bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical impact of acquired risk factors in TTN-mediated dilated cardiomyopathy
Authors: Giudicessi J , Ackerman M , Pereira N 
Published: November 2020

Abstract

Background/Introduction
Truncating variants in TTN-encoded titin (TTNtvs) underlie ∼25% of familial dilated cardiomyopathy (DCM) cases. In addition, TTNtvs are over-represented in alcoholic, peripartum, and chemotherapy-induced CM suggesting that risk factors may play a substantive role in the penetrance and expressivity of TTN-mediated DCM.

Purpose
To determine the prevalence and clinical impact of risk factors for TTN-mediated DCM within a single center cohort of unrelated patients with pathogenic (P)/likely pathogenic (LP) TTNtvs.

Methods
In this retrospective study, an institutionally developed natural language processing algorithm was used to identify all TTNtv-positive patients evaluated clinically between 01/2012 and 12/2019. Each TTNtv was then mapped to the TTN reference sequence (NM_133378.4) and classified according to a strict interpretation of the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. After exclusion of individuals with complex congenital heart disease, ischemic heart disease, and those without ACMG P/LP TTNtvs, available medical records were reviewed for risk factors such as long-term heavy alcohol consumption (&gt;80 grams/day), cardiotoxic chemotherapy exposure, morbid obesity (body mass index &gt;40), biopsy/imaging-confirmed myocarditis, peripartum/tachycardia-mediated CM, and valvular heart disease.

Results
Overall, 33 ACMG P/LP TTNtv-positive patients were identified (40% female; mean age at presentation 45±16 years; mean LVEF at presentation 38%±17%). Of note, 17/33 (52%) presented with heart failure (HF) and 4/33 (12%) presented with sustained ventricular arrhythmias (VAs). The remaining 12 (36%) TTNtv-positive patients presented with incidentally detected asymptomatic left ventricular systolic dysfunction (n=9) or as a result of genetic cascade screening (n=3). In comparison to TTNtv-positive patients with non-HF presentations, those with HF had worse left ventricular function (mean LVEF: 26% ± 11% vs 51% ±12%; p&lt;0.001) and were more likely to have ≥1 risk factor [11/17 (65%) vs 4/16 (25%); p=0.04]. Unexpectedly, the 7 TTNtv-positive patients that presented with (n=4) or subsequently developed (n=3) sustained VAs were younger at the time of presentation (34±13 years vs 48±15 years; p=0.04) and displayed a similar degree of left ventricular dysfunction to those without sustained VAs (mean LVEF: 42% ± 17% vs 36% ± 17%; p=ns). Interestingly, the only risk factor over-represented amongst those with sustained VAs was bileaflet mitral valve prolapse [3/7 (43%) vs 0/26 (0%); p=0.006].

Conclusion
The majority of TTNtv-positive patients (14/23; 61%) with a history of HF and/or sustained VAs possessed ≥1 acquired risk factor providing further evidence that gene-environment interaction(s) exert a crucial role in the manifestation of TTN-mediated disease.

Funding Acknowledgement
Type of funding source: None
Novel risk factor for fatal arrhythmia in Brugada syndrome
Authors: Nishinarita R , Niwano S , Ishizue N , Satoh T , Matsuura G , Arakawa Y , Kobayashi S , Shirakawa Y , Horiguchi A , Nakamura H , Oikawa J , Kishihara J , Fukaya H , Niwano H , Ako J 
Published: November 2020

Abstract

Background
Brugada syndrome (BrS) is a genetic disease associated with increased risk of ventricular fibrillation (VF)/ventricular tachycardia (VT). The VF/VT in BrS occurs more frequently during a night time or at a rest with parasympathetic nerve activation. Some risk factors of VF/VT occurrence in BrS have been elucidated, however, it remains controversial about risk stratification. Salusin-β is an endogenous bioactive peptide that systemically exerts rapid and profound hypotensive and bradycardic activities and parasympathomimetic hemodynamic actions in vivo. Previous reports suggested that salusin-β is suppressed following physiological parasympathetic stimulation and appears to constitute a negative feedback relationship with the parasympathetic nervous system.

Purpose
We hypothesized that salusin-β is associated with the occurrence of VF/VT in BrS.

