Europace (2020) 22, 1873–1879. doi:10.1093/europace/euaa136

Pyotr G. Platonov, Anna I. Castrini, Anneli Svensson, Morten K. Christiansen, Thomas Gilljam, Henning Bundgaard, Trine Madsen, Tiina Heliö, Alex H. Christensen, Meriam Aneq Åström, Jonas Carlson, Thor Edvardsen, Henrik K. Jensen, Kristina H. Haugaa, and Jesper H. Svendsen

Aims

Women with arrhythmogenic right ventricular cardiomyopathy (ARVC) are at relatively lower risk of ventricular arrhythmias (VAs) than men, but the physical burden associated with pregnancy on VA risk remains insufficiently studied. We aimed to assess the risk of VA in relation to pregnancies in women with ARVC.

Methods and results

We included 199 females with definite ARVC (n = 121) and mutation-positive family members without ascertained ARVC diagnosis (n = 78), of whom 120 had at least one childbirth. Ventricular arrhythmia-free survival after the latest childbirth was compared between women with one (n = 20), two (n = 67), and three or more (n = 37) childbirths. Cumulative probability of VA for each pregnancy (n = 261) was assessed from conception through 2 years after childbirth and compared between those pregnancies that occurred before (n = 191) or after (n = 19) ARVC diagnosis and in mutation-positive family members (n = 51). The nulliparous women had lower median age at ARVC diagnosis (38 vs. 42 years, P < 0.001) and first VA (22 vs. 41 years, P < 0.001). Ventricular arrhythmia-free survival after the latest childbirth was not related to the number of pregnancies. No regnancy-related VA was reported among the family members. Women who gave birth after ARVC diagnosis had elevated risk of VA postpartum (hazard ratio 13.74, 95% confidence interval 2.9–63, P = 0.001), though only two events occurred during pregnancies.

Conclusion

In women with ARVC, pregnancy was uneventful for the overwhelming majority and the number of prior completed pregnancies was not associated with VA risk. Pregnancy-related VA was primarily related to the phenotypical severity rather than pregnancy itself.

Europace (2021) 00, 1–7. doi:10.1093/europace/euab112

Alex Hørby Christensen, Pyotr G. Platonov, Anneli Svensson, Henrik K. Jensen, Christine Rootwelt-Norberg, Pia Dahlberg, Trine Madsen, Tanja Charlotte Frederiksen, Tiina Heliö, Kristina H. Haugaa, Henning Bundgaard, and Jesper H. Svendsen

Aims

Treatment with implantable cardioverter-defibrillators (ICD) is a cornerstone for prevention of sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy (ARVC). We aimed at describing the complications associated with ICD treatment in a multinational cohort with long-term follow-up.

Methods and results

The Nordic ARVC registry was established in 2010 and encompasses a large multinational cohort of ARVC patients, including their clinical characteristics, treatment, and events during follow-up. We included 299 patients (66% males, median age 41 years). During a median follow-up of 10.6 years, 124 (41%) patients experienced appropriate ICD shock therapy, 28 (9%) experienced inappropriate shocks, 82 (27%) had a complication requiring surgery (mainly lead-related, n = 75), and 99 (33%) patients experienced the combined endpoint of either an inappropriate shock or a surgical complication. The crude rate of first inappropriate shock was 3.4% during the first year after implantation but decreased after the first year and plateaued over time. Contrary, the risk of a complication requiring surgery was 5.5% the first year and remained high throughout the study period. The combined risk of any complication was 7.9% the first year. In multivariate cox regression, presence of atrial fibrillation/flutter was a risk factor for inappropriate shock (P < 0.05), whereas sex, age at implant, and device type were not (all P > 0.05).

Conclusion

Forty-one percent of ARVC patients treated with ICD experienced potentially life-saving ICD therapy during longterm follow-up. A third of the patients experienced a complication during follow-up with lead-related complications constituting the vast majority.

