Publications by authors named "Carlo Pappone"

169 Publications

Second-generation laser balloon ablation for the treatment of atrial fibrillation assessed by continuous rhythm monitoring: the LIGHT-AF study.

Europace 2021 Apr 9. Epub 2021 Apr 9.

Arrhythmology Department, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy.

Aims: Balloon-based technologies have been developed to simplify catheter ablation of atrial fibrillation (AF), to improve the clinical outcome of the procedure and to achieve durable pulmonary vein isolation (PVI). The objective of this study is to evaluate the safety and efficacy of second-generation laser balloon (LB2) ablation in the treatment of AF using a continuous cardiac rhythm monitoring strategy. Atrial tachyarrhythmias (ATas) recurrences were assessed with implantable cardiac monitors (ICMs) or devices.

Methods And Results: All patients underwent LB2 ablation procedure. The primary endpoint was the first recurrence of any, >5.5 and >24 h duration ATas after the blanking period (90 days). In-hospital visits were performed at 3, 6, and 12 months. Seventy-three patients (68% male, mean age 59.8 ± 11.3) were included in the study. The average procedure, fluoroscopy, and laser ablation times were 81.5 ± 30.1, 21.5 ± 12.4, and 33.8 ± 9.7, respectively. All PVs were isolated using the LB2 with no need of touch-up using focal catheters. No major complications occurred during or after the procedures. The one-year freedom from recurrences was 66.9% (95% CI: 57.0-76.7%), 81.0% (69.5-88.5%), and 86.8% (76.1-92.9%) considering any, 5.5-h and 24-h cut-off duration, respectively. At 3, 6, and 12 months, any ATas was recorded in 22%, 32%, and 25% of patients, with a ≥5% arrhythmic burden documented in 4%, 5%, and 3%, respectively. Few patients reported AF-related symptoms (7%, 8%, and 5%).

Conclusion: LB2 ablation is a safe and effective procedure, showing a high freedom from recurrences and low arrhythmic burden as documented by a continuous rhythm monitoring strategy.
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http://dx.doi.org/10.1093/europace/euab085DOI Listing
April 2021

The omics of channelopathies and cardiomyopathies: what we know and how they are useful.

Eur Heart J Suppl 2020 Nov 18;22(Suppl L):L105-L109. Epub 2020 Nov 18.

Arrhythmology and Electrophysiology Department, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy.

Sudden cardiac death results from arrhythmias commonly caused by channelopathies and cardiomyopathies, often due to several genetic factors. An emerging concept is that these disease states may in fact overlap, with variants in traditionally classified 'cardiomyopathy genes' resulting in 'channelopathies phenotypes'. Another important concept is the influence of both genetic and non-genetic factors in disease expression, leading to the utilization of systems biology approaches, such as genomics/epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and glycomics, to understand the disease severity and progression and to determine the prognosis and the best course of treatment. In fact, our group has discovered significant differences in metabolites, proteins, and lipids between controls and Brugada syndrome patients. Omics approaches are useful in overcoming the dogma that both channelopathies and cardiomyopathies exist as Mendelian disorders (caused by a mutation in a single gene). This shift in understanding could lead to new diagnostic and therapeutic approaches.
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http://dx.doi.org/10.1093/eurheartj/suaa146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904073PMC
November 2020

Common modulators of Brugada syndrome phenotype do not affect SCN5A prognostic value.

Eur Heart J 2021 Mar;42(13):1273-1274

Arrhythmia and Electrophysiology Department, IRCCS Policlinico San Donato, Piazza E. Malan 1, 20097 San Donato Milanese, Milan, Italy.

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http://dx.doi.org/10.1093/eurheartj/ehab071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014514PMC
March 2021

Case Report: Efficacy of Rituximab in a Patient With Familial Mediterranean Fever and Multiple Sclerosis.

Front Neurol 2020 6;11:591395. Epub 2021 Jan 6.

Foundation Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Donato, Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit & MS Centre, Milan, Italy.

Familial Mediterranean Fever (FMF) is a genetic autoinflammatory disease characterized by recurrent episodes of fever and serositis caused by mutations in the MEFV gene, while Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the CNS with genetic and environmental etiology. The two diseases rarely occur in association with relevant implications for clinical management and drug choice. In this paper, we present the case of a 53-year-old male with an autosomal dominant FMF since childhood who presented acute paresthesia at the right part of the body. He performed a brain and spinal cord MRI, which showed multiple brain lesions and a gd-enhancing lesion in the cervical spinal cord, and then received a diagnosis of MS. He then started Interferonβ-1a which was effective but not tolerated and caused hepatotoxicity, and then shifted to Rituximab with 3-month clinical and neuroradiological efficacy.
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http://dx.doi.org/10.3389/fneur.2020.591395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874168PMC
January 2021

Clinical Considerations for a Family with Dilated Cardiomyopathy, Sudden Cardiac Death, and a Novel Frameshift Mutation.

Int J Mol Sci 2021 Jan 12;22(2). Epub 2021 Jan 12.

Department of Arrhythmology, IRCCS Policlinico San Donato, Piazza Edmondo Malan 1, San Donato Milanese, 20097 Milan, Italy.

Dilated cardiomyopathy (DCM) is the leading indication for heart transplantation. gene truncating mutations account for about 25% of familial DCM cases and for 18% of sporadic DCM cases. The clinical relevance of specific variants in has been difficult to determine because of the sheer size of the protein for which encodes, as well as existing extensive genetic variation. Clinicians should communicate novel clinically-relevant variants and genotype-phenotype associations, so that animal studies evaluating the molecular mechanisms are always conducted with a focus on clinical significance. In the present study, we report for the first time the novel truncating heterozygous variant NM_001256850.1:c.72777_72783del (p.Phe24259Leufs*51) in the gene and its association with DCM in a family with sudden death. This variant occurs in the A-band region of the sarcomere, in a known mutational hotspot of the gene. Truncating titin variants that occur in this region are the most common cause of DCM and have been rarely reported in asymptomatic individuals, differently from other pathogenic gene variants. Further studies are warranted to better understand this particular clinically-relevant variant.
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http://dx.doi.org/10.3390/ijms22020670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826882PMC
January 2021

The antithetic role of ceramide and sphingosine-1-phosphate in cardiac dysfunction.

