Flecainide is an IC antiarrhythmic drug (AAD) that received in 1984 Food and Drug Administration approval for the treatment of sustained ventricular tachycardia (VT) and subsequently for rhythm control of atrial fibrillation (AF). Currently, flecainide is mainly employed for sinus rhythm maintenance in AF and the treatment of idiopathic ventricular arrhythmias (IVA) in absence of ischaemic and structural heart disease on the basis of CAST data. Recent studies enrolling patients with different structural heart diseases demonstrated good effectiveness and safety profile of flecainide. The purpose of this review is to assess current evidence for appropriate and safe use of flecainide, 30 years after CAST data, in the light of new diagnostic and therapeutic tools in the field of ischaemic and non-ischaemic heart disease. Flecainide is a class IC antiarrhythmic drug (AAD) that was first synthesized in 1972. It was approved by Food and Drug Administration in 1984 for the treatment of symptomatic sustained Ventricular Tachycardia (VT), with a 90% efficacy and without significant adverse events ,4. The CThe CAST study provided a major revision of the role of flecainide, which is therefore recommended in selected patients with preserved systolic function and without ischaemic heart disease . OtherwiThus, the CAST significantly affected and restricted the current use of flecainide in clinical practice causing a fall in employment of class IC AADs in favor of class III AADs ,8 and exIt is important to underline the paucity of available regarding patients with subcritical coronary artery disease (CAD) without previous MI or inducible ischemia with preserved systolic function and in patients with non-ischaemic structural heart disease. On the other side, recent studies demonstrated safety and efficacy of flecainide in patients with extrasystole-induced cardiomyopathy or Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) and no Left Ventricular (LV) dysfunction ,12,13,14VT is commonly seen in medical practice, not rarely in its most feared consequence, Sudden Cardiac Death (SCD). The American Heart Association (AHA) reports over 550,000 annual cardiac arrests, representing half of all cardiovascular deaths .Most patients with sustained VT have underlying structural heart disease such as prior MI, dilated non-ischaemic cardiomyopathy, cardiac sarcoidosis and ARVC . The oveVT can also arise in otherwise normal hearts, Idiopathic Ventricular Arrhythmias (IVA); idiopathic PVCs are the most common arrhythmia in patients with normal heart: approximately 40% of adults experience PVCs on 24-h Holter monitoring . IVAs maIdiopathic left VTs include verapamil-sensitive left fascicular VT (10%), Bundle Branch Reentry Tachycardia (BBRT) 6%) and rarely interfascicular VT and focal Purkinje VT % and rar.In a minority of patients VTs or PVCs may arise from the right or left ventricular papillary muscles (7%) and from the mitral or tricuspid annulus (10%) ,21.Overall, three mechanisms could be the cause of ventricular arrhythmias: abnormal automaticity, triggered activity and reentry ,23.Abnormal automaticity refers to spontaneous depolarization of cells without pacemaker function, as working atrial and ventricular myocardial cells, due to a decrease of membrane potential. Abnormal automaticity is the leading cause of accelerated idioventricular rhythm and it’s caused by ischaemia, electrolyte disturbances and drugs increasing adrenergic tone .The triggered activity results from early or delayed afterdepolarization in ventricular myocytes during phases 2 and 3 or phase 4 of the action potential. It occurs as a result of cyclic adenosine monophosphate dependent diastolic release of intracellular calcium; idiopathic RVOT tachycardia is an example of triggered activity ,26.Reentry is the most frequent mechanism causing serious ventricular arrhythmias and occurs when a PVC encounters a heterogeneously conductive substrate within the ventricular myocardium, consisting of two conduction pathways with a different conduction velocity and refractory period. Reentry is the postulated mechanism for VT occurring in a patient with an established scar from prior infarction . VT in nDuring IVAs haemodynamic impairment or serious symptoms are unusual, but patients can have palpitations, atypical chest pain or LV dysfunction. IVAs are distinguished by whether or not they originate from the outflow tracts and display specific electrocardiographic features .The RVOT is the most common site of origin of idiopathic outflow tract ventricular arrhythmias and is characterized on electrocardiogram (ECG) by a positive QRS complex in the inferior leads and a Left Bundle Branch Block (LBBB) morphology. The origins of RVOT and LVOT can be distinguished on the ECG by the precordial R-wave transition from a predominate S wave to a predominate R wave (rS to Rs). Transitions before V3 indicate an LVOT source and after V3 indicate an RVOT source ,30,31,32Among non-outflow tract IVAs, LV papillary muscles are a common site of origin. The postero-medial papillary muscle origin, which is the most common, is characterized by RBBB morphology with superior axis, while the antero-lateral papillary muscle origin is characterized by RBBB and inferior axis .In structurally normal hearts, fascicular VT is generally caused by reentry circuit ; ECG morBBRT is a macro reentrant tachycardia which uses the bundle branches as reentrant circuit pathways and is typically described in patients with bundle branch block. The most common morphology is the LBBB with a QRS ≥ 160 ms [+ channel Nav 1.5 in a rate and voltage-dependent manner [Flecainide binds to open-state of fast inward Nat manner . The mait manner . Moreove+ current and Kito channels [+ channels [In addition flecainide has an inhibitory action on the rapid component of the delayed rectifier Kchannels . Globallchannels . On the channels . In thischannels .Above mechanisms of action contribute to the efficacy of the drug in the treatment of ventricular arrhythmias, as seen in + current, causing a shortening of the QT interval. This form, indeed, is caused by mutations that increase the late Na+ current [+ and Ca2+ influx into myocardiocytes causing a negative inotropic effect and a reduction of cardiac output, particularly in patients with CAD or LV dysfunction [Flecainide is also effective in Long QT Syndrome (LQT) type 3 as it inhibits not only the peak but also the late component of the Na current . In addifunction .Flecainide, due to its pharmacodynamics, widens the PR (17–29%), QT interval (3–8%) and QRS complex (11–27%) ,45. In 3The gastrointestinal tract almost entirely absorbs flecainide, which has bioavailability of 85–90% and achieves peak concentration in approximately 1–3 h . FlecainControlled-release flecainide has a reduced and delayed maximum concentration (26 h) and less fluctuations in blood levels than the immediate-release form, allowing once-daily administration. The steady-state blood level is reached after 4–5 days and ranges from 0.27 to 0.33 mcg/mL, far from the blood level at risk of adverse reactions. Thus, the controlled-release form increases treatment compliance and lowers the risk of adverse events and interactions with other drugs while maintaining clinical efficacy .Current Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden death have been published in 2015 by the European Society of Cardiology (ESC)  and in 2Except for beta-blockers, these documents state that there is no evidence from randomized controlled trials that AADs for ventricular arrhythmias increase survival when used for primary or secondary prevention of SCD ,15. FurtFlecainide at immediate or controlled release is recommended for treatment of PVC and of VT in absence of structural heart disease and in some specific forms of genetic channelopathies, namely CPVT, LQTS type 3 and Andersen–Tawil Syndrome (LQTS type 7).In patients with IVAs, PVC/VT treatment is recommended only in symptomatic patients or in case of decline of LV function. Class IC AADs may be an alternative to radiofrequency catheter ablation in such patients when catheter ablation is too complex, not available, not desired or unsuccessful . CatheteIt is a rare congenital arrhythmogenic disorder triggered by physical or emotional stress. It mainly affects children and younger adults and is characterized by rapid polymorphic and bidirectional VT. Symptoms can range from palpitations and presyncope to syncope and SCD. CPVT is caused by the perturbations in Ca ion handling in the sarcoplasmic reticulum of cardiac myocytes . The twoLiterature showed that some sodium current blockers (mainly class IB mexiletine and class IC flecainide) inhibit the peak sodium current and the late component of the sodium current. Consequently, these drugs can lead to a shortening of the QT interval in patients with LQTS type 3 because this syndrome is caused by mutations that enhance the late sodium current.Clinical studies in SCN5A mutation carriers demonstrated that flecainide significantly shorten the QTc with no cardiac events during long-term follow up ,67. SodiAndersen-Tawil syndrome is a rare disorder characterized by a triad of ventricular arrhythmias, including bidirectional and polymorphic VT, dysmorphic features and periodic paralysis. QT prolongation due to abnormal U wave with T+U fusion is the key feature. About 60% are caused by mutations in the KCNJ2 gene. Preliminary studies demonstrated successful use of flecainide in ventricular arrhythmia control in this setting .In summary, immediate-release or controlled-release flecainide plays a key role in management of PVC and VT in structurally normal hearts with a class I indication and should be employed as first line therapy in these patients beside radiofrequency ablation. Choice between drug therapy and ablation is based on patient choice and procedure complexity and risks. Flecainide may be useful as add-on therapy in management of some rare channelopathies such as CPVT and some subtypes of LQTS.Current Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden death state that the choice of a specific drug should be based on the underlying type and severity of concurrent heart disease ,15. Spec+ channel blockade by class IC AADs, thereby favoring a late pro-arrhythmic effect, causing ventricular fibrillation, as well as promoting a negative inotropic effects related to reduced Na+ entry  and blocked intracellular interaction between Ca2+ and the RYR [The prohibition of flecainide in patients with ischaemic heart disease is based on the results of the CAST  which de the RYR . However the RYR . In CAST the RYR . In fact the RYR .As a result, patients with CAD, preserved ejection fraction, no previous MI and no evidence of inducible ischaemia represents a gray area where the absolute paucity of scientific evidence unjustifiably limits its widespread use. Indeed, there are no scientific data demonstrating an increased proarrhythmic risk of flecainide among patients with CAD in the absence of underlying scar and myocardial ischaemia. Conversely, the study by Pantlin et al. showed the safety of IC AADs in a population of AF patients with occult CAD on coronary flow capacity at positron emission tomography without history of clinically significant CAD . MoreoveThus, there is a compelling need to update the CAST data given the scientific progress in recent years in which an increasingly widespread use of modern therapeutic tools  made it possible to select a large population of patients with CAD without myocardial scar and residual ischaemia and for whom there is no scientific evidence against the use of flecainide.Current guidelines, despite the limited scientific evidence, prudently extended the results of the CAST study to non-ischaemic structural heart disease ,15. IndeHowever, several recent studies showed encouraging results regarding the employment of flecainide in patients with non-ischaemic structural heart disease. In this regard, a study by Hyman conducted in patients with extrasystole-induced cardiomyopathy in whom catheter ablation was unsuccessful demonstrated, over a mean follow-up of 4 years, the safety and efficacy of IC AADs to suppress PVCs with recovery of LV ejection fraction in the absence of sustained ventricular arrhythmias .ClinicalTrials.gov Identifier: NCT03685149).Furthermore, in patients with ARVC with implantable cardioverter defibrillator who were refractory to single-agent antiarrhythmic therapy and/or catheter ablation, Ermakov et al. demonstrated that the addition of flecainide with sotalol or metoprolol was effective in the management of recurrent ventricular arrhythmias over a mean follow-up period of 3 years . A randoIn addition, Chung, in a study involving patients with the widespread clinical condition of LV hypertrophy , highlighted that treatment with IC AADs did not increase mortality in AF patients in comparison with patients receiving amiodarone . MoreoveTherefore, it anachronistic to accept as dogma the contraindication to flecainide in patients with non-ischaemic structural heart disease, due either to the paucity of data in this regard and to the studies cited above, that showed an increasing evidence of efficacy and safety in the use of flecainide. Instead, it is more appropriate to seek a more precise definition of structural heart disease, using current diagnostic tools such as cardiac magnetic resonance imaging (CMR). In fact, in a recent prospective study involving 946 consecutive patients with ventricular arrhythmias without cardiac ischemia and apparent structural heart disease on transthoracic echocardiography, CMR allowed the diagnosis of structural heart disease in 241 patients (25.5%) .Consequently, the improved assessment of structural heart disease by CMR may allow us to define more precisely the type of structural heart disease that may contraindicate flecainide treatment, reducing the gray area in which the actual paucity of data on the safety of flecainide prevents its possible use but also its contraindication. In the meanwhile, the criteria shown in Flecainide showed its efficacy and safety in the treatment of AF and ventricular arrhythmias. However, flecainide is currently underused because of a restrictive use resulting from an excessively cautious and anachronistic interpretation of the CAST data. In fact, although flecainide is recommended in the treatment of IVAs, it is largely underused in common clinical practice. Conversely, in these patients, the first-line use of amiodarone is often improperly favored, with well-known complications. Even in patients with ischaemic and non-ischaemic structural heart disease, the absolute contraindication to the use of flecainide is widely questionable, also on the basis of modern and widespread diagnostic and therapeutic tools: in fact, in ischaemic heart disease, the spread of primary PCI made it possible to identify a cohort of patients without scar and residual ischaemia who could benefit from the use of flecainide. Future studies will be needed to better define the concept of structural heart disease to avoid a large population of patients who would benefit from the efficacy of flecainide not receiving it.


