bluuebunny/crossref_metadata_2025_split huggingface dataset:
Calmodulinopathy is a common cause of critical cardiac phenotypes in fetus and infancy
Authors: Fukuyama M , Horie M , Kato K , Ozawa T , Fujii Y , Okuyama Y , Makiyama T , Ohno S , Nakagawa Y 
Published: October 2022

Abstract

Background
Cardiac calmodulinopathy is a life-threatening arrhythmia syndrome which presents several phenotypes of inherited primary arrhythmia syndrome (IPAS), and caused by mutations in calmodulin-encoded genes (CALM1–3). We aimed clarify the frequency and their clinical characteristics of calmodulinopathy in our IPAS cohort.

Methods
By using next generation sequencing, we screened arrhythmia related genes including calmodulin-encoding genes in 322 unrelated symptomatic children (0–12 years) who were suspected as IPAS; they included 40 cases with lethal arrhythmic attacks (LAE) under 6-year-old. After gene screening, we investigated their physiological and clinical characteristics about mutation carriers.

Results
Among 322 children, we identified 6 mutations of calmodulin-encoded genes in 9 probands (2.8%); one CALM1 in 2 probands (N98S), and 5 CALM2 in 7 probands (E46K, D96V, D96G, N98S, E141K). Their clinical diagnoses were long QT syndrome (LQTS, n=4), catecholaminergic polymorphic ventricular tachycardia (CPVT, n=3) and both (n=2). Their age of diagnosis ranges at 0–9 with the median of 5 years. There were three major clinical phenotypes; 1) CALM2-D96V, and E141K: two infants with advanced atrio-ventricular block, significant QTc prolongation, severe heart failure from their fetal period – both of them deceased within 1.5-year-old. Their clinical phenotypes resembled classical Timothy syndrome caused by CACNA1C mutations. 2) CALM1-N98S (n=2), CALM2-N98S (n=2), and CALM2-D96G: four preschoolers with LAEs and one syncope: all of them were 3–5 years old. In addition, a T wave morphology of CALM2-D96G carrier was very similar to LQT1. 3) CALM2-E46K (n=2): two were first diagnosed with neurological and developmental disorders, and showed phenotype of CPVT: their cardiac phenotypes were milder compared with that of 1) or 2). Overall, these phenotypes seemed to be mutation specific (indicated in figure). Their cardiac features were severer, and the onset of LAEs was earlier compared with other genotypes of LQTS/CPVT. As the treatment, β-blocker was effective for control of LAEs.

Conclusion
Cardiac calmodulinopathy presented serious and potentially lethal phenotypes in fetus or infancy. To prevent cardiac death in them, we must correctly diagnose and start the treatment as earlier as possible.

Funding Acknowledgement
Type of funding sources: Public Institution(s). Main funding source(s): MEXT KAKENHI from the Ministry of Education, Culture, Sports, Science, and Technology of Japan
Characterization and long-term follow-up of children with brugada syndrome: experience from a tertiary paediatric referral centre
Authors: Fernandes S , Saleiro C , Palma A , Faim D , Dias J , Borges I , Santos I , Andrade H , Martins H , Pires A 
Published: October 2022

Abstract

Introduction
Brugada syndrome (BrS) is an autosomal dominant channelopathy, which typically presents in young adults. It can also be diagnosed in children, but data in this age group is scarce.

Purpose
To describe the clinical features, management and long-term follow-up of children with BrS history followed-up in a tertiary paediatric referral centre.

Methods
Single centre retrospective study of consecutive patients with history of BrS, defined as having a BrS positive phenotype (BrS(+)), or a negative phenotype-positive genotype (BrS(−)). They were all followed up in a paediatric heart rhythm clinic. Clinical and demographical data were collected and analysed according to the phenotype.