J Cell Physiol 2021 Jul 11;236(7):4857-4873. Epub 2021 Jan 11.

Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Milan, Italy.

Cardiovascular diseases (CVDs) are the leading cause of death globally and the number of cardiovascular patients, which is estimated to be over 30 million in 2018, represent a challenging issue for the healthcare systems worldwide. Therefore, the identification of novel molecular targets to develop new treatments is an ongoing challenge for the scientific community. In this context, sphingolipids (SLs) have been progressively recognized as potent bioactive compounds that play crucial roles in the modulation of several key biological processes, such as proliferation, differentiation, and apoptosis. Furthermore, SLs involvement in cardiac physiology and pathophysiology attracted much attention, since these molecules could be crucial in the development of CVDs. Among SLs, ceramide and sphingosine-1-phosphate (S1P) represent the most studied bioactive lipid mediators, which are characterized by opposing activities in the regulation of the fate of cardiac cells. In particular, maintaining the balance of the so-called ceramide/S1P rheostat emerged as an important novel therapeutical target to counteract CVDs. Thus, this review aims at critically summarizing the current knowledge about the antithetic roles of ceramide and S1P in cardiomyocytes dysfunctions, highlighting how the modulation of their metabolism through specific molecules, such as myriocin and FTY720, could represent a novel and interesting therapeutic approach to improve the management of CVDs.
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http://dx.doi.org/10.1002/jcp.30235DOI Listing
July 2021

HIF-1α Directly Controls WNT7A Expression During Myogenesis.

Front Cell Dev Biol 2020 11;8:593508. Epub 2020 Nov 11.

Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, San Donato Milanese, Italy.

Herein we unveil that Hypoxia-inducible factor-1α (HIF-1α) directly regulates expression during myogenesis. In fact, chromatin immunoprecipitation (ChiP) and site-directed mutagenesis experiments revealed two distinct hypoxia response elements (HREs) that are specific HIF-1α binding sites on the promoter. Remarkably, a pharmacological activation of HIF-1α induced expression and enhanced muscle differentiation. On the other hand, silencing of using CRISPR/Cas9 genome editing blocked the effects of HIF-1α activation on myogenesis. Finally, treatment with prolyl hydroxylases (PHDs) inhibitors improved muscle regeneration and in a cardiotoxin (CTX)-induced muscle injury mouse model, paving the way for further studies to test its efficacy on acute and chronic muscular pathologies.
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http://dx.doi.org/10.3389/fcell.2020.593508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686515PMC
November 2020

Brugada syndrome genetics is associated with phenotype severity.

Eur Heart J 2021 Mar;42(11):1082-1090

Arrhythmia and Electrophysiology Department, IRCCS Policlinico San Donato, Piazza E. Malan 1, 20097 San Donato Milanese, Milano, Italy.

Aims : Brugada syndrome (BrS) is associated with an increased risk of sudden cardiac death due to ventricular tachycardia/fibrillation (VT/VF) in young, otherwise healthy individuals. Despite SCN5A being the most commonly known mutated gene to date, the genotype-phenotype relationship is poorly understood and remains uncertain. This study aimed to elucidate the genotype-phenotype correlation in BrS.

Methods And Results: Brugada syndrome probands deemed at high risk of future arrhythmic events underwent genetic testing and phenotype characterization by the means of epicardial arrhythmogenic substrate (AS) mapping, and were divided into two groups according to the presence or absence of SCN5A mutation. Two-hundred probands (160 males, 80%; mean age 42.6 ± 12.2 years) were included in this study. Patients harbouring SCN5A mutations exhibited a spontaneous type 1 pattern and experienced aborted cardiac arrest or spontaneous VT/VF more frequently than the other subjects. SCN5A-positive patients exhibited a larger epicardial AS area, more prolonged electrograms and more frequently observed non-invasive late potentials. The presence of an SCN5A mutation explained >26% of the variation in the epicardial AS area and was the strongest predictor of a large epicardial area.

Conclusion : In BrS, the genetic background is the main determinant for the extent of the electrophysiological abnormalities. SCN5A mutation carriers exhibit more pronounced epicardial electrical abnormalities and a more aggressive clinical presentation. These results contribute to the understanding of the genetic determinants of the BrS phenotypic expression and provide possible explanations for the varying degrees of disease expression.
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http://dx.doi.org/10.1093/eurheartj/ehaa942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955973PMC
March 2021

Intramolecular Lactones of Sialic Acids.

Int J Mol Sci 2020 Oct 30;21(21). Epub 2020 Oct 30.

Faculty of Medicine, University of Vita-Salute San Raffaele, 20132 Milan, Italy.

The so-called "" has become an attractive research area, as an increasing number of natural products containing a sialic acid moiety have been shown to play important roles in biological, pathological, and immunological processes. The intramolecular lactones of sialic acids are a subclass from this crucial family that could have central functions in the discrimination of physiological and pathological conditions. In this review, we report an in-depth analysis of the synthetic achievements in the preparation of the intramolecular lactones of sialic acids (1,4-, 1,7- and γ-lactones), in their free and/or protected form. In particular, recent advances in the synthesis of the 1,7-lactones have allowed the preparation of key sialic acid derivatives. These compounds could be used as authentic reference standards for their correct determination in biological samples, thus overcoming some of the limitations of the previous analytical procedures.
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http://dx.doi.org/10.3390/ijms21218098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663150PMC
October 2020

Assessing QT interval in COVID-19 patients:safety of hydroxychloroquine-azithromycin combination regimen.