His bundle pacing (HBP) is an alternative to biventricular pacing (BVP) for delivering cardiac resynchronization therapy (CRT) in patients with heart failure and left bundle branch block (LBBB). It is not known whether ventricular activation times and patterns achieved by HBP are equivalent to intact conduction systems and not all patients with LBBB are resynchronized by HBP.To compare activation times and patterns of His‐CRT with BVP‐CRT, LBBB and intact conduction systems.In patients with LBBB, noninvasive epicardial mapping (ECG imaging) was performed during BVP and temporary HBP. Intrinsic activation was mapped in all subjects. Left ventricular activation times (LVAT) were measured and epicardial propagation mapping (EPM) was performed, to visualize epicardial wavefronts. Normal activation pattern and a normal LVAT range were determined from normal subjects.p = .04).Forty‐five patients were included, 24 with LBBB and LV impairment, and 21 with normal 12‐lead ECG and LV function. In 87.5% of patients with LBBB, His‐CRT successfully shortened LVAT by ≥10 ms. In 33.3%, His‐CRT resulted in complete ventricular resynchronization, with activation times and patterns indistinguishable from normal subjects. EPM identified propagation discontinuity artifacts in 83% of patients with LBBB. This was the best predictor of whether successful resynchronization was achieved by HBP (logarithmic odds ratio, 2.19; 95% confidence interval, 0.07–4.31; Noninvasive electrocardiographic mapping appears to identify patients whose LBBB can be resynchronized by HBP. In contrast to BVP, His‐CRT may deliver the maximum potential ventricular resynchronization, returning activation times, and patterns to those seen in normal hearts. BVPbiventricular pacingCRTcardiac resynchronization therapyECGelectrocardiographECGIECG imagingHBPHis bundle pacingHis‐CRTcardiac resynchronization therapy delivered by His bundle pacingLBBBleft bundle branch blockLVAT‐95left ventricular activation time of 95% of activations1Left bundle branch block (LBBB) causes dyssynchronous ventricular activation.However, BVP does not completely correct the disordered ventricular activation that occurs with LBBB. In fact, it produces only relatively modest reductions in ventricular activation time and results in nonphysiological ventricular activation patterns.However, it does not appear to be possible to shorten ventricular activation time in all patients with 12‐lead ECG features of LBBB.A second challenge is that it is difficult, using the 12‐lead ECG, to quantify left ventricular resynchronization and therefore to determine whether the maximum potential resynchronization has been achieved: LVAT cannot be easily identified with the 12‐lead ECG. This can be particularly challenging in the presence of nonselective His bundle capture, which results in a pseudo‐delta wave as a result of local right ventricular myocardial capture at the lead tip.1)Noninvasive identification of patients in whom His‐CRT is likely to be successful would allow resynchronization strategy to be targeted to underlying conduction disorder.2)Quantification of ventricular electrical resynchronization, with a normal range, will allow operators to easily establish whether ventricular resynchronization has been delivered and assess whether maximum activation time reduction has been realized.Therefore, although His‐CRT is a promising alternative to BVP, before proceeding to long‐term head‐to‐head randomized control trials it would be helpful to develop tools for improving patient selection and intra‐procedural targets:We addressed these two questions by analysing the activation times and patterns of HBP, BVP, and intrinsic activation during LBBB and compared these to intact conduction systems using noninvasive epicardial activation and propagation mapping.22.1Two groups of patients were recruited at a single tertiary cardiac center : (1) patients with LBBB and left ventricular impairment scheduled for biventricular pacemaker implantation with or without defibrillator function; (2) a comparison group of patients with normal 12‐lead QRS morphology and narrow QRSd undergoing epicardial mapping for ventricular ectopy ablation, arrhythmia risk stratification, or recruited specifically as normal subjects. Inclusion criteria for the CRT group were LBBB morphology on 12‐lead ECG with QRSd > 130 ms, EF < 35%, NYHA II–IV. Patients who were unable to give consent, or were clinically unstable, were excluded. Patients undergoing research protocols gave written, informed consent and the study was approved by the local ethics committee and health research authority . The 12‐lead surface ECG for each patient with LBBB was studied for adherence of the QRS morphology to pre‐defined LBBB criteria2.2All patients were fitted with a 252‐electrode ECGI vest (Medtronic) and underwent low dose thoracic computed tomography to acquire cardiac anatomy and electrode positions. The ECGI methodology has been described and validated previously2.3Activations from individual electrodes were temporally annotated based on the most negative dv/dt (the steepest slope of the voltage‐time relationship) and visualized on patients' three‐dimensional (3D) cardiac model. The total LVAT was calculated from the earliest to the latest activation. This value can be skewed by outliers caused by noise and anatomical/temporal mis‐annotation, therefore the activation time of 95% of activations (left ventricular activation time of 95% of activations [LVAT‐95]) was used to quantify resynchronization.2.4To determine activation patterns, custom software was used to render movies of wavefront propagation across the epicardium. The entire duration of a single beat's EGM for each virtual epicardial electrode was visually represented on the 3D cardiac model. The EGM voltage was represented by circles moving outward from the cardiac model proportionate with the negative dv/dt with values <0  clipped. By displaying the entire EGM, rather than the most negative dv/dt, visual interpretation was used to determine activation wavefronts rather than relying on potentially mis‐annotated activations.2.5Temporary HBP was performed in patients with LBBB and was achieved via either the femoral or subclavian approach. If the femoral route was used, a quadripolar electrophysiology catheter was placed on the bundle of His. If the subclavian route was used, a SelectSecure 3830 lead was delivered via either a C304‐His deflectable sheath or C315 fixed curve sheath (leads and delivery system: Medtronic).2.63. Therefore, smaller reductions in LVAT‐95 may be due to measurement variation rather than true resynchronization. Failed His‐CRT was defined as a <10 ms reduction in LVAT‐95 compared to intrinsic activation (as long as 12‐lead ECG criteria for His bundle capture were fulfilled). His‐CRT was further subclassified into incomplete His‐CRT and complete His‐CRT. Complete His‐CRT was defined as HBP LVAT‐95 within the 99% range (mean ± 2.58 × SD) for intrinsic LVAT‐95 in patients with normal QRS. Incomplete His‐CRT was defined as patients with mean HBP shortening of LVAT‐95 by >10 ms but with mean HBP LVAT‐95 above the upper limit of normal defined by the 99% range for LVAT‐95 in patients with normal QRS. The unpaired t test was used to compare electrical parameters between groups, with paired t tests for within‐patient comparisons.Patients were classified by the degree of resynchronization occurring with HBP. Successful resynchronization, referred to as His‐CRT, was defined as reduction in LVAT‐95 by 10 ms from intrinsic activation. This cut‐off was applied because we have previously demonstrated that the variation of LVAT‐95 in this setting is 10 msAn ordinal regression model predicting the HBP LVAT (LVAT‐95) and including intrinsic LVAT‐95 was used to assess the impact of propagation pattern on the change in LVAT95. To present the data, the results of the ordinal regression model were transformed to produce LVAT‐95 times. Analyses were performed using the statistical environment “R,” using the package “rms.”3Forty‐six subjects were recruited, 25 with LBBB and left ventricular impairment, and 21 with narrow QRS and normal ventricular function. Due to technical error with the ECGI system, data was unavailable during HBP in one patient in the LBBB group. Therefore 24 patients with LBBB undergoing CRT device insertion were included alongside 21 subjects with normal ventricular function and narrow QRS. All 24 patients with LBBB underwent HBP and 20 had BVP ECGI recordings (due to unsuitable coronary sinus anatomy in four patients). Baseline demographics for both groups of patients are displayed in Table 3.1SD of this mean difference) was higher for LVAT‐95 (−1.69) as compared to QRSd (−1.22).The activation times in intrinsic rhythm, HBP, and BVP are displayed in Table 3.2Visual analysis of ventricular propagation maps identified revealed two distinct patterns of LV activation during intrinsic LBBB. In the majority of patients , there were appearances of regions of epicardial propagation block, which we term “propagation discontinuities.” In most of these patients  propagation discontinuities manifested as distinct “lines of block,” where wavefront propagation appeared to halt simultaneously along a line. Beyond the line of discontinuity, epicardium appeared to be activated from a different direction than the original propagation wavefront. This was not necessarily the opposite direction: the wavefronts could be orthogonal resulting in the appearance of “U‐shaped” activation. In the remaining 15%, epicardial propagation discontinuity was instead observed as “zones of slow conduction,” where epicardium beyond the line of block appeared to be activated, after a delay, in the same direction that the original wavefront was traveling in. Two patients displayed more than one line of discontinuity (anterior and posterior). The majority of lines of discontinuity were longitudinal  and found on the anterior LV  with fewer found on the anterolateral LV  and the remaining discontinuities visualized on the