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.
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.
AF was diagnosed in 42 patients (10%): in 41 patients with definite ARVC diagnosis (14%) vs in one genotype-positive family member (1%), p < 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 < 0.001).
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.
•Atrial fibrillation is common in arrhythmogenic right ventricular cardiomyopathy.•Atrial fibrillation prevalence is related to the severity of disease phenotype.•Atrial fibrillation is associated with right ventricular structural abnormalities.
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.
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.
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).
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.
Background Arrhythmogenic cardiomyopathy (AC) is characterized by biventricular dysfunction, exercise intolerance, and high risk of ventricular tachyarrhythmias and sudden death. Predisposing factors ...for left ventricular (LV) disease manifestation and its prognostic implication in AC are poorly described. We aimed to assess the associations of exercise exposure and genotype with LV dysfunction in AC, and to explore the impact of LV disease progression on adverse arrhythmic outcome. Methods and Results We included 168 patients with AC (50% probands, 45% women, 40±16 years old) with 715 echocardiographic exams (4.1±1.7 exams/patient, follow-up 7.6 interquartile range (IQR), 5.4-10.9 years) and complete exercise and genetic data in a longitudinal study. LV function by global longitudinal strain was -18.8% IQR, -19.2% to -18.3% at presentation and was worse in patients with greater exercise exposure (global longitudinal strain worsening, 0.09% IQR, 0.01%-0.17% per 5 MET-hours/week,
=0.02). LV function by global longitudinal strain worsened, with 0.08% IQR, 0.05%-0.12% per year; (
<0.001), and progression was most evident in patients with desmoplakin genotype (
for interaction <0.001). Deterioration of LV function predicted incident ventricular tachyarrhythmia (aborted cardiac arrest, sustained ventricular tachycardia, or implantable cardioverter defibrillator shock) (adjusted odds ratio, 1.1 IQR, 1.0-1.3 per 1% worsening by global longitudinal strain;
=0.02, adjusted for time and previous arrhythmic events). Conclusions Greater exercise exposure was associated with worse LV function at first visit of patients with AC but did not significantly affect the rate of LV progression during follow-up. Progression of LV dysfunction was most pronounced in patients with desmoplakin genotypes. Deterioration of LV function during follow-up predicted subsequent ventricular tachyarrhythmia and should be considered in risk stratification.
Abstract
Aims
We aimed to assess structural progression in arrhythmogenic cardiomyopathy (AC) patients and mutation-positive family members and its impact on arrhythmic outcome in a longitudinal ...cohort study.
Methods and results
Structural progression was defined as the development of new Task Force imaging criteria from inclusion to follow-up and progression rates as annual changes in imaging parameters. We included 144 AC patients and family members (48% female, 47% probands, 40 ± 16 years old). At genetic diagnosis and inclusion, 58% of family members had penetrant AC disease. During 7.0 inter-quartile range (IQR) 4.5–9.4 years of follow-up, 47% of family members without AC at inclusion developed AC criteria, resulting in a yearly new AC penetrance of 8%. Probands and family members had a similar progression rate of right ventricular outflow tract diameter (0.5 mm/year vs. 0.6 mm/year, P = 0.28) by mixed model analysis of 598 echocardiographic examinations. Right ventricular fractional area change progression rate was even higher in family members (−0.6%/year vs. −0.8%/year, P < 0.01). Among 86 patients without overt structural disease or arrhythmic history at inclusion, a first severe ventricular arrhythmic event occurred in 8 (9%), of which 7 (88%) had concomitant structural progression. Structural progression was associated with higher incidence of severe ventricular arrhythmic events adjusted for age, sex, and proband status (HR 21.24, 95% CI 2.47–182.81, P < 0.01).
Conclusion
More than half of family members had AC criteria at genetic diagnosis and yearly AC penetrance was 8%. Structural progression was similar in probands and family members and was associated with higher incidence of severe ventricular arrhythmic events.
