Publications by authors named "Kristina H Haugaa"

194 Publications

Prevalence of Mitral Annulus Disjunction and Mitral Valve Prolapse in Patients With Idiopathic Ventricular Fibrillation.

J Am Heart Assoc 2022 Aug 5;11(16):e025364. Epub 2022 Aug 5.

Department of Cardiology University Medical Center Utrecht Utrecht the Netherlands.

Background Idiopathic ventricular fibrillation (IVF) is diagnosed in patients with ventricular fibrillation of which the origin is not identified after extensive evaluations. Recent studies suggest an association between mitral annulus disjunction (MAD), mitral valve prolapse (MVP), and ventricular arrhythmias. The prevalence of MAD and MVP in patients with IVF in this regard is not well established. We aimed to explore the prevalence of MAD and MVP in a consecutive cohort of patients with IVF compared with matched controls. Methods and Results In this retrospective, multicenter cohort study, cardiac magnetic resonance images from patients with IVF (ie, negative for ischemia, cardiomyopathy, and channelopathies) and age- and sex-matched control subjects were analyzed for the presence of MAD (≥2 mm) and MVP (>2 mm). In total, 72 patients (mean age 39±14 years, 42% women) and 72 control subjects (mean age 41±11 years, 42% women) were included. MAD in the inferolateral wall was more prevalent in patients with IVF versus healthy controls (7 [11%] versus 1 [1%], =0.024). MVP was only seen in patients with IVF and not in controls (5 [7%] versus 0 [0%], =0.016). MAD was observed in both patients with (n=4) and without (n=3) MVP. Conclusions Inferolateral MAD and MVP were significantly more prevalent in patients with IVF compared with healthy controls. The authors advocate that evaluation of the mitral valve region deserves extra attention in the extensive screening of patients with unexplained cardiac arrest. These findings support further exploration of the pathophysiological mechanisms underlying a subset of IVF that associates with MAD and MVP.
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http://dx.doi.org/10.1161/JAHA.121.025364DOI Listing
August 2022

Cardiovascular magnetic resonance in autoimmune rheumatic diseases: a clinical consensus document by the European Association of Cardiovascular Imaging.

Eur Heart J Cardiovasc Imaging 2022 Aug;23(9):e308-e322

Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

Autoimmune rheumatic diseases (ARDs) involve multiple organs including the heart and vasculature. Despite novel treatments, patients with ARDs still experience a reduced life expectancy, partly caused by the higher prevalence of cardiovascular disease (CVD). This includes CV inflammation, rhythm disturbances, perfusion abnormalities (ischaemia/infarction), dysregulation of vasoreactivity, myocardial fibrosis, coagulation abnormalities, pulmonary hypertension, valvular disease, and side-effects of immunomodulatory therapy. Currently, the evaluation of CV involvement in patients with ARDs is based on the assessment of cardiac symptoms, coupled with electrocardiography, blood testing, and echocardiography. However, CVD may not become overt until late in the course of the disease, thus potentially limiting the therapeutic window for intervention. More recently, cardiovascular magnetic resonance (CMR) has allowed for the early identification of pathophysiologic structural/functional alterations that take place before the onset of clinically overt CVD. CMR allows for detailed evaluation of biventricular function together with tissue characterization of vessels/myocardium in the same examination, yielding a reliable assessment of disease activity that might not be mirrored by blood biomarkers and other imaging modalities. Therefore, CMR provides diagnostic information that enables timely clinical decision-making and facilitates the tailoring of treatment to individual patients. Here we review the role of CMR in the early and accurate diagnosis of CVD in patients with ARDs compared with other non-invasive imaging modalities. Furthermore, we present a consensus-based decision algorithm for when a CMR study could be considered in patients with ARDs, together with a standardized study protocol. Lastly, we discuss the clinical implications of findings from a CMR examination.
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http://dx.doi.org/10.1093/ehjci/jeac134DOI Listing
August 2022

Exercise training during childhood and adolescence is associated with favorable diastolic function in hypertrophic cardiomyopathy.

Int J Cardiol 2022 Oct 15;364:65-71. Epub 2022 Jun 15.

Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute for Experimental Medical Research, Oslo University Hospital Ullevål and University of Oslo, Oslo, Norway; K. G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway. Electronic address:

Background: Diastolic dysfunction is an important part of the clinical phenotype in hypertrophic cardiomyopathy (HCM). While exercise training is known to improve left ventricular (LV) diastolic function in normal hearts, the effects of exercise training during childhood and adolescence in carriers of HCM-associated genetic variants are unknown.

Methods: In a cross-sectional and retrospective study, we combined clinical and echocardiographic data with history of exercise training from childhood to time of examination in 187 participants with HCM or an HCM-causative genotype. Multiple linear regression was used to identify correlations between exercise training performed prior to 20 years of age and LV diastolic parameters from echocardiography.

Results: Exercise training during childhood and adolescence was correlated with a favorable e', E/e', E deceleration time, and end-diastolic volume (EDV), when adjusting for the effects of age at examination, and presence of left ventricular hypertrophy (LVH). This correlation was evident both in patients with a HCM phenotype (HCM LVH+), and in individuals with an HCM-causative genotype without LV hypertrophy (G+ LVH-). None of the diastolic parameters correlated unfavorably with increasing exercise exposure.

Conclusion: More exercise training during childhood and adolescence was associated with favorable LV diastolic function in both HCM LVH+ and G+ LVH- groups, regardless of presence of hypertrophy at the time of examination. These results indicate that exercise training initiated during childhood and adolescence has positive effects on cardiac function later in life for individuals with HCM or an HCM-causative genotype.
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http://dx.doi.org/10.1016/j.ijcard.2022.06.042DOI Listing
October 2022

A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy.

Eur Heart J 2022 Apr 20. Epub 2022 Apr 20.

Department of Genetics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen, The Netherlands.

Aims: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients.

Methods And Results: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.3% reduction of ICD placements with the same proportion of protected patients (P < 0.001).

Conclusion: Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).
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http://dx.doi.org/10.1093/eurheartj/ehac180DOI Listing
April 2022

Pregnancy and Progression of Cardiomyopathy in Women With LMNA Genotype-Positive.

J Am Heart Assoc 2022 04 18;11(8):e024960. Epub 2022 Apr 18.

Institute of Clinical Medicine Faculty of Medicine University of Oslo Norway.

Background We aimed to assess the association between number of pregnancies and long-term progression of cardiac dysfunction, arrhythmias, and event-free survival in women with pathogenic or likely pathogenic variants of gene encoding for Lamin A/C proteins ( LMNA+). Methods and Results We retrospectively included consecutive women with LMNA+ and recorded pregnancy data. We collected echocardiographic data, occurrence of atrial fibrillation, atrioventricular block, sustained ventricular arrhythmias, and implantation of cardiac electronic devices (implantable cardioverter defibrillator/cardiac resynchronization therapy defibrillator). We analyzed retrospectively complications during pregnancy and the peripartum period. We included 89 women with LMNA+ (28% probands, age 41±16 years), of which 60 had experienced pregnancy. Follow-up time was 5 [interquartile range, 3-9] years. We analyzed 452 repeated echocardiographic examinations. Number of pregnancies was not associated with increased long-term risk of atrial fibrillation, atrioventricular block, sustained ventricular arrhythmias, or implantable cardioverter defibrillator/cardiac resynchronization therapy defibrillator implantation. Women with previous pregnancy and nulliparous women had a similar annual deterioration of left ventricular ejection fraction (-0.5/year versus -0.3/year, =0.37) and similar increase of left ventricular end-diastolic diameter (0.1/year versus 0.2/year, =0.09). Number of pregnancies did not decrease survival free from death, left ventricular assist device, or need for cardiac transplantation. Arrhythmias occurred during 9% of pregnancies. No increase in maternal and fetal complications was observed. Conclusions In our cohort of women with LMNA+, pregnancy did not seem associated with long-term adverse disease progression or event-free survival. Likewise, women with LMNA+ generally well-tolerated pregnancy, with a small proportion of patients experiencing arrhythmias.
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http://dx.doi.org/10.1161/JAHA.121.024960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9238471PMC
April 2022

Cardiac Structure and Function in Epilepsy Patients with Drug-Resistant Convulsive Seizures.

