Arrhythmogenic cardiomyopathy as cause of severe heart failure leading to heart transplantation

Scopo dello studio: la cardiomiopatia aritmogena (CA) è conosciuta come causa di morte improvvisa, la sua relazione con lo scompenso cardiaco (SC) è stata scarsamente indagata. Scopo dello studio è la definizione della prevalenza e incidenza dello SC, nonché della fisiopatologia e delle basi morfologiche che conducono i pazienti con CA a SC e trapianto di cuore. Metodi: abbiamo analizzato retrospettivamente 64 pazienti con diagnosi di CA e confrontato i dati clinici e strumentali dei pazienti con e senza SC (NYHA III-IV). Abbiamo analizzato i cuori espiantati dei pazienti sottoposti a trapianto presso i centri di Bologna e Padova. Risultati: la prevalenza dello SC alla prima osservazione era del 14% e l’incidenza del 2,3% anno-persona. Sedici pazienti (23%) sono stati sottoposti a trapianto. I pazienti con SC erano più giovani all’esordio dei sintomi (46±16 versus 37±12 anni, p=0.04); il ventricolo destro (VD) era più dilatato e ipocinetico all’ecocardiogramma (RVOT 41±6 versus 37±7 mm, p=0.03; diametro telediastolico VD 38±11 versus 28±8 mm, p=0.0001; frazione di accorciamento 23%±7 versus 32%±11, p= 0.002). Il ventricolo sinistro (VS) era lievemente più dilatato (75±29 ml/m2 versus 60±19, p= 0.0017) e globalmente più ipocinetico (frazione di eiezione = 35%±14 versus 57%±12, p= 0.001). Il profilo emodinamico dei pazienti sottoposti a trapianto era caratterizzato da un basso indice cardiaco (1.8±0.2 l/min/m2) con pressione capillare e polmonare tendenzialmente normale (12±8 mmHg e 26±10 mmHg). L’analisi dettagliata dei 36 cuori dei pazienti trapiantati ha mostrato sostituzione fibro-adiposa transmurale nel VD e aree di fibrosi nel VS. Conclusioni: Nella CA lo SC può essere l’unico sintomo alla presentazione e condurre a trapianto un rilevante sottogruppo di pazienti. Chi sviluppa SC è più giovane, ha un interessamento del VD più severo accanto a un costante interessamento del VS, solo lievemente dilatato e ipocinetico, con sostituzione prevalentemente fibrosa.Purpose: Arrythmogenic right ventricular cardiomyopathy (ARVC) is predominantly known as a cause of sudden death in the young, whereas the relationship with heart failure (HF) has been scarcely investigated. We aimed this study to evaluate prevalence, incidence, pathophysiology and morphologic basis of ARVC leading to severe HF. Methods: We retrospectively analysed 64 patients with ARVC evaluated at a single referral centre. We compared the clinical and instrumental findings of ARVC patients with/without severe HF (NYHA III-IV) at first evaluation or during follow up. We analysed the explanted hearts of patients who underwent heart transplantation in two referral centre, Bologna and Padua University. Results: Severe HF was present in 9 patients at presentation (prevalence=14%) and occurred in 10 during follow up (incidence=2.3% person-years). Sixteen patients (23%) required heart transplantation. Patients with advanced HF were younger at symptom onset (46±16 versus 37±12 years, p=0.04); right ventricle (RV) was larger and more hypokinetic at echocardiography (RVOT 41±6 versus 37±7 mm, p=0.03; RV end diastolic diameter 38±11 versus 28±8 mm, p=0.0001; fractional shortening area 23%±7 versus 32%±11, p= 0.002). Left ventricle (LV) was slightly more dilated (75±29 ml/m2 versus 60±19, p= 0.0017) and globally hypokinetic (Ejection Fraction = 35%±14 versus 57%±12, p= 0.001). The hemodynamic profile of patients who underwent cardiac transplantation showed low cardiac index (1.8±0.2 l//min/m2) with nearly normal capillary wedge and pulmonary pressure (12±8 mmHg and 26±10 mmHg). A detailed histological analysis of 36 explanted hearts showed extensive fibro-fatty infiltration of the RV and isolated or confluent areas of LV fibrosis. Conclusions: In ARVC, HF can be the only symptom at presentation and leads to heart transplantation in a relevant subset of patients. Patients who develop advanced HF are younger, have more severe RV involvement associated with slight dilation and global hypokinesia of the LV, due to fibrotic infiltration