The implications of exercise-induced cardiac troponin elevation in healthy individuals are unclear. This study aimed to determine if individuals with a high exercise-induced cardiac troponin I (cTnI) ...response have alterations in myocardial function following high-intensity endurance exercise compared with normal-cTnI responders.BACKGROUNDThe implications of exercise-induced cardiac troponin elevation in healthy individuals are unclear. This study aimed to determine if individuals with a high exercise-induced cardiac troponin I (cTnI) response have alterations in myocardial function following high-intensity endurance exercise compared with normal-cTnI responders.Study individuals were recruited from previous participants in a 91-km mountain bike cycling race (the North Sea Race) and were classified as high- (n=34) or normal-cTnI responders (n=25) based on maximal cTnI values after the recruitment race. The present study exposed all participants to 2 prolonged high-intensity exercises: a combined lactate threshold and cardiopulmonary exercise test and repeated participation in the North Sea Race. Echocardiography was performed before, immediately after, and 24 hours following exercise. All study individuals (n=59) had normal coronary arteries, and were aged 51±10 years; 46 (74%) were men. There were no differences in baseline characteristics between the high- and normal-cTnI responders. Maximal cTnI levels 3 hours after exercise were significantly higher in the high- compared with normal-cTnI group (P<0.001-0.027). Following exercise, there were no differences in global ventricular function between the 2 groups. In contrast, high-cTnI responders had significantly lower regional strain in the anteroseptal segments following exercise, with more profound changes after the race.METHODS AND RESULTSStudy individuals were recruited from previous participants in a 91-km mountain bike cycling race (the North Sea Race) and were classified as high- (n=34) or normal-cTnI responders (n=25) based on maximal cTnI values after the recruitment race. The present study exposed all participants to 2 prolonged high-intensity exercises: a combined lactate threshold and cardiopulmonary exercise test and repeated participation in the North Sea Race. Echocardiography was performed before, immediately after, and 24 hours following exercise. All study individuals (n=59) had normal coronary arteries, and were aged 51±10 years; 46 (74%) were men. There were no differences in baseline characteristics between the high- and normal-cTnI responders. Maximal cTnI levels 3 hours after exercise were significantly higher in the high- compared with normal-cTnI group (P<0.001-0.027). Following exercise, there were no differences in global ventricular function between the 2 groups. In contrast, high-cTnI responders had significantly lower regional strain in the anteroseptal segments following exercise, with more profound changes after the race.High-cTnI responders had lower anteroseptal segmental strain shortly after exercise than normal-cTnI responders. However, there were no permanent alterations in myocardial strain, indicating no short- or long-term adverse consequences of these exercise-induced alterations in myocardial function.CONCLUSIONSHigh-cTnI responders had lower anteroseptal segmental strain shortly after exercise than normal-cTnI responders. However, there were no permanent alterations in myocardial strain, indicating no short- or long-term adverse consequences of these exercise-induced alterations in myocardial function.URL: https://www.clinicaltrials.gov; Unique identifier: NCT02166216.REGISTRATIONURL: https://www.clinicaltrials.gov; Unique identifier: NCT02166216.
This study aimed to perform an external validation of the value of right ventricular (RV) deformation patterns and RV mechanical dispersion in patients with arrhythmogenic cardiomyopathy (AC). ...Secondly, this study assessed the association of these parameters with life-threatening ventricular arrhythmia (VA).
Subtle RV dysfunction assessed by echocardiographic deformation imaging is valuable in AC diagnosis and risk prediction. Two different methods have emerged, the RV deformation pattern recognition and RV mechanical dispersion, but these have neither been externally validated nor compared.
We analyzed AC probands and mutation-positive family members, matched from 2 large European referral centers. We performed speckle tracking echocardiography, whereby we classified the subtricuspid deformation patterns from normal to abnormal and assessed RV mechanical dispersion from 6 segments. We defined VA as sustained ventricular tachycardia, appropriate implantable cardioverter-defibrillator therapy, or aborted cardiac arrest.
We included 160 subjects, 80 from each center (43% proband, 55% women, age 41 ± 17 years). VA had occurred in 47 (29%) subjects. In both cohorts, patients with a history of VA showed abnormal deformation patterns (96% and 100%) and had greater RV mechanical dispersion (53 ± 30 ms vs. 30 ± 21 ms; p < 0.001 for the total cohort). Both parameters were independently associated to VA (adjusted odds ratio: 2.71 95% confidence interval: 1.47 to 5.00 per class step-up, and 1.26 95% confidence interval: 1.07 to 1.49/10 ms, respectively). The association with VA significantly improved when adding RV mechanical dispersion to pattern recognition (net reclassification improvement 0.42; p = 0.02 and integrated diagnostic improvement 0.06; p = 0.01).
We externally validated 2 RV dysfunction parameters in AC. Adding RV mechanical dispersion to RV deformation patterns significantly improved the association with life-threatening VA, indicating incremental value.
A novel risk calculator based on clinical characteristics and noninvasive tests that predicts the onset of clinical sustained ventricular arrhythmias (VA) in patients with arrhythmogenic right ...ventricular cardiomyopathy (ARVC) has been proposed and validated by recent studies. It remains unknown whether programmed ventricular stimulation (PVS) provides additional prognostic value.
All patients with a definite ARVC diagnosis, no history of sustained VAs at diagnosis, and PVS performed at baseline were extracted from 6 international ARVC registries. The calculator-predicted risk for sustained VA (sustained or implantable cardioverter defibrillator treated ventricular tachycardia VT or fibrillation, aborted sudden cardiac arrest) was assessed in all patients. Independent and combined performance of the risk calculator and PVS on sustained VA were assessed during a 5-year follow-up period.