Case Rep Neurol 2022 Jan-Apr;14(1):88-97. Epub 2022 Mar 10.

Department of Neurology, Stavanger University Hospital, Stavanger, Norway.

High frequency of convulsive seizures and long-lasting epilepsy are associated with an increased risk of sudden unexpected death in epilepsy (SUDEP). Structural changes in the myocardium have been described in SUDEP victims. It is speculated that these changes are secondary to frequent convulsive seizures and may predispose to SUDEP. The aim of this cross-sectional study was to investigate the impact of chronic drug-resistant epilepsy on cardiac function and structure in patients with a high frequency of convulsive seizures. We consecutively included 21 patients (17 women, 4 men) aged 18-40 years, with at least 10 years with epilepsy and a minimum of six convulsive seizures in the last year and without a history of status epilepticus or nonepileptic events. A complete clinical examination, resting 12-lead electrocardiogram, 72-h Holter monitoring, and echocardiography were recorded in all patients. Ten patients were assessed by 3-Tesla cardiac magnetic resonance imaging. Echocardiography and MRI data were compared with those from age- and sex-matched healthy control individuals. No significant changes in cardiac structure or function were found among patients with chronic drug-resistant epilepsy and high frequency of convulsive seizures. However, we cannot exclude that there are subgroups of patients who are more prone to epilepsy-associated cardiac alterations.
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http://dx.doi.org/10.1159/000522237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8958580PMC
March 2022

Electrical markers and arrhythmic risk associated with myocardial fibrosis in mitral valve prolapse.

Europace 2022 Jul;24(7):1156-1163

Department of Cardiology, ProCardio Centre for Innovation, Oslo University Hospital, Rikshospitalet, PO Box 4950 Nydalen, 0424 Oslo, Norway.

Aims: We aimed to characterize the substrate of T-wave inversion (TWI) using cardiac magnetic resonance (CMR) and the association between diffuse fibrosis and ventricular arrhythmias (VA) in patients with mitral valve prolapse (MVP).

Methods And Results: TWI was defined as negative T-wave ≥0.1 mV in ≥2 adjacent ECG leads. Diffuse myocardial fibrosis was assessed by T1 relaxation time and extracellular volume (ECV) fraction by T1-mapping CMR. We included 162 patients with MVP (58% females, age 50 ± 16 years), of which 16 (10%) patients had severe VA (aborted cardiac arrest or sustained ventricular tachycardia). TWI was found in 34 (21%) patients. Risk of severe VA increased with increasing number of ECG leads displaying TWI [OR 1.91, 95% CI (1.04-3.52), P = 0.04]. The number of ECG leads displaying TWI increased with increasing lateral ECV (26 ± 3% for TWI 0-1leads, 28 ± 4% for TWI 2leads, 29 ± 5% for TWI ≥3leads, P = 0.04). Patients with VA (sustained and non-sustained ventricular tachycardia) had increased lateral T1 (P = 0.004), also in the absence of late gadolinium enhancement (LGE) (P = 0.008).

Conclusions: Greater number of ECG leads with TWI reflected a higher arrhythmic risk and higher degree of lateral diffuse fibrosis by CMR. Lateral diffuse fibrosis was associated with VA, also in the absence of LGE. These results suggest that TWI may reflect diffuse myocardial fibrosis associated with VA in patients with MVP. T1-mapping CMR may help risk stratification for VA.
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http://dx.doi.org/10.1093/europace/euac017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9301977PMC
July 2022

Echocardiographic Deformation Imaging for Early Detection of Genetic Cardiomyopathies: JACC Review Topic of the Week.