International Journal of Cardiology 317 (2020) 152–158. doi.org/10.1016/j.ijcard.2020.05.095

Mathis K. Stokke, Anna I. Castrini, Meriam Åström Aneq, Henrik Kjærulf Jensen, Trine Madsen, Jim Hansen, Henning Bundgaard, Thomas Gilljam, Pyotr G. Platonov, Jesper Hastrup Svendsen, Thor Edvardsen, Kristina H. Haugaa

Aims

In Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), electrophysiological pathology has been claimed to precede morphological and functional pathology. Accordingly, an ECG without ARVC markers should be rare in ARVC patients with pathology identified by cardiac imaging. We quantified the prevalence of ARVC patients with evidence of structural disease, yet without ECG Task Force Criteria (TFC).

Methods and results

We included 182 probands and family members with ARVC-associated mutations (40 ± 17 years, 50% women, 73% PKP2 mutations) from the Nordic ARVC Registry in a cross-sectional analysis. For echocardiography and cardiac MR (CMR), we differentiated between “abnormalities” and TFC. “Abnormalities” were defined as RV functional or structural measures outside TFC reference values, without combinations required to fulfill TFC. ECG TFC were used as defined, as these are not composite parameters. We found that only 4% of patients with ARVC fulfilled echocardiographic TFC without any ECG TFC. However, importantly, 38% of patients had imaging abnormalities without any ECG TFC. These results were supported by CMR data from a subset of 51 patients: 16% fulfilled CMR TFC without fulfilling ECG TFC, while 24% had CMR abnormalities without any ECG TFC. In a multivariate analysis, echocardiographic TFC were associated with arrhythmic events.

Conclusion

More than one third of ARVC genotype positive patients had subtle imaging abnormalities without fulfilling ECG TFC. Although most patients will have both imaging and ECG abnormalities, structural abnormalities in ARVC genotype positive patients cannot be ruled out by the absence of ECG TFC.

Am J Cardiol 2019;123:1156−1162. doi.org/10.1016/j.amjcard.2018.12.049

Pyotr G. Platonov, Kristina H. Haugaa, Henning Bundgaard, Anneli Svensson, Thomas Gilljam, Jim Hansen, Trine Madsen, MD, Anders Gaarsdal Holst, Jonas Carlson, Öyvind H. Lie, Morten Kvistholm Jensen, Thor Edvardsen, Henrik K. Jensen, and Jesper H. Svendsen

Implantable cardioverter-defibrillator (ICD) therapy remains a corner stone of sudden cardiac death (SCD) prevention in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). We aimed to assess predictors of appropriate ICD therapies in the Scandinavian cohort of ARVC patients who received ICD for primary prevention of SCD. Study group comprised of 79 definite ARVC patients by 2010 Task Force criteria (60% male, age at ICD implant 39 § 14 years) who were enrolled in the Nordic ARVC Registry and received an ICD for primary SCD prevention. The primary end point of appropriate ICD shock or death from any cause was assessed and compared with 137 definite ARVC patients who received ICD for secondary SCD prevention (74% male, age at ICD implant 42 § 15 years). In the study group, 38% were ≤35 years of age at baseline, 25% had nonsustained ventricular tachycardia, and 29% had syncope at baseline. Major repolarization abnormality (hazard ratio = 4.00, 95% confidence interval 1.30 to 12.30, p = 0.015) and age ≤35 years (hazard ratio = 4.21, 95% confidence interval 1.49 to 11.85, p = 0.001) independently predicted the primary end point. The outcome did not differ between the primary prevention patients with either of these risk factors and the secondary prevention cohort (2% to 4% annual event rate) whereas patients without risk factors did not have any appropriate ICD shocks during follow-up. In conclusion, young age at ARVC diagnosis and major repolarization abnormality independently predict ICD shocks or death in the primary prevention ICD recipients and associated with the event rate similar to the one observed in the secondary prevention cohort. Our data indicate the benefit of ICD for primary prevention in patients with any of these risk factors.