Int J Cardiol 2021 02 19;324:242-248. Epub 2020 Sep 19.

Arrhythmology Department, IRCCS Policlinico San Donato, San Donato Milanese, Milano, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address:

Background: Hydroxychloroquine (HCQ) and azithromycin (AZT) have been proposed for COVID-19 treatment. Data available in the literature reported a potential increased risk of fatal arrhythmias under these therapies. The aim of this study was to assess the effects of these drugs on QT interval and outcome in a COVID-19 population.

Method: A total of 112 consecutive COVID-19 patients were included in this analysis and were divided in 3 groups according to the receiving therapeutic regimens: 19 (17%) patients in Group 1 (no treatment), 40 (36%) in Group 2 (HCQ only), 53 (47%) in Group 3 (HCQ/AZT).

Results: A prolonged QTc interval was found in 61% of patients treated with HCQ alone or in combination with AZT, but only 4 (4%) patients showed a QTc > 500 ms. HCQ/AZT combination determined a greater increase of QTc duration compared to the other two strategies (Group 3 452 ± 26.4 vs Group 2 436.3 ± 28.4 vs Group 1 424.4 ± 24.3 ms, respectively; p < 0.001). Multivariate analysis demonstrated that HCQ/AZT combination (OR 9.02, p = 0.001) and older age (OR 1.04, p = 0.031) were independent predictors of QTc prolongation. The risk increased with age (incremental utility analysis p = 0.02). Twenty patients (18%) died, and no cardiac arrest neither arrhythmic fatalities were documented.

Conclusions: The HCQ/AZT combination therapy causes a significantly increase of QT interval compared to HCQ alone. Older patients under such regimen are at higher risk of experiencing QT prolongation. The use of such drugs may be considered as safe relating to arrhythmic risk in the treatment of COVID-19 patients as no arrhythmic fatalities occurred.
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http://dx.doi.org/10.1016/j.ijcard.2020.09.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501148PMC
February 2021

Atrial fibrillation ablation long-term ESC-EHRA EORP AFA LT registry: in-hospital and 1-year follow-up findings in Italy.

J Cardiovasc Med (Hagerstown) 2020 Oct;21(10):740-748

Division of Cardiology, Department of Medical Sciences, 'Città della Salute e della Scienza di Torino' Hospital, University of Turin, Turin.

Aim: To report the Italian data deriving from the European Society of Cardiology-EURObservational Research Program atrial fibrillation ablation long-term registry.

Methods And Results: Ten Italian centers enrolled up to 50 consecutive patients undergoing atrial fibrillation ablation. Of the 318 patients included, 5 (1.6%) did not undergo catheter ablation, 1 had ablation partially done and 62 were lost at 1-year follow-up. Women were less represented (23.6%) and the median age was 60.0 years. A total of 195 patients (62.3%) suffered paroxysmal atrial fibrillation, whereas only 9 (2.9%) had long-standing persistent atrial fibrillation. Most Italian patients (92.3%) were symptomatic but suffering fewer symptomatic events than patients enrolled in other countries (median of two events in the month preceding the ablation vs. three, respectively; P < 0.0001). The main finding of the study is that the success rate at 1 year, with and without antiarrhythmic drugs, was 76.4%, consistently with other participating countries (73.4%). This result was obtained however, with a significantly lower prevalence of 1-year adverse events (7.3 vs. 16.6%, P < 0.0001). Procedure duration and fluoroscopy total time resulted as being shorter in Italy (145 vs. 160, P = 0.0005 and 16.9 vs. 20.0 min, P = 0.0018, respectively); however, the radiation dose per BSA was greater (37.5 vs. 26.0 mGy/cm, P = 0.0022).

Conclusion: The demographic characteristics of patients undergoing atrial fibrillation ablation are similar to those reported in other countries. The success rate in Italy is consistent with those in other countries, whereas the complications rate is lower.
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http://dx.doi.org/10.2459/JCM.0000000000000999DOI Listing
October 2020

Role of sialidase Neu3 and ganglioside GM3 in cardiac fibroblasts activation.

Biochem J 2020 09;477(17):3401-3415

Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy.

Cardiac fibrosis is a key physiological response to cardiac tissue injury to protect the heart from wall rupture. However, its progression increases heart stiffness, eventually causing a decrease in heart contractility. Unfortunately, to date, no efficient antifibrotic therapies are available to the clinic. This is primarily due to the complexity of the process, which involves several cell types and signaling pathways. For instance, the transforming growth factor beta (TGF-β) signaling pathway has been recognized to be vital for myofibroblasts activation and fibrosis progression. In this context, complex sphingolipids, such as ganglioside GM3, have been shown to be directly involved in TGF-β receptor 1 (TGF-R1) activation. In this work, we report that an induced up-regulation of sialidase Neu3, a glycohydrolytic enzyme involved in ganglioside cell homeostasis, can significantly reduce cardiac fibrosis in primary cultures of human cardiac fibroblasts by inhibiting the TGF-β signaling pathway, ultimately decreasing collagen I deposition. These results support the notion that modulating ganglioside GM3 cell content could represent a novel therapeutic approach for cardiac fibrosis, warranting for further investigations.
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http://dx.doi.org/10.1042/BCJ20200360DOI Listing
September 2020

Novel p.V1429M Variant Segregation in a Family with Brugada Syndrome.

Int J Mol Sci 2020 Aug 17;21(16). Epub 2020 Aug 17.

Arrhythmology Department, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy.

