Proposed diagnostic criteria for arrhythmogenic cardiomyopathy: European Task Force consensus report.

Arrhythmogenic cardiomyopathy (ACM) is a heart muscle disease characterized by prominent "non-ischemic" myocardial scarring predisposing to ventricular electrical instability. Diagnostic criteria for the original phenotype, arrhythmogenic right ventricular cardiomyopathy (ARVC), were first proposed in 1994 and revised in 2010 by an international Task Force (TF). A 2019 International Expert report appraised these previous criteria, finding good accuracy for diagnosis of ARVC but a lack of sensitivity for identification of the expanding phenotypic disease spectrum, which includes left-sided variants, i.e., biventricular (ABVC) and arrhythmogenic left ventricular cardiomyopathy (ALVC). The ARVC phenotype together with these left-sided variants are now more appropriately named ACM. The lack of diagnostic criteria for the left ventricular (LV) phenotype has resulted in clinical under-recognition of ACM patients over the 4 decades since the disease discovery. In 2020, the "Padua criteria" were proposed for both right- and left-sided ACM phenotypes. The presently proposed criteria represent a refinement of the 2020 Padua criteria and have been developed by an expert European TF to improve the diagnosis of ACM with upgraded and internationally recognized criteria. The growing recognition of the diagnostic role of CMR has led to the incorporation of myocardial tissue characterization findings for detection of myocardial scar using the late­gadolinium enhancement (LGE) technique to more fully characterize right, biventricular and left disease variants, whether genetic or acquired (phenocopies), and to exclude other "non-scarring" myocardial disease. The "ring-like' pattern of myocardial LGE/scar is now a recognized diagnostic hallmark of ALVC. Additional diagnostic criteria regarding LV depolarization and repolarization ECG abnormalities and ventricular arrhythmias of LV origin are also provided. These proposed upgrading of diagnostic criteria represents a working framework to improve management of ACM patients.

Pregnancy in arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (AC) is a rare heart muscle disease with a genetic background and autosomal dominant mode of transmission. The clinical manifestation is characterized by ventricular arrhythmias (VA), heart failure (HF) and the risk of sudden cardiac death (SCD). Pregnancy in young female patients with AC represents a challenging condition for the life and family planning of young affected women. In addition to genetic mechanisms that influence the complex pathophysiology of AC, experimental and clinical data have confirmed the pathogenetic role of strenuous exercise and competitive sports in the early onset and rapid progression of AC symptoms and complications. Pregnancy and exercise share a number of physiological aspects of adaptation. In AC, both result in ventricular volume overload and myocardial stretch. Therefore, pregnancy has been postulated as a potential risk factor for HF, VA, SCD, and pregnancy-related obstetric complications in patients with AC. However, the available evidence on pregnancy in AC does not confirm this hypothesis. In most women with AC, pregnancies are well tolerated, uneventful, and follow a benign course. Pregnancy-related symptoms (VA, syncope, HF) and mortality, as well as obstetric complications, are uncommon in AC patients and range in the order of background populations and cohorts with AC and no pregnancy. The number of completed pregnancies is not associated with an acceleration of AC pathology or an increased risk of VA or HF during pregnancy and follow-up. Accordingly, there is no medical indication to advise against pregnancy in patients with AC. Preconditions include stability of rhythm and hemodynamics at baseline, as well as clinical follow-ups and the availability of multidisciplinary expert consultation during pregnancy and postpartum. Genetic counseling is recommended prior to pregnancy for all couples and their families affected by AC.

Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23.

AIMS: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. METHODS AND RESULTS: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. CONCLUSION: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.

Diagnosis of arrhythmogenic cardiomyopathy: The Padua criteria.