Cardiology DOI: 10.1159/000519231

Anneli Svensson, Pyotr G. Platonov, Kristina H. Haugaa, Wojciech Zareba, Henrik Kjærulf Jensen, Henning Bundgaard, Thomas Gilljam, Trine Madsen, Jim Hansen, Lars A. Dejgaard, Lars O. Karlsson, Anna Gréen, Bronislava Polonsky, Thor Edvardsen, Jesper Hastrup Svendsen, Cecilia Gunnarsson

Introduction

Whether detailed genetic information contributes to risk stratification of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) remains uncertain. Pathogenic genetic variants in some genes seem to carry a higher risk for arrhythmia and earlier disease onset than others, but comparisons between variants in the same gene have not been done. Combined Annotation Dependent Depletion (CADD) score is a bioinformatics tool that measures the pathogenicity of each genetic variant. We hypothesized that a higher CADD score is associated with arrhythmic events and earlier age at ARVC manifestations in individuals carrying pathogenic or likely pathogenic genetic variants in plakophilin-2 (PKP2).

Methods

CADD scores were calculated using the data from pooled Scandinavian and North American ARVC cohorts, and their association with cardiac events defined as ventricular tachycardia/ventricular fibrillation (VT/VF) or syncope and age at definite ARVC diagnosis were assessed.

Results

In total, 33 unique genetic variants were reported in 179 patients (90 males, 71 probands, 96 with definite ARVC diagnosis at a median age of 35 years). Cardiac events were reported in 76 individuals (43%), of whom 53 had sustained VT/VF (35%). The CADD score was neither associated with age at cardiac events (HR 1.002, 95% CI: 0.953–1.054, p = 0.933) nor with age at definite ARVC diagnosis (HR 0.992, 95% CI: 0.947–1.039, p = 0.731).

Conclusion

No correlation was found between CADD scores and clinical manifestations of ARVC, indicating that the score has no additional risk stratification value among carriers of pathogenic or likely pathogenic PKP2 genetic variants.

International Journal of Cardiology 298 (2020) 39–43. doi.org/10.1016/j.ijcard.2019.07.086

Maria A. Baturova, Kristina H. Haugaa, Henrik K. Jensen, Anneli Svensson, Thomas Gilljam, Henning Bundgaard, Trine Madsen, Jim Hansen, Monica Chivulescu, Morten Krogh Christiansen, Jonas Carlson, Thor Edvardsen, Jesper H. Svendsen, Pyotr G. Platonov

Background

Recent studies in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients have drawn attention to atrial fibrillation (AF) as an arrhythmic manifestation of ARVC and as an indicator of atrial involvement in the disease progression. We aimed to assess the prevalence of AF in the Scandinavian cohort of ARVC patients and to evaluate its association with disease clinical manifestations.

Methods

Study sample comprised of 293 definite ARVC patients by 2010 Task Force criteria (TFC2010) and 141 genotype-positive family members (total n = 434, 43% females, median age at ARVC diagnosis 41 years [interquartile range (IQR) 28–52 years]). ARVC diagnostic score was calculated as the sum of major (2 points) and minor (1 point) criteria in all categories of the TFC2010.

Results

AF was diagnosed in 42 patients (10%): in 41 patients with definite ARVC diagnosis (14%) vs in one genotype-positive family member (1%), p b 0.001. The median age at AF onset was 51 (IQR 38–58) years. The prevalence of AF was related to the ARVC diagnostic score: it significantly increased starting with the diagnostic score 4 (2% in those with score 3 vs 13% in those with score 4, p = 0.023) and increased further with increased diagnostic score (Somer's d value is 0.074, p b 0.001).

Conclusion

AF is seen in 14% of definite ARVC patients and is related to the severity of disease phenotype thus suggesting AF being an arrhythmic manifestation of this cardiomyopathy indicating atrial myocardial involvement in the disease progression.

Europace (2021) 23, i29–i37. doi:10.1093/europace/euaa388

Maria A. Baturova, Anneli Svensson, Meriam Åström Aneq, Jesper H. Svendsen, Niels Risum, Valeriia Sherina, Henning Bundgaard, Carl Meurling, Catarina Lundin, Jonas Carlson, and Pyotr G. Platonov

Aims

Patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) have increased prevalence of atrial arrhythmias indicating atrial involvement in the disease. We aimed to assess the long-term evolution of P-wave indices as electrocardiographic (ECG) markers of atrial substrate during ARVC progression.