Brugada syndrome (BrS) is diagnosed by the presence of an elevated ST-segment and can result in sudden cardiac death. The most commonly found mutated gene is , which some argue is the only gene that has been definitively confirmed to cause BrS, while the potential causative effect of other genes is still under debate. While the issue of BrS genetics is currently a hot topic, current knowledge is not able to result in molecular confirmation of over half of BrS cases. Therefore, it is difficult to develop research models with wide potential. Instead, the clinical genetics first need to be better understood. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.4285G>A (p.Val1429Met) in the gene, and demonstrate its segregation with BrS, suggesting a pathogenic effect. These results provide the first disease association with this variant and are crucial clinical data to communicate to basic scientists, who could perform functional studies to better understand the molecular effects of this clinically-relevant variant in BrS.
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http://dx.doi.org/10.3390/ijms21165902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460631PMC
August 2020

Novel CineECG Derived From Standard 12-Lead ECG Enables Right Ventricle Outflow Tract Localization of Electrical Substrate in Patients With Brugada Syndrome.

Circ Arrhythm Electrophysiol 2020 09 28;13(9):e008524. Epub 2020 Jul 28.

Department of Arrhythmology and Electrophysiology, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy (E.T.L., G.C., V.B., V.S., G.V., M.M.M., E.M., L.G., V.M., Z.C., L.A, C.P.).

Background: In Brugada syndrome (BrS), diagnosed in presence of a spontaneous or ajmaline-induced type-1 pattern, ventricular arrhythmias originate from the right ventricle outflow tract (RVOT). We developed a novel CineECG method, obtained by inverse electrocardiogram (ECG) from standard 12-lead ECG, to localize the electrical activity pathway in patients with BrS.

Methods: The CineECG enabled the temporospatial localization of the ECG waveforms, deriving the mean temporospatial isochrone from standard 12-lead ECG. The study sample included (1) 15 patients with spontaneous type-1 Brugada pattern, and (2) 18 patients with ajmaline-induced BrS (at baseline and after ajmaline), in whom epicardial potential duration maps were available; (3) 17 type-3 BrS pattern patients not showing type-1 BrS pattern after ajmaline (ajmaline-negative); (4) 47 normal subjects; (5) 18 patients with right bundle branch block (RBBB). According to CineECG algorithm, each ECG was classified as Normal, Brugada, RBBB, or Undetermined.

Results: In patients with spontaneous or ajmaline-induced BrS, CineECG localized the terminal mean temporospatial isochrone forces in the RVOT, congruent with the arrhythmogenic substrate location detected by epicardial potential duration maps. The RVOT location was never observed in normal, RBBB, or ajmaline-negative patients. In most patients with ajmaline-induced BrS (78%), the RVOT location was already evident at baseline. The CineECG classified all normal subjects and ajmaline-negative patients at baseline as Normal or Undetermined, all patients with RBBB as RBBB, whereas all patients with spontaneous and ajmaline-induced BrS as Brugada. Compared with standard 12-lead ECG, CineECG at baseline had a 100% positive predictive value and 81% negative predictive value in predicting ajmaline test results.

Conclusions: In patients with spontaneous and ajmaline-induced BrS, the CineECG localized the late QRS activity in the RVOT, a phenomenon never observed in normal, RBBB, or ajmaline-negative patients. The possibility to identify the RVOT as the location of the arrhythmogenic substrate by the noninvasive CineECG, based on the standard 12-lead ECG, opens new prospective for diagnosing patients with BrS.
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http://dx.doi.org/10.1161/CIRCEP.120.008524DOI Listing
September 2020

Electrical synchronization achieved by multipoint pacing combined with dynamic atrioventricular delay.

J Interv Card Electrophysiol 2020 Aug 1. Epub 2020 Aug 1.

Cleveland Clinic, Cleveland, OH, USA.

Purpose: Multipoint pacing (MPP) improves left ventricular (LV) electrical synchrony in cardiac resynchronization therapy (CRT). SyncAV automatically adjusts atrioventricular delay (AVD) according to intrinsic AV intervals and may further improve synchrony. Their combination has not been assessed. The objective was to evaluate the improvement in electrical synchrony achieved by SyncAV combined with MPP in an international, multicenter study.

Methods: Patients with LBBB undergoing CRT implant with a quadripolar lead (Abbott Quartet™) were prospectively enrolled. QRS duration (QRSd) was measured by blinded observers from 12-lead ECG during: intrinsic conduction, BiV pacing (conventional biventricular pacing, nominal static AVD), MPP (2 LV cathodes maximally spaced, nominal static AVD), BiV + SyncAV, and MPP + SyncAV. All SyncAV offsets were individualized for each patient to yield the narrowest QRSd during BiV pacing. QRSd changes were compared by ANOVA and post hoc Tukey-Kramer tests.

Results: One hundred and three patients were enrolled (65.7 ± 12.1 years, 67% male, 37% ischemic, EF 26.4 ± 6.5%, PR 190.3 ± 39.1 ms). Relative to intrinsic conduction (QRSd of 165 ± 16 ms), BiV reduced QRSd by 11.9% to 145 ± 18 ms (P < 0.001 vs intrinsic), and MPP reduced QRSd by 13.3% to 142 ± 19 ms (P < 0.001 vs intrinsic). However, enabling SyncAV with a patient-optimized offset nearly doubled this QRSd reduction. BiV + SyncAV reduced QRSd by 22.0% to 128 ± 13 ms (P < 0.001 vs BiV), while MPP + SyncAV reduced QRSd further by 25.6% to 122 ± 14 ms (P < 0.05 vs BiV + SyncAV).