posterior LV . They were seen in patients with ischemic and nonischemia etiology of heart failure.accompanying videos and illustrative single‐frames of EPM cines are shown in Figure In the remainder of patients with a 12‐lead appearance of LBBB , lines of block were not observed. Instead, a second pattern was observed: slow propagation across the LV epicardium without any appearance of discontinuity. This was termed diffusely slowed propagation (DSP). Examples of both patterns are shown in During HBP, in 15 (75%) of the 20 patients where propagation discontinuity was observed, the appearance of discontinuity resolved with rapid, unidirectional activation proceeding through the regions where propagation discontinuity was observed in intrinsic activation. In the remaining five patients, the appearance of discontinuity was preserved. In patients without the appearance of discontinuity, HBP produced an activation pattern of slow, but unblocked, propagation across the LV epicardium consistent with intrinsic activation. EPM maps of BVP in patients with LBBB showed collision of slowly propagating wavefronts on the LV epicardium. All patients with narrow QRS showed rapid, smooth activation of the LV epicardium without any appearance of block or regionally slowed conduction. All patients who displayed complete His‐CRT , displayed resolution of the propagation discontinuity and the LV activation pattern was indistinguishable from subjects with a normal QRS.accompanying videos).Where regional discontinuity was seen to disappear with HBP yet incomplete His‐CRT occurred, the change in propagation pattern from intrinsic LBBB to HBP showed that lines of propagation discontinuity in some regions were intact with HBP while others disappeared, allowing postulation of mechanisms of incompleteness of His‐CRT. For example, in two patients the basal portion of a longitudinal line of discontinuity disappeared with HBP with the apical portion left intact. This suggests selective recruitment of the anterior fascicle of the left bundle but failure to recruit the posterior fascicle (demonstrated in the 3.33.3.1p = .04). For ease of comprehension, we also used the presence of discontinuity as a dichotomized positive test and successful His‐CRT (LVAT‐95 shortening by at least 10 ms) as a dichotomized positive outcome of interest. In this model, the power of LVAT‐95 shortening as a continuous value is lost in favor of ease of comprehension: for the prediction of successful His‐CRT, the presence of propagation discontinuity has a specificity and positive predictive value of 100% and a sensitivity of 95% with a negative predictive value of 75%. When propagation discontinuity was resolved by HBP, HBP was much more likely to result in a shorter LVAT‐95 than if propagation discontinuity remained present during HBP or discontinuity was not present , 2.19; 95% confidence interval [CI], 0.07–4.31; 3.3.2In every patient in which HBP failed to shorten LVAT (failed His‐CRT), intrinsic LVAT‐95 was <80 ms. These short intrinsic LVAT‐95 times occurred despite the presence of a broad 12‐lead ECG QRS . The predictive ability was not as high as that of propagation discontinuity. If the full set of AHA/ACC/HRS criteria for LBBB were met, HBP was less likely to result in a shorter LVAT‐95 than if the criteria were not met .When the full set of Strauss criteria for LBBB were met, HBP was much more likely to result in a shorter LVAT‐95 than if Strauss criteria were not fully met EPM is a novel tool for noninvasively assessing ventricular activation patterns.(2)The activation pattern in LBBB can identify patients in whom HBP is likely to result in ventricular resynchronization.(3)Noninvasive electrical mapping can quantify ventricular resynchronization and identify mechanisms of incomplete resynchronization.(4)Successful His‐CRT results in normalization of ventricular activation with a more physiological activation pattern than BVP.In this study we demonstrate the novelty and utility of analysing activation patterns and times of His‐CRT for LBBB in several ways:4.1We used noninvasive mapping to identify two distinct types of the ventricular activation patterns in patients with 12‐lead ECG appearances of LBBB: those with the appearance of regions of propagation block, which we term “propagation discontinuity” and those with slow propagation without regions of discontinuity. Our findings are consistent with those from previous studies investigating ventricular activation patterns during LBBB, using both endocardial and epicardial mapping.The presence of this proximal conduction system block appears to be a useful predictor of whether HBP is likely to be successful in delivering ventricular resynchronization. Upadhyay et al.4.2It is important to conceptually and anatomically distinguish disease within the His‐Purkinje conduction system from the appearance of propagation discontinuity on the LV epicardial surface. Upadhyay et al.'sPropagation discontinuity is not observed on direct endocardial contact mapping,4.3Regardless of their pathophysiological basis, ECGI‐derived activation patterns in LBBB allow accurate, noninvasive prediction of patients whose LVAT‐95 is shortened by HBP. We have previously demonstrated that LVAT‐95 shortening is a key mechanism through which successful His‐CRT improves cardiac output, with incremental activation time shortening correlating with hemodynamic improvement.LVAT‐95 also provides an intra‐procedural target with complete His‐CRT representing activation normalization that is not affected by selectivity of His bundle capture and with superior signal‐to‐noise ratio than QRSd. QRSd is affected by capture selectivity  but subtraction of Stim‐endQRS time from His‐endQRS time is an alternative 12‐lead ECG surrogate for electrical resynchronization that, like LVAT‐95, also ignores selectivity of His bundle capture. However, LVAT‐95 shortening correlates with hemodynamic response and avoids arbitrary and variable QRSd offset measurement and mistaken inclusion of HV shortening into resynchronization. Where the ECGI technology is not available, our findings show that the next best alternative is to ensure that only patients meeting full Strauss LBBB 12‐lead ECG criteria are selected for His‐CRT. The presence of lateral notching and anterior QS/rS appear to be important markers of conduction system disease amenable to HBP, whereas the lateral monophasic R wave requirement of the ACC/AHA/HRS guidance does not appear to be predictive. Similar discrepancies between the two criteria have been reported for BVP response.The HIS‐SYNC randomized pilot evaluation of His‐CRT vs BVP for heart failure with LBBB did not demonstrate the superiority of His‐CRT over BVP.4.4HBP has been hailed as a method for physiological resynchronization due to the normalized appearance and short duration of the QRS complex that are often seen as well as the purported mechanism of recruitment of the left bundle which would then activate the ventricles physiologically. However, QRSd and morphology are not reliable measures of resynchronization by HBP, particularly as selectivity of His bundle capture affects both. We have, for the first time, defined a normal range for LVAT and have found that when HBP produces activation times within this range, left ventricular activation pattern is indistinguishable from normal left ventricular activation. Both produce rapid, smooth, unimpeded activation of the left ventricle. This suggests that HBP has the potential to fulfill the maximum potential of CRT. Alongside Upadhyay et al.'sIn contrast, EPM reveals the nonphysiological character of BVP. Wavefronts emanate from the positions of the right and left ventricular electrodes traveling at slow myocardial conduction speeds rather than rapid conduction‐system speed. These wavefronts then collide on the surface of the left ventricle. Although regions of conduction block are not observed, they are replaced by lines of wavefront collision. We have previously shown that the within‐patient incremental activation shortening seen with His‐CRT over BVP closely correlates with the incremental hemodynamic improvement. However, the correlation is not perfect: further hemodynamic benefits are seen with HBP over BVP than anticipated by LVAT‐95 shortening alone.4.5In three patients HBP did not improve LVAT‐95 by at least 10 ms “failed His‐CRT” and 13 patients reduced LVAT by more than 10 ms but did not achieve LVAT‐95 within the normal range defined in this study. We have previously demonstrated that even when no resynchronization occurs there is still scope for hemodynamic improvement through AV optimization.4.6This study introduces EPM as a novel method for noninvasively assessing activation patterns. Conventional activation maps that annotate an activation time at most negative dv/dt are prone to potential mis‐annotation of activation when electrodes' EGMs show multiple waves. This occurs in bundle branch block but EPM visualizes the entire EGM so that human analysis can determine the true wavefront. This provides a powerful tool for accurately depicting patterns of activation that makes use of all electrical information acquired by ECGI systems.4.7ECGI‐derived measures provide information on epicardial activation; the septum, where the conduction system lesion is likely to be located, is thus not analysed. However, LVAT‐95 measures the downstream effect of conduction system behavior in the septum on the LV myocardium overall. Furthermore, our findings are consistent with those produced by septal mapping of the conduction system and LVAT‐95 correlates with hemodynamic outcomes.5EPM derived from ECGI allows accurate noninvasive discrimination of LBBB with regions of propagation discontinuity that is potentially amenable to resynchronization by HBP from diffuse slow conduction that cannot be corrected. When HBP normalizes LVAT, the activation pattern produced is physiological and indistinguishable from normal activation with intact conduction system.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.