Methods and results

We included 100 patients with a definite ARVC diagnosis according to 2010 Task Force criteria [34% females, median age 41 (inter-quartile range 30–55) years]. All available sinus rhythm ECGs (n = 1504) were extracted from the regional electronic ECG databases and automatically processed using Glasgow algorithm. P-wave duration, Pwave area, P-wave frontal axis, and prevalence of abnormal P terminal force in lead V1 (aPTF-V1) were assessed and compared at ARVC diagnosis, 10 years before and up to 15 years after diagnosis.

Prior to ARVC diagnosis, none of the P-wave indices differed significantly from the data at ARVC diagnosis. After ascertainment of ARVC diagnosis, P-wave area in lead V1 decreased from 1 to 30 mV ms at 5 years (P = 0.002). P-wave area in lead V2 decreased from 82 mV ms at ARVC diagnosis to 42 mV ms 10 years after ARVC diagnosis (P = 0.006). The prevalence of aPTF-V1 increased from 5% at ARVC diagnosis to 18% by the 15th year of follow-up (P = 0.004). P-wave duration and frontal axis did not change during disease progression.

Conclusion

Initial ARVC progression was associated with P-wave flattening in right precordial leads and in later disease stages an increased prevalence of aPTF-V1 was seen.

European Heart Journal – Cardiovascular Imaging (2014) 15, 1219–1225. doi:10.1093/ehjci/jeu109

Rasmus Borgquist, Kristina H. Haugaa, Thomas Gilljam, Henning Bundgaard, Jim Hansen, Ole Eschen, Henrik Kjærulf Jensen, Anders G. Holst, Thor Edvardsen, Jesper H. Svendsen, and Pyotr G. Platonov

Aims

This study evaluates the agreement between echocardiographic and cardiacmagnetic resonance (CMR) imaging data, and the impact a discrepancy between the two may have on the clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC).

Methods and results

From the Nordic ARVC Registry, 102 patients with definite ARVC who had undergone both echocardiography and CMR were included (median age 42+16 years, 36% female, 78% probands). Patients were divided into two groups according to CMR-positive or -negative criteria, and the echocardiographic data were compared between the two. There were 72 CMR-positive patients. They had significantly larger RV dimensions and lower fractional area change on echocardiography compared with CMR-negative patients; parasternal long-axis right ventricular outflow tract (RVOT) 37+7 vs. 32+5 mm, parasternal short-axis RVOT 38+7 vs. 32+6 mm, fractional area shortening 31+9 vs. 39+9% (P , 0.003 for all). Only 36 (50%) of the CMR-positive patients fulfilled ARVC criteria by echocardiography, hence the diagnostic performance was low; sensitivity 50% and specificity 70%, positive predictive value 80% and negative predictive value 37%. Individuals with regional wall abnormalities on CMR were more likely to have ventricular arrhythmias (77 vs. 57%, P ¼ 0.047).

Conclusion

A significant proportion of patients with imaging-positive ARVC by CMR did not fulfil echocardiographic ARVC 2010 criteria. These findings confirm that echocardiographic valuation of subtle structural changes in the right ventricle may be unreliable, and the diagnostic performance of CMR compared with echocardiography should be reflected in the guidelines.

Am J Cardiol 2020;125:803−811. doi.org/10.1016/j.amjcard.2019.11.026

Morten K. Christiansen, Kristina H. Haugaa, Anneli Svensson, Thomas Gilljam, Trine Madsen, Jim Hansen, Anders G. Holst, Henning Bundgaard, Thor Edvardsen, Jesper H. Svendsen, Pyotr G. Platonov, and Henrik K. Jensen