The original designation of "Arrhythmogenic right ventricular (dysplasia/) cardiomyopathy"(ARVC) was used by the scientists who first discovered the disease, in the pre-genetic and pre-cardiac magnetic resonance era, to describe a new heart muscle disease predominantly affecting the right ventricle, whose cardinal clinical manifestation was the occurrence of malignant ventricular arrhythmias. Subsequently, autopsy investigations, genotype-phenotype correlations studies and the increasing use of contrast-enhancement cardiac magnetic resonance showed that the fibro-fatty replacement of the myocardium represents the distinctive phenotypic feature of the disease that affects the myocardium of both ventricles, with left ventricular involvement which may parallel or exceed the severity of right ventricular involvement. This has led to the new designation of "Arrhythmogenic Cardiomyopathy" (ACM), that represents the evolution of the original term of ARVC. The present International Expert Consensus document proposes an upgrade of the criteria for diagnosis of the entire spectrum of the phenotypic variants of ACM. The proposed "Padua criteria" derive from the diagnostic approach to ACM, which has been developed over 30 years by the multidisciplinary team of basic researchers and clinical cardiologists of the Medical School of the University of Padua. The Padua criteria are a working framework to improve the diagnosis of ACM by introducing new diagnostic criteria regarding tissue characterization findings by contrast-enhanced cardiac magnetic resonance, depolarization/repolarization ECG abnormalities and ventricular arrhythmia features for diagnosis of the left ventricular phenotype. The proposed diagnostic criteria need to be further validated by future clinical studies in large cohorts of patients.

Mid-regional proatrial natriuretic peptide for predicting prognosis in hypertrophic cardiomyopathy.

OBJECTIVES: N-terminal probrain natriuretic peptide (NT-proBNP) predicts mortality and the development of heart failure in hypertrophic cardiomyopathy (HCM). Mid-regional proatrial natriuretic peptide (MR-proANP) is a stable by-product of production of atrial natriuretic peptide. We sought to compare the prognostic value of MR-proANP and NT-proBNP in HCM. METHODS: We prospectively enrolled a cohort of patients with HCM from different European centres and followed them. All patients had clinical, ECG and echocardiographic evaluation and measurement of MR-proANP and NT-proBNP at inclusion. RESULTS: Of 357 patients enrolled, the median age was 52 (IQR: 36-65) years. MR-proANP and NT-proBNP were both independently associated with age, weight, New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), wall thickness and left atrial dimension. During a median follow-up of 23 months, 32 patients had a primary end point defined as death (n=6), heart transplantation (n=8), left ventricular assist device implantation (n=1) or heart failure hospitalisation (n=17). Both NT-proBNP and MR-proANP (p<10-4) were strongly associated with the primary endpoint, and the areas under the receiver operating characteristic (ROC) curves for both peptides were not significantly different. However, in a multiple stepwise regression analysis, the best model for predicting outcome was NYHA 1-2 vs 3-4 (HR=0.35, 95% CI 0.16 to 0.77, p<0.01), LVEF (HR=0.96, 95% CI 0.94 to 0.98, p=0.0005) and MR-proANP (HR=3.77, 95% CI 2.01 to 7.08, p<0.0001). CONCLUSIONS: MR-proANP emerges as a valuable biomarker for the prediction of death and heart failure related events in patients with HCM.

Closure of Left Atrial Appendage With Persistent Distal Thrombus Using an Amplatzer Amulet Occluder.

A 73-year-old patient with permanent atrial fibrillation presented for left atrial appendage (LAA) occlusion. Transesophageal echocardiography demonstrated a thrombus in the distal LAA. This image series illustrates a "no touch" technique that was used to ensure successful implantation of an Amplatzer Amulet LAA occlusion device without the use of an embolization protection system.

Sex differences in absolute myocardial perfusion. Non-invasive H2(15)O-PET in young healthy adults.

