Year: 2019
Type: editorial
Abstract: This editorial refers to ‘High penetrance and similar disease progression in probands and in family members with arrhythmogenic cardiomyopathy’†, by M. Chivulescu et al., on page 1401. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy with onset ranging from adolescence to late midlife characterized by frequent ventricular arrhythmias, an increased risk of sudden cardiac death, and variably progressive ventricular dysfunction.1 ARVC is typically an inherited, autosomal dominant condition with reduced penetrance and variable expressivity. Pathogenic variants (e.g. mutations) typically in genes encoding the cardiac desmosome can be detected in up to two-thirds of ARVC probands.2 After identifying a pathogenic variant in a family, ‘cascade’ genetic testing is indicated to identify genetically at-risk family members for whom serial cardiovascular screening is recommended with the goal of detecting and treating onset of ARVC prior to a life-threatening arrhythmic event.3 Unfortunately, little is known about the incidence and manifestations of the development of ARVC in these at-risk individuals. While several professional organizations have recommended serial evaluation regimens,3 , 4 the evidence base for these recommendations has been limited. Questions remain as to the optimal timing, best cardiac tests, and whether screening can be personalized based on genotype, clinical, or exercise characteristics. It is from this perspective that we appreciated the article by Chivulescu et al. in this issue of the European Heart Journal. 5 The authors describe clinical outcomes of 68 probands and 76 family members with pathogenic desmosomal variants followed for a median of 7.0 years [interquartile range (IQR) 4.5–9.4] at Oslo University Hopsital, Rikshospitalet. The study had three primary goals: (i) to assess ARVC penetrance and progression in family members; (ii) to compare structural progression of probands and family members; and finally (iii) to determine the association of structural progression with incident sustained ventricular arrhythmias. A major strength of this publication is the authors’ comprehensive analysis of 598 echocardiographic assessments (median four per patient, IQR 3–5). A detailed serial analysis of structural disease using echocardiogram had never before been described in ARVC family members. In their study, the authors defined penetrance and progression based on the 2010 Task Force Criteria.6 Patients meeting any major or minor criterion in addition to their major criterion for genotype were considered to have penetrant disease. Fulfilment of an individual Task Force criterion in follow-up not fulfilled at first evaluation was considered progression. This is a reasonable approach to identifying early disease, although it does limit the capacity to track disease evolution after patients meet an individual diagnostic criterion. For instance, using this definition, a family member with 500 premature ventricular complexes (PVCs) with an ECG showing t-wave inversions V1–V3 at baseline who then has 5000 PVCs with an ECG with t-wave inversions V1–V5 in follow-up would be considered a ‘non-progressor’. The authors found that 41% of family members met full Task Force Criteria at initial evaluation and an additional 17% met one minor diagnostic criterion. During follow-up, half of the family members without ARVC at baseline developed evidence of disease, including nine meeting only electrical criteria, three with isolated structural criteria, and three with both electrical and structural disease. These penetrance and progression data are in line with previous research. For example, Quarta et al.7 reported 34% of genotype-positive first-degree relatives with a definite diagnosis of ARVC and 27% with a borderline diagnosis. Similarly, in work from our group, 40% of 385 family members with a pathogenic variant detected via cascade screening met diagnostic criteria.2 In a study of relatives undergoing serial evaluation, we recently found that one-third of relatives who were unaffected at baseline developed new diagnostic criteria during a median 4-year follow-up.8 The novelty of the current study stems from the robust characterization of structural progression of disease, particularly among family members, and the implications of structural progression for predicting incident arrhythmias. Chivulescu et al. characterized right and left ventricular structure and function, established that right ventricular fractional area change, right ventricular basal diameter, right ventricular outflow tract diameter, right ventricular end-diastolic volume, and left ventricular global longitudinal strain all deteriorated, and provided average rates of change for each parameter. These patterns were apparent in probands and family members, in patients with and without structural abnormalities at baseline, and when gene-elusive probands were excluded. Furthermore, the authors found that exercise intensity prior to presentation was associated with structural progression in both family members and probands. These striking findings confirm that while there is variability in the extent and evolution of structural disease of individual patients, ARVC is a progressive condition, confirming results of smaller studies with less robust imaging data (Take home figure). While family members typically have milder ARVC than probands,2 these results strongly suggest that genotype-positive family members do not have a fundamentally different disease, at least from a structural perspective, but rather that they are ascertained at earlier disease stages. That exercise intensity prior to clinical presentation predicted structural progression in both probands and family members is novel and somewhat sobering given that the authors claim that all