Catheter ablation may reduce ventricular tachycardia (VT) burden in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. However, little is known about factors predicting need for ablation. Therefore, we sought to investigate predictors and use of VT ablation and to evaluate the postprocedural outcome in ARVC patients. We studied 435 patients from the Nordic ARVC registry including 220 probands with definite ARVC according to the 2010 task force criteria and 215 mutation-carrying relatives identified through cascade screening. Patients were followed until first-time VT ablation, death, heart transplantation, or January 1st 2018. Additionally, patients undergoing VT ablation were further followed from the time of ablation for recurrent ventricular arrhythmias. The cumulative use of VT ablation was 4% (95% confidence interval [CI] 3% to 6%) and 11% (95% CI 8% to 15%) after 1 and 10 years. All procedures were performed in probands in whom cumulative use was 8% (95% CI 5% to 12%) and 20% (95% CI 15% to 26%). In adjusted analyses among probands, only young age predicted ablation. In patients undergoing ablation, risk of recurrent arrhythmias was 59% (95% CI 44% to 71%) and 74% (95% CI 59% to 84%) 1 and 5 years after the procedure. Despite high recurrence rates, the burden of ventricular arrhythmias was reduced after ablation (p = 0.0042). Young age, use of several antiarrhythmic drugs and inducibility to VT after ablation were associated with an unfavorable outcome. In conclusion, twenty percent of ARVC probands developed a clinical indication for VT ablation within 10 years whereas mutation-carrying relatives were without such need. Although the burden of ventricular arrhythmias decreased after ablation, risk of recurrence was substantial.

International Journal of Cardiology 250 (2018) 201–206. doi.org/10.1016/j.ijcard.2017.10.076

Thomas Gilljam, Kristina H. Haugaa, Henrik K. Jensen, Anneli Svensson, Henning Bundgaard, Jim Hansen, Göran Dellgren, Finn Gustafsson, Hans Eiskjær, Arne K. Andreassen, Johan Sjögren, Thor Edvardsen, Anders G. Holst, Jesper Hastrup Svendsen, Pyotr G. Platonov

Objective

There is a paucity of data on heart transplantation (HTx) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), and specific recommendations on indications for listing ARVC patients for HTx are lacking. In order to delineate features pertinent to HTx assessment, we explored the pre-HTx characteristics and clinical history in a cohort of ARVC patients who received heart transplants.

Methods

Data from 31 ARVC/HTx patients enrolled in the Nordic ARVC Registry, transplanted between 1988 and 2014 at a median age of 46 years (14–65), were compared with data from 152 non-transplanted probands with Definite ARVC according to 2010 Task Force Criteria from the same registry.

Results

The HTx patients were younger at presentation, median 31 vs. 38 years (p = 0.001). There was no difference in arrhythmia-related events. The indication for HTx was heart failure in 28 patients (90%) and ventricular arrhythmias in 3 patients (10%). During median follow-up of 4.9 years (0.04–28), there was one early death and two late deaths. Survival was 91% at 5 years after HTx. Age at first symptoms under 35 years independently predicted HTx in our cohort (OR = 7.59, 95% CI 2.69–21.39, p b 0.001).

Conclusion

HTx in patients with ARVC is performed predominantly due to heart failure. This suggests that current 2016 International Society for Heart and Lung Transplantation heart transplant listing recommendations for other cardiomyopathies could be applicable in many cases when taking into account the haemodynamic consequences of right ventricular failure in conjunction with ventricular arrhythmia.

Scandinavian Cardiovascular Journal, 49:6, 299-307. doi.org/10.3109/14017431.2015.1086017

Kristina H. Haugaa, Henning Bundgaard, Thor Edvardsen, Ole Eschen, Thomas Gilljam, Jim Hansen, Henrik Kjærulf Jensen, Pyotr G. Platonov, Anneli Svensson & Jesper H. Svendsen

Objectives

Diagnostics of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) are complex, and based on the 2010 Task Force document including different diagnostic modalities. However, recommendations for clinical management and follow-up of patients with ARVC and their relatives are sparse. This paper aims to give a practical overview of management strategies, risk stratifi cation, and selection of appropriate therapies for patients with ARVC and their family members.

Design

This paper summarizes follow-up and treatment strategies in ARVC patients in the Nordic countries. The author group represents cardiologists who are actively involved in the Nordic ARVC Registry which was established in 2009, and contains prospectively collected clinical data from more than 590 ARVC patients from Denmark, Norway, Sweden, and Finland.

Results

Different approaches of management and follow-up are required in patients with defi nite ARVC and in genetic-mutation-positive family members. Furthermore, ARVC patients with and without implantable cardioverter defibrillators (ICDs) require different follow-up strategies.

Conclusion

Careful follow-up is required in patients with ARVC diagnosis to evaluate the need of anti-arrhythmic therapy and ICD implantation. Mutation-positive family members should be followed regularly for detection of early disease and risk stratifi cation of ventricular arrhythmias.