Regional right ventricular (RV) dysfunction is the hallmark of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C), but is currently only qualitatively evaluated in the clinical ...setting. Feature Tracking Cardiovascular Magnetic Resonance (FT-CMR) is a novel quantitative method that uses cine CMR to calculate strain values. However, most prior FT-CMR studies in ARVD/C have focused on global RV strain using different software methods, complicating implementation of FT-CMR in clinical practice. We aimed to assess the clinical value of global and regional strain using FT-CMR in ARVD/C and to determine differences between commercially available FT-CMR software packages.
We analyzed cine CMR images of 110 subjects (39 overt ARVD/C mutation+/phenotype+, 40 preclinical ARVD/C mutation+/phenotype- and 31 control) for global and regional (subtricuspid, anterior, apical) RV strain in the horizontal longitudinal axis using four FT-CMR software methods (Multimodality Tissue Tracking, TomTec, Medis and Circle Cardiovascular Imaging). Intersoftware agreement was assessed using Bland Altman plots.
For global strain, all methods showed reduced strain in overt ARVD/C patients compared to control subjects (p < 0.041), whereas none distinguished preclinical from control subjects (p > 0.275). For regional strain, overt ARVD/C patients showed reduced strain compared to control subjects in all segments which reached statistical significance in the subtricuspid region for all software methods (p < 0.037), in the anterior wall for two methods (p < 0.005) and in the apex for one method (p = 0.012). Preclinical subjects showed abnormal subtricuspid strain compared to control subjects using one of the software methods (p = 0.009). Agreement between software methods for absolute strain values was low (Intraclass Correlation Coefficient = 0.373).
Despite large intersoftware variability of FT-CMR derived strain values, all four software methods distinguished overt ARVD/C patients from control subjects by both global and subtricuspid strain values. In the subtricuspid region, one software package distinguished preclinical from control subjects, suggesting the potential to identify early ARVD/C prior to overt disease expression.
In arrhythmogenic cardiomyopathy (ACM) pathogenic variants are found in genes encoding desmosomal proteins and in non-desmosomal genes, such as
(
, p.Arg14del variant). Previous research showed that ...plakoglobin protein levels and localization in the cardiac tissue of ACM patients, and
p.Arg14del patients diagnosed with an ACM phenotype, are disturbed. Moreover, the effects of pathogenic variants in desmosomal genes are reflected in non-cardiac tissues like buccal mucosa cells (BMC) which could serve as a promising new and non-invasive tool to support diagnosis. We collected the BMC of 33 ACM patients, 17
p.Arg14del patients and 34 controls, labelled the BMC with anti-plakoglobin antibodies at different concentrations, and scored their membrane labelling. We found that plakoglobin protein levels were significantly reduced in BMC obtained from diagnosed ACM patients and preclinical variant carriers when compared to controls. This effect was independent from age and sex. Moderate to strong correlations were found with the revised 2010 Task Force Criteria score which is commonly used for ACM diagnosis (r
= -0.67,
= 64,
< 0.0001 and r
= -0.71,
= 64,
< 0.0001). In contrast, plakoglobin scores in
p.Arg14del patients were comparable to controls (
> 0.209), which suggests differences in underlying etiology. However, for the individual diagnosis of the 'classical' ACM patient, this method might not be discriminative enough to distinguish true patients from variant carriers and controls, because of the high interindividual variability.
Structural Atrial Involvement in ARVD/C
Introduction
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is associated with desmosomal mutations. Although desmosomal disruption affects ...both ventricles and atria, little is known about atrial involvement in ARVD/C.
Objective
To describe the extent and clinical significance of structural atrial involvement and atrial arrhythmias (AA) in ARVD/C stratified by genotype.