In children with severe advanced heart failure where medical management has failed, mechanical circulatory support in the form of veno-arterial extracorporeal membrane oxygenation (VA ECMO) or ventricular assist device represents life-sustaining therapy. This review provides an overview of VA ECMO used for cardiovascular support including medical and surgical heart disease. Indications, contraindications, and outcomes of VA ECMO in the pediatric population are discussed.VA ECMO provides biventricular and respiratory support and can be deployed in rapid fashion to rescue patient with failing physiology. There have been advances in conduct and technologic aspects of VA ECMO, but survival outcomes have not improved. Stringent selection and optimal timing of deployment are critical to improve mortality and morbidity of the patients supported with VA ECMO. Mechanical circulatory support is an essential tool in the care of children with severe refractory cardiac failure, acute or chronic, when conventional medical management has failed. The two primary forms of mechanical circulatory support are veno-arterial extracorporeal membrane oxygenation (VA ECMO) and ventricular assist devices (VAD). The two technologies have unique advantages and disadvantages and could be considered as complementary devices and, at times, used in sequence as the clinical scenario dictates . In thisBased on John Gibbons’ pioneering work on the development of heart-lung machine for cardiac surgery, Bartlett and his colleagues developed and utilized ECMO for an extended period to support critically ill neonates with respiratory failure in the 1970s ,3. As thThe primary indications for cardiac ECMO can be divided into two main categories: medical and surgical. The physiologic state of the failing heart regardless of the etiology is of bilaterally increased preload and low cardiac output due to impaired contractility. The primary emphasis of ECMO support is to restore end-organ perfusion. Every effort must be taken to identify the cause of decompensation and reason for the ECMO support including identification of residual lesion in setting of post cardiotomy ECMO. Predictors for the use of ECMO for medical indications include elevated markers of cardiac injury (troponin), elevated markers of congestion (BNP), and higher levels of inotropic support ,18,22,23In VA ECMO, the right heart is decompressed via the venous cannula while the left heart is at risk for congestion and elevation of left atrial or left ventricular end-diastolic pressure if there is minimal or no ejection across the aortic valve. Left atrial hypertension results in pulmonary congestion and can lead to significant pulmonary dysfunction. In order to protect the lungs, the left heart is decompressed in a number of ways that are addressed in the special considerations section. When cardiac recovery is delayed, determination of heart transplant or VAD candidacy is indicated.VA ECMO can occur through peripheral or central cannulation. Central cannulation is a strategy employed when there has been recent sternotomy, single ventricle lesions secondary to cavo-pulmonary connections, or sepsis where high flow rates may be necessary . PeripheAnticoagulation is necessary in the use of VA ECMO to prevent thromboses both in the circuit and in the patient. In the setting of post-cardiotomy, where the risk of bleeding is inherently high, the management of anticoagulation is challenging and may be avoided for periods of time. Monitoring of anticoagulation has evolved over time with the development of novel techniques such as thromboelastography. New medications for anticoagulation have become available, yet the relative risks and benefits in pediatric VA-ECMO are unknown.The contra-indications to VA ECMO include severe coagulopathy, irreversible neurological deficit, extreme prematurity, extreme low birth weight, major genetic abnormalities, co-morbidities, or irreversible primary disease state. In a patient who is unlikely to have cardiac recovery, the use of VA ECMO without an exit strategy such as long-term bridging with VAD for heart transplant, would not be appropriate.While VA ECMO for post-surgical cardiogenic shock has represented much of the use of extracorporeal life support (ECLS), there are multiple indications for the use of VA ECMO in patients with cardiac failure . Common Myocarditis is an infective process involving the myocardium leading to systolic dysfunction and/or dysrhythmias. This is usually a self-limited process, although the disease may become so severe as to require ECMO. A significant portion of these patients will “burn out” and develop a persistent cardiomyopathy and may need transplantation or mechanical circulatory support. Several investigators have described ways to predict which children may have hemodynamic compromise using clinical data  ,34 or biThe clinical outcomes of children who require ECMO for fulminant myocarditis are promising ,38. In aVA ECMO has been used in the setting of cardiomyopathies with the best description by Almond et al. . The ELSIn pediatrics, there is only case report and case series data  related Sepsis represents complicated pathophysiology that includes myocardial dysfunction as well as vasoplegia. Supporting children with this physiology is challenging as the flow requirements may be high. The flow provided by ECMO is limited by patient size, catheter size, hemolysis, and other factors yet ECMO remains as a modality in the treatment of sepsis in recent guidelines . ConventIn an elegant study using the National Inpatient Sample, the use of VA-ECMO in children with sepsis was associated with considerable resource utilization, but had 59% survival to discharge . A novelSARS-CoV-2 has been demonstrated in the myocardium of an adult and pediatric patient with myocarditis ,46,47. WThe use of ECMO during acute resuscitation—extracorporeal cardiopulmonary resuscitation (ECPR)—is becoming increasingly frequent ,50 in chThere is little data to understand why the survival and neurological outcomes are different in the cardiac surgical patients. Potential factors include the ability to intervene if there is an anatomic or functional cardiac problem, team organization and early deployment of ECPR, or more ready recognition of cardiac decompensation. The most recent pediatric life support guideline recommendations do not support the of ECPR for out-of-hospital cardiac arrest, but suggest that it may be used for in-hospital cardiac arrest if there are conditions such as rapid access to ECLS equipment and skilled ECLS personnel as there are improved neurologic outcomes. 2, and SaO2 did not distinguish survivors from non-survivors.Patients with hypoplastic left heart syndrome (HLHS) or other single ventricle physiology lesions represent a special population at risk for cardiac arrest who are difficult to resuscitate with conventional CPR. Conventional CPR may not be able to achieve flows required to support parallel circulations. A study published in 2014 reports 293 infants with HLHS who had ECPR with survival at 36% and neurologic injury noted in 16% of survivors as compared to 24% of non-survivors . CharactSurvival for children with congenital heart disease has progressively improved, and one of the reasons has been widely available use of ECMO. According to the 2019 Extracorporeal life support ELSO report, HLHS was the most common congenital cardiac lesion supported by ECMO in neonates . In chilECMO support is used in neonates pre-operatively when they present with profound cyanosis, shock, or end-organ dysfunction. In Ebstein’s anomaly and functional pulmonary atresia, VA ECMO helps to stabilize the shock state secondary to circular shunt. Similarly, in d-Transposition of great arteries, with significant pulmonary hypertension and profound cyanosis, there are reports of successful use of VA ECMO for pre-operative stabilization .Failure to separate from cardiopulmonary bypass in the operating room.Low cardiac output state in the immediate post-operative period secondary to ventricular dysfunction, pulmonary hypertension or intractable arrhythmias recalcitrant to medical therapies.Cardiopulmonary arrest occurring in the acute post-operative period.In children, VA ECMO is most commonly used in the acute postoperative period after congenital cardiac surgery. The frequent indications are:Rapid deployment of VA ECMO in patients undergoing ECPR was first reported in 1992 and has resulted in a decline in operative mortality in patients after complex cardiac surgeries . IndicatUtilization of peri operative ECMO varies among centers performing congenital cardiac surgery. An analysis of the Society of Thoracic Surgeons (STS) Congenital Heart Surgery database revealed that 2.4% of patients were supported by VA ECMO after cardiac surgery from 2000 to 2017 . NeonateLorusso et al. performed a comprehensive review and summarized the current literature regarding use of VA ECMO after surgery for congenital heart disease . They reFord et al. analyzed the ELSO registry for outcomes of neonates supported with VA ECMO who had medical or surgical cardiac diagnoses . Of the Mascio et al. reported that in-hospital mortality was highest after repair of truncus arteriosus and Norwood palliation for HLHS . FactorsMultiple studies have emphasized the importance of early cardiac catheterization aimed at identifying and treating residual lesions to facilitate timely liberation from ECMO. Agarwal et al. reported the presence of residual lesions in approximately 25% of post-operative cardiac surgery patients receiving VA ECMO support, thus concluding that those unable to be weaned off VA ECMO should have detailed evaluation for residual lesions, preferably by cardiac catheterization in addition to echocardiography . MultiplChildren living with functionally single ventricle physiology undergo stage 1 palliative surgery involving the construction of neo-aorta and creation of pulmonary blood flow with a systemic to pulmonary artery shunt and atrial septectomy. Following their stage 1 surgery for HLHS, 13–20% have been supported by ECMO ,64. In aWhile the outcomes for the Glenn procedure are excellent, patients are still at risk of decompensation and may need ECMO support. The Glenn surgery results in separation of superior vena caval pathway from the heart, so the venous drainage site must be carefully considered. Some centers routinely cannulate superior vena cava (SVC) first to preserve cerebral perfusion and after initial stabilization, decide on additional venous drainage cannulas or transition to central cannulation.Booth et al. described a single center series of 6 patients supported by VA ECMO post Glenn surgery with only 3 successfully decannulated who suffered significant neurological injury . In the After Fontan operation, the inferior vena cava (IVC) is incorporated into the superior cavopulmonary anastomosis, so the passive pulmonary blood flow is followed by the pulmonary venous return to the systemic ventricle. This physiology can fail either acutely or gradually with impaired hemodynamics and end organ perfusion necessitating ECMO support. Critical to support of the patient with Fontan physiology is decompression of the Fontan circuit with maintenance of adequate perfusion pressure. To accomplish these goals, additional venous cannula (upper and lower) or central cannulation may be necessary. Additionally, venous stasis in the Fontan circuit should be avoided. To address this, some centers consider a veno-arterial-venous strategy, in which there is there is one drainage cannula and two return cannulae. One of the return cannula is placed in the carotid and the other in the internal jugular. This allows for flow of oxygenated blood into the caval system with simultaneous decompression preventing stasis.Rood et al. describes the largest cohort of 230 patients in Fontan physiology who were supported by ECMO . 56% of Fontan failure can be classified into early, mid and late phases. Early failure is often due to cavopulmonary obstruction that may be relieved surgically with short term rescue using VA ECMO. Mid and late phase failure often present with end-organ dysfunction, protein losing enteropathy, or plastic bronchitis, that present significant risk factors for VA ECMO and carry even higher risk of mortality. Although most of the focus of the mid and late phase Fontan failure patients has shifted towards VAD, the outcomes continue to remain grim in this cohort.Hybrid procedure is palliative and combines bilateral pulmonary artery bands and stent to maintain patency of ductus arteriosus for patients who are considered to have higher risk of mortality with Norwood operation. Roeleveld et al. identified 44 patients with HLHS and hybrid palliation who needed ECMO support . The indA review from Mitchell et al. from a single center that selectively performs hybrid procedure as its stage 1 palliation, included 181 patients . IncidenHeart transplant is a well-established treatment for heart failure refractory to medical therapies. Acute graft failure represents the most common reason for VA ECMO post-operatively and may occur for many reasons ,17,70. WWhile ECMO effectively restores systemic organ perfusion to end organs in cardiogenic shock, it has detrimental effects on the left ventricle. When the aortic valve fails to open, the ongoing venous return, via thebesian and bronchial veins, leads to LV distension. This cascades to impaired myocardial perfusion pressure, intra-cardiac thrombus, dysrhythmias, and LA hypertension with resultant pulmonary hemorrhage, and hinders myocardial recovery. Measures to facilitate LV ejection with inotropic support and decreasing mean arterial blood pressure may help, but decompressing the left heart with an atrial septostomy or LA vent may be required.There are no defined diagnostic criteria for LV distension, although lack of pulsatility via arterial line, clinical and radiographic evidence of significant pulmonary edema, elevated pulmonary capillary wedge pressure, echocardiographic evidence of LV distension and stasis, intermittent or absent opening of the aortic valve aid in detecting the LV distension. There are currently no consensus guidelines to delineate the optimal timing and method of decompression, although the decompression has been accomplished by surgical and percutaneous methods.Xie et al. performed a metanalysis investigating the current evidence for incidence, diagnosis, prevention, and intervention for LV overload in both adult and pediatric patients . The incZampi et al., in a retrospective multicenter study of pediatric patients receiving VA ECMO, observed that late left atrial decompression (≥18 h) was associated with longer duration of ECMO support and mechanical ventilation . Early dWe have described the major surgical and medical indications for use of VA ECMO for cardiogenic shock. The overall use of VA ECMO has increased over time and the number of indications has expanded. Despite the growing familiarity with VA ECMO and technical advances, survival and other outcome measures have not improved. The potential complications of VA ECMO limit the use of VA ECMO to weeks at best. When quick recovery is expected, the risk factors associated with VA ECMO do not impose limitations, but when recovery is longer or requires bridge to diagnosis or transplant, these factors are more relevant. Transition to VAD may prove to be a better strategy . SeveralHow can we optimize outcomes in VA ECMO? Perhaps we should have a more restrictive thought process related to candidacy. In our institution , candidacy for VA ECMO and ECPR are considered independently for all patients in the cardiovascular intensive care unit and discussed in a multidisciplinary format. Literature provides some guidance on which patients will have a positive outcome, but other considerations include not just survival, but developmental sequelae, or parental perceptions of all forms of extracorporeal support. More research is needed to understand the long-term sequela of VA ECMO. In those patients for whom we offer VA ECMO or ECPR, timing is critical and should avoid end-organ dysfunction in which there is no hope of recovery. SARS-CoV-2 associated disease remains a novel front for VA ECMO and requires significant study. The single ventricle population, especially after Glenn and Fontan surgery, remains at high risk of mortality and morbidity with ECPR, and their candidacy for ECPR has to be carefully evaluated.