their patients were following recommendations to abstain from vigorous exercise and reduce overall exercise. We can only speculate as to whether the rate of structural progression would be higher if those patients continued an athletic lifestyle. Nonetheless, these findings highlight the importance of recent guidelines recommending that clinicians counsel individuals with a positive genetic test for ARVC but who are phenotype negative that competitive or frequent high-intensity endurance exercise is associated with increased penetrance and risk of ventricular arrhythmias.3 This study strongly suggests that the likelihood of structural progression should be added to these risks. Schematic drawing showing the stages of atrial fibrillation and highlighting the progressive nature of ARVC in both probands and gene-positive family members. The authors complete their study by evaluating whether structural progression is associated with survival free from a first sustained ventricular arrhythmia. Here structural progression was defined as the development of new minor or major Task Force imaging criteria during follow-up. A severe ventricular arrhythmic event appropriately included sudden cardiac arrest, sustained ventricular tachycardia, or appropriate implantable cardioverter therapy. Among patients with neither a history of sustained ventricular tachycardia nor structural disease meeting major Task Force criteria at baseline, a first sustained ventricular arrhythmia occurred in eight patients (9%), of whom seven, including all four family members, had concomitant structural progression. Using Cox regression, the authors suggest that structural progression was associated with arrhythmic events independent of age, sex, and proband status. These data contribute to our understanding of arrhythmic risk in genotype-positive family members and inform a current discussion in the field. A long-standing paradigm suggests three phases of ARVC: a ‘concealed’ stage in which patients have genetic risks and molecular abnormalities but no disease detectable on cardiac screening; an ‘electrical’ stage with abnormalities on ECG or Holter monitoring, but a normal or near-normal structure on conventional imaging; and a ‘structural’ stage with the full phenotype expressed. Whether patients have an appreciable risk of life-threatening arrhythmias during the ‘concealed’ and ‘electrical’ stages—probably due to triggered arrhythmias—is a subject of considerable debate. There have been several recent reports of sudden cardiac arrest in the setting of an apparently structurally normal heart associated with PKP2 variants.9 The current study suggests that evidence of structural progression in genotype-positive family members—most of whom have PKP2 variants—is certainly a useful marker of increasing arrhythmic risk. This is consistent with an investigation by te Riele et al. which showed that among 274 first-degree relatives, the 8% who experienced a sustained ventricular arrhythmia during follow-up all had evidence of both structural and electrical abnormalities.10 Together these studies suggest the importance of both structural and electrical parameters in estimating arrhythmic risk and making decisions about timing of implantable cardioverter defibrillator placement for genotype-positive family members. This is consistent with a risk prediction model recently developed for estimating risk of incident ventricular arrhythmias in ARVC patients meeting Task Force Criteria that includes both electrical and structural parameters.11 This study does have a few important limitations. Most importantly it is underpowered for arrhythmia risk prediction. With only eight first arrhythmic events in the Cox regression analysis, entering four variables into the multivariable model is far from ideal. The problems with this approach can be easily seen in the enormous confidence intervals reported. Furthermore, in the regression analysis and in the Kaplan–Meier curves presented in their figure 3, patients are defined as ‘progressors’ vs. ‘non-progressors’ at last follow-up but grouped at baseline. Additionally, whether a case was a progressor or non-progressor was determined at last clinical visit including an echocardiogram, while the severe arrhythmic events occurred during the course of follow-up, so potentially before structural progression was evident. To more fully address the predictive role of structural progression, evaluation of the echocardiogram performed nearest the time of the first arrhythmic event would have been useful. The limitations related to power highlight the potential value to be gained through a collaborative approach to defining family member outcomes. This approach has recently been fruitful in developing a model for incident arrhythmic risk prediction in ARVC patients. A larger sample size of family members would also allow for a more refined analysis of the influence of genotype and possibly exercise on outcomes. In summary, we wish to congratulate our Norwegian colleagues for this important research. As the best clinical research does, this manuscript has both generated new ideas about the pathogenesis of ARVC and provided data that can be directly translated to clinical management. We anticipate using the progression rate echocardiographic ‘norms’ provided to assist clinical evaluation of our patients and we expect that these data will be rapidly integrated into serial screening paradigms for ARVC families. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. We would like to thank Anneline te Riele for her assistance in creating the figure. Conflict of interest: none declared.
Source: European Heart Journal
Authors: Cynthia A James, Hugh Calkins
Institutions: Johns Hopkins University, Johns Hopkins Hospital
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2980960013