Deep neural network-based clustering of deformation curves reveals novel disease features in PLN pathogenic variant carriers.

Echocardiographic deformation curves provide detailed information on myocardial function. Deep neural networks (DNNs) may enable automated detection of disease features in deformation curves, and improve the clinical assessment of these curves. We aimed to investigate whether an explainable DNN-based pipeline can be used to detect and visualize disease features in echocardiographic deformation curves of phospholamban (PLN) p.Arg14del variant carriers. A DNN was trained to discriminate PLN variant carriers (n = 278) from control subjects (n = 621) using raw deformation curves obtained by 2D-speckle tracking in the longitudinal axis. A visualization technique was used to identify the parts of these curves that were used by the DNN for classification. The PLN variant carriers were clustered according to the output of the visualization technique. The DNN showed excellent discriminatory performance (C-statistic 0.93 [95% CI 0.87-0.97]). We identified four clusters with PLN-associated disease features in the deformation curves. Two clusters showed previously described features: apical post-systolic shortening and reduced systolic strain. The two other clusters revealed novel features, both reflecting delayed relaxation. Additionally, a fifth cluster was identified containing variant carriers without disease features in the deformation curves, who were classified as controls by the DNN. This latter cluster had a very benign disease course regarding development of ventricular arrhythmias. Applying an explainable DNN-based pipeline to myocardial deformation curves enables automated detection and visualization of disease features. In PLN variant carriers, we discovered novel disease features which may improve individual risk stratification. Applying this approach to other diseases will further expand our knowledge on disease-specific deformation patterns. Overview of the deep neural network-based pipeline for feature detection in myocardial deformation curves. Firstly, phospholamban (PLN) p.Arg14del variant carriers and controls were selected and a deep neural network (DNN) was trained to detect the PLN variant carriers. Subsequently, a clustering-based approach was performed on the attention maps of the DNN, which revealed 4 distinct phenotypes of PLN variant carriers with different prognoses. Moreover, a cluster without features and a benign prognosis was detected.

Left atrial remodeling in mitral regurgitation: A combined experimental-computational study.

AIMS: Progressive changes to left atrial (LA) structure and function following mitral regurgitation (MR) remain incompletely understood. This study aimed to demonstrate potential underlying mechanisms using experimental canine models and computer simulations. METHODS: A canine model of MR was created by cauterization of mitral chordae followed by radiofrequency ablation-induced left bundle-branch block (LBBB) after 4 weeks (MR-LBBB group). Animals with LBBB alone served as control. Echocardiography was performed at baseline, acutely after MR induction, and at 4 and 20 weeks, and correlated with histology and computer simulations. RESULTS: Acute MR augmented LA reservoir and contractile strain (40±4 to 53±6% and -11±5 to -22±9% respectively, p<0.05). LA fractional area change increased significantly (47±4 to 56±4%, p<0.05) while LA end-systolic area remained unchanged (7.2±1.1 versus 7.9±1.1 cm2 respectively, p = 0.08). LA strain 'pseudonormalized' after 4 weeks and decompensated at 20 weeks with both strains decreasing to 25±6% and -3±2% respectively (p<0.05) together with a progressive increase in LA end-systolic area (7.2±1.1 to 14.0±6.3 cm2, p<0.05). In the LBBB-group, LA remodeling was less pronounced. Histology showed a trend towards increased interstitial fibrosis in the LA of the MR-LBBB group. Computer simulations indicated that the progressive changes in LA structure and function are a combination of progressive eccentric remodeling and fibrosis. CONCLUSION: MR augmented LA strain acutely to supranormal values without significant LA dilation. However, over time, LA strain gradually decreases (pseudornormal and decompensated) with LA dilation. Histology and computer simulations indicated a correlation to a varying degree of LA eccentric remodeling and fibrosis.

Feasibility, safety and outcomes of upgrading to left bundle branch pacing in patients with right ventricular pacing induced cardiomyopathy.