However, 30% of treated patients are non-responders despite all efforts. Cardiac magnetic resonance imaging (CMR) can be used to quantify regional contributions to stroke volume (SV) as potential CRT predictors. The aim of this study was to determine if LV longitudinal  from end diastole (ED) to end systole (ES) divided by total SV. SVlat%, and SVsept% were calculated as the volume encompassed by radial contraction from ED to ES. Twenty age- and sex-matched healthy volunteers were used as controls. The regional measures were compared to outcome response defined as ≥ 15% decrease in echocardiographic LV end-systolic volume (LVESV) from pre- to 6-months post CRT .Sixty-five patients  with symptomatic HF (LVEF ≤ 35%) and broadened QRS (≥ 120 ms) underwent CMR. SVlong% were lower in patients compared to controls . SVsept% was lower  with a higher SVlat% in the patient group . There were no differences between responders and non-responders in neither SVlong% (P = 0.87), SVlat% (P = 0.09), nor SVsept% (P = 0.65). In patients with septal net motion towards the right ventricle (n = 28) ΔLVESV was − 18 ± 22% and with septal net motion towards the LV (n = 37) ΔLVESV was − 19 ± 23% (P = 0.96).AVPD and SVLongitudinal function, expressed as AVPD and longitudinal contribution to SV, is decreased in patients with HF scheduled for CRT. A larger lateral contribution to SV compensates for the abnormal septal systolic net movement. However, LV reverse remodeling could not be predicted by these regional contributors to SV. Cardiac dyssynchrony in chronic heart failure (HF) may be restored by cardiac resynchronization therapy (CRT), which induces coordinated contraction in the left ventricle . The curConflicting results have been presented regarding the ability of multi-modality imaging to guide CRT-lead placement. Sommer et al. showed in a single-center randomized controlled trial that a multi-modality imaging approach improved the CRT effect . HoweverCMR can quantify the stroke volume (SV) generated from LV septal net movement in addition to the longitudinal and lateral contributions to SV , 9. In hlong%) is generated by the atrioventricular plane displacement (AVPD). Impaired longitudinal ventricular function has been shown to be associated with adverse events, even in the absence of reduced LVEF [The longitudinal component of LV stroke volume  determine if longitudinal, lateral, and septal contributions to SV in patients with HF and eligible for CRT differ from healthy controls, (2) investigate if these parameters predict CRT-treatment outcome defined as reverse remodeling at 6 months after CRT implantation, and (3) investigate if there were differences in regional contribution to SV in patients with ischemic versus non-ischemic etiology.P = 0.96 [This is a sub-study of a randomized clinical trial, which prospectively included patients with indication for CRT between 2011 to 2017 at Skåne University Hospital, Sweden . Indication for CRT was New York Heart Association (NYHA) class II-IV despite optimal medical therapy, QRS-complex ≥ 120 ms on standard electrocardiogram (ECG), and LVEF ≤ 35% . PatientP = 0.96 . TherefoIschemic heart disease was defined as fulfillment of at least one of the following criteria: (1) medical history of myocardial infarction or revascularization (percutaneous coronary intervention or coronary artery bypass grafting), (2) lumen stenosis ≥ 50% in left main coronary artery or proximal left anterior descending artery, and (3) lumen stenosis ≥ 75% in any epicardial vessel. Non-ischemic heart disease was defined as patients not fulfilling any of these criteria .As control group, 20 healthy age- and sex-matched individuals  with normal blood pressure (< 140/90 mmHg), no past cardiovascular diseases, no cardiovascular treatments, and with normal ECG findings were recruited.All subjects underwent CMR examination at baseline using a Philips Intera 1.5 T or 3.0 T , or Siemens Aera 1.5 T . Balanced steady-state free precession cine images were collected in the supine position during end-expiratory apnea and included a short-axis cine stack, and long-axis cines in 2-chamber, 3-chamber, and 4-chamber views. CMR was not performed at six months follow-up due to CRT devices were not MRI compatible.Retrospective ECG triggering was used to acquire images with reconstructed temporal resolution of 30 time frames per cardiac cycle. Typical imaging parameters were TR/TE 3 ms/1.3–1.8 ms, flip angle 45° (3 T) or 60° (1.5 T), and slice thickness 6–10 mm with 0–2 mm slice gap.In patients, late gadolinium (Gd) enhancement (LGE) images were acquired to quantify the extent of myocardial fibrosis. Intravenous Gd-based contrast of 0.2 mmol/kg  was injected in an antecubital vein after which inversion-recovery or phase sensitive inversion recovery sequences were used to generate LGE images. Typical image parameters were TR/TE 4.2–5.2 ms/1.0–3.3 ms, flip angle 15° (1.5 T) or 25° (3 T), and slice thickness 6–10 mm with 0–2 mm slice gap.http://segment.heiberg.se) [CMR image analysis was performed using the software Segment v2.0 R5039  . Short-aberg.se) . LV epiclong%) was measured as previously described [long%) was calculated by dividing the absolute longitudinal contribution to SV (in ml) with the total LVSV.The longitudinal contribution to SV  was defined by the area enclosed by the septal epicardial contours and the RV insertion points between ED and ES in the short-axis images  was defined by the area enclosed by the lateral LV epicardial contours and the RV insertion points in ED and ES in the short-axis images  using an M5Sc-D probe with standard projections according to guidelines . EchocarThe effect of CRT was evaluated with echocardiography at baseline prior to CRT implantation and at six months follow-up after implantation to assess reverse remodeling. Response to CRT was defined as previously proposed  as ≥ 15%Statistical analyses were performed using IBM SPSS version 25 .sept%, the cutoff value was 0%, with negative contribution to LVSV as a sign of cardiac dyssynchrony [P values < 0.05 were considered statistically significant. Univariable and multivariable logistic regression analyses were conducted with responder as dependent variable and SVlong%, SVlat%, and SVsept% as predictors. Demographic, clinical, and echocardiographic predictors were added to the model to adjust for confounding factors. Candidate predictors in the univariable logistic analysis that had a P value of < 0.25 were included in the multivariable analysis [P < 0.05. Post-hoc sample size analysis was conducted using the software PS: Power and Sample Size Calculation  [Continuous variables are expressed as mean ± SD. Normal distribution was determined by visual assessment of histograms. For SVynchrony . Groups er 2018) . AssumptSixty-five patients fulfilled the study protocol. Nineteen were women, mean age was 67 ± 9 years. 51% had non-ischemic etiology and QRS duration on standard ECG was 167 ± 17 ms. Mean ejection fraction was 26 ± 8%, and 86% had typical LBBB. The characteristics of the cohort are in detail presented in Table long% 53 ± 18%, for SVlat% 41 ± 16%, and for SVsept% 0 ± 15%. Negative  SVsept% was found in 43% of the patients eligible for CRT. Thus, just above half of the selected CRT candidates did not have a septal net movement towards the right ventricle during systole.In patients receiving CRT, the relative regional contributions to LVSV were for SVP < 0.001) and SVlong% were lower in patients . Also, patients had a lower SVsept%  accompanied with an increase in SVlat% . Absolute SV was lower  and the short-axis area was larger in patients compared to controls  , as an objective marker of reverse remodeling and a positive response to CRT. The mean ΔLVESV was − 18 ± 22% (P = 0.66) and NYHA functional classification improved ≥ 1 (P = 0.47).Forty-six patients (71%) improved in NYHA functional classification ≥ 1 at six months follow-up. Twenty-seven out of 63 patients (43%) had dyssynchrony on echocardiography at baseline. Two patients were not assessable for dyssynchrony analysis. There were no associations between dyssynchrony and CRT outcomes, defined as LVESV reduction ≥ 15% . When demographic, clinical, and echocardiographic variables were added to account for confounding to the model, the model remained non-significant  and proportion of LBBB . Out of the 33 patients with non-ischemic etiology of heart failure, there were more responders than non-responders to CRT . There was no difference in reverse remodeling between patients with ischemic heart disease compared to patients with non-ischemic heart disease . Longitudinal shortening did not differ in patients with ischemic compared to non-ischemic etiology . There were no differences in regional contributions to SV between patients with ischemic vs non-ischemic heart disease  due to too few participants. To investigate the risk of type II error, a post-hoc sample size analysis was performed. Sample sizes of n = 342, n = 3975, n = 96 and n = 4362 respectively for LVAVPD, SVlong%, SVlat%, and SVsept% would have been needed to detect a signal.There were no significant differences in LVAVPD, SVThis study shows that patients eligible for CRT treatment have both lower longitudinal systolic atrioventricular plane displacement and septal contribution to SV, compared to healthy controls. However, patients have higher lateral contribution to SV, which is interpreted as a compensatory mechanism to the decreased septal contribution. While this is the first study showing these differences between patients with HF and electromechanical dyssynchrony and healthy controls, the suggested measures of regional function could not predict CRT outcome in terms of reverse remodeling at six months follow-up. In non-ischemic cardiomyopathy, reverse remodeling was more common compared to ischemic disease. Despite this, no difference in regional contribution to SV could be seen between ischemic and non-ischemic patients. Even when assessing with multivariable analysis of demographic, clinical and CMR characteristics, there was no association with responding on CRT treatment in the CMR parameters. Thus, our study is in line with previous studies that could not show any added value of regional function measures to further decrease the number of non-responders in patients selected for CRT treatment compared to current guidelines , 27.As of today, presence of LBBB, non-ischemic etiology, sex, QRS-duration, and sinus rhythm are the only factors that have been found to consistently predict response to CRT in randomized prospective trials . Mechanilong% was lower in patients eligible for CRT compared to healthy controls. Even if decreased AVPD carries prognostic information of poor outcome in a multitude of diseases, longitudinal function defined as AVPD and SVlong% was