Results
30 patients were included, with a median age at diagnosis of 7 years (IQR 1–13) and a mean follow-up time of 7±3 years. Sixteen patients were BrS(+), predominantly male (n=13, 81%). 88% (n=14) performed a genetic test, which was positive in 57% (n=8); the most frequent mutation was SCN5A (n=5). Family history of BrS was present in 56% (n=9) and almost one third had family history of sudden cardiac death (SCD). Most of the patients had a type 1 Brugada ECG pattern (n=14) and 2 patients presented a fever and drug induced pattern, respectively. Fourteen patients were BrS(−), mostly female (n=11, 79%) with a loss-of-function mutation in the SCN5A gene (n=10). They all had family members with BrS, mainly from the paternal side, and 43% (n=6) mentioned SCD history. Although most of the patients were asymptomatic, the prevalence of rhythm or conduction disturbances was not infrequent, particularly in BrS(+) patients (n=12, 75%). Also, in this group and during follow-up, 3 patients had documented supraventricular tachyarrhythmias, and 2 patients had syncope episodes, one of which required an implantable cardioverter-defibrillator. No events were reported in the BrS(−) patients. Nine patients (n=9/30, 30%) were hospitalized, 3 due to an arrhythmic event (all in the BrS(+) group). Overall, no sudden cardiac death event was reported during follow-up.

Conclusion
In our study, although the majority of the patients were asymptomatic, the occurrence of arrhythmic events was not negligible, especially in the BrS(+) patients. Despite the significant family history, patients with BrS(−) had no events reported during follow-up. Nevertheless, the management of these patients is not clear cut, and a personalized therapeutic strategy with close follow-up is essential.

Funding Acknowledgement
Type of funding sources: None.
Clinical features of drug-induced long QT syndrome in a large prospective cohort
Authors: Campos Garcia B , Hernandez-Ontiveros H , Avila-Parcet A , Garcia-Hernando V , Carceller-Sindreu M , Salazar-Blanco J , Rodriguez-Santiago B , Juanes-Borrego A , Alonso-Martin C , Rodriguez-Font E , Moreno-Weidmann Z , Mendez-Zurita F , Vinolas-Prat X , Guerra Ramos J M 
Published: October 2022

Abstract

Introduction
Drug-induced long QT syndrome (DI-LQTS) is a clinical entity with prevalence and arrhythmic risk not well defined.

Purpose
To determine the clinical characteristics of patients with DI-LQTS diagnosed in the setting of a tertiary hospital center.

Methods
Prospective observational study with consecutive inclusion of patients with the diagnosis of DI-LQTS as per standard criteria, in a tertiary hospital, between 2018 and 2022.

Results
Eighty-five patients were included (age 65±15 years, 59% male). The mean corrected QT interval (QTc) of the entire cohort was 545±56 ms. The drugs responsible for QTc prolongation were: psychotropic drugs 51%, antiarrhythmics 38%, anesthetics 29%, antibiotics 15%, antineoplastics 3%, other 2%. QTc prolongation was due to the combination of ≥2 responsible drugs in 46 (54%) patients, and to the use of a single drug in 39 (46%).
Twenty-one patients (25%) presented ventricular arrhythmias at the time of drug-induced QT prolongation: 10 (12%) ventricular fibrillation, 7 (8%) sustained ventricular tachycardia, 3 (3%) non-sustained ventricular tachycardia, 1 (1%) frequent ventricular extrasystole. Patients with ventricular arrhythmias were older (73±12 vs 62±15 years, p&lt;0.05) and exhibited longer QTc prolongation (600±59 vs 528±42 ms, p&lt;0.05).

Conclusion
The DI-LQTS is a rare clinical entity but may be cause of clinically-relevant ventricular arrhythmias. Older age and greater prolongation of the QTc interval are associated with an increased risk of ventricular arrhythmic events.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Health Institute Carlos III, Spain
Brugada syndrome in Portugal: a cohort characterization
Authors: Oliveira C , Silverio Antonio P , Couto Pereira S , Brito J , Valente Silva B , Alves Da Silva P , Garcia B , Martins M , Raposo M , Nunes Ferreira A , Lima Silva G , Carpinteiro L , Cortez-Dias N , J Pinto F , Sousa J 
Published: October 2022

Abstract

Introduction
Brugada syndrome (BrS) is an inherited cardiac arrhythmic disorder that can lead to sudden death. Although SCN5A was the first pathogenic associated gene, other potential genes have been described. The relationship between SCN5A, spontaneous type 1 pattern and the predisposition to ventricular arrhythmias is not totally understood.

Purpose
To characterize mutations in a Portuguese cohort with BrS and explore the genotype-phenotype association in terms of electrocardiographic pattern and arrhythmic risk.

Methods
Prospective single-center study of patients (pts) with BrS. Genetic test included SCN5A direct sequencing from 2003 a broad panel of 120 genes associated with cardiomyopathies and arrhythmic disorders from 2018. Genetic test results were classified according to pathogenicity: mutations of unknown significance (MUS), mutations potentially pathogenic (MPP) and known pathogenic mutations (KPM). Kaplan-Meyer survival analysis was used to explore the association between genetic test results and the risk of arrhythmic events.

Results
A total of 94 pts [46±12 years, 67% male,64.9% with type 1 spontaneous pattern] were submitted to genetic testing. No relevant mutations were identified in 68pts and suspicious or pathogenic mutations were recognized in 26pts. The most frequent mutations occurred in SCN5A (N=20,76.9%), and included 8 KPM: 4 in exon 23 (3 of them had the same mutation,c.4018G&gt;A), 2 in exon 26 (c.4534C&gt;T), 1 in exon 28 and 1 in exon 16. All MPP in SCN5A occurred either in exon 23 or 28. Considering MUS, different mutations were described in 6 different exons (8,15,18,23,25 and two in 28). Additionally, 6 pts presented MUS in other genes: SCN10A (N=2), ANK2 (N=2), SFM13A, CAV2 (associated with long QT), CACNA1D and PXDNL.
We found no differences in the prevalence of spontaneous type 1 pattern considering gene mutation or mutation pathogenicity. A non-significant trend to higher arrhythmic risk was observed in pts presenting genetic mutations (either KPM, MPP or MUS), Long-Rank: 1.743, p=0.187.

Conclusion
Gene mutations are identified in a minority of BrS pts, mostly at SCN5A gene. No association was noticed between genetic test results and the ECG pattern. However, pts with identified mutation presented a tendency to higher arrhythmic risk. At present time, genetic tests in BrS are only relevant for familial screening, but long-term collection of data is crucial to elucidate the genotype-phenotype relation and arrhythmic risk.

Funding Acknowledgement
Type of funding sources: None.
Characterization of sudden death etiologies in a Portuguese population younger than 40 years-old
Authors: Carrington M , Henriques De Gouveia R , Corte-Real F , Goncalves L , Providencia R 
Published: October 2022

Abstract

Background
The incidence and pathogenesis of sudden death (SD) in the young adult population in Portugal remains to be clarified. Some of the causes are known to be hereditary and a better understanding of these can have implications on the development of a national screening program for relatives of SD victims.

Purpose
To describe the leading causes of sudden cardiac and non-cardiac death in a young adult Portuguese population (≤40 years-old).

Methods
The authors retrospectively reviewed cases from a national database regarding individuals who underwent an autopsy, between 2012 and 2016, at 6 districts of mainland Portugal plus the islands. All young adults (1–40 years-old) who had a sudden unexpected death were included and violent deaths were excluded. This study was approved by the Institute Ethics Committee. We reviewed the autopsy files and collected demographic, clinical, necropsic, anatomopathological and toxicological data from each case. We performed statistical analysis using Stata 13.0 software.

Results
During a 5-year period, out of an estimated total of 2101 deaths in ages 1 to 40, 175 SD were identified. SD victims had a mean age of 32±9 years-old, the majority being of male gender (69%,n=120). There were 115 (66%) cases of SD of confirmed cardiac origin (see Table 1). The remaining causes were respiratory (18%), cerebral (7%), digestive (6%), endocrinologic (2%), urinary (1%), infectious (1%). The most frequent cardiac cause being coronary atherosclerosis (n=40,35%), which included lesions with estimated luminal narrowing &gt;75% and/or documented type 1 acute myocardial infarction. These patients were older (31±8 vs 35±4, p&lt;0.020), had a minimum age of 26 years, and more frequently male (85% vs 61%, p=0.011). There were 17 (15%) victims who had cardiopathy with histopathological hypertrophy (5 of them with associated fibrosis), and the diagnosis of hypertrophic cardiomyopathy (HCM) was possible in only 3 (3%) victims. In addition, there were 15 (13%) who died from pulmonary embolism who were predominantly women (23% vs 80%, p&lt;0.001). There were 8 (7%) victims with a final diagnosis of cardiopathy with histopathological dilation, 2 possibly corresponding to post-partum cardiomyopathy (CMP), 1 to ethanolic CMP and 1 to ventricular dilation and fibrosis due to previous myocarditis, who had associated hepatitis with signs of activity. Six cases of acute myocarditis were identified, who were significantly younger, comparing to patients dying from other cardiac causes (23±13 vs 33±7, p=0,011). There were 2 cases of HCM with genetic data, one of which was complemented during molecular autopsy.

Conclusions
During a 5-year period, the cumulative incidence of SD in a region of Portugal is very low (n=175), cardiac causes being present in 66% of the cases. The most frequent cardiac cause is coronary atherosclerosis (35%).

Funding Acknowledgement
Type of funding sources: None.
Late gadolinium enhancement is a strong predictor of life threatening arrhythmias in patients with dilated cardiomyopathy undergoing ICD implantation for primary prevention of sudden cardiac death
Authors: Lopes Da Cunha G J , Lopes P , Freitas P , Rocha B , Gomes D , Paiva M , Amador R , Abecasis J , Guerreiro S , Matos D , Rodrigues G , Carvalho M S , Mendes M , Adragao P , Ferreira A 
Published: October 2022

Abstract

Background
The usefulness of implantable cardioverter defibrillators (ICD) for primary prevention of arrhythmic sudden cardiac death (SCD) in patients with non-ischemic dilated cardiomyopathy (DCM) has been questioned. Efforts to improve risk stratification have included scores such as the “MADIT-ICD benefit score”, and the use of late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR).
The purpose of this study was to evaluate the potential usefulness of these two tools to assess the risk of life-threatening arrhythmias in patients with non-ischemic DCM undergoing ICD implantation for primary prevention of SCD.

Methods
We conducted a single-center retrospective study of consecutive patients who underwent contrast-enhanced CMR before ICD implantation for primary prevention of SCD. Patients with ischemic cardiomyopathy were used as reference. Patients with non-dilated cardiomyopathies were excluded.
The arrhythmic component of the MADIT-ICD benefit score (VT/VF score) was calculated for each patient, and considered high if ≥7, as recommended.
The primary endpoint was the occurrence of SCD or life-threatening arrhythmias (VF or VT &gt;200 bpm). Follow-up was performed by device interrogation in all patients except those who suffered SCD.

Results
A total of 151 patients (93 ischemic, mean age 62±13 years, 75% male) with mean left ventricular ejection fraction (LVEF) of 27±8% were included. Overall, 72% (n=67) ischemic and 45% (n=26) non-ischemic patients had scores ≥7 and were considered high-risk. LGE was present in all patients with ischemic cardiomyopathy, and in 76% (n=44) of patients with non-ischemic DCM.
During a median follow-up of 21 (8–38) months, 21 patients (13.9%, 11 ischemic and 10 non-ischemic) met the primary endpoint.
Overall, the event-free survival of non-ischemic patients was similar to that of ischemic patients (log rank p=0.269). In patients with non-ischemic DCM, there were 7 arrhythmic events (26.9%) in those with MADIT-ICD VT/VF scores ≥7, and 3 events (9.4%) in those with scores &lt;7 (log rank p=0.104).
In the same population, there were 10 arrhythmic events (23%) in patients with LGE, but no events in patients without LGE (log rank p=0.036).
LVEF was similar in patients with and without arrhythmic events (26±8% vs. 27±7%, p=0.717), and in those with and without LGE (26±7% vs. 28±9%, p=0.342).

Conclusion
The presence of LGE is a strong predictor of life threatening arrhythmias in patients in non-ischemic DCM undergoing ICD implantation for primary prevention, seemingly outperforming the clinical MADIT-ICD benefit score.

Funding Acknowledgement
Type of funding sources: None.
High prevalence of malignant ventricular arrhythmias in patients with early-stage left ventricular noncompaction
Authors: Sivilotti F , Villatore A , Berg J , Romano S C , Parciante A , Pili G , Fioravanti F , El Sawaf B , Sala S , Della Bella P , Peretto G 
Published: October 2022

Abstract

Background
Early-stage left ventricular non compaction (LVNC) is a nonischemic cardiomyopathy characterized with nondilated phenotype and unpredictable risk of malignant ventricular arrhythmias (MVA).

Purpose
To report the occurrence of MVA in patients with early-stage LVNC.

Methods
Consecutive patients (n=63) diagnosed with LVNC according to recognized criteria either on transthoracic echocardiogram or cardiac magnetic resonance were retrospectively enrolled. Patients with late-stage LVNC, defined by a coexistent dilated cardiomyopathy phenotype, were excluded (n=49). Patient-tailored medical treatment, as well as ICD implantation strategies, were based on the updated ESC guidelines integrated by the experience of a referral center for arrhythmia management. The study endpoint was the occurrence of MVA (defined as sustained VT, VF, or appropriate ICD therapy) by 5-year follow-up.

Results
The study cohort consisted of 14 patients (mean age 37±17 y, 64% males), presenting with palpitation (n=4), syncope (n=4), or dyspnea on effort (n=6). LVNC was diagnosed by echocardiogram and cardiac magnetic resonance in 13 and 1 patients, respectively. Because of nonmalignant VA, seven patients (50%) underwent ICD implant before discharge. By 5-year follow-up, 5 patients (36%) experienced MVA, including VF or appropriate ICD shocks for fast VT. Left ventricular ejection fraction (LVEF) ≥45% was the only factor associated with the occurrence of MVA (5/11 event in cases with LVEF ≥45% vs. 0/3 events in controls with LVEF &lt;45%; p=0.145). Baseline features, including age, gender, NC/C ratio, and clinical presentation were comparable between cases with LVEF ≥45% and controls, all p&gt;0.05. Drug treatment, including RAAS inhibitors, betablockers and antiarrhythmics was also comparable.

Conclusions
Our preliminary data show that in early-stage LVNC the occurrence of MVA is higher for patients with LVEF ≥45%. Efforts are needed to identify earlier predictors of arrhythmic risk, to improve patient selection for ICD implant.

Funding Acknowledgement
Type of funding sources: None.
Prediction of programmed ventricular stimulation inducibility using machine learning in post-myocardial infarction patients at risk for sudden cardiac arrest with preserved ejection fraction ≥40%
Authors: Xintarakou A , Arsenos P , Gatzoulis K , Manis G , Trachanas K , Soulaidopoulos S , Dilaveris P , Doundoulakis I , Kordalis A , Laina A , Xydis P , Tsimos K , Korantzopoulos P , Kolettis T , Tsioufis K 
Published: October 2022

Abstract

Introduction
Sudden cardiac death (SCD) in post myocardial infarction (post-MI) patients with a relatively preserved left ventricular ejection fraction (LVEF ≥40%) has 1% annual incidence. In the PRESERVE-EF study, we used a two-step SCD risk stratification approach to detect patients with a relatively preserved left ventricular ejection fraction ≥40% at risk for major arrhythmic events. Seven noninvasive risk factors (NIRFs) were extracted from ambulatory electrocardiography. Patients with at least one NIRF present were referred for invasive programmed ventricular stimulation (PVS). Inducible patients received an ICD.

Purpose
The present study examines the performance of machine learning technology for the prediction of the inducible patients in PRESERVE-EF study.

Methods
After first step screening with NIRFs, 152 out of 575 patients underwent PVS and 41 of them were inducible. For the present analysis, data from these 152 patients were analysed. We used machine learning of NIRFs to predict these inducible high risk patients. We selected as classification method the Nearest Neighbour (NN) algorithm, after experimentation with several classifiers. NN classifies each subject according to the class of the N nearest neighbours. For each subject, we created a vector with the following 7 features: SAECG Late Potentials, Ventricular Premature beats ≥30/hour, Non-sustained Ventricular Tachycardia ≥1 episode (s)/24 hours, Fredericia corrected QT interval ≥45 0ms, SDNN/HRV ≤75 ms, T Wave Alternans ≥65 μV, Combined Deceleration capacity (DC) ≤4.5 ms and Heart Rate Turbulence Onset (To) ≥0% and Heart Rate Turbulence Slope (Ts) ≤2.5 ms.

Results
The achieved accuracy reached up to 72.2% when N was set to 7. We had totally 144 samples, 41 of which were inducible high risk patients. Results were similar for other values of N. To ensure independence of train and test sets, we employed 10-fold cross validation.

Conclusions
Inducible on PVS patients in PRESERVE-EF study were predicted with machine learning classification of NIRFs.

Funding Acknowledgement
Type of funding sources: None.
Risk factors for the development of premature ventricular complex-induced cardiomyopathy: a systematic review and meta-analysis
Authors: Serban T , Du Fay De Lavallaz J , Mezier J , Mertz L , Mannhart D , Kuehne M , Sticherling C , Badertscher P 
Published: October 2022

Abstract

Background
Premature ventricular complexes (PVCs) can be a reversible cause of heart failure. To date, it is unclear which risk factors contribute to the development of impaired left ventricular function.

Objective
Systematically assessing risk factors for the development of PVC-induced cardiomyopathy (PVC-CM).

Methods
We performed a structured database search of the scientific literature for studies investigating risk factors for the development of PVC-induced Cardiomyopathy. We investigated the reporting of PVC-induced Cardiomyopathy risk factors (RF) and assessed the comparative association of the different RF using random-effect meta-analysis.

Results
A total of 26 studies (9 prospective and 17 retrospective studies) involving 16.764.641 patients were analyzed (mean age 55 y, 58% women, mean PVC burden 17%). Suitable for quantitative analysis were 25 studies examining 6738 (0.04%) patients and 11 RF (≥3 occurrences in multivariable model assessing a binary change in left ventricular - LV- function). Among these risk factors, age (OR 1.02 per increase in the year of age, 95%-CI [1.01, 1.02]), the presence of symptoms (OR 0.18, 95%-CI [0.05, 0.64]), non-sustained VTs (OR 3.01, 95%-CI [1.39, 6.50]), LV origin (OR 2.20, 95%-CI [1.14, 4.23]), epicardial origin (OR 4.72, 95%-CI [1.81, 12.34]), the presence of interpolation - PVCs that do not reset the RR interval (OR 4.93, 95%-CI [1.66, 14.69]) and overall PVC burden (OR 1.06, 95%-CI [1.04, 1.08]) were all significantly associated with PVC-induced Cardiomyopathy. (Figures 1,2)

Conclusion
In this meta-analysis, the most consistent risk factors for PVC-CM were age, non-sustained VTs, LV and epicardial origin, interpolation, and PVC burden, while the presence of symptoms significantly reduced the risk. These findings help tailor stringent follow-up to patients presenting with frequent PVCs and normal LV function.

Funding Acknowledgement
Type of funding sources: None.