BACKGROUND: Right ventricular pacing (RVP) induces abnormal electrical activation and asynchronous ventricular contraction and leads to pacing induced cardiomyopathy (PICM) in 10%-20% of patients. Cardiac resynchronization therapy (CRT) utilizing biventricular pacing (BVP) is the recommended treatment. Left bundle branch pacing (LBBP) is a novel physiological pacing technique which may serve as an alternative to CRT. This study assessed feasibility and outcomes of LBBP delivered CRT in patients with PICM. METHODS: Total 20 consecutive patients with PICM who received an upgrade of their pacemaker to LBBP were prospectively studied. Acute success rate, complications, functional and echocardiographic response, and hospitalization for heart failure within 6 months from implantation were evaluated. RESULTS: LBBP was successfully delivered in all patients. Median duration of RVP before upgrade to LBBP was 3.8 years and the RVP was 99%. LBBP resulted in significant QRS narrowing (from 193 ± 18 ms to 130 ± 17 ms [p < .001]), improvement in LVEF (from 32% ± 6 % to 47% ± 8% [p < .001]) and NYHA class (from 2.8 ± 0.4 to 1.4 ± 0.5 [p < .001]) at 6 months. No LBBP-related complications occurred. No patients were hospitalized for heart failure or died. CONCLUSION: LBBP is feasible and safe in delivering CRT in PICM. Preliminary analyses demonstrated significant electrical resynchronization and favorable improvement in LV function and NYHA functional class at short term follow-up. Data needs to be validated in large randomized controlled trials.

Hypothermia for Cardioprotection in Patients with St-Elevation Myocardial Infarction: Do Not Give It the Cold Shoulder Yet!

The timely revascularization of an occluded coronary artery is the cornerstone of treatment in patients with ST-elevation myocardial infarction (STEMI). As essential as this treatment is, it can also cause additional damage to cardiomyocytes that were still viable before reperfusion, increasing infarct size. This has been termed "myocardial reperfusion injury". To date, there is still no effective treatment for myocardial reperfusion injury in patients with STEMI. While numerous attempts have been made to overcome this hurdle with various experimental therapies, the common denominator of these therapies is that, although they often work in the preclinical setting, they fail to demonstrate the same results in human trials. Hypothermia is an example of such a therapy. Although promising results were derived from experimental studies, multiple randomized controlled trials failed to do the same. This review includes a discussion of hypothermia as a potential treatment for myocardial reperfusion injury, including lessons learned from previous (negative) trials, advanced techniques and materials in current hypothermic treatment, and the possible future of hypothermia for cardioprotection in patients with STEMI.

Left atrial reverse remodeling predicts long-term survival after cardiac resynchronization therapy.

BACKGROUND: Left ventricular (LV) reverse remodeling has been identified as a strong predictor of long-term survival in patients receiving CRT. Interestingly, CRT induces reverse remodeling in the left atrium (LA) as well. It is currently unknown to what extent LA reverse remodeling is correlated to long-term survival after CRT. This study aims to assess the long-term prognostic value of left atrium (LA) reverse remodeling in patients undergoing cardiac resynchronization therapy (CRT). METHODS: Baseline and 3-months follow-up echocardiograms after CRT implantation were prospectively assessed to determine changes in left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), left atrial volume (LAV), and left atrial reservoir strain (LASr). Multivariate Cox regression analysis was performed to identify predictors for long-term survival. RESULTS: In our study population of 99 patients with a mean follow-up of 6.3 ± 2.1 years, 43 patients (43%) reached the end-point of all-cause mortality. More extensive LA reverse remodeling, as measured by a relative increase in LASr, was observed in survivors compared to non-survivors (43 [29-64] % vs. 8 [2-28] %, P < 0.001, respectively). After multivariate analysis, delta LASr remained the only significant predictor of mortality [HR per 5%: 0.90 (0.86-0.95); AUC 0.78 (0.68-0.88)]. CONCLUSION: An increase in LASr is associated with favorable long-term outcome after CRT. The observed clinical importance of LA reverse remodeling after CRT asks for further validation in larger prospective cohorts.

Deep learning for prediction of fractional flow reserve from resting coronary pressure curves.