not related to treatment response in CRT-eligible patients.The present prospective observational study aimed to test if longitudinal and septal movements quantified by CMR can predict response to CRT. Longitudinal function defined as AVPD and SVsept% is that the measurement was not time resolved. Abnormal septal contractions happening before and after end-systole might therefore have been missed. Post-systolic contraction/shortening is an inefficient contraction after aortic valve closure and has recently gained attention as a potential diagnostic predictor [In patients referred for CRT, we found a net inverse motion of the septum and thus negative contribution to SV in almost half the patients. This contrasted to healthy controls who all had a positive contribution to SV. However, there was no difference in reverse remodeling 6 months after treatment between patients with negative vs positive septal contribution to LVSV. One explanation for the heterogenous response to CRT may be that differences in regions affected by disease or presence of LBBB give rise to different patterns of mechanical dyssynchrony . Electriredictor . It is pGuiding of CRT using a multi-modality imaging strategy, with a combination of cardiac venous anatomy using cardiac computer tomography, myocardial perfusion using single-photon emission computed tomography, and deformation using speckle-tracking echocardiography, showed improvement of a composite clinical outcome in a prospective randomized controlled single-center trial . Also, cThe response rate to CRT is dependent on the selected outcome measure and study population characteristics . In thisThe present study investigated the ability of a novel functional measure using CMR to predict outcome after CRT. Regional contributions to SV with this method were not sufficient in their prognostic ability, despite showing decreased longitudinal and septal function with a relatively increased lateral contribution function when compared with healthy volunteers. Currently, there is no single predictor of response to CRT, reflecting a complex syndrome with multifactorial causes. Recently a multicenter study showed that integrating multiple variables such as wasted work from echocardiography strain in combination with septal viability from CMR had the best capability to identify CRT responders . TherefoCMR exams at follow-up would have been preferred to echocardiography, but CMR-compatible devices were not clinically available at the course of the study. However, all echocardiographic exams were performed by one sonographer (> 15 years of experience) at both inclusion and at follow-up, and all analyses were performed by one expert reader (> 25 years of experience) at a tertiary high-volume center.long%, SVlat%, and SVsept% were affected similarly in ischemic and non-ischemic HF with a trend towards lower SVlong% and higher SVlat% in ischemic etiology, albeit not statistically significant.The study group consisted of a heterogenous HF population: 49% of study participants had ischemic etiology, a group that has been shown to have a higher non-response rate to CRT than patients with non-ischemic heart failure , 44. SubThe CMR protocol in the present study used LGE for tissue characterization. Since the conceptualization of the present study, T1 mapping and extra cellular volume index (ECV) measurements have become a standard part of heart failure evaluation with CMR, providing added prognostic value in non-ischemic heart failure , 46. In The post-hoc sample size analysis resulted in larger sample sizes than in the present study. Assuming there are true differences between responders and non-responders, they are probably small and would not be of clinical relevance to facilitate the selection of CRT responders on an individual level.Quantitative CMR assessment shows that patients eligible for CRT have decreased longitudinal function and that only half of the patients have a net shift of the septum towards the right ventricle during systole despite the majority of patients had LBBB. However, responders with reverse LV remodeling do not differ from non-responders regarding the longitudinal, lateral, nor septal contribution to SV. Patients with ischemic HF did not differ in regional contributions to SV compared to patients with non-ischemic HF. Thus, these regional contributions to SV are not applicable as predictors of LV remodeling in patients with LBBB eligible for CRT.


The application of high-sensitivity cardiac troponins in clinical practice has led to an increase in the recognition of elevated concentrations in patients without myocardial ischaemia. The Fourth Universal Definition of Myocardial Infarction encourages clinicians to classify such patients as having an acute or chronic myocardial injury based on the presence or absence of a rise or a fall in cardiac troponin concentrations. Both conditions may be caused by a variety of cardiac and non-cardiac conditions, and evidence suggests that clinical outcomes are worse than patients with myocardial infarction due to atherosclerotic plaque rupture, with as few as one-third of patients alive at 5 years. Major adverse cardiovascular events are comparable between populations, and up to three-fold higher than healthy individuals. Despite this, no evidence-based strategies exist to guide clinicians in the investigation of non-ischaemic myocardial injury. This review explores the aetiology of myocardial injury and proposes a simple framework to guide clinicians in early assessment to identify those who may benefit from further investigation and treatment for those with cardiovascular disease. The Fourth Universal Definition of Myocardial Infarction (UDMI) is an international expert consensus document which aims to promote a better understanding of the aetiology of myocardial injury and infarction, and to encourage a systematic approach to the subsequent investigation, treatment and clinical outcomes. This new definition challenges physicians to always consider the mechanisms of injury to ensure accurate diagnosis and treatment.Myocardial injury is an umbrella term which describes an elevation in cardiac troponin concentration with at least one value above the 99th percentile upper reference limit (URL). This term can be applied irrespective of aetiology and can be classified into acute or chronic myocardial injury on the basis of a dynamic change in cardiac troponin concentration. Typically, a relative change in troponin concentration of 20% is used .The diagnosis of myocardial infarction is applied when acute myocardial injury occurs in a patient with symptoms or signs of myocardial ischaemia on the electrocardiogram (ECG), or new imaging evidence of a regional wall motion abnormality in a coronary territory. Myocardial infarction is further stratified into five main subtypes  1,2]. T,2. T1,2]The clinical application of cardiac biomarkers for the diagnosis of myocardial infarction has evolved from the use of non-specific indicators of muscle ischaemia and breakdown, including creatine kinase myocardial band (CK-MB), myoglobin, lactate dehydrogenase (LDH) and aspartate aminotransferase (AST), to the use of cardiac troponin as the only recommended biomarker ,7. CardiCardiac myocytes may release troponin into the blood plasma through a variety of mechanisms beyond cell necrosis and membrane rupture , but theCardiac troponin assays have evolved from contemporary sensitive to the hs-cTn immunoassays widely utilised today . These aTroponin elevation is common in conditions other than acute coronary syndromes. A number of studies in both selected and unselected populations suggest that non-ischaemic myocardial injury is the most common cause of elevation in cardiac troponin concentration, ,17,18,19The High-Sensitivity Troponin in the Evaluation of Patients with Suspected Acute Coronary Syndrome (High-STEACS) trial evaluated 48,282 consecutive patients with suspected acute coronary syndrome tested using a hs-cTnI assay and demonstrated that of the 9115 patients with elevated cardiac troponin concentrations, 33% had non-ischaemic myocardial injury (18% acute and 12% chronic), with the remaining 67% having a diagnosis of myocardial infarction . In a further study of unselected consecutive patients who attended the emergency department (ED) and underwent blood testing on clinical indication, hs-cTnI measurements were conducted in all patients as a suppressed test. This found elevated cardiac troponin concentrations in 13.7% (114/1054), of which 96% were due to non-ischaemic myocardial injury ,31.In an observational cohort study of 1640 consecutive unselected patients in which troponin sampling was performed on clinical indication in the ED, 56% of the 497 patients with elevated troponin concentrations had non-ischaemic myocardial injury . The widIt is now widely recognised that a plethora of cardiac and non-cardiac conditions may be responsible for both acute and chronic myocardial injury . CardiacTakotsubo or stress cardiomyopathy is a poorly understood condition thought to be caused by catecholamine induced coronary vasospasm. Despite this presumed ischaemic aetiology, it is not considered a cause of myocardial infarction. Characteristically, there is ballooning of the apical segment of the heart. These patients, however, quite often only display a modest rise in troponin level in comparison to the degree of left ventricular dysfunction and studies have suggested patients with high troponin levels at presentation are unlikely to have Takotsubo cardiomyopathy ,39. CompNon-cardiac causes of acute myocardial injury include pulmonary embolism (PE), with myocardial injury occurring due to hypoxia ,42, or hOther systemic stressors such as non-cardiac surgery  have beeto 9% after walking. During an average of 43 [Myocardial injury has also been documented as a transient phenomenon after high-intensity exercise ,53. Tropge of 43 ,75,76,77ge of 43 .Chronic myocardial injury tends to reflect a steady disease state, and is frequently observed in chronic heart failure . A meta-Valvular heart disease is also commonly associated with elevation in cardiac troponin concentration. The Early Valve Replacement Guided by Biomarkers of LV Decompensation in Asymptomatic Patients with Severe AS (EVoLVeD) (NCT:03094143) is a randomised controlled trial in patients with asymptomatic severe aortic stenosis aiming to optimise the timing of valvular surgery. In this trial, cardiac troponin is used as a screening marker of early cardiac fibrosis to identify patients for cardiac magnetic resonance imaging. Patients with evidence of mid-wall fibrosis are randomised to early valve replacement or watchful waiting.The mechanisms responsible for chronic myocardial injury in patients with severe or diffuse coronary artery disease are