Differences in cardiac phenotype and natural history of laminopathies with and without neuromuscular onset

Objective: To investigate differences in cardiac manifestations of patients affected by laminopathy, according to the presence or absence of neuromuscular involvement at presentation.Methods: We prospectively analyzed 40 consecutive patients with a diagnosis of laminopathy followed at a single centre between 1998 and 2017. Additionally, reports of clinical evaluations and tests prior to referral at our centre were retrospectively evaluated.Results: Clinical onset was cardiac in 26 cases and neuromuscular in 14. Patients with neuromuscular presentation experienced first symptoms earlier in life (11 vs 39 years; p < 0.0001) and developed atrial fibrillation/flutter (AF) and required pacemaker implantation at a younger age (28 vs 41 years [p = 0.013] and 30 vs 44 years [p = 0.086] respectively), despite a similar overall prevalence of AF (57% vs 65%; p = 0.735) and atrio-ventricular (A-V) block (50% vs 65%; p = 0.500). Those with a neuromuscular presentation developed a cardiomyopathy less frequently (43% vs 73%; p = 0.089) and had a lower rate of sustained ventricular tachyarrhythmias (7% vs 23%; p = 0.387). In patients with neuromuscular onset rhythm disturbances occurred usually before evidence of cardiomyopathy. Despite these differences, the need for heart transplantation and median age at intervention were similar in the two groups (29% vs 23% [p = 0.717] and 43 vs 46 years [p = 0.593] respectively).Conclusions: In patients with laminopathy, the type of disease onset was a marker for a different natural history. Specifically, patients with neuromuscular presentation had an earlier cardiac involvement, characterized by a linear and progressive evolution from rhythm disorders (AF and/or A-V block) to cardiomyopathy

Importance of genotype for risk stratification in arrhythmogenic right ventricular cardiomyopathy using the 2019 ARVC risk calculator

none41siTo study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC).Protonotarios, Alexandros; Bariani, Riccardo; Cappelletto, Chiara; Pavlou, Menelaos; García-García, Alba; Cipriani, Alberto; Protonotarios, Ioannis; Rivas, Adrian; Wittenberg, Regitze; Graziosi, Maddalena; Xylouri, Zafeirenia; Larrañaga-Moreira, José M; de Luca, Antonio; Celeghin, Rudy; Pilichou, Kalliopi; Bakalakos, Athanasios; Lopes, Luis Rocha; Savvatis, Konstantinos; Stolfo, Davide; Dal Ferro, Matteo; Merlo, Marco; Basso, Cristina; Freire, Javier Limeres; Rodriguez-Palomares, Jose F; Kubo, Toru; Ripoll-Vera, Tomas; Barriales-Villa, Roberto; Antoniades, Loizos; Mogensen, Jens; Garcia-Pavia, Pablo; Wahbi, Karim; Biagini, Elena; Anastasakis, Aris; Tsatsopoulou, Adalena; Zorio, Esther; Gimeno, Juan R; Garcia-Pinilla, Jose Manuel; Syrris, Petros; Sinagra, Gianfranco; Bauce, Barbara; Elliott, Perry MProtonotarios, Alexandros; Bariani, Riccardo; Cappelletto, Chiara; Pavlou, Menelaos; García-García, Alba; Cipriani, Alberto; Protonotarios, Ioannis; Rivas, Adrian; Wittenberg, Regitze; Graziosi, Maddalena; Xylouri, Zafeirenia; Larrañaga-Moreira, José M; de Luca, Antonio; Celeghin, Rudy; Pilichou, Kalliopi; Bakalakos, Athanasios; Lopes, Luis Rocha; Savvatis, Konstantinos; Stolfo, Davide; Dal Ferro, Matteo; Merlo, Marco; Basso, Cristina; Freire, Javier Limeres; Rodriguez-Palomares, Jose F; Kubo, Toru; Ripoll-Vera, Tomas; Barriales-Villa, Roberto; Antoniades, Loizos; Mogensen, Jens; Garcia-Pavia, Pablo; Wahbi, Karim; Biagini, Elena; Anastasakis, Aris; Tsatsopoulou, Adalena; Zorio, Esther; Gimeno, Juan R; Garcia-Pinilla, Jose Manuel; Syrris, Petros; Sinagra, Gianfranco; Bauce, Barbara; Elliott, Perry