Methods
We included 71 patients who met ARVD/C Task Force Criteria and underwent cardiac magnetic resonance (CMR) imaging and molecular genetic analysis. Indexed atrial end‐diastolic volume and area‐length‐ejection‐fraction (ALEF) were evaluated on CMR and compared to controls with idiopathic right ventricular outflow tract tachycardia (n = 40). The primary outcome was occurrence of AA (atrial fibrillation or atrial flutter) during follow‐up, recorded by 12‐lead ECG, Holter monitoring or implantable cardioverter defibrillator (ICD) interrogation.
Results
Patients harbored a desmosomal plakophilin‐2 (PKP2) (n = 37) or nondesmosomal phospholamban (PLN) (n = 14) mutation. In 20 subjects, no pathogenic mutation was identified. Compared to controls, right atrial (RA) volumes were reduced in PKP2 (P = 0.002) and comparable in PLN (P = 0.441) mutation carriers. In patients with no mutation identified, RA (P = 0.011) and left atrial (P = 0.034) volumes were increased. Bi‐atrial ALEF showed no significant difference between the groups. AA were experienced by 27% of patients and occurred equally among PKP2 (30%) and no mutation identified patients (30%), but less among PLN mutation carriers (14%).
Conclusion
Genotype influences atrial volume and occurrence of AA in ARVD/C. While the incidence of AA is similar in PKP2 mutation carriers and patients with no mutation identified, PKP2 mutation carriers have significantly smaller atria. This suggests a different arrhythmogenic mechanism.
Pathogenic variants in
(
, like p. Arg14del), are found in patients diagnosed with arrhythmogenic (ACM) and dilated cardiomyopathy (DCM). Fibrosis formation in the heart is one of the hallmarks in
...p.Arg14del carriers. During collagen synthesis and breakdown, propeptides are released into the circulation, such as procollagen type I carboxy-terminal propeptide (PICP) and C-terminal telopeptide collagen type I (ICTP).
To investigate if PICP/ICTP levels in blood are correlative biomarkers for clinical disease severity and outcome in
p.Arg14del variant carriers.
Serum and EDTA blood samples were collected from 72
p.Arg14del carriers (age 50.5 years, 63% female) diagnosed with ACM (
= 12), DCM (
= 14), and preclinical variant carriers (
= 46). PICP levels were measured with an enzyme-linked immune sorbent assay and ICTP with a radio immuno-assay. Increased PICP/ICTP ratios suggest a higher collagen deposition. Clinical data including electrocardiographic, and imaging results were adjudicated from medical records.
No correlation between PICP/ICTP ratios and late gadolinium enhancement (LGE) was found. Moderate correlations were found between the PICP/ICTP ratio and end-diastolic/systolic volume (both
= 0.40,
= 23,
= 0.06). PICP/ICTP ratio was significantly higher in patients with T wave inversion (TWI), especially in leads V4-V6, II, III, and aVF (
< 0.022) and in patients with premature ventricular contractions (PVCs) during an exercise tolerance test (
= 0.007).
High PICP/ICTP ratios correlated with clinical parameters, such as TWI and PVCs. Given the limited size and heterogeneity of the patient group, additional studies are required to substantiate the incremental prognostic value of these fibrosis biomarkers in
p.Arg14del patients.
Arrhythmogenic cardiomyopathy (ACM) is a progressive inheritable disease which is characterized by a gradual fibro-(fatty) replacement of the myocardium. Visualization of diffuse and patchy fibrosis ...patterns is challenging using clinically applied cardiac imaging modalities (e.g., late gadolinium enhancement, LGE). During collagen synthesis and breakdown, carboxy-peptides are released into the bloodstream, specifically procollagen type-I carboxy-terminal propeptides (PICP) and collagen type-I carboxy-terminal telopeptides (ICTP). We collected the serum and EDTA blood samples and clinical data of 45 ACM patients (age 50.11 ± 15.53 years, 44% female), divided into 35 diagnosed ACM patients with a 2010 ARVC Task Force Criteria score (TFC) ≥ 4, and 10 preclinical variant carriers with a TFC < 4. PICP levels were measured using an enzyme-linked immune sorbent assay and ICTP levels with a radio immunoassay. Increased PICP/ICTP ratios suggest a higher collagen deposition. We found significantly higher PICP and PICP/ICTP levels in diagnosed patients compared to preclinical variant carriers (
< 0.036 and
< 0.027). A moderate negative correlation existed between right ventricular ejection fractions (RVEF) and the PICP/ICTP ratio (
= -0.46,
= 0.06). In addition, significant correlations with left ventricular function (LVEF
= -0.53,
= 0.03 and end-systolic volume
= 0.63,
= 0.02) were found. These findings indicate impaired contractile performance due to pro-fibrotic remodeling. Follow-up studies including a larger number of patients should be performed to substantiate our findings and the validity of those levels as potential promising biomarkers in ACM.
