Feddo P. Kirkels Towards Clinical Implementation of Deformation Imaging in Genetic Cardiomyopathies
TOWARDS CLINICAL IMPLEMENTATION OF DEFORMATION IMAGING IN GENETIC CARDIOMYOPATHIES Feddo P. Kirkels
ISBN: 978-94-6506-077-4 Provided by thesis specialist Ridderprint, ridderprint.nl Printing: Ridderprint Layout and design: Puck Paassen, persoonlijkproefschrift.nl Financial support by the Dutch Heart Foundation for the publication of this thesis is gratefully acknowledged. Copyright © F.P. Kirkels, 2024 All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form or by any means without prior permission of the copyright owner.
TABLE OF CONTENTS Introduction Chapter 1 General Introduction and Thesis Outline 9 Part I. Deformation imaging methods in ARVC Chapter 2 Improving Diagnostic Value of Echocardiography in Arrhythmogenic Right Ventricular Cardiomyopathy Using Deformation Imaging JACC Cardiovasc Imaging. 2021;14(12):2481-2483. 25 Chapter 3 Right Ventricular Functional Abnormalities in Arrhythmogenic Cardiomyopathy: Association With Life-Threatening Ventricular Arrhythmias JACC Cardiovasc Imaging. 2021;14(5):900-910. 31 Part II. Characterizing the disease substrate underlying deformation abnormalities Chapter 4 Electromechanical Substrate Characterization in Arrhythmogenic Cardiomyopathy Using Imaging-Based Patient-Specific Computer Simulations Europace. 2021;23(Suppl1):i153-i160. 59 Chapter 5 Uncertainty Quantification of Regional Cardiac Tissue Properties in Arrhythmogenic Cardiomyopathy Using Adaptive Multiple Importance Sampling Frontiers in Physiology. 2021;12:738926. 79 Chapter 6 Monitoring of Myocardial Involvement in Early Arrhythmogenic Right Ventricular Cardiomyopathy Across the Age Spectrum J Am Coll Cardiol. 2023;82(9):785-97. 103 Part III. Towards clinical implementation of deformation imaging Chapter 7 Echocardiographic Deformation Imaging for Early Detection of Genetic Cardiomyopathies: A Systematic Review J Am Coll Cardiol. 2022;79(6):594-608. 127 Chapter 8 The Added Value of Abnormal Regional Myocardial Function for Risk Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy Eur Heart J Cardiovasc Imaging. 2023;24(12):1710-1718. 163
Discussion Chapter 9 General Discussion and Future Perspectives 185 Addendum: Left sided wall stress causing arrhythmia Chapter 10 Prevalence of Mitral Annulus Disjunction and Mitral Valve Prolapse in Patients With Idiopathic Ventricular Fibrillation J Am Heart Assoc. 2022;11(16):e025364. 201 Appendices Nederlandstalige samenvatting List of publications Dankwoord/Acknowledgements Curriculum Vitae 222 226 228 234
CHAPTER 1 General Introduction and Thesis Outline
10 | Chapter 1 INTRODUCTION Sudden cardiac death (SCD) resulting from cardiac arrest represents a major public health concern worldwide, accounting for an estimated 15-20% of all deaths.1 Particularly in young, seemingly healthy individuals, it is an event with devastating impact. Families and physicians are left with many unanswered questions: Did we miss any signs? Could it have been prevented? And who else is at risk? It was estimated that in the Netherlands, every three days an individual below the age of 40 dies of SCD.2 While in older patients coronary artery disease is the most common cause of SCD, typical causes in the young are congenital heart disease, heritable electrical disease and heritable cardiomyopathy. Arrhythmogenic right ventricular cardiomyopathy (ARVC), subject of a large part of this thesis, is a relatively common cause of SCD within the latter category. However, both at autopsy and in survivors of sudden cardiac arrest, a substantial amount of cardiac arrests remains unexplained. When no underlying cause is identified after extensive diagnostic testing, patients are diagnosed with idiopathic ventricular fibrillation. This subset of patients is subject of the addendum of this thesis. Arrhythmogenic Right Ventricular Cardiomyopathy ARVC is a genetic cardiomyopathy which is characterized by progressive loss of primarily right ventricular myocardium and its substitution by fibrous and fatty tissue.3 Over the years, several terms were introduced related to this disease. The original term, arrhythmogenic right ventricular dysplasia, refers to the developmental disorder (“dysplasia”) that this disease was thought to be at the time. Later, ARVD was recognized as a progressive disease which develops after birth (“cardiomyopathy”) and after a transition period with the term ARVD/C, it was replaced with ARVC. While the classical and most comprehensively described phenotype primarily affects the right ventricle (RV), a proportion of patients has predominant LV disease. In recent years, the term arrhythmogenic cardiomyopathy (AC) was introduced to cover the whole spectrum of biventricular involvement. In this thesis, the terms AC and ARVC are used interchangeably, but focus is on the classical predominant RV phenotype. Genetic background Early observations of familial disease clustering suggested a genetic basis for ARVC. The Greek physician couple Nikos Protonotarios and Adalena Tsatsopoulou recognized that individuals on the Greek island of Naxos had a form of ARVC in conjunction with a cardiocutaneous syndrome (wooly hair and palmoplantar keratosis).4 In 2000, genetic linkage analysis of patients with socalled Naxos disease started an important breakthrough in defining the genetic background of ARVC.5 The typical phenotype is explained by similar junction structures in myocardial and epidermal tissue. Genetic variants in the gene encoding for plakoglobin were the first disease causing genetic variants identified in patients with ARVC. Plakoglobin is a component of the cardiac desmosome, which is responsible for cell-to-cell adhesion of cardiomyocytes (Figure 1). In subsequent years, more desmosomal variants were linked to ARVC and nowadays likely- (pathogenic) variants are identified in the majority of patients. Most of these disease causing variants in ARVC are inherited in an autosomal dominant pattern. Currently, the most common ARVC-associated gene is plakophilin-2 (PKP2), which was identified in about half of the ARVC patients in the Netherlands and the USA.6 However, also genetic variants in non-desmosomal proteins can cause ARVC, suggesting other pathogenic mechanisms in a final common pathway leading to myocardial fibrosis, fat infiltration and ventricular arrhythmias.7