Long-Term Arrhythmic Follow-Up and Risk Stratification of Patients With Desmoplakin-Associated Arrhythmogenic Right Ventricular Cardiomyopathy

Background: Patients with likely pathogenic/pathogenic desmoplakin (DSP) variants are poorly characterized. Some of them meet diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC), but it is unclear how risk stratification strategies for ARVC perform in this setting. Objectives: The purpose of this study was to characterize arrhythmic outcomes and to test the performance of the recently validated ARVC risk calculator in patients with DSP likely pathogenic/pathogenic variants fulfilling definite 2010 ARVC Task Force Criteria (DSP-TFC+). Methods: DSP-TFC+ patients were enrolled from 20 institutions across 3 continents. Ventricular arrhythmias (VA), defined as a composite of sustained ventricular tachycardia (VT), appropriate implantable cardioverter defibrillator therapies, and ventricular fibrillation/sudden cardiac death events in follow-up, were reported as the primary outcome. We tested the performance of the ARVC risk calculator for VA prediction, reporting c-statistics. Results: Among 252 DSP-TFC+ patients (age 39.6 ± 16.9 years, 35.3% male), 94 (37.3%) experienced VA over 44.5 [IQR: 19.6-78.3] months. Patients with left ventricle involvement (n = 194) were at higher VA risk (log-rank P = 0.0239). History of nonsustained VT (aHR 2.097; P = 0.004) showed the strongest association with VA occurrence during the first 5-year follow-up. Neither age (P = 0.723) nor male sex (P = 0.200) was associated with VAs at follow-up. In 204 patients without VA at diagnosis, incident VA rate was high (32.8%; 7.37%/y). The ARVC risk calculator performed poorly overall (c-statistic 0.604 [0.594-0.614]) and very poorly in patients with left ventricular disease (c-statistic 0.558 [0.556-0.560]). Conclusions: DSP-TFC+ patients are at substantial risk for VAs. The ARVC risk calculator performs poorly in DSP-TFC+ patients suggesting need for a gene-specific risk algorithm. Meanwhile, DSP-TFC+ patients with nonsustained VT should be considered as high-risk

Right ventricular arrhythmogenic cardiomyopathy: Genetic and MR for modern clinical diagnosis

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Right ventricular arrhythmogenic cardiomyopathy: Genetic and MR for modern clinical diagnosis

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The uncertainty of causes of sudden cardiac death: the promising role of the molecular autopsy and family screening to weight scientific evidence

In sudden cardiac deaths (SCD), the identification of the cause(s) of death at autopsy may be challenging, especially in some conditions where the border between physiological and pathological changes is not defined. This paper describes a case of SCD in an 18-month-old child with two abnormalities of uncertain significance. The multi-disciplinary approach included PMCT, autopsy, histological, toxicological and genetic analysis. Parental screening and targeted genetic testing were performed. Two potentially pathogenic abnormalities were detected: a high take-off origin of the left coronary artery from the tubular aorta and a heterozygous variant, harbored by the mother and the grandfather, within exon 1 of the KCNQ1 (potassium voltage-gated channel subfamily Q member 1) gene (p.Ala46Thr). The clinical examination, basal ECG and Holter ECG were normal, except for a single borderline QTc interval measurement in the mother. The high coronary origin is classified by the International Guidelines for autopsy investigation in SCD as an “uncertain” cause of death and the genetic variant is classified as of “uncertain” or “likely pathogenic” significance in Clinvar and Varsome, respectively. The possibility to perform an extended family screening revealed the lack of a solid genotype-phenotype correlation, and the KCNQ1 variant cannot with any certainty be regarded as disease-causing. When autopsy findings fall into the grey zone between physiological and pathological changes, as well as post-mortem genetic analysis, the standardized clinical testing of families should be emphasized in order to understand the role of gene variants, and to produce evidences for the realization of personalized medicine

The elusive link between aortic wall histology and echocardiographic anatomy in bicuspid aortic valve: implications for prophylactic surgery