Abstract
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 20.6% 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).
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.
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).
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).
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with ventricular arrhythmias (VA) and sudden cardiac death (SCD). A model was recently developed to predict incident sustained VA ...in patients with ARVC. However, since this outcome may overestimate the risk for SCD, we aimed to specifically predict life-threatening VA (LTVA) as a closer surrogate for SCD.
We assembled a retrospective cohort of definite ARVC cases from 15 centers in North America and Europe. Association of 8 prespecified clinical predictors with LTVA (SCD, aborted SCD, sustained, or implantable cardioverter-defibrillator treated ventricular tachycardia >250 beats per minute) in follow-up was assessed by Cox regression with backward selection. Candidate variables included age, sex, prior sustained VA (≥30s, hemodynamically unstable, or implantable cardioverter-defibrillator treated ventricular tachycardia; or aborted SCD), syncope, 24-hour premature ventricular complexes count, the number of anterior and inferior leads with T-wave inversion, left and right ventricular ejection fraction. The resulting model was internally validated using bootstrapping.
A total of 864 patients with definite ARVC (40±16 years; 53% male) were included. Over 5.75 years (interquartile range, 2.77-10.58) of follow-up, 93 (10.8%) patients experienced LTVA including 15 with SCD/aborted SCD (1.7%). Of the 8 prespecified clinical predictors, only 4 (younger age, male sex, premature ventricular complex count, and number of leads with T-wave inversion) were associated with LTVA. Notably, prior sustained VA did not predict subsequent LTVA (
=0.850). A model including only these 4 predictors had an optimism-corrected C-index of 0.74 (95% CI, 0.69-0.80) and calibration slope of 0.95 (95% CI, 0.94-0.98) indicating minimal over-optimism.
LTVA events in patients with ARVC can be predicted by a novel simple prediction model using only 4 clinical predictors. Prior sustained VA and the extent of functional heart disease are not associated with subsequent LTVA events.
Abstract
Aims
Exercise increases arrhythmia risk and cardiomyopathy progression in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, but the mechanisms remain unknown. We investigated ...transcriptomic changes caused by endurance training in mice deficient in plakophilin-2 (PKP2cKO), a desmosomal protein important for intercalated disc formation, commonly mutated in ARVC and controls.
Methods and results
Exercise alone caused transcriptional downregulation of genes coding intercalated disk proteins. The changes converged with those in sedentary and in exercised PKP2cKO mice. PKP2 loss caused cardiac contractile deficit, decreased muscle mass and increased functional/transcriptomic signatures of apoptosis, despite increased fractional shortening and calcium transient amplitude in single myocytes. Exercise accelerated cardiac dysfunction, an effect dampened by pre-training animals prior to PKP2-KO. Consistent with PKP2-dependent muscle mass deficit, cardiac dimensions in human athletes carrying PKP2 mutations were reduced, compared to matched controls.
Conclusions
We speculate that exercise challenges a cardiomyocyte “desmosomal reserve” which, if impaired genetically (e.g., PKP2 loss), accelerates progression of cardiomyopathy.
Graphical Abstract
Graphical Abstract
Exercise challenges a cardiomyocyte “desmosomal reserve” which, if impaired genetically (e.g., Plakophilin2 loss), can cause accelerated progression of the cardiomyopathy.
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