J Am Coll Cardiol 2022 02;79(6):594-608

Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address:

Clinical screening of the relatives of patients with genetic cardiomyopathies is challenging, as they often lack detectable cardiac abnormalities at presentation. Life-threatening adverse events can already occur in these early stages of disease, so sensitive tools to reveal the earliest signs of disease are needed. The utility of echocardiographic deformation imaging for early detection has been explored for this population in multiple studies but has not been broadly implemented in clinical practice. The authors discuss contemporary evidence on the utility of deformation imaging in relatives of patients with genetic cardiomyopathies. The available body of data shows that deformation imaging reveals early disease-specific abnormalities in dilated cardiomyopathy, hypertrophic cardiomyopathy, and arrhythmogenic cardiomyopathy. Deformation imaging seems promising to enhance the screening and follow-up protocols in relatives, and the authors propose measures to accelerate its implementation in clinical care.
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http://dx.doi.org/10.1016/j.jacc.2021.11.045DOI Listing
February 2022

Integrating Exercise Into Personalized Ventricular Arrhythmia Risk Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy.

Circ Arrhythm Electrophysiol 2022 02 28;15(2):e010221. Epub 2022 Jan 28.

Department of Medicine, Division of Cardiology, Johns Hopkins University, School of Medicine, Baltimore, MD (W.W., B.M., C.T., H.C., C.A.J.).

Background: Exercise is associated with sustained ventricular arrhythmias (VA) in Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) but is not included in the ARVC risk calculator (arvcrisk.com). The objective of this study is to quantify the influence of exercise at diagnosis on incident VA risk and evaluate whether the risk calculator needs adjustment for exercise.

Methods: We interviewed ARVC patients without sustained VA at diagnosis about their exercise history. The relationship between exercise dose 3 years preceding diagnosis (average METh/wk) and incident VA during follow-up was analyzed with time-to-event analysis. The incremental prognostic value of exercise to the risk calculator was evaluated by Cox models.

Results: We included 176 patients (male, 43.2%; age, 37.6±16.1 years) from 3 ARVC centers, of whom 53 (30.1%) developed sustained VA during 5.4 (2.7-9.7) years of follow-up. Exercise at diagnosis showed a dose-dependent nonlinear relationship with VA, with no significant risk increase <15 to 30 METh/wk. Athlete status, using 3 definitions from literature (>18, >24, and >36 METh/wk), was significantly associated with VA (hazard ratios, 2.53-2.91) but was also correlated with risk factors currently in the risk calculator model. Thus, adding athlete status to the model did not change the C index of 0.77 (0.71-0.84) and showed no significant improvement (Akaike information criterion change, <2).

Conclusions: Exercise at diagnosis was dose dependently associated with risk of sustained VA in ARVC patients but only above 15 to 30 METh/wk. Exercise does not appear to have incremental prognostic value over the risk calculator. The ARVC risk calculator can be used accurately in athletic patients without modification.
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http://dx.doi.org/10.1161/CIRCEP.121.010221DOI Listing
February 2022

Cardiac desmosomal reserve: another piece of the exercise-induced arrhythmogenic cardiomyopathy puzzle?

Eur Heart J 2022 03;43(12):1265-1267

ProCardio Center for Innovation, Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

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http://dx.doi.org/10.1093/eurheartj/ehab873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8934689PMC
March 2022

EACVI survey on hypertrophic cardiomyopathy.

Eur Heart J Cardiovasc Imaging 2022 04;23(5):590-597

BHF Centre for Cardiovascular Science, University of Edinburgh, Chancellors Building, Little France Crescent, Edinburgh EH16 4SB, UK.

Aims: The European Association of Cardiovascular Imaging (EACVI) Scientific Initiatives Committee performed a global survey to evaluate current practice for the assessment and management of patients with hypertrophic cardiomyopathy (HCM).

Methods And Results: A total of 213 centres from 38 different countries (87% European) responded to the survey. One hundred twenty-one (57%) centres followed HCM patients in a general cardiology outpatient clinic and 85 (40%) centres in a specialized HCM/cardiomyopathy clinic. While echocardiography was the primary imaging modality, cardiovascular magnetic resonance (CMR) has become an important complementary tool. Cardiac anatomy, left ventricular (LV) systolic, and diastolic function were assessed according to current European guidelines and recommendations. To evaluate LV obstruction, 49% of the centres performed bedside provocation manoeuvres in every patient and 55% of the centres used exercise stress echocardiography. The majority of centres used the 5-year risk assessment of sudden cardiac death (SCD) calculated with the HCM Risk-SCD score. However, 34% of the centres also used extensive non-infarct late gadolinium enhancement on CMR and 27% the presence of LV apical aneurysm to help select patients for primary prevention implantable cardioverter-defibrillator therapy. Ninety-nine percent of the responding centres performed regular imaging follow-up of HCM patients.

