutionalized elderly, since they were considered to be at high risk for heart failure.Japan has been becoming a super-aging society over the last few decades, and the number of patients with heart failure has been increasing rapidly.This is a cross-sectional study conducted from April 2017 to November 2017. The participants were fifty-five residents and users in four care facilities. Written consent to participate in this study was obtained from each subject after explanation of the objective and protocol of this study. The study protocol was approved by the Ethical Committee of Kyoto Women’s University , and the study was done complying with the Declaration of Helsinki. 146.3 nmol/L. A total of 51  subjects were included in this analysis.Participants who were under oral thiamine administration were excluded. To exclude subjects with undeclared use of thiamine supplementation, we have also excluded subjects with their whole blood thiamine concentration above the third tertile + 1.5 × interquartile range; Plasma brain natriuretic peptide (BNP) concentration was measured by chemiluminescent enzyme immunoassay (CLEIA). These measurements were done in Special Reference Laboratories . BNP is a cardiac hormone which is produced by ventricular myocardium in response to cardiomyocyte stretch. Its high levels reflect atrial/ventricular volume and pressure overload. Therefore, BNP is used as a biomarker for heart failure. Serum albumin concentration was measured by dye-binding (BCG) methods and serum total cholesterol concentration was measured by enzymatic (cholesterol oxidase) methods. Estimated glomerular filtration rate  was calculated as 194 × creatinine−1.094 × age−0.287 for men and 194 × creatinine−1.094 × age−0.287 × 0.739 for women.Non-fasting blood was obtained. Serum, plasma or whole blood was stored at −70°C until measurement. Whole blood thiamine concentration was measured by liquid chromatography tandem mass spectrometry (LC/MS/MS), using UHPLC System (Shimadzu) with MS detector LCMS-8040. Inter-assay and intra-assay variation were 0.62 to 3.99% and 1.46 to 3.36%, respectively.t test or Mann Whitney’s U test. The variables were analyzed using multiple regression analysis to assess the contribution of whole blood thiamine concentration for plasma BNP concentration. The association of whole blood thiamine concentration with the outcome; plasma BNP concentration over 40 pg/ml was examined by logistic regression analysis. For correlation analysis and multiple regression analysis, natural-log-transformed plasma BNP concentration was employed due to its skewed distribution. The significance level of the associations was set at p<0.05.Statistical analyses were done using SPSS ver. 22 . Pearson’s correlation was used to examine the relationship between whole blood thiamine concentration and plasma BNP concentration. The difference between two independent groups was analyzed by Student’s 2. Although it is slightly lower than the reference value of 60 ml/min/1.73 m2, it was considered to reflect the age-related decline of renal function.,19 There was no significant gender difference in whole blood thiamine concentration. The number of subjects with diuretics use was 10 , and it included both single use and multiple use. It consisted of loop diuretics (n = 5), angiotensin II receptor blocker with diuretics (n = 8), potassium holding diuretics (n = 3), and thiazide (n = 1).Fifty one individuals were included in this analysis , and their characteristics are shown in Table p = 0.007).Whole blood thiamine concentration has the significant negative correlation with plasma BNP concentration   and eGFR to adjust this analysis. Whole blood thiamine concentration was a significant negative contributor  Table .We have examined whether whole blood thiamine concentration contributes to heart failure. Plasma BNP concentration higher than 40 pg/ml was used as an indicator for suspected mild heart failure. The adjustment was made with age, sex, BMI, and eGFR. There were 27 subjects with plasma BNP concentration higher than 40 pg/ml. Whole blood thiamine concentration significantly increased the risk of heart failure  (Table p = 0.023) (Table When whole blood thiamine concentration in subjects with using diuretics was significantly lower than those without it (3) Table . Elderly subjects have been reported to be prone to thiamine inadequacy. Considering that the average age of the current study subjects was 84.2, they were considered at least not to be thiamine deficient.In this paper, we have studied whether thiamine insufficiency is associated with heart failure in the institutionalized elderly. These subjects were selected since they were considered at high risk for heart failure. Since our primary research question was whether even thiamine insufficiency, which is milder than deficiency, increases the risk of heart failure, we first wanted to make sure that they were not severely thiamine deficient. In this study, the mean whole blood thiamine concentration was 88.7 ± 22.3 nmol/L in men and 92.0 ± 16.5 nmol/L in women. Although established reference range for whole blood thiamine is not available, whole blood thiamine concentration in healthy Japanese college students was 104 ± 17 pmol/ml in men and 90 ± 23 pmol/ml in women.In our analysis, whole blood thiamine concentration contributed significantly and negatively to plasma BNP