Conclusion: SyncAV can significantly improve acute electrical synchrony beyond conventional CRT, with further improvement achieved by superimposing MPP.
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http://dx.doi.org/10.1007/s10840-020-00842-7DOI Listing
August 2020

Right ventricular electromechanical abnormalities in Brugada syndrome: is this a cardiomyopathy?

Eur Heart J Suppl 2020 Jun 25;22(Suppl E):E101-E104. Epub 2020 Mar 25.

Arrhythmology and Electrophysiology Department, IRCCS Policlinico San Donato, San Donato Milanese, Milano, Italy.

Brugada syndrome (BrS) has been often described as a purely electrical disease. However, current dogma surrounding this concept has shifted to accept that BrS is associated with structural abnormalities. Brugada syndrome is now associated with epicardial surface and interstitial fibrosis, reduced gap junction expression, increased collagen, and reduced contractility. The ventricular arrhythmias observed in BrS have been linked to an arrhythmogenic substrate (AS) located rather consistently in the right ventricular outflow tract, sparking much debate as to the significance of this anatomical position. The size of the AS is dynamic and can be altered due to a number of factors. A larger AS is associated with reduced contractility, and this impaired mechanical function may be responsible for syncopal episodes in BrS patients in the absence of arrhythmic events. While BrS is generally regarded as a channelopathy, recent studies have now identified also mutations in genes encoding for sarcomeric proteins to be associated with BrS. Future studies should evaluate electromechanical coupling in BrS, including calcium handling and sarcomeric alterations, and evaluate whether BrS should be classified as a cardiomyopathy.
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http://dx.doi.org/10.1093/eurheartj/suaa071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270919PMC
June 2020

Brugada Syndrome: Oligogenic or Mendelian Disease?

Int J Mol Sci 2020 Mar 1;21(5). Epub 2020 Mar 1.

Arrhythmology Department, IRCCS Policlinico San Donato, Piazza E. Malan 1, San Donato Milanese, 20097 Milan, Italy.

Brugada syndrome (BrS) is diagnosed by a coved-type ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), and it is associated with an increased risk of sudden cardiac death (SCD) compared to the general population. Although BrS is considered a genetic disease, its molecular mechanism remains elusive in about 70-85% of clinically-confirmed cases. Variants occurring in at least 26 different genes have been previously considered causative, although the causative effect of all but the gene has been recently challenged, due to the lack of systematic, evidence-based evaluations, such as a variant's frequency among the general population, family segregation analyses, and functional studies. Also, variants within a particular gene can be associated with an array of different phenotypes, even within the same family, preventing a clear genotype-phenotype correlation. Moreover, an emerging concept is that a single mutation may not be enough to cause the BrS phenotype, due to the increasing number of common variants now thought to be clinically relevant. Thus, not only the complete list of genes causative of the BrS phenotype remains to be determined, but also the interplay between rare and common multiple variants. This is particularly true for some common polymorphisms whose roles have been recently re-evaluated by outstanding works, including considering for the first time ever a polygenic risk score derived from the heterozygous state for both common and rare variants. The more common a certain variant is, the less impact this variant might have on heart function. We are aware that further studies are warranted to validate a polygenic risk score, because there is no mutated gene that connects all, or even a majority, of BrS cases. For the same reason, it is currently impossible to create animal and cell line genetic models that represent all BrS cases, which would enable the expansion of studies of this syndrome. Thus, the best model at this point is the human patient population. Further studies should first aim to uncover genetic variants within individuals, as well as to collect family segregation data to identify potential genetic causes of BrS.
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http://dx.doi.org/10.3390/ijms21051687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084676PMC
March 2020

Novel Deletion Variant in Patient with Atypical Alagille Syndrome.

Int J Mol Sci 2019 Dec 11;20(24). Epub 2019 Dec 11.

Arrhythmology and Clinical Electrophysiology Department, IRCCS Policlinico San Donato, 20097 San Donato Milanese, Milan, Italy.

Alagille syndrome (AGS) is an autosomal-dominant disorder characterized by various degrees of abnormalities in the liver, heart, eyes, vertebrae, kidneys, face, vasculature, skeleton, and pancreas. This case report describes a newborn child exhibiting a congenital neural tube defect and peculiar craniofacial appearance characterized by a prominent forehead, deep-set eyes, bulbous nasal tip, and subtle upper lip. Just a few hours after birth, congenital heart disease was suspected for cyanosis and confirmed by heart evaluation. In particular, echocardiography indicated pulmonary atresia with ventricular septal defect with severe hypoplasia of the pulmonary branches (1.5 mm), large patent ductus arteriosus and several major aortopulmonary collateral arteries. Due to the association of peculiar craniofacial appearance and congenital heart disease, a form of Alagille syndrome was suspected. In addition, on the fifth day after birth, the patient developed jaundice, had acholic stools, and high levels of conjugated bilirubin and gamma-glutamyltransferase (GGT) were detected in the blood. Genetic testing revealed the novel variant c.802del in a single copy of the gene. No variants in the gene were detected. To the best of our knowledge, this is the first clinical description of a congenital neural tube defect in a molecularly confirmed Alagille patient. This work demonstrates a novel pathogenic heterozygous mutation is associated with an atypical form of Alagille syndrome, suggesting an increased risk for neural tube defects compared to other Alagille patients.
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http://dx.doi.org/10.3390/ijms20246247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940840PMC
December 2019

New electromechanical substrate abnormalities in high-risk patients with Brugada syndrome.

Heart Rhythm 2020 04 19;17(4):637-645. Epub 2019 Nov 19.

Arrhythmology Department, IRCCS Policlinico San Donato, San Donato Milanese, Italy.

Background: The relationship between the typical electrocardiographic pattern and electromechanical abnormalities has never been systematically explored in Brugada syndrome (BrS).

Objectives: The aims of this study were to characterize the electromechanical substrate in patients with BrS and to evaluate the relationship between electrical and mechanical abnormalities.