General Introduction and Thesis Outline | 11 Figure 1. The cardiac desmosome The cardiac desmosome provides mechanical cell-cell contact by connecting the cytoskeletons between cardiac myocytes. The encoded proteins (genes) associated with ARVC are divided into desmosomal (the most common being Plakophilin-2, or PKP2) and non-desmosomal proteins (for instance Phospholamban, or PLN). Pathophysiology The exact pathophysiological mechanism of ARVC is still a matter of debate. Besides the characteristic histopathologic pattern of fibrofatty replacement of myocardium, patchy inflammatory infiltrates are often observed in association with dying myocytes, suggesting that the pathologic process may be immunologically mediated. Wall thinning and aneurysmal dilatation are typically localized in the inflow tract (subtricuspid region) and outflow tract (infundibular region) of the RV.3 While the initial report of ARVC described the RV apex as typical localization for disease manifestation, more recent data showed that the apex is only involved in end-stage disease. On the other hand, the revised “triangle of dysplasia” includes the posterolateral wall of the LV as early affected region.8 It is thought that genetically abnormal desmosomes lead to disruption of intercellular junctions with myocyte detachment and cell death. This process of mechanical uncoupling occurs in reaction to mechanical wall stress and is aggravated by for instance physical exercise.9 The fibrofatty tissue that replaces myocardium forms a substrate for ventricular arrhythmias by slowing intra-ventricular conduction and through scar-related macro-reentry circuits, similar to that in myocardial infarction. Besides mechanical coupling, the desmosome also plays a crucial role in electrical coupling of cardiomyocytes by interacting with gap junctions and the sodium channel complex within the intercalated disc.10 Complex mechanisms operating at this molecular and cellular level may also contribute to occurrence of life-threatening ventricular arrhythmias in ARVC. Clinical presentation The estimated prevalence of ARVC is around 1:2000 to 1:5000 in the general population.9 Inheritance is characterized by incomplete penetrance and varying disease expression. There is age-related penetrance, whereby patients typically become symptomatic between the second and fourth decade of life.6 Clinical presentation of ARVC is variable and may include palpitations, exercise-induced (pre-)syncope, chest pain, and dyspnea. However, life-threatening arrhythmias 1
12 | Chapter 1 and SCD may also be the first clinical manifestation.11 The clinically overt stage is preceded by a “concealed phase” in which no, or only subtle electrical or structural disease manifestation can be identified. The “electrical phase“ is characterized by T-wave inversions and terminal QRS prolongation on electrocardiogram (ECG), premature ventricular complexes (PVCs) and ventricular tachycardia originating from the RV. In the “structural phase”, changes on tissue level lead to regional wall motion abnormalities and in the end-stage potentially heart failure.12 Diagnosis No single test has sufficient sensitivity and specificity to serve as gold standard for ARVC diagnosis. To standardize the clinical diagnosis, a combination of clinical tests was defined in the Task Force Criteria (TFC) from 1994, and later modified in 2010.13 Criteria were divided into six categories: structure/function, tissue characterization, repolarization abnormalities, depolarization abnormalities, arrhythmias, and family history. Criteria considered to have high specificity were classified as major, other criteria as minor. At least two major, 1 major with 2 minor, or 4 minor criteria are required for a definite diagnosis. In general, low specificity of abnormalities associated with ARVC confronts clinicians with the challenge of differentiating ARVC from conditions like idiopathic RV outflowtract tachycardia, cardiac sarcoidosis and other causes of a volume overloaded RV. (Table 1) Treatment and risk stratification With no curative treatment options, current therapeutic strategies aim for symptom reduction and prevention of disease progression and SCD. Restriction of intense sports activity is regarded important in both ARVC patients and family members at risk, since exercise has been shown to provoke arrhythmias and accelerate disease progression. Unfortunately, it remains unclear to what extent exercise should be reduced to prevent harmful effects, while maintaining the physical and mental health benefits of exercise in general.14,15 Despite limited supportive data, beta-blockers are currently recommended in all patients since adrenergic stimulation seems to play a role in provoking ventricular arrhythmias.16 A central component of clinical management of ARVC patients and family members at risk is consideration of an implantable cardioverter defibrillator (ICD). Patients who benefit most from an ICD are those who have had an episode of ventricular fibrillation or sustained ventricular tachycardia. It remains a clinical challenge to select patients who will benefit from primary preventive ICD implantation. Different multivariable models have been developed to assist clinicians in this decision, of which the ARVC risk calculator published in 2019 (www.ARVCrisk.com) is currently the most extensively validated model.17 This tool estimates the 5-year risk of developing a first episode of sustained ventricular arrhythmia in patients with a definite ARVC diagnosis according to the 2010 TFC. Family screening Since ARVC is an inherited cardiomyopathy, family members of ARVC patients may be at risk of developing the disease. With the identification ARVC-causing genetic variants, integration of targeted genetic testing into clinical practice is proliferating. Given the autosomal dominant inheritance, first-degree relatives have a 50% chance of carrying the genetic predisposition for ARVC. However, even in family members carrying the same pathogenic variant as the index patient, cardiac screening is a major challenge because of incomplete penetrance and variable disease expression. Since life-threatening arrhythmias can already occur early in the disease, detection of the earliest signs of disease manifestation in family members is an ongoing quest.