concentration in the multiple regression analysis, and it was a significant contributor to the plasma BNP concentration higher than 40 pg/ml in the logistic regression analysis. Of note, whole blood thiamine concentration in those with their plasma BNP concentration higher than 40 pg/ml was 84.3 ± 14.9 nmol/L, which is at least not severely decreased. Thus, thiamine insufficiency was considered to be associated with increased plasma BNP concentration and increased risk of heart failure. Regarding the relationship between thiamine and diuretics in patients with heart failure, inconsistent results have been reported. According to a previous study, furosemide, which is a loop diuretic, causes increased urinary loss of thiamine. On the contrary, a cross-sectional study showed that there was no difference in the thiamine level between patients on loop diuretics and controls. Such discrepancy is probably due to the difference in the dosage and characteristics of subjects, and further studies are needed.Next, the possible involvement of diuretics use for the occurrence of thiamine insufficiency was considered. Whole blood thiamine concentration in subjects using diuretics was significantly lower than those without it. Thus, a vicious circle described below was considered likely to occur. Namely, thiamine deficiency/insufficiency leads to heart failure and patients with heart failure are usually prescribed diuretics. Since thiamine is easily filtered in glomeruli and excreted in the urine, when the volume of urine increases, loss of thiamine also increases and it causes deterioration of heart failure.,22–24 The prevalence of thiamine deficiency in congestive heart failure patients has been reported to range from 3% to 91%. Previous reports on the relationship between thiamine and heart failure have not been necessarily consistent. Many factors are likely to be responsible. In addition to the differences in measurement techniques, geographical differences in average daily dietary thiamine intake are also likely to be responsible.Although reports are limited to those from abroad, there have been intervention studies with thiamine in patients with heart failure. Previous reports including systematic review and metaanalysis have shown that thiamine supplementation significantly improved left ventricular ejection fraction (LVEF) which is a marker for the cardiac function.Thus, the possible association of thiamine nutritional status with heart failure must be studied in each country. In our literature search, we could not find papers from Japan on the possible involvement of thiamine insufficiency in the elderly heart failure even the observational ones. Then, we have carried out this cross-sectional study as a preliminary survey using plasma BNP concentration as a marker for heart failure. their measurement is quite difficult to perform. Finally, since this study was a cross-sectional study, causal relationship could not be concluded.Our study has several limitations. First, the fact that the study subjects were the institutionalized elderly has imposed some limitation. Nursing homes do not possess diagnostic equipment as available in hospitals, and we could not evaluate the subjects’ heart failure status using such sensitive indicators as LVEF, and we have employed plasma BNP concentration as the parameter of heart failure. Since most Japanese nursing homes are rather small-sized, number of subjects included in the current study remained only modest. Second, erythrocyte transketolase activity was not measured. Although this parameter has been reported to be sensitive markers for thiamine status, which is due to the rapid increase of the elderly heart failure reflecting the super-aging society. Thus, identifying modifiable risk factor for elderly heart failure is an urgent need. As written above, however, there seem to have been no previous reports on the possible role of thiamine insufficiency for the elderly heart failure. Therefore, our present paper, although a preliminary one, would shed light on the modifiable risk for elderly heart failure. We are planning additional studies such as a cross-sectional study for non-institutionalized patients with heart failure, and intervention one for the patients with heart failure.Nevertheless, our current data would be of clinical relevance. In recent decades, heart failure patients have increased rapidly in Japan, and it is expected to increase further in the future,In conclusion, we have shown that blood thiamine concentration is a significant contributor to elevated plasma BNP concentration, and suggested the possibility that thiamine insufficiency is related to the heart failure in the elderly. Beriberi is generally thought to be almost overcome in Japan, and little attention seems to be paid on the role of thiamine in health promotion. Our results, however, suggest that even thiamine insufficiency can be a risk for elderly heart failure, and the role of vitamins in disease prevention must be re-emphasized.MA was the principal investigator, and contributed to the conception and the design of the study with KT, MA, KY, JO, YA, NN, SI and ST were responsible for the evaluation the subjects’ general condition and nutritional status. MA, AK, TM and KT were responsible for statistical analyses. All authors have critically reviewed the final version of the manuscript and approved it.