AIM: To investigate sex differences in myocardial perfusion especially in healthy individuals since former studies are rare and findings are controversial. Participants, methods: 26 subjects were enrolled: 16 healthy women (age: 34 ±7 years) were compared with 10 healthy men (age: 34 ± 3 years; p = ns). Myocardial blood flow (MBF) and coronary vascular resistance (CVR) were quantified at rest, during adenosine infusion and cold-pressor-testing, using positron emission tomography and radioactive-labelled water (H2(15)O-PET). RESULTS: Women showed higher MBF than men at rest (1.10 ± 0.18 vs. 0.85 ± 0.20 ml/min/ml; p = 0.003) and cold-stress (1.39 ± 0.38 vs. 1.06 ± 0.28 ml/min/ml; p = 0.026). Corrected for rate-pressure-product, baseline findings maintained significance (1.41 ± 0.33 vs. 1.16 ± 0.19 ml/min/ml; p = 0.024). CVR was lower in women at baseline (81 ± 14 vs. 107 ± 22 mmHg*ml(-1)*min*ml; p = 0.006) and during cold-pressor-testing (71 ± 17 vs. 91 ± 20 mmHg*ml(-1)*min*ml; p = 0.013). Under adenosine neither maximal MBF (4.06 ± 1.0 vs. 3.91 ± 0.88 ml/min/ml; p = ns) nor coronary flow reserve (3.07 ± 1.12 vs. 3.44 ± 0.92; p = ns) nor CVR (24 ± 8 vs. 24 ± 6 mmHg*ml(-1)*min*ml; p = ns) showed sex-related differences. CONCLUSION: Women show higher myocardial perfusion and lower coronary vascular resistance than men in physiologic states. Maximum perfusion and vasodilation under adenosine are not sex-specific.

High interobserver variability in the assessment of epsilon waves: Implications for diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia.

BACKGROUND: Revision of the Task Force diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) has increased their sensitivity for the diagnosis of early and familial forms of the disease. The epsilon wave is a major diagnostic criterion in the context of ARVC/D, which, however, remains not quantifiable and therefore may leave room for substantial subjective interpretation. OBJECTIVE: The purpose of this study was to assess interobserver agreement in epsilon wave definition and epsilon wave importance for ARVC/D diagnosis. METHODS: Electrocardiographic (ECG) tracings depicting leads V1, V2, and V3 collected from individuals evaluated for ARVC/D (n = 30) were given to panel members who were asked to respond to the question whether ECG patterns meet epsilon wave definition outlined by the Task Force diagnostic criteria. The prevalence and importance of epsilon waves for ARVC/D diagnosis were assessed in a pooled data set of patients with definite ARVC/D from European and American registries (n = 815). RESULTS: The number of ECG patterns identified as epsilon waves varied from 5 to 18 per reviewer (median 13 per reviewer). A unanimous agreement was reached for only 10 cases (33%), 2 of which qualified as epsilon waves and 8 as non-epsilon waves by all panel members. From a pooled data set, 106 patients reportedly had epsilon waves (13%). In 105 of 106 patients with epsilon waves (99%), exclusion of epsilon waves from the diagnostic score would not affect the "definite" diagnostic category. CONCLUSION: Interobserver variability in the assessment of epsilon waves is high; however, the impact of epsilon waves on ARVC/D diagnosis is negligibly low. The results urge to exercise caution in the assessment of epsilon waves, especially in patients who would not otherwise meet diagnostic criteria.

Biventricular myocardial strain analysis in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) using cardiovascular magnetic resonance feature tracking.