General Introduction and Thesis Outline | 13 Currently, life-long follow-up with intervals of 2-3 years is recommended in all family members at risk.18 The diagnostic framework is provided by the 2010 TFC and requires frequent ECG and Holter monitoring and repeated cardiac imaging with CMR or echocardiography. However, since disease manifestation in family members may be subtle, conventional diagnostics included in the 2010 TFC may lack sensitivity to reveal the earliest structural and functional changes. Table 1. 2010 Task Force criteria proposed by Marcus et al13 Global or regional dysfunction and structural alterations 2D-echo Major Presence of a regional RV akinesia, dyskinesia, or aneurysm and 1 of the following (enddiastole) • PLAX RVOT ≥ 32 mm (corrected for BSA: PLAX RVOT/BSA ≥ 19 mm/m2) or • PSAX RVOT ≥ 36 mm (corrected for BSA: PLAX RVOT/BSA ≥ 21 mm/m2) or • RV-FAC ≤ 33% Minor Presence of a regional RV akinesia, dyskinesia, or aneurysm and 1 of the following (enddiastole): • PLAX RVOT ≥29 to < 32 mm (corrected for BSA: PLAX RVOT/BSA ≥16 to < 19 mm/m2) or • PSAX RVOT ≥ 32 to < 36 mm (corrected for BSA: PSAX RVOT ≥ 18 to < 21 mm/m2) or • RV-FAC > 33% to ≤ 40% MRI Major Presence of a regional RV akinesia or dyskinesia, or dyssynchronous RV contraction and 1 of the following: • Ratio of RV-EDV to BSA ≥ 110 ml/m2 (male) ≥ 100 ml/m2 (female) or • RVEF ≤ 40% Minor Presence of a regional RV akinesia or dyskinesia, or dyssynchronous RV contraction and 1 of the following: • Ratio of RV-EDV to BSA ≥100 < 110 ml/m2 (male) ≥ 90 to < 100 ml/m2 (female) or • RVEF > 40% to ≤ 45% RV angiography Major Presence of regional RV akinesia, dyskinesia, or aneurysm Tissue characterization Major Residual myocytes < 60% by morphometric analysis (or < 50% if estimated), with fibrous replacement of the RV free wall myocardium in ≥1 sample, with or without fatty replacement of tissue on endomyocardial biopsy Minor Residual myocytes 60-75% by morphometric analysis (or 50% to 65% if estimated), with fibrous replacement of the RV free wall myocardium in ≥1 sample, with or without fatty replacement of tissue on endomyocardial biopsy Repolarization abnormalities (ECG) Major Inverted T waves in right precordial leads (V1, V2, and V3) or beyond in individuals >14 years of age (in the absence of complete RBBB QRS ≥ 120 ms) Minor Inverted T waves in leads V1 and V2 in individuals >14 years of age (in the absence of complete RBBB) or Inverted T waves in leads in V4-V6 or Inverted T waves in leads V1-V4 in individuals >14 years of age in the presence of complete RBBB 1
14 | Chapter 1 Table 1. 2010 Task Force criteria proposed by Marcus et al13 (continued) Depolarization abnormalities (ECG) Major Epsilon wave (reproducible low-amplitude signals between end of QRS complex to onset of the T wave) in the right precordial leads (V1 -V3) Minor Late potentials by SA-ECG in ≥ 1 of 3 parameters in the absence of a QRS duration of 110 ms on the standard ECG • Filtered QRS duration (fQRS) ≥ 114 ms • Duration of terminal QRS < 40 µV (low-amplitude signal duration) ≥ 38 ms • Root-mean-square voltage of terminal 40 ms ≤ 20 µV Terminal activation duration of QRS ≥ 55 ms measured from the nadir of the S wave to the end of the QRS, including R’, in V1, V2, or V3, in the absence of complete RBBB Ventricular arrhythmias Major Nonsustained or sustained ventricular tachycardia of LBBB morphology with superior axis (negative or indeterminate QRS in leads II, III, and aVF and positive in lead aVL) Minor Nonsustained or sustained ventricular tachycardia of RV outflow configuration, LBBB morphology with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis >500 premature ventricular complexes per 24 hours (Holter) Family history Major ARVC definite diagnosis confirmed in a first-degree relative who meets current 2010 Task Force criteria ARVC definite diagnosis confirmed pathologically at autopsy or surgery in a firstdegree relative Identification of a pathogenic ARVC related mutation categorized as associated or probably associated with ARVC. Plakoglobin (JUP), Desmoplakin (DSP), Plakophilin-2 (PKP2), Desmoglein-2 (DSG2), Desmocollin-2 (DSC2), transforming growth factor beta-3 (TGFβ3), and transmembrane protein 43 (TMEM43) Minor History of ARVC in a first-degree relative in whom it is not possible or practical to determine whether the family member meets current Task Force criteria ARVC confirmed pathologically or by current Task Force Criteria in second-degree relative Premature sudden death (<35 years of age) due to suspected ARVC in a first-degree relative Definite ARVC diagnosis requires: 2 major, 1 major + 2 minor or 4 minor criteria from different categories of the abovementioned criteria, in the absence of another cause of disease. Abbreviations: ARVC = arrhythmogenic right ventricular cardiomyopathy, ECG = electrocardiography, PLAX/PSAX = parasternal long/short axis view, RVOT = RV outflow tract, BSA = body surface area, RBBB/LBBB = right/left bundle branch block. Echocardiographic deformation imaging Echocardiographic deformation imaging has been proposed as an additional method for detection of early disease manifestation in ARVC.19 This technique has developed over the past two decades as a sensitive method for quantitative assessment of both global and regional contractile function of myocardial tissue. Acoustic markers called “speckles” are tracked in a two-dimensional image plane to estimate relative changes in myocardial length through