Mineralocorticoid receptor antagonist (MRA) therapy has been shown to prevent adverse left ventricular (LV) remodeling in ST-segment elevation myocardial infarction (STEMI) patients with heart failure. Whether initiating MRA therapy prior to primary percutaneous coronary intervention (PPCI) accrues additional benefit of reducing myocardial infarct size and preventing adverse LV remodeling is not known. We aimed to investigate whether MRA therapy initiated prior to reperfusion reduces myocardial infarct (MI) size and prevents adverse LV remodeling in STEMI patients.STEMI patients presenting within 12 hours and with a proximal coronary artery occlusion with Thrombolysis In Myocardial Infarction flow grade 0 were consented and randomized to either an intravenous bolus of potassium canrenoate, followed by oral spironolactone for 3 months or matching placebo. The primary endpoint was MI size by cardiovascular magnetic resonance at 3 months.P = .574). There was also no difference in acute MI size  or myocardial salvage . At follow-up, there was a trend towards an improvement in LVEF , and the MRA group had significantly greater percentage decrease in LVEDV (mean difference: −12.2 (95% CI −20.3 to −4.4)%, P = .003) and LVESV (mean difference: −18.2 (95% CI −30.1 to −6.3)%, P = .003).Sixty-seven patients completed the study. There was no significant difference in the final MI size at 3 months between the 2 groups (placebo: 17 ± 11%, MRA: 16 ± 10%, This pilot study showed no benefit of MRA therapy in reducing MI size in STEMI patients when initiated prior to reperfusion, but there was an improvement in LV remodeling at 3 months. Adequately powered studies are warranted to confirm these findings. Mortality in patients with acute ST-segment elevation myocardial infarction (STEMI) has declined over the past 4 decadesin vivo models of MI have demonstrated that administering either intravenous potassium canrenoate (a compatible metabolite of spironolactone) or eplerenone after a sustained episode of myocardial ischemia and 5 minutes prior to reperfusion, protected the heart against myocardial reperfusion injury and reduced MI size by 40–50%.Pre-clinical data in murine, rat and rabbit Therefore, the MINIMIZE STEMI trialhttps://clinicaltrials.gov, NCT01882179) was a prospective, proof-of-concept, multi-center, double-blinded randomized placebo controlled clinical trial.The MINIMIZE-STEMI trial  imaging were excluded.In brief, the main inclusion criteria were patients >18 years, with an acute STEMI  in 2 or more contiguous precordial leads or ≥1 mm (0.1 mm) in 2 or more adjacent limb leads), presenting within 12 hours of symptoms onset. The angiography inclusion criteria were TIMI 0 in a proximal left anterior descending, circumflex or right coronary artery territory STEMI and the initial serum potassium of <5.0 mmol/l. Patients with known previous MI, heart failure or LVEF ≤40%, in cardiogenic shock, estimated glomerular filtration rate <30 mL/min per 1.73 mwww.SealedEnvelope.com) in a 1:1 manner to either MRA therapy or matching placebo. Randomization was stratified by recruiting site. The study drug or placebo was administered by the unblinded research investigator. The patient, PPCI operator, and research staff collecting the data were blinded to the treatment allocation.On immediate arrival at the primary percutaneous coronary intervention (PPCI) center, eligible patients were consented to enter the MINIMIZE STEMI trial. Patients were randomized via a web-based service (Patients randomized to MRA therapy received an intravenous bolus of 200 mg (10 ml) of potassium canrenoatePatients randomized to placebo received a 10 ml intravenous bolus of normal saline followed by placebo tablets for the 3 months.Patients with an LVEF ≤40% on the initial CMR scan and evidence of heart failure or who were diabetic were started on open-label eplerenone according to current practice guidelines. These patients were included in the intention-to-treat analysis. A CMR was performed within the first week following PPCI and was repeated 3 months later. A pre-specified interim analysis was planned on safety grounds.The primary endpoint was MI size by CMR at 3 months. Pre-specified secondary endpoints included acute MI size by CMR, extent and incidence of microvascular obstruction (MVO) on CMR, myocardial salvage and indices of LV remodeling (end-diastolic volume (LVEDV), end-systolic volume (LVESV) and LVEF.In addition to the above analysis of pre-specified outcomes, two post-hoc outcomes were examined: percentage change in LVEDV and percentage change in LVESV. These were defined using the equation below:The CMR protocol has been previously described.All imaging analysis was performed using CVI42 software . The