OBJECTIVE: Prediction of aortic dissection or rupture is extremely difficult in patients with bicuspid aortic valve. We aimed to identify clinical and echocardiography predictors of histological abnormalities of the aortic wall in patients with bicuspid aortic valve undergoing aortic surgery. METHODS: We assessed the histology of the aortic wall and clinical and echocardiography variables in a cohort of patients with bicuspid aortic valve (n = 127) and a wide spectrum of valvar disease who underwent replacement of the ascending aorta (with or without aortic valve surgery). Histology was classified using a 5-grade system developed by Larson and Edward. RESULTS: Histological alterations of the aortic wall were absent/mild (grade 0-1) in 77 patients (61%) and moderate/severe (grade 2-3) in 50 (39%). Patients with moderate/severe histological alterations were younger (47 ± 17 vs 53 ± 16; p = 0.042). Eighteen patients out of 48 (38%) with an ascending aorta diameter ≤ 4.5 cm had grade 2-3 aortic wall disease as did 8 out of 18 (44%) with a diameter ≤ 4 cm. Nineteen out of 46 (41%) patients with a maximal ascending aortic area/height ratio < 10 cm(2) m(-1) had moderate/severe histological alterations. Multivariate logistic regression analysis showed that the indexed diameter of the aortic annulus was significantly associated with grade 2-3 aortic wall disease (odds ratio (OR): 12.22, 95% confidence interval (CI): 1.65-90.38, p = 0.014). CONCLUSIONS: A high proportion of patients with bicuspid aortic valve and mild to moderate aortic dilatation have severe histological abnormalities of the aortic wall that are not predictable by clinical and echocardiographic findings. These observations suggest that risk stratification for aortic dissection or rupture in patients with bicuspid aortic valve is so far quite suboptimal and future investigations are warranted

Postmortem diagnosis of left dominant arrhythmogenic cardiomyopathy: the importance of a multidisciplinary network for sudden death victims. "HIC mors gaudet succurere vitae"

An apparently healthy man died suddenly at the age of 49 during physical activity. The heart was referred to our Cardiovascular Pathology Unit for valve tissue banking. Pathology findings led to the diagnosis of arrhythmogenic left ventricular cardiomyopathy. Molecular autopsy was performed and two variants of interest were identified in genes associated with arrhythmogenic cardiomyopathy. The 19-year-old son underwent a cardiac screening comprehensive of electrocardiogram (ECG), echocardiogram, cardiac magnetic resonance and genetic testing, and the diagnosis of arrhythmogenic left ventricular cardiomyopathy was achieved.This case report highlights the need of a systematic evaluation of all sudden death victims with autopsy performed by expert cardiovascular pathologists and implemented by molecular analysis, aiming to identify also rare hereditary diseases and activate proper family screening. (C) 2019 Elsevier Inc. All rights reserved

Contribution of PET imaging to mortality risk stratification in candidates to lead extraction for pacemaker or defibrillator infection: a prospective single center study

Purpose: 18F-FDG PET/CT is an emerging technique for diagnosis of cardiac implantable electronic devices infection (CIEDI). Despite the improvements in transvenous lead extraction (TLE), long-term survival in patients with CIEDI is poor. The aim of the present study was to evaluate whether the extension of CIEDI at 18F-FDG PET/CT can improve prediction of survival after TLE. Methods: Prospective, monocentric observational study enrolling consecutive candidates to TLE for a diagnosis of CIEDI. 18F-FDG PET/CT was performed in all patients prior TLE. Results: There were 105 consecutive patients with confirmed CIEDI enrolled. An increased 18F-FDG uptake was limited to cardiac implantable electrical device (CIED) pocket in 56 patients, 40 patients had a systemic involvement. We had nine negative PET in patients undergoing prolonged antimicrobial therapy (22.5 \ub1 14.0 days vs. 8.6 \ub1 13.0 days; p = 0.005). Implementation of 18F-FDG PET/CT in modified Duke Criteria lead to reclassification of 23.8% of the patients. After a mean follow-up of 25.0 \ub1 9.0 months, 31 patients died (29.5%). Patients with CIED pocket involvement at 18F-FDG PET/CT presented a better survival independently of presence/absence of systemic involvement (HR 0.493, 95%CI 0.240\u20130.984; p = 0.048). After integration of 18F-FDG PET/CT data, absence of overt/hidden pocket involvement in CIEDI and a (glomerular filtration rate) GFR < 60 ml/min were the only independent predictors of mortality at long term. Conclusions: Patient with CIEDI and a Cold Closed Pocket (i.e., a CIED pocket without skin erosion/perforation nor increased capitation at 18F-FDG PET/CT) present worse long-term survival. Patient management can benefit by systematic adoption of pre-TLE 18F-FDG PET/CT through improved identification of CIED related endocarditis (CIEDIE) and hidden involvement of CIED pocket