poorly understood. The Dual Antiplatelet Therapy to Reduce Myocardial Injury (DIAMOND); (NCT:02110303) trial identified a cohort of patients with high-risk coronary plaque using coronary 18F-fluoride positron emission tomography/coronary computed tomography. In the subset of patients with elevated hs-cTn I concentrations ≥5 ng the addition of ticagrelor compared to placebo to standard preventative therapy did not reduce cardiac troponin levels over one year. This implies that subclinical plaque instability leading to ongoing micro-thrombosis is not the primary contributing cause of measurable troponin concentrations in these patients .p < 0.001 for trend) and the pravastatin group . This suggests there may be value of repeated sampling in patients with chronic troponin elevation to target those at high risk of future events and monitor response to treatment [The West of Scotland Coronary Prevention Study (WOSCOPS) trial randomised a population of 6595 men with moderate hypercholesterolaemia to a placebo or pravastatin 40 mg. In a secondary analysis of this trial, troponin concentrations were predictive of coronary events and were modified by statin therapy, with the change in LDL at 1 year associated with future coronary risk independent of cholesterol lowering. Furthermore, those with decreasing troponin concentration by more than one-quarter, rather than increasing by more than one-quarter, had a five-fold lower rate of future coronary events in both the placebo group  enrolled 3664 patients with chronic renal disease and performed cardiac biomarker testing in all. High-sensitivity cardiac troponin T concentrations were found to be independently associated with all-cause mortality . A further analysis of this cohort modelled to adjust for age, sex, presence of cardiovascular disease and cardiac risk factors revealed increased risk of cardiovascular death . There may be merit in using cardiac troponin concentration to stratify cardiovascular risk in those with chronic renal failure, identifying those with high circulating cardiac troponin concentrations for aggressive primary and secondary preventative therapies for cardiovascular disease.Outcomes in patients with acute and chronic myocardial injury are poor, with up to 72% of patients dead at five years  Figure . In nearSarkisian and colleagues evaluated a consecutive patient cohort in Denmark who had troponin measured on clinical indication. They found that 29% (1089/3762) of all patients had non-ischaemic myocardial injury. In this cohort, 59% (645/1089) of patients with myocardial injury were dead at 3.2 years, which was significantly higher than those with type 1 myocardial infarction (29%) but not type 2 myocardial infarction (63%). Patients with myocardial injury were more likely to present with dyspnoea and were older, and there was a higher incidence of heart failure with lower peak troponin concentrations compared to those with type 1 myocardial infarction.Smilowitz et al. studied a similar cohort of patients with troponin concentration measured on clinical indication. They found non-ischemic myocardial injury in 175/710 (25%) of patients with a mean age of 74.9. However, in this cohort no difference in all cause death was observed between those with type 1, type 2 myocardial infarction and myocardial injury  at a median of 1.8 years. Differences in outcomes may perhaps be explained by selection, as this cohort was nearly all male, with a much higher proportion of type two myocardial infarction and less myocardial injury. This cohort had a higher incidence of previous heart failure in the type 1 group and no difference in incidence of chronic kidney disease, diabetes and chronic obstructive pulmonary disease between all groups. When evaluating outcome studies in patients with myocardial injury attention to the baseline characteristics, underlying concomitant disease profiles, treatment and diagnostic adjudication must be considered as these variables are likely to differ between both research and clinical sites.Most studies demonstrate that cardiovascular death and recurrent myocardial infarction are more common in patients with type 1 myocardial infarction, but patients with both acute and chronic myocardial injury have a substantially higher risk than those without myocardial injury ,22,23,75Sandoval et al. evaluated 1640 unselected patients presenting to the emergency department using a contemporary sensitive cardiac troponin assay. They report a 19% MACE rate at 180 days in the 280 patients with myocardial injury. Interestingly, the only independent predictors for death in this group were congestive heart failure  and peak cardiac troponin  . In the Given the increased incidence of future MACE in patients with acute and chronic myocardial injury, further cardiac investigation may plausibly improve care in this population. There may be an opportunity for treatment optimisation whilst in hospital or at the point of discharge with the potential to modify outcomes in this group.In the absence of formal guidelines, we propose a simple framework to guide clinicians when interpreting troponin results in patients who do not have myocardial infarction .The primary goal of the assessing clinician should be to determine the correct diagnosis at the first consultation to guide subsequent investigation and treatment. After myocardial injury has been diagnosed on serial cardiac troponin testing, it is important to revisit the history and ensure there are no features consistent with myocardial ischaemia which could indicate myocardial infarction. In practice, differentiating acute non-ischaemic myocardial injury from type 2 myocardial infarction can be challenging. This often occurs as the classification of myocardial ischaemia is subjective on the basis of the clinical history and electrocardiogram. Difficulties in discriminating between acute myocardial injury and type 2 myocardial infarction can be exacerbated by atypical presentation of symptoms and non-specific ECG changes. Interestingly, patients with type 2 myocardial infarction and objective myocardial ischaemia on the electrocardiogram have been shown to have worse outcomes than those with only subjective ischaemic features . IdentifA 12-lead electrocardiogram should be performed in all patients with myocardial injury. This is not only useful for exclusion of ischaemia, but may also indicate abnormalities suggestive of cardiomyopathy, brady/tachyarrhythmias or pulmonary hypertension and embolism which should be further investigated with monitoring or imaging. Haematology and biochemistry investigations should be considered including a full blood count, clotting screen, liver function tests, inflammatory markers, estimated glomerular filtration rate and electrolytes, with additional tests such as thyroid function and d-dimer considered if appropriate.Further investigations should be guided by the history. In the acute setting, pleuritic pain may represent a multitude of pathologies and a plain chest radiograph may indicate infection or a primary lung pathology. Other causes such as myopericarditis should be considered by interrogating the electrocardiogram for ST segment or T-wave changes across different coronary territories. When pain occurs concomitantly with tachycardia and hypoxia then PE should be excluded, with risk stratification using the Geneva score, d-dimer and a CT pulmonary angiogram considered. Central chest pain which radiates through to the back may represent aortic dissection which is a surgical emergency and ECG-gated CT imaging should be performed if this condition is suspected. Other cardiovascular symptoms such as breathlessness, leg swelling, orthopnoea and reduced exercise tolerance may indicate heart failure which may have a valvular, structural, or chronic ischaemic cause. In this instance echocardiography should be considered. Palpitations and syncope may represent arrythmias in which case rhythm monitoring should be commenced. Detailed clinical examination is important as this may indicate signs of systematic illness or infection. An accurate medication history for both prescribed and not prescribed drugs is also essential as these may be causal for myocardial injury including previous chemotherapy agents and use of illicit substances such as methamphetamine or cocaine.When there is a <20% change in troponin concentration on serial sampling then myocardial injury should be classified as chronic. Similar consideration of the underlying mechanism of myocardial injury is important, particularly the exclusion of structural or hypertensive heart disease, and treatment should be optimised such as the case in heart failure or chronic kidney disease.In instances where cardiac imaging does not identify a clear cause of myocardial injury in otherwise healthy individuals, clinicians should always consider laboratory error and the possibility of analytical false positive results. This may occur due to heterophilic antibodies or interferents, which can occur in ~1 in 1000 patients. In addition to laboratory testing, clinicians should consider measuring an alternative commercially available troponin assay to determine if results are concordant. This is particularly relevant for future admissions to avoid unnecessary investigation or treatment.Patients with acute and chronic myocardial injury are heterogenous, and an individualised management strategy is needed for each patient. Careful attention to the underlying mechanism of injury is important as a given treatment pathway may be advantageous for one patient but cause harm to another. For example, consider an elderly patient with a background of chronic kidney disease and known moderate aortic stenosis. They present with breathlessness and have stable troponin concentrations above the 99th percentile. Their last echocardiogram was within one month which demonstrated unchanged left ventricular function and similar aortic valve velocities to six months prior. Further investigation is unlikely to influence management and will increase the healthcare burden with no clear benefit to the patient, although it would be important to review the echocardiogram to ensure the assessment of severity is accurate as if severe, elevated cardiac troponin concentrations are independently associated with mid-wall fibrosis and may merit assessment for early valve replacement as outcomes in this group are much worse . On the The implementation of highly sensitive troponin testing in an aging population has increased the prevalence of acute and chronic myocardial injury in practice. Myocardial injury is associated with worse outcomes irrespective of the underlying mechanism. Defining the underlying cause of myocardial injury is important and may have therapeutic implications that could change care and prognosis.