Conclusion: Most centres followed European guidelines and recommendations for the diagnosis and management of patients with HCM. The importance of bedside provocation manoeuvres and exercise stress echocardiography to diagnose LV outflow obstruction requires emphasis. Additional risk markers for SCD are used in many centres and might indicate the need for an update of current European recommendations.
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http://dx.doi.org/10.1093/ehjci/jeab270DOI Listing
April 2022

Cardiac Arrest in a Patient With Arrhythmic Mitral Valve Prolapse Syndrome: Multiple Possible Etiologies.

JACC Case Rep 2021 Nov 17;3(16):1769-1773. Epub 2021 Nov 17.

ProCardio Centre for Innovation, Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Arrhythmic mitral valve prolapse syndrome is associated with a high risk of death. A 60-year-old man with arrhythmic mitral valve prolapse syndrome was monitored with an implantable loop recorder. Nine months later dyspnea developed, followed by cardiac arrest. Echocardiography showed mitral valve chordal rupture. He underwent successful surgical mitral valve repair. ().
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http://dx.doi.org/10.1016/j.jaccas.2021.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603045PMC
November 2021

Uncertainty Quantification of Regional Cardiac Tissue Properties in Arrhythmogenic Cardiomyopathy Using Adaptive Multiple Importance Sampling.

Front Physiol 2021 30;12:738926. Epub 2021 Sep 30.

Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.

Computational models of the cardiovascular system are widely used to simulate cardiac (dys)function. Personalization of such models for patient-specific simulation of cardiac function remains challenging. Measurement uncertainty affects accuracy of parameter estimations. In this study, we present a methodology for patient-specific estimation and uncertainty quantification of parameters in the closed-loop CircAdapt model of the human heart and circulation using echocardiographic deformation imaging. Based on patient-specific estimated parameters we aim to reveal the mechanical substrate underlying deformation abnormalities in patients with arrhythmogenic cardiomyopathy (AC). We used adaptive multiple importance sampling to estimate the posterior distribution of regional myocardial tissue properties. This methodology is implemented in the CircAdapt cardiovascular modeling platform and applied to estimate active and passive tissue properties underlying regional deformation patterns, left ventricular volumes, and right ventricular diameter. First, we tested the accuracy of this method and its inter- and intraobserver variability using nine datasets obtained in AC patients. Second, we tested the trueness of the estimation using nine generated virtual patient datasets representative for various stages of AC. Finally, we applied this method to two longitudinal series of echocardiograms of two pathogenic mutation carriers without established myocardial disease at baseline. Tissue characteristics of virtual patients were accurately estimated with a highest density interval containing the true parameter value of 9% (95% CI [0-79]). Variances of estimated posterior distributions in patient data and virtual data were comparable, supporting the reliability of the patient estimations. Estimations were highly reproducible with an overlap in posterior distributions of 89.9% (95% CI [60.1-95.9]). Clinically measured deformation, ejection fraction, and end-diastolic volume were accurately simulated. In presence of worsening of deformation over time, estimated tissue properties also revealed functional deterioration. This method facilitates patient-specific simulation-based estimation of regional ventricular tissue properties from non-invasive imaging data, taking into account both measurement and model uncertainties. Two proof-of-principle case studies suggested that this cardiac digital twin technology enables quantitative monitoring of AC disease progression in early stages of disease.
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http://dx.doi.org/10.3389/fphys.2021.738926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514656PMC
September 2021

Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region.

Eur Heart J 2021 12;42(46):4743-4755

Department of Cardiology, CARIM, Maastricht University Medical Center, PO Box 5800, 6202 Maastricht, The Netherlands.