BACKGROUND: Fibrofatty degeneration of myocardium in ARVC is associated with wall motion abnormalities. The aim of this study was to examine whether Cardiovascular Magnetic Resonance (CMR) based strain analysis using feature tracking (FT) can serve as a quantifiable measure to confirm global and regional ventricular dysfunction in ARVC patients and support the early detection of ARVC. METHODS: We enrolled 20 patients with ARVC, 30 with borderline ARVC and 22 subjects with a positive family history but no clinical signs of a manifest ARVC. 10 healthy volunteers (HV) served as controls. 15 ARVC patients received genotyping for Plakophilin-2 mutation (PKP-2), of which 7 were found to be positive. Cine MR datasets of all subjects were assessed for myocardial strain using FT (TomTec Diogenes Software). Global strain and strain rate in radial, circumferential and longitudinal mode were assessed for the right and left ventricle. In addition strain analysis at a segmental level was performed for the right ventricular free wall. RESULTS: RV global longitudinal strain rates in ARVC (-0.68 ± 0.36 sec⁻¹) and borderline ARVC (-0.85 ± 0.36 sec⁻¹) were significantly reduced in comparison with HV (-1.38 ± 0.52 sec⁻¹, p ≤ 0.05). Furthermore, in ARVC patients RV global circumferential strain and strain rates at the basal level were significantly reduced compared with HV (strain: -5.1 ± 2.7 vs. -9.2 ± 3.6%; strain rate: -0.31 ± 0.13 sec(-1) vs. -0.61 ± 0.21 sec⁻¹). Even for patients with ARVC or borderline ARVC and normal RV ejection fraction (n=30) global longitudinal strain rate proved to be significantly reduced compared with HV (-0.9 ± 0.3 vs. -1.4 ± 0.5 sec(-1); p < 0.005). In ARVC patients with PKP-2 mutation there was a clear trend towards a more pronounced impairment in RV global longitudinal strain rate. On ROC analysis RV global longitudinal strain rate and circumferential strain rate at the basal level proved to be the best discriminators between ARVC patients and HV (AUC: 0.9 and 0.92, respectively). CONCLUSION: CMR based strain analysis using FT is an objective and useful measure for quantification of wall motion abnormalities in ARVC. It allows differentiation between manifest or borderline ARVC and HV, even if ejection fraction is still normal.

Autonomic dysfunction in patients with arrhythmogenic right ventricular cardiomyopathy: biochemical evidence of altered signaling pathways.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of sudden cardiac death especially in times of increased sympathetic tone, for example, during sports, which have been confirmed by nuclear imaging studies. However, the underlying biochemical pathways remain to be delineated. Therefore, we investigated the expression levels of proteins of the signaling cascade in patients with ARVC. METHODS: During diagnostic work-up, right ventricular endomyocardial biopsies (EMBs) were sampled from 15 consecutive male ARVC patients (52 ± 14 years). Tissue levels of key proteins of the signaling cascade were analyzed. Results were compared to those obtained from EMBs of 10 patients with idiopathic right ventricular outflow-tract tachycardia (RVOT; 41 ± 14 years) and of five control subjects without identifiable structural heart disease (42 ± 13 years; P = ns). RESULTS: Among the proteins analyzed, only tissue levels of norepinephrine (NE; P < 0.04) and cyclic adenosine-3´,5´-monophospate (cAMP; P < 0.01) were significantly lower in ARVC when compared to RVOT patients. When compared to controls, mean cAMP levels were lower in patients with ARVC but did not reach statistical significance. No differences in cAMP were observed between RVOT and controls. CONCLUSIONS: The current findings confirm and expand the concept of adrenergic dysfunction in ARVC: the reduction of NE in ARVC could lead to an impaired stimulation of ß-adrenoceptor subsequent signaling pathways with potential implication for cardiac fibrosis and arrhythmogenesis.

Connexin expression patterns in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inheritable myocardial disease accounting for ventricular tachycardia and sudden death in the young and arising from areas of fibrofatty replacement of predominantly right ventricular myocardium. That some patients manifest life-threatening ventricular tachycardia in the absence of substantial myocardial replacement suggests that gap junction remodeling might be acting synergistically to ventricular remodeling to promote arrhythmogenesis. Hence, we sought to verify gap junction composition and distribution by analyzing the expression and occurrence of specific gap junction proteins (connexins [Cxs]) in patients with ARVC. Right ventricular endomyocardial biopsy specimens were taken from 16 patients with definite ARVC (age 48 ± 16 years) and analyzed for Cx40, Cx43, and Cx45 messenger ribonucleic acid expression (relative to glyceraldehyde-3-phosphate-dehydrogenase messenger ribonucleic acid expression). The results were compared to those obtained from nondiseased donor hearts (n = 6; age 32 ± 11 years). The patients with ARVC showed a significant reduction in the messenger ribonucleic acid expression of Cx40 (p <0.0001) and Cx45 (p <0.0001) compared to that of the controls. The expression of Cx43 was similar in patients with ARVC and controls (p = 0.098). Mutations in plakophilin-2 were identified in 7 of 16 patients (25%). The Cx expression levels were comparable between the mutation carriers and noncarriers (p = NS). In conclusion, ARVC features alterations in the expression of Cxs and their distribution at cardiac intercalated discs. Apart from the deposition of extracellular matrix, the potential loss of gap junctions and shift in the composition of gap junctional Cxs in the ventricular conduction system might further contribute to the development of ventricular arrhythmias in patients with ARVC.