BACKGROUND: It would be ideal for a non-hyperaemic index to predict fractional flow reserve (FFR) more accurately, given FFR's extensive validation in a multitude of clinical settings. AIMS: The aim of this study was to derive a novel non-hyperaemic algorithm based on deep learning and to validate it in an internal validation cohort against FFR. METHODS: The ARTIST study is a post hoc analysis of three previously published studies. In a derivation cohort (random 80% sample of the total cohort) a deep neural network was trained (deep learning) with paired examples of resting coronary pressure curves and their FFR values. The resulting algorithm was validated against unseen resting pressure curves from a random 20% sample of the total cohort. The primary endpoint was diagnostic accuracy of the deep learning-derived algorithms against binary FFR ≤0.8. To reduce the variance in the precision, we used a fivefold cross-validation procedure. RESULTS: A total of 1,666 patients with 1,718 coronary lesions and 2,928 coronary pressure tracings were included. The diagnostic accuracy of our convolutional neural network (CNN) and recurrent neural networks (RNN) against binary FFR ≤0.80 was 79.6±1.9% and 77.6±2.3%, respectively. There was no statistically significant difference between the accuracy of our neural networks to predict binary FFR and the most accurate non-hyperaemic pressure ratio (NHPR). CONCLUSIONS: Compared to standard derivation of resting pressure ratios, we did not find a significant improvement in FFR prediction when resting data are analysed using artificial intelligence approaches. Our findings strongly suggest that a larger class of hidden information within resting pressure traces is not the main cause of the known disagreement between resting indices and FFR. Therefore, if clinicians want to use FFR for clinical decision making, hyperaemia induction should remain the standard practice.

Development of an algorithm for automatic classification of right ventricle deformation patterns in arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Different disease stages of arrhythmogenic right ventricular cardiomyopathy (ARVC) can be identified by right ventricle (RV) longitudinal deformation (strain) patterns. This requires assessment of the onset of shortening, (systolic) peak strain, and postsystolic index, which is time-consuming and prone to inter- and intra-observer variability. The aim of this study was to design and validate an algorithm to automatically classify RV deformation patterns. METHODS: We developed an algorithm based on specific local characteristics from the strain curves to detect the parameters required for classification. Determination of the onset of shortening by the algorithm was compared to manual determination by an experienced operator in a dataset containing 186 RV strain curves from 26 subjects carrying a pathogenic plakophilin-2 (PKP2) mutation and 36 healthy subjects. Classification agreement between operator and algorithm was solely based on differences in onset shortening, as the remaining parameters required for classification of RV deformation patterns could be directly obtained from the strain curves. RESULTS: The median difference between the onset of shortening determined by the experienced operator and by the automatic detector was 5.3 ms [inter-quartile range (IQR) 2.7-8.6 ms]. 96% of the differences were within 1 time frame. Both methods correlated significantly with ρ = 0.97 (P < .001). For 26 PKP2 mutation carriers, there was 100% agreement in classification between the algorithm and experienced operator. CONCLUSION: The determination of the onset of shortening by the experienced operator was comparable to the algorithm. Our computer algorithm seems a promising method for the automatic classification of RV deformation patterns. The algorithm is publicly available at the MathWorks File Exchange.

The Prognostic Value of Right Ventricular Deformation Imaging in Early Arrhythmogenic Right Ventricular Cardiomyopathy.

OBJECTIVES: The aim of this study was to investigate the prognostic value of echocardiographic deformation imaging in arrhythmogenic right ventricular cardiomyopathy (ARVC) to optimize family screening protocols. BACKGROUND: ARVC is characterized by variable disease expressivity among family members, which complicates family screening protocols. Previous reports have shown that echocardiographic deformation imaging detects abnormal right ventricular (RV) deformation in the absence of established disease expression in ARVC. METHODS: First-degree relatives of patients with ARVC were evaluated according to 2010 task force criteria, including RV deformation imaging (n = 128). Relatives fulfilling structural task force criteria were excluded for further analysis. At baseline, deformation patterns of the subtricuspid region were scored as type I (normal deformation), type II (delayed onset, decreased systolic peak, and post-systolic shortening), or type III (systolic stretching and large post-systolic shortening). The final study population comprised relatives who underwent a second evaluation during follow-up. Disease progression was defined as the development of a new 2010 task force criterion during follow-up that was absent at baseline. RESULTS: Sixty-five relatives underwent a second evaluation after a mean follow-up period of 3.7 ± 2.1 years. At baseline, 28 relatives (43%) had normal deformation (type I), and 37 relatives (57%) had abnormal deformation (type II or III) in the subtricuspid region. Disease progression occurred in 4% of the relatives with normal deformation at baseline and in 43% of the relatives with abnormal deformation at baseline (p < 0.001). Positive and negative predictive values of abnormal deformation were, respectively, 43% (95% confidence interval: 27% to 61%) and 96% (95% confidence interval: 82% to 100%). CONCLUSIONS: Normal RV deformation in the subtricuspid region is associated with absence of disease progression during nearly 4-year follow-up in relatives of patients with ARVC. Abnormal RV deformation seems to precede the established signs of ARVC. RV deformation imaging may potentially play an important role in ARVC family screening protocols.

The concept of triple wavefront fusion during biventricular pacing: Using the EGM to produce the best acute hemodynamic improvement in CRT.

BACKGROUND: Previous reports suggest that biventricular pacing (BiVp) fused with intrinsic conduction (BiVp-fusion, triple wavefront fusion) is associated with improved resynchronization compared to pure-BiVp in cardiac resynchronization therapy (CRT). This study aimed to assess the association between acute hemodynamic benefit of CRT and signs of BiVp-fusion by using a novel electrogram (EGM)-based method. METHODS: In 17 patients undergoing CRT implantation, 28 combinations of atrioventricular (AV) and interventricular (VV) delays were applied while invasively measuring acute hemodynamic response based on maximum rate of left ventricular (LV) pressure rise (LV dP/dtmax ) to assess optimal BiVp settings. BiVp-fusion was noted if farfield signal (caused by first intrinsic ventricular depolarization) was seen prior to right ventricular (RV) pacing (RVp) artifact on integrated bipolar RV EGM, or QRS morphology changed compared to pure-BiVp (short AV-delay) as seen on electrocardiogram (ECG). RESULTS: Mean optimal RVp timing was at 98 ± 17% of intrinsic right atrial (RA)-RVfarfield (interval from right atrial pace or sense to RV farfield signal) interval, while preactivating the LV at 50 ± 11% of RA-RVsense (interval from right atrial pace or sense to RV sense interval) interval. BiVp-fusion was noted in 16 of 17 (94%) patients on ECG during optimal BiVp. Eight of these patients showed intrinsic farfield signal prior to RVp artifact on RV EGM. In the remaining eight, the RVp was paced just within the RA-RVfarfield interval with a mean of 25 ± 14 ms prior to the onset; therefore, the intrinsic farfield was masked. CONCLUSION: Optimal hemodynamic BiVp facilitates triple wavefront fusion, by pacing the RV around the onset of intrinsic farfield signal on RV EGM, while preactivating the LV. Aiming at BiVp-fusion could be a target for noninvasive EGM-based CRT device setting optimization.

Cardiac phenotype and long-term prognosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia patients with late presentation.

BACKGROUND: The clinical profile of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) patients with late presentation is unknown. OBJECTIVE: The purpose of this study was to characterize the genotype, cardiac phenotype, and long-term outcomes of ARVC/D patients with late presentation (age ≥50 years at diagnosis). METHODS: Five hundred two patients with an ARVC/D diagnosis from Johns Hopkins and Utrecht Registries were studied and long-term clinical outcomes ascertained. RESULTS: Late presentation was seen in 104 patients (21%; 38% PKP2 carriers); 3% were ≥65 years at diagnosis. Sustained ventricular tachycardia was the major (43%) mode of presentation in patients with late presentation, whereas cardiac syncope was infrequent (P <.001). Those with late presentation were significantly less likely to harbor a known pathogenic mutation (53%; P = .005), have less precordial T-wave repolarization changes (P <.001), and have lower ventricular ectopy burden (P = .026). Over median 6-year follow-up, 68 patients with late presentation (65%) experienced sustained ventricular arrhythmias, with similar arrhythmia-free survival at 5-year follow up (P = .48). Left ventricular dysfunction and heart failure were seen in 24 (32%) and 15 patients (14%), respectively, without need for cardiac transplantation. In the late presentation cohort, male sex, pathogenic mutation, right ventricular structural disease, lack of family history, and electrophysiologic study inducibility were associated with increased arrhythmic risk. CONCLUSION: One-fifth of all ARVC/D patients present after age 50 years, often with sustained ventricular tachycardia, and are less likely to have prior syncope, ECG changes, ventricular ectopy, or identifiable pathogenic mutation. In ARVC/D, late presentation does not confer a benign prognosis and is associated with high arrhythmic risk.

Evaluation of Structural Progression in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy.

Importance: Considerable research has described the arrhythmic course of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). However, objective data characterizing structural progression, such as ventricular enlargement and cardiac dysfunction, in ARVD/C are relatively scarce. Objectives: To define the extent of structural progression, identify determinants of structural progression, and determine the association between structural progression and electrocardiographic (ECG) changes in patients with ARVD/C. Design, Setting, and Participants: In this cohort study, first- and last-available echocardiograms of 85 patients with ARVD/C fulfilling 2010 Task Force diagnostic criteria (TFC) from a transatlantic ARVD/C registry were retrospectively compared to assess structural disease progression. Right ventricular (RV) size and systolic function between baseline and last follow-up were compared. The RV size was determined by RV outflow tract dimension, and RV and left ventricular (LV) systolic function were determined by RV fractional area change (RV-FAC) and LV ejection fraction (LVEF), respectively. Multivariable logistic regression was used to study associations between baseline characteristics and the occurrence of structural progression. Main Outcomes and Measures: The main outcome was the change in variables indicating structural progression. Secondary outcomes were the correlation with electrical progression and identification of the association between baseline characteristics and occurence structural progression. Results: Among the 85 patients with ARVD/C, mean (SD) age at baseline was 42.8 (14.4) years and 47 (55%) were men. After a mean (SD) follow-up of 6.4 (2.5) years, RV outflow tract dimension increased from 35 mm (interquartile range [IQR], 31 to 39) to 37 mm (IQR, 33 to 41) (P < .001), RV-FAC decreased from 39% (IQR, 33% to 44%) to 34% (IQR, 24% to 42%) (P < .001) (rate -3.3% per 5 years; IQR, -8.9% to 1.2%), indicating large interpatient variability. The LVEF decreased from 55% (IQR, 52% to 60%) to 54% (IQR, 49% to 57%) (P = .001) (rate, -0.2% per 5 years; IQR, -6.5% to 1.7%). Forty examinations were reanalyzed to establish the measurement error. Patients exceeding the measurement error by ±2 SDs were identified with significant progressive disease for RV, with a decrease in RV-FAC greater than 10% (n = 21) and, for LV, a decrease in LVEF greater than 7% (n = 23). Progression of RV disease was associated with depolarization criteria at baseline (odds ratio [OR], 9.0; 95% CI, 1.1-74.2; P = .04), whereas progression of LV disease was associated with phospholamban (PLN) mutation (OR, 8.8; 95% CI, 2.1-37.2; P = .003). There was no association between progressive RV/LV structural disease and newly developed ECG TFC. Conclusions and Relevance: Structural dysfunction in ARVD/C is progressive with substantial interpatient variability. Significant structural RV progression was associated with prior depolarization abnormalities, whereas LV progression is modified by genetic background. Structural progression was not associated with development of new ECG TFC. The results of this study pave the way for designing and launching trials aimed at reducing structural progression in patients with ARVD/C.

Right Ventricular Imaging and Computer Simulation for Electromechanical Substrate Characterization in Arrhythmogenic Right Ventricular Cardiomyopathy.

BACKGROUND: Previous studies suggested that electrical abnormalities precede overt structural disease in arrhythmogenic right ventricular cardiomyopathy (ARVC). Abnormal RV deformation has been reported in early ARVC without structural abnormalities. The pathophysiological mechanisms underlying these abnormalities remain unknown. OBJECTIVES: The authors used imaging and computer simulation to differentiate electrical from mechanical tissue substrates among ARVC clinical stages. METHODS: ARVC desmosomal mutation carriers (n = 84) were evaluated by electrocardiography (ECG), Holter monitoring, late-enhancement cardiac magnetic resonance imaging, and echocardiographic RV deformation imaging. Subjects were categorized based on the presence of 2010 International Task Force criteria: 1) subclinical stage (n = 21); 2) electrical stage (n = 15); and 3) structural stage (n = 48). Late enhancement was not present in any subclinical or electrical stage subjects. RESULTS: Three distinctive characteristic RV longitudinal deformation patterns were identified: type I: normal deformation (n = 12); type II: delayed onset of shortening, reduced systolic peak strain, and mild post-systolic shortening (n = 35); and type III: systolic stretching with large post-systolic shortening (n = 37). A majority (69%) of structural staged mutation carriers were type III, whereas a large proportion of both electrical and subclinical stage subjects (67% and 48%, respectively) were type II. Computer simulations demonstrated that the type II pattern can be explained by a combination of reduced contractility and mildly increased passive myocardial stiffness. This evolved into type III by aggravating both mechanical substrates. Electrical activation delay alone explained none of the patterns. CONCLUSIONS: Different ARVC stages were characterized by distinct RV deformation patterns, all of which could be reproduced by simulating different degrees of mechanical substrates. Subclinical and electrical staged ARVC subjects already showed signs of local mechanical abnormalities. Our novel approach could lead to earlier disease detection and, thereby, influence current definitions of electrical and subclinical ARVC stages.