Two hundred eighty-eight patients (41.0±14.5 years, 55.9% male, right ventricular ejection fraction 42.5±11.1%) were enrolled. At PVS, 137 (47.6%) patients had inducible ventricular tachycardia. During a median of 5.31 2.89-10.17 years of follow-up, 83 (60.6%) patients with a positive PVS and 37 (24.5%) with a negative PVS experienced sustained VA (
<0.001). Inducible ventricular tachycardia predicted clinical sustained VA during the 5-year follow-up and remained an independent predictor after accounting for the calculator-predicted risk (HR, 2.52 1.58-4.02;
<0.001). Compared with ARVC risk calculator predictions in isolation (C-statistic 0.72), addition of PVS inducibility showed improved prediction of VA events (C-statistic 0.75; log-likelihood ratio for nested models,
<0.001). PVS inducibility had a 76% 67-84 sensitivity and 68% 61-74 specificity, corresponding to log-likelihood ratios of 2.3 and 0.36 for inducible (likelihood ratio+) and noninducible (likelihood ratio-) patients, respectively. In patients with a ARVC risk calculator-predicted risk of clinical VA events <25% during 5 years (ie, low/intermediate subgroup), PVS had a 92.6% negative predictive value.
PVS significantly improved risk stratification above and beyond the calculator-predicted risk of VA in a primary prevention cohort of patients with ARVC, mainly for patients considered to be at low and intermediate risk by the clinical risk calculator.
This study aimed to assess whether patients with MAD also have disjunction of the tricuspid annulus.
Mitral annulus disjunction (MAD) is an abnormal atrial displacement of the mitral annulus. Whether ...the disjunction extends to the right side of the heart is not known.
In a cohort of patients with MAD, we assessed the presence of tricuspid annulus disjunction (TAD) with the use of cardiac magnetic resonance. We explored the associations between TAD and MAD characteristics and the relationship to ventricular arrhythmias (nonsustained/sustained ventricular tachycardias and aborted cardiac arrest).
We included 84 patients (mean age: 48 ± 16 years; 63% female). We observed TAD in 42 (50%). Patients with TAD were older (age 52 ± 16 years vs. 43 ± 15 years; p = 0.02), had greater circumferential extent of MAD (164 ± 57° vs. 115 ± 58°; p = 0.002), greater maximum longitudinal MAD distance (9.4 ± 2.9 mm vs. 6.2 ± 2.8 mm; p < 0.001), and more frequent mitral valve prolapse (39 patients 92% vs. 24 patients 57%; p < 0.001). Ventricular arrhythmias had occurred in 34 patients (41%), who were younger (age 39 ± 14 years vs. 54 ± 14 years; p < 0.001) and had lower prevalence of TAD (22 patients 29% vs. 12 patients 52%; p = 0.03). TAD was not associated with ventricular arrhythmias when adjusted for age (odds ratio adjusted for age: 0.54; 95% confidence interval: 0.20 to 1.45; p = 0.22).
We report for the first time the existence of right-sided annulus disjunction as a common finding in patients with MAD. TAD was associated with more severe left-sided annulus disjunction and mitral valve prolapse, but not with ventricular arrhythmias.
Arrhythmic mitral valve syndrome is linked to life-threatening ventricular arrhythmias. The incidence, morphology and methods for risk stratification are not well known. This prospective study aimed ...to describe the incidence and the morphology of ventricular arrhythmia and propose risk stratification in patients with arrhythmic mitral valve syndrome.
Arrhythmic mitral valve syndrome patients were monitored for ventricular tachyarrhythmias by implantable loop recorders (ILR) and secondary preventive implantable cardioverter-defibrillators (ICD). Severe ventricular arrhythmias included ventricular fibrillation, appropriate or aborted ICD therapy, sustained ventricular tachycardia and non-sustained ventricular tachycardia with symptoms of hemodynamic instability.
During 3.1 years of follow-up, severe ventricular arrhythmia was recorded in seven (12%) of 60 patients implanted with ILR first event incidence rate 4% per person-year, 95% confidence interval (CI) 2-9 and in four (20%) of 20 patients with ICD (re-event incidence rate 8% per person-year, 95% CI 3-21). In the ILR group, severe ventricular arrhythmia was associated with frequent premature ventricular complexes, more non-sustained ventricular tachycardias, greater left ventricular diameter and greater posterolateral mitral annular disjunction distance (all P < 0.02).
The yearly incidence of ventricular arrhythmia was high in arrhythmic mitral valve syndrome patients without previous severe arrhythmias using continuous heart rhythm monitoring. The incidence was even higher in patients with secondary preventive ICD. Frequent premature ventricular complexes, non-sustained ventricular tachycardias, greater left ventricular diameter and greater posterolateral mitral annular disjunction distance were predictors of first severe arrhythmic event.
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).
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).
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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