Aims: Mutation type, location, dominant-negative IKs reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent IKs stimulation via protein kinase A (PKA) influence the clinical severity of long QT syndrome type 1 (LQT1). Given the malignancy of KCNQ1-p.A341V, we assessed whether mutations neighbouring p.A341V in the S6 channel segment could also increase arrhythmic risk.

Methods And Results: Clinical and genetic data were obtained from 1316 LQT1 patients [450 families, 166 unique KCNQ1 mutations, including 277 p.A341V-positive subjects, 139 patients with p.A341-neighbouring mutations (91 missense, 48 non-missense), and 900 other LQT1 subjects]. A first cardiac event represented the primary endpoint. S6 segment missense variant characteristics, particularly cAMP stimulation responses, were analysed by cellular electrophysiology. p.A341-neighbouring mutation carriers had a QTc shorter than p.A341V carriers (477 ± 33 vs. 490 ± 44 ms) but longer than the remaining LQT1 patient population (467 ± 41 ms) (P < 0.05 for both). Similarly, the frequency of symptomatic subjects in the p.A341-neighbouring subgroup was intermediate between the other two groups (43% vs. 73% vs. 20%; P < 0.001). These differences in clinical severity can be explained, for p.A341V vs. p.A341-neighbouring mutations, by the p.A341V-specific impairment of IKs regulation. The differences between the p.A341-neighbouring subgroup and the rest of LQT1 mutations may be explained by the functional importance of the S6 segment for channel activation.

Conclusion: KCNQ1 S6 segment mutations surrounding p.A341 increase arrhythmic risk. p.A341V-specific loss of PKA-dependent IKs enhancement correlates with its phenotypic severity. Cellular studies providing further insights into IKs-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management.
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http://dx.doi.org/10.1093/eurheartj/ehab582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851466PMC
December 2021

Genetic Variant Score and Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Plakophilin-2 Mutation Carriers.

Cardiology 2021;146(6):763-771. Epub 2021 Sep 1.

Department of Clinical Genetics, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.

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.
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http://dx.doi.org/10.1159/000519231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743907PMC
December 2021

Genotype-phenotype correlation in arrhythmogenic right ventricular cardiomyopathy-risk of arrhythmias and heart failure.

J Med Genet 2021 Aug 16. Epub 2021 Aug 16.

Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen, Denmark.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is predominantly caused by desmosomal genetic variants, and clinical hallmarks include arrhythmias and systolic dysfunction. We aimed at studying the impact of the implicated gene(s) on the disease course.

Methods: The Nordic ARVC Registry holds data on a multinational cohort of ARVC families. The effects of genotype on electrocardiographic features, imaging findings and clinical events were analysed.

Results: We evaluated 419 patients (55% men), with a mean follow-up of 11.2±7.4 years. A pathogenic desmosomal variant was identified in 62% of the 230 families: in 41%, in 13%, in 7% and in 3%. Reduced left ventricular ejection fraction (LVEF) ≤45% on cardiac MRI was more frequent among patients with // than ARVC (27% vs 4%, p<0.01). In contrast, in Cox regression modelling of patients with definite ARVC, we found a higher risk of arrhythmias among than // carriers: HR 0.25 (0.10-0.68, p<0.01) for atrial fibrillation/flutter, HR 0.67 (0.44-1.0, p=0.06) for ventricular arrhythmias and HR 0.63 (0.42-0.95, p<0.05) for any arrhythmia. Gene-negative patients had an intermediate risk (16%) of LVEF ≤45% and a risk of the combined arrhythmic endpoint comparable with // carriers. Male sex was a risk factor for both arrhythmias and reduced LVEF across all genotype groups (p<0.01).

Conclusion: In this large cohort of ARVC families with long-term follow-up, we found genotype to be more arrhythmic than /2/ or gene-negative carrier status, whereas reduced LVEF was mostly seen among /2/ carriers. Male sex was associated with a more severe phenotype.
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http://dx.doi.org/10.1136/jmedgenet-2021-107911DOI Listing
August 2021

The Authors' Reply.

JACC Cardiovasc Imaging 2021 08;14(8):1684-1685

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http://dx.doi.org/10.1016/j.jcmg.2021.06.006DOI Listing
August 2021

Strain echocardiography improves prediction of arrhythmic events in ischemic and non-ischemic dilated cardiomyopathy.