Influence of Genotype on Structural Atrial Abnormalities and Atrial Fibrillation or Flutter in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy.

INTRODUCTION: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is associated with desmosomal mutations. Although desmosomal disruption affects both ventricles and atria, little is known about atrial involvement in ARVD/C. OBJECTIVE: To describe the extent and clinical significance of structural atrial involvement and atrial arrhythmias (AA) in ARVD/C stratified by genotype. METHODS: We included 71 patients who met ARVD/C Task Force Criteria and underwent cardiac magnetic resonance (CMR) imaging and molecular genetic analysis. Indexed atrial end-diastolic volume and area-length-ejection-fraction (ALEF) were evaluated on CMR and compared to controls with idiopathic right ventricular outflow tract tachycardia (n = 40). The primary outcome was occurrence of AA (atrial fibrillation or atrial flutter) during follow-up, recorded by 12-lead ECG, Holter monitoring or implantable cardioverter defibrillator (ICD) interrogation. RESULTS: Patients harbored a desmosomal plakophilin-2 (PKP2) (n = 37) or nondesmosomal phospholamban (PLN) (n = 14) mutation. In 20 subjects, no pathogenic mutation was identified. Compared to controls, right atrial (RA) volumes were reduced in PKP2 (P = 0.002) and comparable in PLN (P = 0.441) mutation carriers. In patients with no mutation identified, RA (P = 0.011) and left atrial (P = 0.034) volumes were increased. Bi-atrial ALEF showed no significant difference between the groups. AA were experienced by 27% of patients and occurred equally among PKP2 (30%) and no mutation identified patients (30%), but less among PLN mutation carriers (14%). CONCLUSION: Genotype influences atrial volume and occurrence of AA in ARVD/C. While the incidence of AA is similar in PKP2 mutation carriers and patients with no mutation identified, PKP2 mutation carriers have significantly smaller atria. This suggests a different arrhythmogenic mechanism.

Prolonged Electromechanical Interval Unmasks Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy in the Subclinical Stage.

INTRODUCTION: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by high incidence of ventricular arrhythmias. Overt ARVD/C is preceded by a subclinical stage with lack of detectable ECG and structural abnormalities. Activation delay is present before structural abnormalities and is a hallmark of arrhythmogenesis. Deformation imaging may unmask activation delay in the subclinical stage. METHODS: Three groups were compared: (1) mutation-positive definite ARVD/C-patients fulfilling 2010 Task Force criteria (TFC) (n = 44); (2) asymptomatic mutation carriers not fulfilling TFC and without history of ventricular arrhythmias (n = 31); and (3) controls (n = 30). All underwent ECG and echocardiographic deformation imaging. As a surrogate for local activation delay the electromechanical interval (EMI) was measured, defined as time between onset-QRS and onset of shortening. Arrhythmic outcome (PVC-count, VT) of asymptomatic mutation carriers was correlated with EMI and ECG TFC. RESULTS: In definite ARVD/C-patients, EMI was prolonged in all lateral RV segments. In asymptomatic mutation carriers, prolonged EMI was detected in the subtricuspid area in 14/31. Terminal activation duration ≥55 milliseconds (definition: supporting information) was the only ECG abnormality in this group (8/31). After a mean follow-up of 4.2 ± 3.1 years 10/31 asymptomatic mutation carriers experienced arrhythmic outcome. Prolonged subtricuspid EMI was the only parameter significantly associated with arrhythmogenesis during follow-up. CONCLUSION: In ARVD/C-patients, EMI prolongation was present throughout the RV. In asymptomatic mutation carriers, prolonged EMI in the subtricuspid area is often detected without any additional abnormalities. These preliminary results indicate that prolonged EMI is a new parameter unmasking activation delay in the subclinical stage and may contribute to risk stratification.

Left Ventricular Involvement in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Assessed by Echocardiography Predicts Adverse Clinical Outcome.

BACKGROUND: Among studies describing the phenotype of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), significant discrepancy exists regarding the extent and impact of left ventricular (LV) involvement. The capability of conventional and new quantitative echocardiographic techniques to accurately detect LV involvement in ARVD/C remains unknown. The aim of this study was to test the hypothesis that accurate detection of LV involvement on echocardiography identifies patients at additional risk for cardiac events during follow-up. METHODS: Thirty-eight patients with ARVD/C, 16 pathogenic mutation-positive relatives, and 55 healthy control subjects were prospectively enrolled. Conventional echocardiography with additional deformation imaging was performed in all subjects to detect LV involvement. In a subgroup (n = 27), cardiac magnetic resonance imaging was performed with late enhancement. All patients and relatives were prospectively followed for events (sustained ventricular tachycardia, appropriate implantable cardioverter-defibrillator intervention, sudden cardiac death, and heart transplantation). RESULTS: Conventional echocardiography detected LV involvement in 32% of patients with ARVD/C and in none of the relatives. Deformation imaging revealed LV involvement in 68% of patients with ARVD/C and 25% of relatives and was correlated closely with late enhancement on cardiac magnetic resonance imaging. During a mean follow-up period of 5.9 ± 2.3 years, 20 patients with ARVD/C (53%) experienced events, and no events occurred in the relatives. LV involvement detected by deformation imaging (hazard ratio, 4.9; 95% CI, 1.7-14.2) and right ventricular outflow tract enlargement (hazard ratio, 1.2; 95% CI, 1.1-1.3) were the only independent predictors of outcomes. CONCLUSIONS: Deformation imaging detected a high incidence of LV involvement in patients with ARVD/C and their relatives. Compared with conventional echocardiography, deformation imaging is superior in detecting minor LV involvement. LV involvement and an enlarged right ventricular outflow tract are independent prognostic markers of outcomes.

Volumetric Response beyond Six Months of Cardiac Resynchronization Therapy and Clinical Outcome.

AIMS: Response to cardiac resynchronization therapy (CRT) is often assessed six months after implantation. Our objective was to assess the number of patients changing from responder to non-responder between six and 14 months, so-called late non-responders, and compare them to patients who were responder both at six and 14 months, so-called stable responders. Furthermore, we assessed predictive values of six and 14-month response concerning clinical outcome. METHODS: 105 patients eligible for CRT were enrolled. Clinical, laboratory, ECG, and echocardiographic parameters and patient-reported health status (Kansas City Cardiomyopathy Questionnaire [KCCQ]) were assessed before, and six and 14 months after implantation. Response was defined as ≥15% LVESV decrease as compared to baseline. Major adverse cardiac events (MACE) were registered until 24 months after implantation. Predictive values of six and 14-month response for MACE were examined. RESULTS: In total, 75 (71%) patients were six-month responders of which 12 (16%) patients became late non-responder. At baseline, late non-responders more often had ischemic cardiomyopathy and atrial fibrillation, higher BNP and less dyssynchrony compared to stable responders. At six months, late non-responders showed significantly less LVESV decrease, and higher creatinine levels. Mean KCCQ scores of late non-responders were lower than those of stable responders at every time point, with the difference being significant at 14 months. The 14 months response was a better predictor of MACE than six months response. CONCLUSIONS: The assessment of treatment outcomes after six months of CRT could be premature and response rates beyond might better correlate to long-term clinical outcome.

Current and future role of echocardiography in arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited progressive cardiomyopathy, clinically characterized by ventricular arrhythmias and increased risk of sudden cardiac death. Echocardiography has a role in the diagnosis and prognosis of ARVD/C. However, in the current era of magnetic resonance imaging (MRI), the role of echocardiography in ARVD/C patients and family member screening is subject to debate. Relatively novel echocardiographic techniques, such as three-dimensional right ventricular (3D-RV) imaging and tissue deformation imaging, may improve the diagnostic and prognostic performance of echocardiography in these patients. 3D-RV imaging provides more insights on RV anatomy and global function compared to conventional echocardiography. Subtle RV regional wall motion abnormalities, and mechanical dyssynchrony, are accurately measured by tissue deformation imaging. Several studies suggest an incremental value of novel echocardiographic parameters in addition to conventional measurements. Moreover, new parameters indicating subtle RV dysfunction, and mechanical dyssynchrony, are of predictive value and could help in risk stratification of ARVD/C patients. New robust parameters, derived from 3D-RV echocardiography and RV tissue deformation imaging, in combination with established conventional parameters, suggest that there is a current and future role for echocardiography in ARVD/C supplementing MRI.