General Introduction and Thesis Outline | 15 the cardiac cycle. Changes are expressed in percentages of lengthening or shortening over time and referred to as myocardial strain (Figure 2). Reproducibility of deformation imaging is superior compared to multiple conventional functional measures. Besides, it is more robust compared to visual assessment of regional wall motion abnormalities, which is especially challenging in the thin walled RV and highly dependent on experience of the observer. When compared to other high-end imaging modalities, the non-invasive nature, low cost and wide availability of echocardiographic deformation imaging are important advantages for routine clinical practice. Figure 2. Echocardiographic speckle tracking deformation imaging In the left ventricle, ventricular wall motion is tracked in the apical long axis (APLAX) view, the apical 4-chamber (4CH) and apical 2-chamber (2CH) view. In the right ventricle (RV), the free wall is tracked in an RV-focused 4CH view. The aortic valve closure (AVC) and pulmonic valve closure (PVC) mark the end of the systole. Longitudinal strain is expressed in percentages of lengthening or shortening over time. Longitudinal strain is displayed for 18 LV segments and for 3 RV free wall segments. Systolic peak strain is the peak negative strain occurring up to the moment of valve closure. Previous studies have repeatedly demonstrated the potential value of deformation imaging in ARVC. It was demonstrated that this technique may help to reveal early disease manifestation in desmosomal genetic variant carriers without an overt ARVC phenotype.12,20,21 One study from our own institute identified characteristic deformation patterns in the subtricuspid segment of the RV free wall, known as the first affected region in ARVC. These abnormal patterns were seen in half of the genetic variant carriers without overt signs of disease by conventional diagnostics.12 The CircAdapt model, a computer simulation model of the heart and circulation developed at Maastricht University, was used to link deformation abnormalities to a possible underlying disease substrate of reduced contractility and increased stiffness (Figure 3). The abnormal deformation pattern with delayed onset to shortening, reduced peak strain and post-systolic shortening was a robust finding22 which turned out to be a precursor of disease progression.23 1
16 | Chapter 1 While abnormal subtricuspid deformation patterns were not yet linked to arrhythmic outcome, researchers from Oslo did relate deformation abnormalities to arrhythmic events in the patients history.24,25 They reported strong correlations between RV and LV mechanical dispersion, measures of regional heterogeneity in contraction, and arrhythmic events. A combination of increased mechanical dispersion, T-wave inversions on the ECG, and a history of high intensity exercise was proposed to characterize a high risk profile regarding incidence of ventricular arrhythmias. Although many studies have confirmed the added value of deformation imaging, the technique is still not widely implemented in clinical practice. A possible contributor to this lagging implementation may be that many deformation methods have been used in single center studies without external validation. Second, most studies focus on deformation imaging as a single parameter, while added value should better be tested in a clinical practice based multimodality approach. In this thesis, ARVC is used as a disease model to demonstrate the road to clinical implementation of deformation imaging in genetic cardiomyopathies in general. It focusses both on detection and characterization of the early disease substrate as well as on arrhythmic risk stratification in patients and family-members at risk. Two major clinical challenges for clinicians which go hand in hand.
General Introduction and Thesis Outline | 17 Figure 3. RV deformation patterns Using deformation imaging and computer simulation, 3 distinctive characteristic RV longitudinal deformation patterns were identified by researchers from our institute in 2016.12 (Left) Type I normal deformation as seen in healthy controls. (Middle) Type II, characterized by delayed onset of shortening, reduced systolic peak strain, and minor post-systolic shortening. This pattern was reproduced by the computer simulation of severely reduced contractility and mildly increased passive stiffness in the basal (subtricuspid) RV segment. (Right) Type III, characterized by little or no systolic peak strain, predominantly systolic stretching, and major post-systolic shortening. This pattern was reproduced by introducing severely reduced contractility and severely increased passive stiffness in the basal segment. ECG = electrocardiogram; PVO/PVC = pulmonary valve opening/closure. (Copyright 2016 by Elsevier; reprinted with permission) 1
18 | Chapter 1 THESIS OUTLINE Part I. Deformation imaging methods in ARVC In a clinical evaluation of the diagnostic 2010 TFC, conventional echocardiography lacked sensitivity for ARVC diagnosis.26 This could be partly caused by visual assessment of RV wall motion abnormalities, prerequisite to fulfill a criterion, which is difficult and highly dependent on the observer’s experience. In Chapter 2, we investigated whether inclusion of RV deformation could lead to better detection of ARVC patients by echocardiography compared to conventional echocardiographic methods. While previous studies in ARVC patients and family members from Utrecht identified characteristic regional RV deformation patterns, studies performed in Oslo focused on RV mechanical dispersion, a measure for regional heterogeneity in contraction. Both methods have been successfully applied in subsequent cohorts in the center where they were developed, but were never externally validated. Chapter 3 describes an external validation study for both methods, designed in a way that a single, newly trained observer applied both methods in both cohorts. Besides, we combined data from Utrecht and Oslo to evaluate incremental value of combining the two methods in association to the occurrence of life-threatening ventricular arrhythmia. Part II. Characterizing the disease substrate underlying deformation abnormalities Although the gold standard for characterization of the disease substrate in ARVC is based on histology on tissue acquired by autopsy or biopsy of the thin walled RV, this is not an option in most patients. Deformation abnormalities most likely reflect the local tissue substrate, as was previously supported by simulations with the CircAdapt computer model.12 In this study, a general disease substrate of reduced contractility and increased stiffness was demonstrated. In part II of this thesis, we describe the steps from a general disease simulation to a patient-specific approach with possible clinical applications. This patient-specific cardiac model was used as a so-called Digital Twin, a virtual representation of reality based on a comprehensive physical and functional description of the heart. The idea was to use this Digital Twin to gain more insight in the structural disease substrate in early-stage ARVC. So in a way to use it as a non-invasive myocardial biopsy. The ultimate goal was to try to distinguish arrhythmogenic substrates from the more benign tissue abnormalities leading to deformation abnormalities. In Chapter 4 we apply this patient-specific approach in the cohort of desmosomal pathogenic variant carriers in which the general disease model was first described.27 Deformation data were used as input and the model estimates the underlying disease substrate in a specific patient. Chapter 5 describes the introduction of uncertainty to model estimations. Since both measurements and model estimations introduce uncertainty, this was a necessary step towards longitudinal follow-up of the disease substrate. In Chapter 6, we combined deformation measurements and model estimations to investigate age-related penetrance of ARVC in a longitudinal cohort of patients and family-members without overt structural abnormalities. In a position statement from 2010, it was suggested that serial screening of relatives can be stopped at the age of 50-60 years, due to completed penetrance.28 By monitoring structural progression and occurrence of events in different age groups, we evaluated if penetrance was indeed completed in the older group. Part III. Towards clinical implementation of deformation imaging Part III of this thesis is focused on proceeding deformation imaging into routine clinical practice. Although echocardiographic deformation imaging has already been in use for
General Introduction and Thesis Outline | 19 over two decades, the technique is still not widely implemented in clinical practice. An important step towards wide implementation could be inclusion in clinical guidelines, which requires convincing evidence of the added value of deformation imaging. One important strength of deformation imaging is that it is a more sensitive method for detection of early disease manifestation compared to conventional global imaging parameters. In Chapter 7, we summarized all available evidence regarding the value of deformation imaging in early detection of genetic cardiomyopathies in relatives. While the value of deformation imaging as a stand-alone index has been extensively published, there is a lack of clinical practice based multi-modality studies. Inclusion in clinical guidelines requires evidence of added value in a real-world setting. In other words, it should improve current clinical practice. In Chapter 8 we used ARVC as a model to investigate added value of deformation imaging for arrhythmic risk prediction in a multimodality approach. We integrated deformation imaging with the validated ARVC risk calculator17 to test added value in a clinical practice based approach. Addendum: left-sided wall stress causing arrhythmia In Chapter 10 we provide an addendum to this thesis. Where the subtricuspid region is a weak spot in the RV, the submitral region can be a similar weak spot in the LV. In both cases, the hypothesis is that high mechanical stress on a thin wall can cause life-threatening arrhythmias. Dedicated imaging may help to identify these weak spots. On the right side, ARVC is an important contributor to this weak spot (desmosomal fragility). On the left side, mitral annular disjunction (MAD), defined as atrial displacement of the mitral valve hinge point may cause a weak spot (Figure 4). In the affected area, the thin atrial wall has to withstand the high wall stress which is normally applied to the thick LV wall. This condition recently received increasing attention in relation to unexplained ventricular arrhythmia.29,30 In this chapter, we reanalyzed cardiac magnetic resonance images of patients who survived an unexplained cardiac arrest with special attention to the mitral valve area. Figure 4. Mitral annular disjunction Mitral annular disjunction (MAD) and mitral valve prolapse at end-systole in the longitudinal 3-chamber view on cardiac magnetic resonance imaging (left panel) and in a schematic overview (right panel). The orange arrow indicates the longitudinal MAD distance along the atrial wall. The dashed line connects the annular hinge points and represents the annular plane. The dotted line perpendicular on the annular plane measures the mitral valve prolapse. LA = left atrium, LV = left ventricle. 1