Int J Cardiol 2021 Nov 26;342:56-62. Epub 2021 Jul 26.

ProCardio Center for Innovation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address:

Background: Recent evidence suggests that an implantable cardioverter defibrillator (ICD) in non-ischemic cardiomyopathy (NICM) may not offer mortality benefit. We aimed to investigate if etiology of heart failure and strain echocardiography can improve risk stratification of life threatening ventricular arrhythmia (VA) in heart failure patients.

Methods: This prospective multi-center follow-up study consecutively included NICM and ischemic cardiomyopathy (ICM) patients with left ventricular ejection fraction (LVEF) <40%. We assessed LVEF, global longitudinal strain (GLS) and mechanical dispersion (MD) by echocardiography. Ventricular arrhythmia was defined as sustained ventricular tachycardia, sudden cardiac death or appropriate shock from an ICD.

Results: We included 290 patients (67 ± 13 years old, 74% males, 207(71%) ICM). During 22 ± 12 months follow up, VA occurred in 32(11%) patients. MD and GLS were both markers of VA in patients with ICM and NICM, whereas LVEF was not (p = 0.14). MD independently predicted VA (HR: 1.19; 95% CI 1.08-1.32, p = 0.001), with excellent arrhythmia free survival in patients with MD <70 ms (Log rank p < 0.001). Patients with NICM and MD <70 ms had the lowest VA incidence with an event rate of 3%/year, while patients with ICM and MD >70 ms had highest VA incidence with an event rate of 16%/year.

Conclusion: Patients with NICM and normal MD had low arrhythmic event rate, comparable to the general population. Patients with ICM and MD >70 ms had the highest risk of VA. Combining heart failure etiology and strain echocardiography may classify heart failure patients in low, intermediate and high risk of VA and thereby aid ICD decision strategies.
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http://dx.doi.org/10.1016/j.ijcard.2021.07.044DOI Listing
November 2021

Complications of implantable cardioverter-defibrillator treatment in arrhythmogenic right ventricular cardiomyopathy.

Europace 2022 02;24(2):306-312

Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

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 long-term follow-up. A third of the patients experienced a complication during follow-up with lead-related complications constituting the vast majority.
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http://dx.doi.org/10.1093/europace/euab112DOI Listing
February 2022

Mitral Annulus Disjunction: Arrhythmic But Not Deadly?

JACC Cardiovasc Imaging 2021 11 16;14(11):2088-2090. Epub 2021 Jun 16.

ProCardio Center for Innovation, Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.

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http://dx.doi.org/10.1016/j.jcmg.2021.05.014DOI Listing
November 2021

Artificial Intelligence for Automatic Measurement of Left Ventricular Strain in Echocardiography.

JACC Cardiovasc Imaging 2021 10 16;14(10):1918-1928. Epub 2021 Jun 16.

Centre for Innovative Ultrasound Solutions and Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; Clinic of Cardiology, St. Olavs Hospital, Trondheim, Norway. Electronic address:

Objectives: This study sought to examine if fully automated measurements of global longitudinal strain (GLS) using a novel motion estimation technology based on deep learning and artificial intelligence (AI) are feasible and comparable with a conventional speckle-tracking application.

Background: GLS is an important parameter when evaluating left ventricular function. However, analyses of GLS are time consuming and demand expertise, and thus are underused in clinical practice.

Methods: In this study, 200 patients with a wide range of left ventricle (LV) function were included. Three standard apical cine-loops were analyzed using the AI pipeline. The AI method measured GLS and was compared with a commercially available semiautomatic speckle-tracking software (EchoPAC v202, GE Healthcare.

Results: The AI method succeeded to both correctly classify all 3 standard apical views and perform timing of cardiac events in 89% of patients. Furthermore, the method successfully performed automatic segmentation, motion estimates, and measurements of GLS in all examinations, across different cardiac pathologies and throughout the spectrum of LV function. GLS was -12.0 ± 4.1% for the AI method and -13.5 ± 5.3% for the reference method. Bias was -1.4 ± 0.3% (95% limits of agreement: 2.3 to -5.1), which is comparable with intervendor studies. The AI method eliminated measurement variability and a complete GLS analysis was processed within 15 s.