Methods: We enrolled 50 consecutive high-risk patients with BrS (mean age 42 ± 7.2 years), with implantable cardioverter-defibrillator implantation for primary or secondary prevention of ventricular tachyarrhythmias (ventricular tachycardia/ventricular fibrillation [VT/VF]), undergoing substrate mapping and ablation. Patients underwent 3-dimensional (3D) echocardiography with 3D wall motion/deformation quantification and electroanatomic mapping before and after ajmaline administration (1 mg/kg in 5 minutes); 3D mechanical changes were compared with 50 age- and sex-matched controls. The effect of substrate ablation on electromechanical abnormalities was also assessed.

Results: In all patients, ajmaline administration induced Brugada type 1 pattern, with a significant increase in the electrical substrate (P < .001), particularly in patients with previous spontaneous VT/VF (P = .007). Induction of Brugada pattern was associated with lowering of right ventricular (RV) ejection fraction (P < .001) and worsening of 3D RV mechanical function (P < .001), particularly in the anterior free wall of the RV outflow tract, without changes in controls. RV electrical and mechanical abnormalities were highly correlated (r = 0.728, P < .001). By multivariate analysis, only the area of RV dysfunction was an independent predictor of spontaneous VT/VF (odds ratio 1.480; 95% confidence interval 1.159-1.889; P = .002). Substrate ablation abolished both BrS-electrocardiographic pattern and mechanical abnormalities, despite ajmaline rechallenge.

Conclusion: BrS is an electromechanical disease affecting the RV. The typical BrS pattern reflects an extensive RV arrhythmic substrate, driving consistent RV mechanical abnormalities. Substrate ablation abolished both Brugada pattern and mechanical abnormalities.
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http://dx.doi.org/10.1016/j.hrthm.2019.11.019DOI Listing
April 2020

Genotype-Phenotype Correlation in a Family with Brugada Syndrome Harboring the Novel p.Gln371* Nonsense Variant in the Gene.

Int J Mol Sci 2019 Nov 6;20(22). Epub 2019 Nov 6.

Arrhythmology Department, IRCCS Policlinico San Donato, 20097 San Donato Milanese, Italy.

Brugada syndrome (BrS) is marked by coved ST-segment elevation and increased risk of sudden cardiac death. The genetics of this syndrome are elusive in over half of the cases. Variants in the gene are the single most common known genetic unifier, accounting for about a third of cases. Research models, such as animal models and cell lines, are limited. In the present study, we report the novel NM_198056.2:c.1111C>T (p.Gln371*) heterozygous variant in the gene, as well as its segregation with BrS in a large family. The results herein suggest a pathogenic effect of this variant. Functional studies are certainly warranted to characterize the molecular effects of this variant.
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http://dx.doi.org/10.3390/ijms20225522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888117PMC
November 2019

Dynamic atrioventricular delay programming improves ventricular electrical synchronization as evaluated by 3D vectorcardiography.

J Electrocardiol 2020 Jan - Feb;58:1-6. Epub 2019 Oct 20.

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands. Electronic address:

Background: Optimal timing of the atrioventricular delay in cardiac resynchronization therapy (CRT) can improve synchrony in patients suffering from heart failure. The purpose of this study was to evaluate the impact of SyncAV™ on electrical synchrony as measured by vectorcardiography (VCG) derived QRS metrics during bi-ventricular (BiV) pacing.

Methods: Patients implanted with a cardiac resynchronization therapy (CRT) device and quadripolar left ventricular (LV) lead underwent 12‑lead ECG recordings. VCG metrics, including QRS duration (QRSd) and area, were derived from the ECG by a blinded observer during: intrinsic conduction, BiV with nominal atrioventricular delays (BiV Nominal), and BiV with SyncAV programmed to the optimal offset achieving maximal synchronization (BiV + SyncAV Opt).

Results: One hundred patients (71% male, 40% ischemic, 65% LBBB, 32 ± 9% ejection fraction) completed VCG assessment. QRSd during intrinsic conduction (166 ± 25 ms) was narrowed successively by BiV Nominal (137 ± 23 ms, p < .05 vs. intrinsic) and BiV + SyncAV Opt (122 ± 22 ms, p < .05 vs. BiV Nominal). Likewise, 3D QRS area during intrinsic conduction (90 ± 42 mV ∗ ms) was reduced by BiV Nominal (65 ± 39 mV ∗ ms, p < .05 vs. intrinsic) and further by BiV + SyncAV Opt (53 ± 30 mV ∗ ms, p = .06 vs. BiV Nominal).

Conclusion: With VCG-based, patient-specific optimization of the programmable offset, SyncAV reduced electrical dyssynchrony beyond conventional CRT.
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http://dx.doi.org/10.1016/j.jelectrocard.2019.09.026DOI Listing
October 2019

Non-invasive assessment of the arrhythmogenic substrate in Brugada syndrome using signal-averaged electrocardiogram: clinical implications from a prospective clinical trial.

Europace 2019 12;21(12):1900-1910

Department of Arrhythmology, IRCCS Policlinico San Donato, Piazza E. Malan 1, 20097 San Donato Milanese, Milano, Italy.

Aims: Brugada syndrome (BrS) represents a major cause of sudden cardiac death in young individuals. The risk stratification to forecast future life-threatening events is still controversial. Non-invasive assessment of late potentials (LPs) has been proposed as a risk stratification tool. However, their nature in BrS is still undetermined. The purpose of this study is to assess the electrophysiological determinants of non-invasive LPs.