Methods
The study population consisted of 26 BrS patients with newly implantation of implantable cardioverter defibrillator (ICD) during 2003–2008. In all patients, salusin-β was measured in supine position after 20 minute rest. The date of salusin-β sampling was set as the registration point for this study. The VF/VT was defined as any episode of fatal ventricular tachyarrhythmia or any appropriate shock. In accordance with the presence or absence of VF/VT events within 5 years, all patients were divided into VF/VT group (n=6) and non-VF/VT group (n=20).Various clinical parameters were compared between the two groups. For analysis of autonomic nervous function, heart rate variability (HRV) and pupil function were evaluated.

Results
The mean age was 54±17 years old. There is no differences between the two groups in clinical parameters. In analysis of HRV, the high-frequency component (0.15–0.40 Hz; HF), low frequency component (0.04–0.15 Hz; LF) and the LF/HF ratio were analyzed over 24 h. LF/HF ratio was significantly lower over 24h in VF/VT groups in comparison with non-VF/VT groups [day-time; 1.8 (1.2–5.6) vs. 5.2 (3.4–8.8), p=0.048, night-time; 1.2 (1.1–1.3) vs. 3.9 (2.5–8.7), p=0.003]. Furthermore, in analysis of pupil function, right/left miosis ratio was higher in VT/VF groups in comparison with non-VT/VF groups [right pupil; 0.39 (0.37–0.59) vs. 0.34 (0.28–0.38), p=0.035, left pupil; 0.43 (0.36–0.50) vs. 0.33 (0.28–0.40), p=0.049]. In plasma total salusin-β levels, the VF/VT groups exhibited significantly lower than non-VF/VT groups (55.2±14.6 vs. 73.2±22.2, p=0.039, Figure).

Conclusions
Salusin-β was associated with the occurrence of VF/VT in Brugada syndrome. Salusin-β might be useful to identify high-risk patients for the occurrence of VT/VF events in Brugada syndrome.

Funding Acknowledgement
Type of funding source: None
Two novel variants in the SLC4A3 gene in two families with Short QT Syndrome: the role of cascade screening
Authors: Kovacs B , Graf U , Magyar I , Baehr L , Maspoli A , Duru F , Berger W , Saguner A.M 
Published: November 2020

Abstract

Background
Short QT syndrome (SQTS) is a rare, autosomal dominant disease causing sudden cardiac death (SCD). Genetic testing is recommended according to current guidelines. Variants in KCNQ1, KCNH2, KCNJ2 and SLC4A3 genes have been reported in SQTS.

Purpose
We report implications of genetic testing and cascade screening (CS) in two families with phenotypical presentation of SQTS and novel genetic variants of unknown significance.

Methods
We performed a thorough clinical and electrophysiological work-up of the index patients of both families. In addition, genetic screening was conducted. Subsequently, segregation analysis of potentially pathogenic variants was carried out in available relatives.

Results
Index patient 1 presented with a history of recurrent syncope. His ECG showed a shortened QTc of 340ms. Family history was unremarkable. Structural heart disease was excluded by cardiac MRI and coronary angiography. Genetic testing detected a rare heterozygous missense variant in the KCNH2 gene (p.(Arg328Cys), frequency 0.053%), predicted to be pathogenic according to various prediction algorithms (Polyphen, SIFT, Align GVGD, mutation taster). CS of relatives did not confirm this variant as the causative mutation. Reanalysis of whole-exome sequencing data revealed a novel heterozygous missense variant, p.(Arg370Cys) in the recently identified SLC4A3 gene. A variant at the same position has previously been associated with SQTS. CS suggested disease association. The second index patient had a SCD at the age of 17. A previously registered ECG showed a shortened QTc of 340ms. Autopsy revealed no structural heart disease. Post-mortem genetic testing revealed variants in the LDB3, MYH7 and a novel heterozygous missense variant, p.(Ser1039Arg) also in the SLC4A3 gene. Family history was positive for SCD in three 2° relatives. The index patient's father had a positive phenotype with a QTc of 365ms. CS again suggested disease association of the variant in the SLC4A3 gene only.

Conclusion
Genetic testing revealed two novel variants in the SLC4A3 gene, which was recently implicated in the pathogenesis of the SQTS. Predictive bioinformatic algorithms to assess the pathogenicity of missense variants are of limited relevance, but genetic analysis of additional unaffected and affected family members may be instrumental to identify pathogenic DNA sequence variations.
Family tree index patients 1 and 2

Funding Acknowledgement
Type of funding source: None
Mutation site-specific risk profile in patients with Type 1 Long QT Syndrome
Authors: Trancuccio A , Mazzanti A , Kukavica D , Marino M , Monteforte N , Bloise R , Braghieri L , Memmi M , Morini M , Napolitano C , Priori S.G 
Published: November 2020

Abstract

Background
Type 1 Long QT Syndrome (LQT1) is an arrhythmogenic disorder, caused by loss-of-function mutations on KCNQ1 gene, coding for Kv7.1 potassium channel. Although LQT1 is described as the most benign form of LQTS, patients still experience arrhythmic events and there is an unmet need for personalized risk stratification. Attempts have been made to correlate the location of mutations with outcome, but the results are unequivocal.

Purpose
We provide in the present study a new mutation site-specific risk profile obtained from a large cohort of LQT1 patients.

Methods
We gathered data on 963 patients with the diagnosis of LQT1 and divided the Kv7.1 channel into 5 functional regions: the N-terminus (NT), the voltage sensor (VS, including transmembrane segments S1 to S4), the cytoplasmic loops (CL), the pore (PO, including the transmembrane segments S5, S6 and the S5-S6 extracellular linker), the C-terminus (CT).

Results
We studied 963 LQT1 patients: 518 (54%) females; average age 20±17 years; mean QTc at baseline ECG 465±38ms. During a mean follow-up of 8±7 years, 172 (18%) patients experienced arrhythmic events: 31 (3%) experienced one or more cardiac arrests, while 141 (15%) experienced one or more syncopal spells. We identified 188 different variants in the KCNQ1 gene, with the following distribution: 15 (8%) in the NT, 33 (18%) in the VS, 27 (14%) in the CL, 43 (23%) in the PO, 70 (37%) in the CT. The frequency of pathogenic variants per number of amino acids (a.a.) was higher in the CL region, as compared to the other domains (1 mutation every 1.4 a.a.). The duration of QTc interval was significantly longer for patients with mutations in the PO region (473±40 ms) and in the CL region (468±38 ms) as compared to the other regions (p&lt;0.01).
Importantly, in a multivariate analysis PO and CL regions were associated with a higher probability of experiencing arrhythmic events (OR 2.89, 95% CI 1.95–4.29, p=0.019 and OR 1.61, 95% CI 1.0–2.49, p=0.05, respectively. Figure) than the other regions. Interestingly, the risk was independent from QTc interval duration.

Conclusions
Mutations affecting the PO and the CL region of the Kv7.1. channel are associated with a higher probability of experiencing arrhythmic events. This finding is clinically relevant, because it will allow for a more personalized, mutation site-specific risk stratification.
Mutation site and arrhythmic events

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Research and University Dipartimenti di Eccellenza 2018–2022 grant to the Molecular Medicine Department (University of Pavia)
Sex-specific differences in risk stratification of ventricular arrhythmias among implantable cardioverter defibrillator patients: do women differ from men?
Authors: Van Der Lingen A.C.J , Theuns D.A.M.J , Becker M.A.J , Van Rossum A.C , Van Halm V.P , Kemme M.J.B , Rijnierse M.T , Yap S.C , Allaart C.P 
Published: November 2020

Abstract

Background
Implantable cardioverter defibrillator (ICD) guidelines and risk stratification models of sudden cardiac death (SCD) are applied without differentiation between men and women, based on the assumption that the incidence of ventricular arrhythmias and risk factors of SCD are similar in both sexes. Sex-specific risk factors of SCD may influence studies evaluating the benefit of ICD therapy, for both men and women.

Purpose
Aim of the study is to assess sex-specific differences in occurrence and predictors of appropriate device therapy (ADT) for ventricular arrhythmias.

Methods
A multicenter retrospective cohort of 2300 consecutive patients was evaluated, including patients referred for ICD implantation between the years 2009–2018 (age 62±13 years, LVEF 32±12%, 53% ischemic cardiomyopathy [CMP], 28% resynchronization therapy, 65% primary prevention). Exclusion criteria were: (1) patients with hypertrophic CMP, arrhythmogenic right ventricular CMP, systemic infiltrative cardiac disease or channelopathy; (2) lost to follow-up immediately after ICD implantation. Primary endpoint was ADT, defined as anti-tachycardia pacing or shock for ventricular tachyarrhythmia. Secondary endpoints were mortality and inappropriate ICD therapy. Univariable and multivariable Cox regression analyses, stratified by sex, were performed to assess predictors of ADT.

Results
The cohort primarily consisted of men (75%). After a mean follow-up of 4.8±3.0 years, men experienced more ADT compared to women (25% versus 16%, HR 1.71, p&lt;0.001) and men displayed a higher mortality compared to women (25% versus 19%, HR 1.37, p&lt;0.01). No difference in inappropriate ICD therapy was observed (9% versus 10%, HR 1.01, p=0.94). In the total study cohort, male sex (HR 1.55, p&lt;0.001), higher age (HR 1.15 per 10 years, p&lt;0.0019), left bundle branch block (LBBB, HR 0.74, p=0.01) and secondary prevention indication (HR 1.89, p&lt;0.001) were independently associated with ADT. In male patients, independent predictors of ADT were comparable with the total study cohort: higher age (HR 1.20 per 10 years, p&lt;0.001), LBBB (HR 0.72, p=0.01) and secondary prevention therapy (HR 1.80, p&lt;0.001). In contrast, age (p=0.54) or LBBB (p=0.29) were not associated with ADT in women. In women, only paroxysmal atrial fibrillation (HR 1.76, p=0.03) and secondary prevention therapy (HR 1.78, p&lt;0.01) were independently associated with ADT.

Conclusion
This study showed that men were at higher risk of ADT compared to women and that risk factors associated with SCD differ between both sexes. The results strongly suggests that SCD risk stratification models are primarily driven by male patients and sex-specific risk models of SCD are needed to identify those women at high risk of SCD.
Figure 1

Funding Acknowledgement
Type of funding source: None
Efficacy of deep sedation for patients with intractable electrical storm refractory to anti-arrhythmic drugs
Authors: Martins R , Urien J.M , Barbarot N , Sellal J.M , Clementy N , Guenancia C , Gandjbakhch E , Duchateau J , Hamon D , Champ-Rigot L , Marijon E , Garcia R , De Chillou C , Sacher F , Galand V 
Published: November 2020

Abstract

Background
Sympathetic overactivity is implicated in the initiation and maintenance of electrical storm (ES). Deep sedation has empirically been considered as an efficient therapeutic option to blunt sympathetic tone and control ES.

Purpose
The aim of this multicenter study was to determine the efficacy of deep sedation in patients presenting intractable ES refractory to anti-arrhythmic drugs.

Methods
Patients requiring deep sedation for refractory ES from January 1st 2007 to July 31st 2018 were retrospectively included in 13 centers. The primary endpoint was the rate of acute response to sedation, defined as ES termination within 15 minutes after deep sedation.

Results
Among the 116 patients, 55 (47.4%) had ES termination within 15 minutes and were considered “acute responders” to deep sedation. Clinical signs of congestive heart failure before deep sedation (OR=3.31, 95% CI:1.001–10.97, p=0.049) was the only independent predictor of non-acute response. Twenty-one non-acute responders (34.4%) had an extracorporeal membrane oxygenation (ECMO) implanted. Non-acute responders had a significantly lower in-hospital survival (Log-rank, p=0.010). ECMO implantation did not influence survival in non-acute responders to sedation. Acute response to deep sedation was an independent protector of in-hospital mortality, decreasing by 73% the risk of death (OR 0.27; 95% CI:0.10–0.70, p=0.008).

Conclusion
To the best of our knowledge, this multicenter study is the first analysis of the efficacy of deep sedation in patients with intractable ES refractory to anti-arrhythmic drugs, and demonstrating the positive impact of “acute response” on in-hospital survival.

Funding Acknowledgement
Type of funding source: None
Impact of an adaptive CRT optimization algorithm on the risk of life-threatening ventricular arrythmias of heart failure patients
Authors: Briongos Figuero S , Estevez A , Perez M.L , Martinez-Ferrer J.B , Alvarez L , Anguera I , Garcia E , Perez-Lorente F , Porres M , Villacastin J , Munoz-Aguilera R 
Published: November 2020

Abstract

Introduction
Adaptive cardiac resynchronization therapy (aCRT) algorithm provides ambulatory CRT optimization and synchronized left-ventricular pacing instead of conventional biventricular pacing.

Purpose
To analyze the impact of aCRT on the risk of life-threatening ventricular arrythmia (VA) in patients with concomitant defibrillator therapy.

Methods
Symptomatic HF patients, in sinus rhythm, with LVEF ≤35% and QRS complex ≥130 ms undergoing first CRT-defibrillator (CRT-D) implant were collected from the multicentre, prospective and nationwide UMBRELLA study (2012–2017). All device information was automatically stored and collected through the remote monitoring system. An experts committee analysed in a blinded manner all electrograms. The endpoint was first appropriate therapy (AT) delivered within ventricular fibrillation zone at 12-months follow-up.

Results
206 patients were collected (66.1±8.7 years; 73.3% male). Fifty nine patients composed the aCRT group and 147 composed the non-aCRT group. At implant, LBBB was present in 93% of patients, functional class III or IV in 69.9%, non-ischemic HF in 63.1% of patients and mean LVEF was 26.5±5.6%. Optimal medical treatment was achieved in a majority (B-blockers in 92%; RAASi in 89% and MRA in 72.2%).
The percentage of ventricular pacing through 12 months was 96.1±9.4% in non-aCRT patients and 97.5±2.7% in aCRT patients (p=0.261). At 1-year of follow-up, 16 patients were delivered an AT (event rate: 7.8%). Most of these episodes (n=14) were due to sustained monomorphic ventricular tachycardia while the rest were caused by sustained polymorphic ventricular tachycardia/VF. A lower incidence of AT was observed in aCRT patients (3.4%) compared to non-aCRT patients (9.5%) but with no statistical differences (OR=0.33, CI 0.07–1.51, p=0.155).

Conclusions
In patients undergoing CRT provided by aCRT algorithm the risk of malign VA after 1-year of follow-up was low. Randomized studies are needed to clarify the impact of this dynamic algorithm on the arrhythmic risk of HF patients.

Funding Acknowledgement
Type of funding source: None
Non-selective para-hisian stimulation used for QRS normalization guided by non-invasive electrical synchrony method in patients with electrical conduction disorders
Authors: Logarzo E , Ortega D , Barja L , Paolucci A , Revollo G , Aboy J , Mangani N 
Published: November 2020

Abstract

Introduction
Para-hisian stimulation produces a physiological cardiac activation through normal conduction system. Frequently it is used in patients with no electrical conduction disorders. We developed an implant technique guided by non-invasive electrical synchrony using conventional screw-in leads. Non-selective para-hisian stimulation can normalize electrical conduction disorders. Synchromax is a novel device used to evaluate non-invasive cardiac electrical synchrony. It is easy to understand, fast to obtain, non-invasive and reproducible. Synchromax was analyzed in previous studies and correlated with other methods.

Objective
Evaluate usefulness and safety of non-selective para-hisian stimulation guided by non-invasive cardiac electrical synchrony method using conventional screw-in leads to normalize electrical conduction disorders.

Materials and methods
421 patients with para-hisian stimulation were analyzed retrospectively. 139 patients had different intraventricular and auriculo-ventricular electrical disorders. Non-selective para-hisian stimulation guided by no-invasive electrical synchrony method (Synchromax) was performed in all cases. Synchrony index and curves were analyzed according curves chart. Type 2 curve and index between 0,1 and 0,4 were considered synchronous. Type 8 curve and index more than 0.7 were considered dyssynchronous.

Results
Mean age 71 years (±7 years). 65,4% males. 30,9% had 2° and 3° grade AV block associated. Patients were divided in 5 groups:
1-Right bundle branch block (RBBB): 43 patients
2-Left bundle branch block (LBBB): 33 patients
3-Brugada Syndrome: 8 patients
4-Left anterior hemi-block (LAHB) 30 patients.
5-RBBB associated with LAHB: 25 patients.
QRS normalization was achieved in 87% of the cases using non-selective para-hisian stimulation guided by Synchromax with conventional screw in leads. A ventricular approach was performed during implantation. Electrical synchrony was not solved in 13% of patients mostly in LBBB and RBBB associated with LAHB. Two dislodgments were evidenced.

Conclusions
Non-selective para-hisian stimulation guided by Synchromax method using conventional screw in leads solved most of intraventricular electrical disorders. It is also safe to use in patients with auriculo-ventricular electrical disorder.

Funding Acknowledgement
Type of funding source: None