endocardial and epicardial borders were manually delineated on all the cine, T2 and LGE short-axis LV images. LVEF, LV volumes and LV mass were quantified using the summation of discs method.Myocardial salvage was calculated as area-at-risk by T2 on the first CMR minus the MI size at 3 months and was expressed as a percentage of the LV.The study was originally powered for a sample size of 50 in each group, to give 80% power to detect a difference in means of 8.0 g infarct mass by CMR assuming that the common standard deviation was 14.0 g.All analysis was performed using Stata version 15.0 . MI size was compared between the 2 groups using linear regression with the MI size as the response variable and the treatment group included as a binary covariate in the model. The distribution of both acute and follow-up MI size in grams showed marked positive skew, but this distribution was normalized by expressing MI size as percentage of the LV and the latter was used for analysis. The extent of MVO was compared between groups using linear regression. Due to non-normal distribution of the outcome, we used non-parametric bias-corrected and accelerated bootstrapped 95% confidence intervals based on 2000 replications stratified by treatment group. Myocardial salvage was expressed as a percentage of LV and compared using linear regression. Linear regression was also used to compare the groups on LVEDV, LVESV, LVEF, and LV mass at 3 months. Analysis of LV mass used robust standard errors to allow for heteroscedasticity in this measure.Due to observed baseline imbalances between the groups in participants with clinical data available, we conducted a post-hoc secondary adjusted analysis of the primary and secondary endpoints. This analysis adjusted for age, history of dyslipidemia, infarct-related artery, and duration of ischemia by including these as predictors in the linear regression model along with treatment group.Nine hundred ninety-five patients were screened from the 4 centers over the 2-year period. Among the 70 patients with clinical data available, there were some imbalances in the baseline characteristics between the MRA group and placebo group. Those in the MRA group were more likely to have higher blood pressure and higher heart rate on admission, and were more likely to be smokers . Those iOne patient in the MRA group died during the follow-up period and 2 patients from the same group had mild and transient episodes of hyperkalemia.Three patients in the MRA group and 1 patient in the placebo group were discharged on open-label MRA therapy (eplerenone) as per current guidelines.P = .574, P = .425, P = .456) between the 2 groups.There was no significant difference in the primary endpoint of MI size at 3 months between the 2 groups  and also significant evidence for more favorable change in LVEDV (mean difference: −12.2 (95% CI −20.3 to −4.4)%, P = .003) (P = .283). There was a trend towards an improvement in LVEF at follow-up but this did not reach statistical significance .The other CMR parameters between the 2 groups are provided in  = .003) c and d. P = .288). There was also no difference in acute MI size  or myocardial salvage  between the 2 groups. However, the MRA group had significantly higher LVEF at follow-up when compared to the placebo group  and significantly greater percentage decrease in LVESV and LVEDV (P < .001 for both).There was no significant difference in the primary endpoint of MI size at 3 months between the 2 groups . There was also no evidence of a difference between the placebo group and MRA group for MVO, myocardial salvage, acute MI size and pre-specified measures of LV remodeling  or eplerenone have been shown to protect the heart against myocardial reperfusion injury and to reduce MI size significantly in rats, mice and rabbits.MRA therapy has already been shown to prevent adverse LV remodeling following acute MI as summarized in a previous meta-analysis,14.On the other hand, in a randomized study of 100 patients with acute MI and LVEF<40%, Weir et al.NCT03048825) study  has been designed to address this and is currently recruiting patients.The results from the pooled studiesThe inclusion criteria were strict but the study was designed to identify those patients most likely to benefit from cardioprotection .This pilot study showed no benefit of intravenous MRA administered prior to reperfusion combined with 3 months of oral MRA therapy on reducing MI size in STEMI patients but there was an improvement in LV remodeling. Our pilot data might help to design further studies that are adequately powered to assess whether MRA therapy in STEMI patients without heart failure could reduce reperfusion injury and translate to an improvement in clinical outcomes.