Methods And Results: Two hundred and fifty consecutive patients with (Group 1, n = 96) and without (Group 2, n = 154) BrS-related symptoms were prospectively enrolled in the registry. Signal-averaged electrocardiogram (SAECG) was performed in all subjects before undergoing epicardial mapping. Group 1 patients exhibited larger arrhythmogenic substrates (AS; 5.8 ± 2.8 vs. 2.6 ± 2.1 cm2, P < 0.001) with more delayed potentials (220.4 ± 46.0 vs. 186.7 ± 42.3 ms, P < 0.001). Late potentials were present in 82/96 (85.4%) Group 1 and in 31/154 (20.1%) Group 2 individuals (P < 0.001). Patients exhibiting LPs had more frequently a spontaneous Type 1 pattern (30.1% vs. 10.9%, P < 0.001), SCN5A mutation (34.5% vs. 21.2%, P = 0.02), and exhibited a larger AS with longer potentials (5.8 ± 2.7 vs. 2.2 ± 1.7 cm2; 231.2 ± 37.3 vs. 213.8 ± 39.0 ms; P < 0.001, respectively). Arrhythmogenic substrate dimension was the strongest predictor of the presence of LPs (odds ratio 1.9; P < 0.001). An AS area of at least 3.5 cm2 identified patients with LPs (area under the curve 0.88, 95% confidence interval 0.843-0.931; P < 0.001) with a sensitivity of 86%, specificity 88%, positive predictive value 85%, and negative predictive value 89%.

Conclusion: The results of this study support the role of the epicardial AS as an electrophysiological determinant of non-invasive LPs, which may serve as a tool in the non-invasive assessment of the BrS substrate, as SAECG-LPs could be considered an expression of the abnormal epicardial electrical activity.

ClinicalTrials.gov number (NCT02641431; NCT03106701).
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http://dx.doi.org/10.1093/europace/euz295DOI Listing
December 2019

Novel p.W697X Nonsense Mutation Segregation in a Family with Brugada Syndrome.

Int J Mol Sci 2019 10 4;20(19). Epub 2019 Oct 4.

Arrhythmology Department, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy.

Brugada syndrome (BrS) is marked by an elevated ST-segment elevation and increased risk of sudden cardiac death. Variants in the gene are considered to be molecular confirmation of the syndrome in about one third of cases, while the genetics remain a mystery in about half of the cases, with the remaining cases being attributed to variants in any of a number of genes. Before research models can be developed, it is imperative to understand the genetics in patients. Even data from humans is complicated, since variants in the most common gene in BrS, are associated with a number of pathologies, or could even be considered benign, depending on the variant. Here, we provide crucial human data on a novel NM_198056.2:c.2091G>A (p.Trp697X) point-nonsense heterozygous variant in the gene, as well as its segregation with BrS. The results herein suggest a pathogenic effect of this variant. These results could be used as a stepping stone for functional studies to better understand the molecular effects of this variant in BrS.
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http://dx.doi.org/10.3390/ijms20194920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801452PMC
October 2019

Out-of-hospital cardiac arrest due to idiopathic ventricular fibrillation in patients with normal electrocardiograms: results from a multicentre long-term registry.

Europace 2019 Nov;21(11):1670-1677

Electrophysiology Unit, Department of Cardiology, Fondazione Cardiocentro Ticino, via Tesserete 48, Lugano, Switzerland.

Aims : To define the clinical characteristics and long-term clinical outcomes of a large cohort of patients with idiopathic ventricular fibrillation (IVF) and normal 12-lead electrocardiograms (ECGs).

Methods And Results: Patients with ventricular fibrillation as the presenting rhythm, normal baseline, and follow-up ECGs with no signs of cardiac channelopathy including early repolarization or atrioventricular conduction abnormalities, and without structural heart disease were included in a registry. A total of 245 patients (median age: 38 years; males 59%) were recruited from 25 centres. An implantable cardioverter-defibrillator (ICD) was implanted in 226 patients (92%), while 18 patients (8%) were treated with drug therapy only. Over a median follow-up of 63 months (interquartile range: 25-110 months), 12 patients died (5%); in four of them (1.6%) the lethal event was of cardiac origin. Patients treated with antiarrhythmic drugs only had a higher rate of cardiovascular death compared to patients who received an ICD (16% vs. 0.4%, P = 0.001). Fifty-two patients (21%) experienced an arrhythmic recurrence. Age ≤16 years at the time of the first ventricular arrhythmia was the only predictor of arrhythmic recurrence on multivariable analysis [hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.18-0.92; P = 0.03].

Conclusion : Patients with IVF and persistently normal ECGs frequently have arrhythmic recurrences, but a good prognosis when treated with an ICD. Children are a category of IVF patients at higher risk of arrhythmic recurrences.
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http://dx.doi.org/10.1093/europace/euz221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826207PMC
November 2019

Sphingolipid Synthesis Inhibition by Myriocin Administration Enhances Lipid Consumption and Ameliorates Lipid Response to Myocardial Ischemia Reperfusion Injury.

Front Physiol 2019 9;10:986. Epub 2019 Aug 9.

Biochemistry and Molecular Biology Laboratory, Health Sciences Department, University of Milan, Milan, Italy.