Conclusions: Through the range of LV function this novel AI method succeeds, without any operator input, to automatically identify the 3 standard apical views, perform timing of cardiac events, trace the myocardium, perform motion estimation, and measure GLS. Fully automated measurements based on AI could facilitate the clinical implementation of GLS.
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http://dx.doi.org/10.1016/j.jcmg.2021.04.018DOI Listing
October 2021

EACVI survey on the evaluation of left ventricular diastolic function.

Eur Heart J Cardiovasc Imaging 2021 09;22(10):1098-1105

BHF Centre for Cardiovascular Science, University of Edinburgh, Chancellors Building, Little France Crescent, Edinburgh EH16 4SB, UK.

Aims: The aim of this study is to analyse how current recommendations on left ventricular (LV) diastolic function assessment have been adopted. Identifying potential discrepancies between recommendations and everyday clinical practice would enable us to better understand and address the remaining challenges in this controversial and complex field.

Methods And Results: A total of 93 centres, mainly from tertiary care settings, responded to the survey. More than three-quarters (77%) of centres follow the 2016 ASE/EACVI recommendations for LV diastolic function evaluation in patients with preserved ejection fraction based upon e', E/e', tricuspid regurgitation velocity, and left atrial (LA) volume. These recommendations were generally preferred to the previous 2009 version. Many centres also consider strain assessments in the LV (48%) and left atrium (53%) as well as diastolic stress echocardiography (33%) to be useful as additional assessments of LV diastolic function. Echocardiographic assessments of LV diastolic function were used frequently to guide therapy in 72% of centres.

Conclusion: There is widespread adoption of current recommendation on the evaluation of LV diastolic function and these are frequently used to guide patient management. Many centres now also consider LV and LA strain assessments useful in the clinical assessment of diastolic function. These may be considered in future recommendations.
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http://dx.doi.org/10.1093/ehjci/jeab087DOI Listing
September 2021

Sex differences in disease progression and arrhythmic risk in patients with arrhythmogenic cardiomyopathy.

Europace 2021 07;23(7):1084-1091

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, PO Box 4950 Nydalen, 0424 Oslo, Norway.

Aims: We aimed to assess sex-specific phenotypes and disease progression, and their relation to exercise, in arrhythmogenic cardiomyopathy (AC) patients.

Methods And Results: In this longitudinal cohort study, we included consecutive patients with AC from a referral centre. We performed echocardiography at baseline and repeatedly during follow-up. Patients' exercise dose at inclusion was expressed as metabolic equivalents of task (MET)-h/week. Ventricular arrhythmia (VA) was defined as aborted cardiac arrest, sustained ventricular tachycardia, or appropriate therapy by implantable cardioverter-defibrillator. We included 190 AC patients (45% female, 51% probands, age 41 ± 17 years). Ventricular arrhythmia had occurred at inclusion or occurred during follow-up in 85 patients (33% of females vs. 55% of males, P = 0.002). Exercise doses were higher in males compared with females [25 (interquartile range, IQR 14-51) vs. 12 (IQR 7-22) MET-h/week, P < 0.001]. Male sex was a marker of proband status [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4-5.0, P = 0.003] and a marker of VA (OR 2.6, 95% CI 1.4-5.0, P = 0.003), but not when adjusted for exercise dose and age (adjusted OR 1.8, 95% CI 0.9-3.6, P = 0.12 and 1.5, 95% CI 0.7-3.1, P = 0.30, by 5 MET-h/week increments). In all, 167 (88%) patients had ≥2 echocardiographic examinations during 6.9 (IQR 4.7-9.8) years of follow-up. We observed no sex differences in deterioration of right or left ventricular dimensions and functions.

Conclusion: Male AC patients were more often probands and had higher prevalence of VA than female patients, but not when adjusting for exercise dose. Importantly, disease progression was similar between male and female patients.
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http://dx.doi.org/10.1093/europace/euab077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286854PMC
July 2021
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