20 | Chapter 1 REFERENCES 1. Hayashi M, Shimizu W, Albert CM. The spectrum of epidemiology underlying sudden cardiac death. Circ Res. 2015;116(12):1887–906. 2. Vaartjes I, Hendrix A, Hertogh EM, et al. Sudden death in persons younger than 40 years of age: Incidence and causes. Eur J Cardiovasc Prev. 2009;16(5):592–6. 3. Marcus FI, Fontaine GH, Guiraudon G, et al. Right ventricular dysplasia: a report of 24 adult cases. Circulation. 1982;65(2):384–98. 4. Protonotarios N, Tsatsopoulou A, Patsourakos P, et al. Cardiac abnormalities in familial palmoplantar keratosis. Heart. 1986;56(4):321–6. 5. McKoy G, Protonotarios N, Crosby A, et al. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet. 2000;355(9221):2119–24. 6. Groeneweg JA, Bhonsale A, James CA, et al. Clinical Presentation, Long-Term Follow-Up, and Outcomes of 1001 Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Patients and Family Members. Circ Cardiovasc Genet. 2015;8(3):437–46. 7. Austin KM, Trembley MA, Chandler SF, et al. Molecular mechanisms of arrhythmogenic cardiomyopathy. Nat Rev Cardiol. 2019;16(9):519–37. 8. Te Riele ASJM, James CA, Philips B, et al. Mutation-positive arrhythmogenic right ventricular dysplasia/ cardiomyopathy: The triangle of dysplasia displaced. J Cardiovasc Electrophysiol. 2013;24(12):1311–20. 9. Corrado D, Link MS, Calkins H. Arrhythmogenic Right Ventricular Cardiomyopathy. Jarcho JA, editor. N Engl J Med. 2017;376(1):61–72. 10. Delmar M, McKenna WJ. The Cardiac Desmosome and Arrhythmogenic Cardiomyopathies. Circ Res. 2010;107(6):700–14. 11. Thiene G, Nava A, Corrado D, Rossi L, Pennelli N. Right Ventricular Cardiomyopathy and Sudden Death in Young People. N Engl J Med. 1988;318(3):129–33. 12. Mast TP, Teske AJ, Walmsley J, et al. Right Ventricular Imaging and Computer Simulation for Electromechanical Substrate Characterization in Arrhythmogenic Right Ventricular Cardiomyopathy. J Am Coll Cardiol. 2016;68(20):2185–97. 13. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/Dysplasia: Proposed modification of the task force criteria. Circulation. 2010;121(13):1533–41. 14. James CA, Bhonsale A, Tichnell C, et al. Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. J Am Coll Cardiol. 2013;62(14):1290–7. 15. Lie ØH, Dejgaard LA, Saberniak J, et al. Harmful Effects of Exercise Intensity and Exercise Duration in Patients With Arrhythmogenic Cardiomyopathy. JACC Clin Electrophysiol. 2018;4(6):744–53. 16. Corrado D, Wichter T, Link MS, et al. Treatment of Arrhythmogenic Right Ventricular Cardiomyopathy/ Dysplasia. Circulation. 2015;132(5):441–53. 17. Cadrin-Tourigny J, Bosman LP, Nozza A, et al. A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy. Eur Heart J. 2019;40(23):1850–8.
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PART I. Deformation imaging methods in ARVC
CHAPTER 2 Improving Diagnostic Value of Echocardiography in Arrhythmogenic Right Ventricular Cardiomyopathy Using Deformation Imaging Feddo P. Kirkels, Laurens P. Bosman, Karim Taha, Maarten J. Cramer, Jeroen F. van der Heijden, Richard N.W. Hauer, Folkert W. Asselbergs, Anneline S.J.M. te Riele, Arco J. Teske JACC Cardiovasc Imaging. 2021;14(12):2481-2483. Research letter
26 | Chapter 2 INTRODUCTION Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited cardiomyopathy diagnosed by a complex set of tests defined in the 2010 Task Force Criteria (TFC).1 This includes echocardiography, which combines measures of right ventricular (RV) dilatation and function with subjective visual wall motion assessment to obtain diagnostic criteria. However, a recent clinical validation study of the TFC demonstrated that these echocardiographic criteria lack sensitivity for ARVC diagnosis.2 Subtle wall motion abnormalities can be missed by visual assessment, hampering diagnosis. In contrast, echocardiographic deformation imaging is known for its high sensitivity for detection of wall motion abnormalities. The performance of deformation imaging within the TFC for ARVC diagnosis remains however unknown. We performed a head-to-head comparison of the diagnostic value of TFC visual wall motion assessment versus deformation imaging in a real-world cohort of consecutive patients evaluated for ARVC. METHODS The study population was derived from a recently published study on TFC performance, which included 160 consecutive patients who were referred for ARVC evaluation at the UMC Utrecht, the Netherlands, between 2009-2011.2 Of those, we included 59 patients who underwent an echocardiogram according to our current protocol3 on a single vendor, allowing deformation analysis. The study was approved by the local ethics board. In absence of a gold standard test for diagnosis of ARVC, the reference standard was diagnosis by consensus of 3 independent ARVC experts (JvdH/RH/AtR) who re-evaluated all available patient data, beyond the scope of the TFC, including a median follow-up of 5.9 years IQR[2.7-7.6 years] after the echocardiographic examination.2 All echocardiograms were performed with a Vivid 7 or E9 scanner and post-processed with EchoPac v.202 (GE Healthcare, Horten, Norway). The original clinical assessment of RV outflow tract dimensions, fractional area change and wall motion was used to determine conventional echocardiographic TFC.1 In addition, RV deformation patterns of the subtricuspid area3 were obtained by two experienced operators (FK/KT) blinded for clinical data. Deformation patterns were scored as either normal or abnormal, according to the presence of regional mechanical dysfunction (type II/III, as previously described in detail).3 We evaluated the effect of replacing visual wall motion assessment with deformation imaging on the sensitivity, specificity and C-statistic of the echocardiographic TFC for ARVC diagnosis. (Figure 1A)
Diagnostic Value of Deformation Imaging in ARVC | 27 Figure 1. ARVC evaluation according to the echocardiographic 2010 TFC (A) ARVC evaluation according to the echocardiographic 2010 TFC by using visual wall motion assessment vs. deformation imaging. An RV-focused 4-chamber view was used to classify local deformation patterns as normal or abnormal.3 (B) Diagnostic performance of echocardiographic TFC when using conventional visual assessment compared to deformation imaging. 2
28 | Chapter 2 RESULTS Of 59 patients (age 38 ± 17 years, 49% male), the experts diagnosed 15 (25%) with ARVC. Conventional echocardiographic TFC, either minor or major, were observed in 10 (67%) patients. Using deformation imaging instead of visual wall motion assessment led to 5 (33%) additional detections of ARVC, whereas none were reclassified to normal. Consequently, deformation imaging increased sensitivity from 67% to 100%, while specificity decreased from 89% to 73%. The C-statistic increased from 0.78, 95%CI (0.64-0.91) to 0.86, 95%CI (0.80-0.93). (Figure 1B) Of note, half (n=6/12) of the patients with “false positive” abnormal deformation patterns were at risk family members of ARVC patients. They all developed new TFC during follow-up and 4 of them later fulfilled criteria for a definite diagnosis. Therefore, it can be debated whether the deformation abnormalities in these patients were truly “false positive” or, more likely, reflective of a very early sign of disease in these patients.3 Deformation imaging detected all patients who developed the diagnosis during follow-up, and including these patients resulted in an increased specificity (80%) and C-statistic (0.74, 95%CI [0.62-0.86] to 0.90, 95%CI [0.84-0.96]). DISCUSSION AND CONCLUSION We showed that RV deformation is highly sensitive for diagnosing ARVC, and improves the diagnostic performance of echocardiographic TFC when replacing the visual wall motion assessment. When the original 1994 TFC were revised in 2010, hypokinesia was disregarded as a criterion and only akinesia/dyskinesia remained.1 This was necessary to prevent overdiagnosing of the disease, but consequently led to a loss in sensitivity. As wall motion abnormalities are a prerequisite to fulfil a criterion, the diagnostic performance of echocardiography depends primarily on visual assessment of RV wall motion abnormalities, which is difficult and highly dependent on the observer’s experience. Replacing visual assessment by deformation imaging offers a solution for this loss in sensitivity, while also being less subjective. In the present study, all patients who were diagnosed with ARVC by the expert panel were detected by RV deformation abnormalities. The cohort size and absence of a true gold standard test for ARVC were limitations in our study design. Because deformation imaging is not able to reliably distinguish ARVC from other RV related disease as a stand-alone index, such diagnostic dilemmas should always be conducted in a clinical multi-modality approach like the TFC. Using deformation imaging instead of visual wall motion assessment improved the overall performance of echocardiographic TFC for diagnosing ARVC. Acknowledgements: This work was supported by the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation (grant number CVON2015-12 eDETECT). Dr Te Riele is supported by the Dutch Heart Foundation (grant number 2015T058) and the UMC Utrecht Fellowship Clinical Research Talent. Dr Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre.
Diagnostic Value of Deformation Imaging in ARVC | 29 REFERENCES 1. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/Dysplasia: Proposed modification of the task force criteria. Circulation. 2010;121(13):1533–41. 2. Bosman LP, Cadrin-Tourigny J, Bourfiss M, et al. Diagnosing arrhythmogenic right ventricular cardiomyopathy by 2010 task force criteria: Clinical performance and simplified practical implementation. Europace. 2020;22(5):787–96. 3. Mast TP, Teske AJ, Walmsley J, et al. Right Ventricular Imaging and Computer Simulation for Electromechanical Substrate Characterization in Arrhythmogenic Right Ventricular Cardiomyopathy. J Am Coll Cardiol. 2016;68(20):2185–97. 2
CHAPTER 3 Right Ventricular Functional Abnormalities in Arrhythmogenic Cardiomyopathy: Association With Life-Threatening Ventricular Arrhythmias Feddo P. Kirkels, Øyvind H. Lie, Maarten J. Cramer, Monica Chivulescu, Christine Rootwelt-Norberg, Folkert W. Asselbergs, Arco J. Teske, Kristina H. Haugaa JACC Cardiovasc Imaging. 2021;14(5):900-910.
32 | Chapter 3 ABSTRACT Objectives In this study, we aimed to perform an external validation of the value of RV deformation patterns and RV mechanical dispersion in patients with arrhythmogenic cardiomyopathy (AC). Secondly, we assessed the association of these parameters with life threatening ventricular arrhythmia (VA). Background Subtle RV dysfunction assessed by echocardiographic deformation imaging is valuable in AC diagnosis and risk prediction. Two different methods have emerged, the RV deformation pattern recognition and RV mechanical dispersion, but these have neither been externally validated nor compared. Methods We analysed AC probands and mutation-positive family members, matched from two large European referral centers. We performed speckle tracking echocardiography, whereby we classified the subtricuspid deformation patterns from normal to abnormal and assessed RV mechanical dispersion from 6 segments. We defined VA as sustained ventricular tachycardia, appropriate ICD therapy, or aborted cardiac arrest. Results We included 160 subjects, 80 from each center (43% proband, 55% female, aged 41 ± 17 years). VA had occurred in 47 (29%) subjects. In both cohorts, patients with a history of VA showed abnormal deformation patterns (96% and 100%) and had greater RV mechanical dispersion (53 ± 30 ms vs. 30 ± 21 ms, p <0.001 for the total cohort). Both parameters were independently associated to VA (adjusted OR 2.71, 95% CI (1.47 – 5.00) per class step-up and 1.26, 95% CI (1.07 – 1.49) per 10 ms, respectively). The association with VA significantly improved when adding RV mechanical dispersion to pattern recognition (NRI 0.42, p = 0.02 and IDI 0.06, p = 0.01). Conclusion We externally validated two RV dysfunction parameters in AC. Adding RV mechanical dispersion to RV deformation patterns significantly improved the association with life-threatening VA, indicating incremental value.
Right Ventricular Functional Abnormalities in ARVC | 33 INTRODUCTION Arrhythmogenic cardiomyopathy (AC, also known as arrhythmogenic right ventricular cardiomyopathy (ARVC)) is an inheritable cardiomyopathy, characterized by life-threatening ventricular arrhythmias (VA) and progressive cardiac failure.1 In the classical phenotype, pathogenic mutations encoding for desmosomal proteins lead to primarily right ventricular (RV) myocyte loss and replacement by fibrofatty tissue.2,3 Already in the early stage of the disease, life-threatening arrhythmias can occur, making it a leading cause of sudden cardiac death amongst young, seemingly healthy, individuals.2,3,4 Early detection of the disease is thus of great importance. Currently, AC is diagnosed according to a complex set of criteria, defined in the 2010 revised Task Force Criteria (TFC), in which cardiac imaging has an important role.5 In addition to conventional imaging parameters, as incorporated in the 2010 TFC, echocardiographic deformation imaging has been described for detection of subtle phenotypic expressions in early AC as well as for risk prediction regarding ventricular arrhythmias.6-11 The technique has been applied to the RV in AC patients in different ways: by recognition of deformation patterns of the RV subtricuspid area6,7, and by using the mechanical dispersion, a measure of heterogeneous contraction, as a parameter of disease expression8-10. These two methods have successfully been tested in separate cohorts of the centers where they were developed, but are not yet implemented in clinical care outside of these centers. In order to advance RV deformation imaging closer to standard clinical care in AC, it is pivotal to show that these results are not only achieved in one center. To date, the value of RV deformation patterns and mechanical dispersion has never been externally validated. Furthermore, the association between RV deformation patterns and ventricular arrhythmias has not been investigated previously, and it is not known whether the two methods measure essentially the same phenomenon or if combining the two methods adds value to risk stratification of VA. We aimed to perform an external validation of the association between RV deformation patterns and disease stage in AC. Furthermore, we aimed to validate mechanical dispersion as a marker of ventricular arrhythmias. Finally, we wanted to explore the added value of combining the parameters. METHODS Study design and population This study was conducted in two academic referral centers for AC in Europe. We used an AC cohort from the University Medical Center Utrecht in the Netherlands and an age- and sex matched AC cohort from the Oslo University Hospital in Norway. Probands underwent genetic testing as described previously12, and cascade genetic screening was performed in family members of genotype positive probands. The Utrecht cohort consisted of 80 AC probands and genotype positive family members with an echocardiographic examination including RV deformation imaging in Utrecht between 2006 and 2015, who have been reported previously.6 During this period, 87 subjects were evaluated, of which 7 were excluded due to inadequate image quality for RV deformation analyses. The Oslo cohort also consisted of 80 AC probands and genotype positive family members. By matching to the Utrecht subjects based on age and sex, the Oslo subjects were selected from a previously reported cohort of 144 subjects which 3
34 | Chapter 3 were referred between 1997 and 2016.13 Due to inadequate image quality for RV deformation analyses, 4 subjects were replaced by other matched subjects from the Oslo cohort during the matching process. For the purpose of external validation, the two cohorts were kept separated first. The association between RV deformation patterns and disease stage was determined in the Oslo cohort and compared to the Utrecht cohort, where the method was initially developed. The external validity of the association between RV mechanical dispersion and arrhythmic events was tested in the Utrecht cohort and compared to the Oslo cohort. Subsequently, the two cohorts were merged to compare both RV deformation techniques and to explore added value of combining them in the total cohort. The study was approved by both local institutional ethics review boards and complies with the declaration of Helsinki. Collection of data Clinical characteristics We recorded clinical characteristics at inclusion, including demographics, anti-arrhythmic or beta blocker medication, presence of an ICD, and history of cardiac syncope (sudden loss of consciousness followed by spontaneous sudden awakening). By applying the 2010 TFC5, we determined fulfilment of a definite AC diagnosis. Date of inclusion was defined as the date of first complete echocardiographic examination suitable for performing deformation imaging. Electrocardiography We performed standard 12-lead ECG recording and 24-hour Holter monitoring at inclusion. The extent of T-wave inversions (TWI), presence of epsilon waves and increased terminal activation duration (TAD) were recorded according to the 2010 TFC. Arrhythmias were recorded on either 12-lead ECG, Holter or ICD monitoring.5 The amount of premature ventricular complexes per 24 hours on Holter monitoring was documented and non-sustained ventricular tachycardia was defined as consecutive runs of ≥3 ventricular beats >100 beats/min for <30s.14 Echocardiography We performed echocardiography, using a GE Vivid 7, E9 or E95 scanner (GE Healthcare, Horten, Norway). Cineloops were stored for post-processing with EchoPac version 202 (GE Healthcare). We assessed structural and functional abnormalities defined in the 2010 TFC5 and parameters from the EACVI consensus paper.15 Details on acquisition of the RV focused 4-chamber view and post-processing in echocardiographic speckle tracking deformation imaging were previously described more extensively.16-18 We assessed the subtricuspid deformation pattern in a single wall tracing of the RV lateral free wall, which was automatically divided into a basal, mid, and apical segment. Timing of the pulmonary valve closure was assessed by Doppler traces in the RV outflow tract, obtained in the parasternal short-axis view. The following deformation parameters were measured in the basal segment: time to onset of shortening (or electro-mechanical interval (EMI))19, systolic peak strain20 and the amount post-systolic shortening21 (definitions in supplementary material). Based on these parameters, a distinction into three different deformation patterns has previously been observed in AC and simulated using a computer model.6 (Figure 1, panel A) For RV mechanical dispersion, we used a 6-segment RV model, including both the lateral wall and the interventricular septum. It was calculated as the standard deviation (SD) of the segmental time intervals from onset Q/R on the surface ECG to maximum shortening, represented by the automatically detected peak negative strain.8,9 (Figure 1, panel
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