Myocardial infarct requires prompt thrombolytic therapy or primary percutaneous coronary intervention to limit the extent of necrosis, but reperfusion creates additional damage. Along with reperfusion, a maladaptive remodeling phase might occur and it is often associated with inflammation, oxidative stress, as well as a reduced ability to recover metabolism homeostasis. Infarcted individuals can exhibit reduced lipid turnover and their accumulation in cardiomyocytes, which is linked to a deregulation of peroxisome proliferator activated receptors (PPARs), controlling fatty acids metabolism, energy production, and the anti-inflammatory response. We previously demonstrated that Myriocin can be effectively used as post-conditioning therapeutic to limit ischemia/reperfusion-induced inflammation, oxidative stress, and infarct size, in a murine model. In this follow-up study, we demonstrate that Myriocin has a critical regulatory role in cardiac remodeling and energy production, by up-regulating the transcriptional factor EB, PPARs nuclear receptors and genes involved in fatty acids metabolism, such as VLDL receptor, Fatp1, CD36, Fabp3, Cpts, and mitochondrial FA dehydrogenases. The overall effects are represented by an increased β-oxidation, together with an improved electron transport chain and energy production. The potent immunomodulatory and metabolism regulatory effects of Myriocin elicit the molecule as a promising pharmacological tool for post-conditioning therapy of myocardial ischemia/reperfusion injury.
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http://dx.doi.org/10.3389/fphys.2019.00986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696899PMC
August 2019

Comparable clinical characteristics in Brugada syndrome patients harboring SCN5A or novel SCN10A variants.

Europace 2019 Oct;21(10):1550-1558

Department of Arrhythmology, IRCCS Policlinico San Donato, Piazza E. Malan 1, San Donato Milanese, Milano, Italy.

Aims: The Brugada syndrome (BrS) is an inherited disease associated with an increased risk of sudden cardiac death. Often, the genetic cause remains undetected. Perhaps due at least in part because the NaV1.8 protein is expressed more in both the central and peripheral nervous systems than in the heart, the SCN10A gene is not included in diagnostic arrhythmia/sudden death panels in the vast majority of cardiogenetics centres.

Methods And Results: Clinical characteristics were assessed in patients harboring either SCN5A or novel SCN10A variants. Genetic testing was performed using Next Generation Sequencing on genomic DNA. Clinical characteristics, including the arrhythmogenic substrate, in BrS patients harboring novel SCN10A variants and SCN5A variants are comparable. Clinical characteristics, including gender, age, personal history of cardiac arrest/syncope, spontaneous BrS electrocardiogram pattern, family history of sudden death, and arrhythmic substrate are not significantly different between probands harboring SCN10A or SCN5A variants.

Conclusion: Future studies are warranted to further characterize the role of these specific SCN10A variants.
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http://dx.doi.org/10.1093/europace/euz186DOI Listing
October 2019

Novel Frameshift Mutation in Brugada Syndrome Associated With Complex Arrhythmic Phenotype.

Front Genet 2019 6;10:547. Epub 2019 Jun 6.

Arrhythmology Department, IRCCS Policlinico San Donato, Milan, Italy.

In this case report, we characterize a novel inherited frameshift mutation c.4700_4701del (p.Phe1567Cysfs221) in a single copy of the gene and its association with Brugada syndrome (BrS). The proband experienced a life-threatening ventricular arrhythmia successfully treated with DC-shock and he also suffered from supraventricular tachycardia. Ajmaline test confirmed the BrS diagnosis. No other mutation nor low frequency variants in the other 23 analyzed genes were detected. The same mutation was found in the father and sister, who were both diagnosed with BrS. We hypothesize that this mutation could be responsible for BrS and potentially linked to supraventricular tachycardias. Further studies are needed to confirm this observation and to assess the clinical relevance of this mutation, in terms of risk-stratification.
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http://dx.doi.org/10.3389/fgene.2019.00547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565861PMC
June 2019

Genotype/Phenotype Relationship in a Consanguineal Family With Brugada Syndrome Harboring the R1632C Missense Variant in the Gene.

Front Physiol 2019 28;10:666. Epub 2019 May 28.

Arrhythmology Department, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy.

Brugada syndrome (BrS) is a known cause of sudden cardiac death. The genetic basis of BrS is not well understood, and no one single gene is linked to even a majority of BrS cases. However, mutations in the gene are the most common, although the high amount of phenotypic variability prevents a clear correlation between genotype and phenotype. Research techniques are limited, as most BrS cases still remain without a genetic diagnosis, thus impairing the implementation of experimental models representative of a general pathogenetic mechanism. In the present study, we report the largest family to-date with the segregation of the heterozygous variant NM_198056:c.4894C>T (p.Arg1632Cys) in the gene. The genotype-phenotype relationship observed suggests a likely pathogenic effect of this variant. Functional studies to better understand the molecular effects of this variant are warranted.
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http://dx.doi.org/10.3389/fphys.2019.00666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546918PMC
May 2019

Unusual response to ajmaline test in Brugada syndrome patient leads to extracorporeal membrane oxygenator support.

Europace 2019 Oct;21(10):1574

Department of Arrhythmology, IRCCS Policlinico San Donato, Piazza E. Malan 1, San Donato Milanese, Milano, Italy.

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http://dx.doi.org/10.1093/europace/euz139DOI Listing
October 2019

Arrhythmias due to Inherited and Acquired Abnormalities of Ventricular Repolarization.

Card Electrophysiol Clin 2019 06 10;11(2):345-362. Epub 2019 Apr 10.

Department of Arryhmology, IRCCS San Donato Hospital, Piazza Edmondo Malan 2, 20097 San Donato Milanese, Milano, Italy.

Several acquired and congenital disease conditions and many cardiac and noncardiac drugs affect ventricular repolarization and increase susceptibility to ventricular arrhythmias. Abnormal ventricular repolarization can be reflected on the surface ECG by prolonged or shortened QT interval, early repolarization, and abnormal T-wave configuration. Reduced outward K+ currents and abnormal or increased sodium or calcium currents increase the vulnerability to ventricular arrhythmias. Multiple mechanisms give rise to ventricular arrhythmias in conditions of congenital or acquired abnormal ventricular repolarization. Ventricular arrhythmias associated with abnormalities of ventricular repolarization typically are rapid, usually polymorphic, ventricular tachycardia or torsades de pointes, often degenerating into ventricular fibrillation.
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http://dx.doi.org/10.1016/j.ccep.2019.02.009DOI Listing
June 2019