Relationships between right ventricular (RV) and left ventricular (LV) shape and function may be useful in determining optimal timing for pulmonary valve replacement in patients with repaired tetralogy of Fallot (rTOF). However, these are multivariate and difficult to quantify. We aimed to quantify variations in biventricular shape associated with pulmonary regurgitant volume (PRV) in rTOF using a biventricular atlas.In this cross-sectional retrospective study, a biventricular shape model was customized to cardiovascular magnetic resonance (CMR) images from 88 rTOF patients . Morphometric scores quantifying biventricular shape at end-diastole and end-systole were computed using principal component analysis. Multivariate linear regression was used to quantify biventricular shape associations with PRV, corrected for age, sex, height, and weight. Regional associations were confirmed by univariate correlations with distances and angles computed from the models, as well as global systolic strains computed from changes in arc length from end-diastole to end-systole.PRV was significantly associated with 5 biventricular morphometric scores, independent of covariates, and accounted for 12.3% of total shape variation (p < 0.05). Increasing PRV was associated with RV dilation and basal bulging, in conjunction with decreased LV septal-lateral dimension (LV flattening) and systolic septal motion towards the RV . Increased global RV radial, longitudinal, circumferential and LV radial systolic strains were significantly associated with increased PRV .A biventricular atlas of rTOF patients quantified multivariate relationships between left–right ventricular morphometry and wall motion with pulmonary regurgitation. Regional RV dilation, LV reduction, LV septal-lateral flattening and increased RV strain were all associated with increased pulmonary regurgitant volume. Morphometric scores provide simple metrics linking mechanisms for structural and functional alteration with important clinical indices.The online version contains supplementary material available at 10.1186/s12968-021-00780-x. The survival rate of repaired tetralogy of Fallot (rTOF) patients has greatly increased due to the improvement of surgical repair. Currently, the early mortality rate is below 2%  and the Studies of RV remodeling in rTOF have demonstrated a strong relationship between RV dilation, RV bulging, and apical dilation with the presence of pulmonary regurgitation –14. HoweHere, we use a biventricular atlas  to quantCardiovascular magnetic resonance (CMR) examinations and clinical data from 88 rTOF patients were obtained from the Cardiac Atlas Project (CAP) congenital heart disease database .CAP is a large-scale database of cardiac images and limited associated clinical data that facilitates data sharing for the development of new methods for image analysis and collaborative statistical analysis of heart shape and function across multiple cohorts . Datasets related to congenital heart disease were added to the CAP beginning in 2015.In this paper, deidentified datasets were contributed from two clinical centers  with approval from local institutional review boards compatible with data sharing. Demographic data are shown in Table CMR images were acquired with either prospectively or retrospectively electrocardiogram (ECG) gated balanced steady-state free-precession cine sequence on 1.5 T CMR scanners  during breath-holding. The short axis slices were acquired parallel to the tricuspid annulus plane and spanned both ventricles. Long-axis slices were obtained through all valves in standard 4-chamber, 2-chamber, LV outflow tract and RV outflow tract views. Typical imaging parameters were: repetition time 24-32 ms; echo time 1.1–1.5 ms; flip angle 70–80°; pixel size reconstructed to in plane 0.59–1.75 3, temporal resolution = 37–41 ms, flip angle of 15°-30°. Scouts were used to set the velocity encoding.Antegrade and retrograde pulmonary flow measurements were obtained from two-dimensional phase contrast (2D PC) imaging. PC analysis of antegrade and retrograde flows in the main artery was performed on a plane at a location just below the pulmonary artery (PA) bifurcation and perpendicular to the axis of the PA. Typical imaging parameters were: acceleration factor 3, echo time = 2.3–3.0 ms, repetition time = 4.8–5.0 ms, field of view = 169–315 mm × 300–420 mm, spatial resolution = (1.4–2.0) × (1.4–2.0) × (5–8) mmContours were drawn manually on both long axis and short axis cine slices by one expert analyst using Segment . ContourA biventricular subdivision surface template mesh was constructed as described previously . An over2 with median of 23.7 and IQR  ml/m2 (Table Pulmonary regurgitation was quantified from CMR imaging using pulmonary regurgitant volume indexed to body surface area (PRVI) as this has been shown to be a more accurate reflection of regurgitation severity compared with pulmonary regurgitant fraction , 33–35.  and IQR 4.2, 33.3A linear regression model was constructed to estimate associations with biventricular heart shape, using the morphometric scores as the response (dependent) variables . PRVI, hRegional shape variations associated with PRVI were confirmed using univariate regression models for specific features derived from the 3D patient-specific biventricular models. These included: basal bulge, tricuspid tilting, apical dilation, RV and LV anterior–posterior dimensions and lateral to septal dimensions Fig. . Basal b0 the length at ED. Changes in geometric arc length have previously shown good agreement with myocardial strain derived from tagging and displacement encoded CMR[To further study interventricular relationships, model-derived systolic deformations for both chambers were assessed. Geometric strain was defined as the change in geometric arc length from ED to ES. Longitudinal strain (LS), which represents the longitudinal shortening of the cardiac muscle, and circumferential strain (CS), shortening along the circular perimeter, and radial strain (RS), thickening of the wall during systole, were derived from length changes between ED and ES using the Cauchy strain formula:coded CMR, 39. Forcoded CMR using thUnivariate regression models were used to quantify the association between LV and RV strains and the amount of regurgitation. Although systolic CS and LS are conventionally negative, their absolute values were used in this study for simpler interpretation of the association with PRVI.Statistical analysis was carried out with R  , are shown in Fig. The first 24 PCA modes accounted for 90.2% of the total shape variance and were selected to perform the multivariate regression. Morphometric scores were used as outcome (dependent) variables and sex, height, weight, age, degree of tricuspid regurgitation, and PRVI were used as predictor (independent) variables. The relationships between each predictor variable and the associated shapes were visualized using the method described in “Appendix”.Height was a significant predictor in modes 1, 4, 9 and 15 , accounting for 27% of the total variation. Weight was a significant predictor in modes 1 and 4 , age in modes 6, 9 and 14  and sex in modes 1, 8, 9 and 14 .Tricuspid regurgitation was significant predictor in modes 4 and 11 (p < 0.001 and p = 0.003 respectively). PRVI had significant effects on mode 1 , mode 2 , mode 4 , mode 7  and mode 8 . Combining these scores, PRVI accounted for 12.3% of the total shape variation. A positive (negative) PE indicates increasing (decreasing) morphometric scores. For example, PRVI was associated with a negative coefficient for mode 1, meaning that as PRVI increased, patients had larger hearts. Figure 2, at both ED and ES. Displacements outward from the LV are shown in red, displacements inwards towards the LV are shown in blue. The dilation of the RV outflow tract and apex are confirmed, as well as diminution of the LV. The associations between shape and PRVI were similar if height and weight were replaced by BSA in the predictor variables, and also if height and weight and age were replaced by BSA. The results were therefore robust to different methods of accounting for body habitus.An animation of these shape differences can be found in Additional file Results of the univariate regression models performed with specific shape features are summarized in Table 2, and a PRVI of 40 ml/m2. Displacements outward from the LV are shown in red, displacements inwards towards the LV are shown in blue.To illustrate and quantify the paradoxical septal motion, Fig. LS, CS, and RS for LV and RV are shown in Table Adults with rTOF are exposed to ongoing physiologic sequelae of surgical interventions, causing remodeling which affects both the LV and RV. This cross-sectional study used atlas-based shape analysis to enable precise quantification of complex shape differences associated with pulmonary regurgitation. We used linear regression methods to control for confounding variables, and quantified independent effects associated with PRVI. PRVI explained more shape variance than any principal component except for the first (size mode), highlighting its importance in biventricular remodeling. Increasing PRVI was associated with dilation of the RV apex and outflow tract, together with a diminution of the LV and flattening in which the lateral free wall to septum distance decreased. Increasing PRVI was also associated with increased RV RS, LS and CS, as well as an increase in LV RS.2 and/or RV end-diastolic volume index (EDVI) > 160 ml/m2 is observed [. [In the INDICATOR cohort study , 45, preobserved , 47. Howobserved  and otheobserved , 50. Smaobserved , as in tobserved , as seenobserved . Fernanderved [. . Our metThe atlas captured regional shape differences and also reproduced global mass and volume with acceptable bias and precision Table . SimilarShape models and atlas-based methods have previously shown RV shape changes associated with PR , 36, 53.In the German Competence Network rTOF study, reduced LV CS and RV LS were independent predictors of adverse outcomes . Decreas. [. [Our study also found a relationship between RV longitudinal shortening and the amount of regurgitation, in agreement with Ylitalo et al. . However.  and Ouya. [.  found an. [. , 22, 43.. [The type of primary repair has also been shown to affect RV shape . Zaidi e.  found diAlthough data sharing mechanisms provided through the CAP enable merging of data from different institutions, access to clinical information was limited. Data on ethnicity was not available. Indices of RV pressure loading were not available, and investigation of pressure effects requires further study, ideally using measurements from catheter recordings. The interpretation of strain measurements in the rTOF population is also difficult due to the competing effects of increased force of contraction with higher preload, and decompensating RV contractility. Another limitation of the study is the use of cross-sectional data. The temporal evolution of ventricular dysfunction in relation to regurgitation should be performed in longitudinal studies. Finally, our study did not quantify dyssynchrony (due to right bundle branch block) or late gadolinium enhancement patterns, which may be have important effects on biventricular function , 62.Future application of these methods will examine quantitative shape changes in relation to interventions and clinically significant metrics, including pulmonary valve replacement and adverse outcomes. The distillation of complex shape features into a small number of morphometric scores allow precise quantification of mechanistic effects linking structural and functional alterations to a variety of clinical measures, including rhythm disturbances, functional score, restrictive RV physiology, and exercise capacity. Relationships between morphometric scores and future adverse outcomes will enable examination of mechanisms of developing risk. Fully automated analysis including quantification of contours, biventricular shape model customization, and computation of scores relative to reference populations, is now possible using machine learning and AI methods.Biventricular morphometric relationships with important clinical features can be quantified in rTOF patients. Increasing PR is associated with LV diminution and septal flattening, in conjunction with RV dilation, especially at the base and apex, as well as an increase in RV systolic strain. Specific and quantifiable biventricular shape characteristics, revealed in biventricular models of rTOF, can be used to quantitatively evaluate RV and LV dysfunction in these patients. This study provides a basis for including quantitative shape analysis into the clinician’s toolbox, providing simple scores which express complex features that experienced clinicians may well recognize but which have been difficult to report until now.Additional file 1. Animation of the first four PCA components. Left: anterior view. Right: posterior view. “s” indicates the number of standard variations.Additional file 2. Shape changes due to pulmonary regurgitation. Left: anterior view. Right: posterior view. “s” indicates the number of standard variations.