Electrophysiological characteristics of ventricular tachyarrhythmias in cardiac sarcoidosis versus arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Recent evidence suggests that cardiac sarcoidosis (CS) and arrhythmogenic right ventricular cardiomyopathy (ARVC) can manifest very similarly. OBJECTIVE: To investigate whether there are significant demographic and electrophysiological differences between patients with CS and ARVC. METHODS: We prospectively compared patients with proven CS or ARVC who underwent radiofrequency catheter ablation of ventricular tachycardias by using 3-dimensional electroanatomical mapping. Furthermore, we evaluated whether the diagnostic criteria for ARVC would have excluded ARVC in patients with CS. RESULTS: Eighteen patients (13 men; mean age 44.9 years) were included. All 18 patients had mild to moderately reduced right ventricular ejection fraction. Patients with cardiac sarcoidosis (n = 8) had a significantly lower mean left ventricular ejection fraction (35.6±19.3 vs 60.6±9.4; P = .002). Patients with CS had a significantly wider QRS (0.146 vs 0.110s; P = .004). Five of 8 (63%) patients with CS fulfilled the diagnostic ARVC criteria. Ventricular tachycardias (VTs) with a left bundle branch block pattern were documented in all but one patient (with CS). Programmed ventricular stimulation induced an average of 3.7 different monomorphic VTs in patients with CS vs 1.8 in patients with ARVC (P = .01). VT significantly more often originated in the apical region of the right ventricle in CS vs ARVC (P = .001), with no other predilection sites. Ablation success and other electrophysiological parameters were not different. CONCLUSIONS: The current diagnostic ARVC guidelines do not reliably exclude patients with CS. Clinical and electrophysiological parameters that were characteristic of CS in our patients include reduced left ventricular ejection fraction, a significantly wider QRS, right-sided apical VT, and more inducible forms of monomorphic VT.

T-wave integral: an electrocardiographic marker discriminating patients with arrhythmogenic right ventricular cardiomyopathy from patients with right ventricular outflow tract tachycardia.

AIMS: Clinical and electrocardiographic (ECG) presentation of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and idiopathic right ventricular outflow-tract tachycardia (RVOT) may be similar. The aim of the study was to assess the validity and utility of T-wave integral measurement as an ECG discriminator of patients with ARVC and RVOT using a body surface mapping (BSM). METHODS AND RESULTS: A 120-channel BSM with quantitative signal analysis of the T-wave integral was performed in 10 patients with ARVC. Results were compared with those obtained from 13 patients with RVOT and a control group of 12 healthy subjects (controls). Age, body mass index, and QRS-axis on surface ECG were not significantly different between the groups. Arrhythmogenic right ventricular cardiomyopathy patients showed a significantly negative T-wave integral in the right lower anterior region of the torso when compared with RVOT (P < 0.001). There was no statistically significant difference between RVOT patients and controls. At a cut-off level of -0.3 mV ms, sensitivity and specificity were 83% [area under curve (AUC) 0.85 ± 0.04 for the comparison of ARVC and RVOT]. These differences were pronounced in ARVC patients with a plakophlin-2 mutation (P < 0.001). CONCLUSION: Quantitative analysis of the BSM T-wave integral in distinct anatomical regions discriminates ARVC patients from RVOT patients and controls and may serve as an additional diagnostic tool.

Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in >40% of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459C>A/C153X and c.827G>C/C276S). Whereas the c.459C>A variant was associated with muscle weakness in some patients, the c.134delA and c.827G>C variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat-engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM.