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Sudden cardiac death (SCD) is a relevant contributor to cardiovascular mortality, often occurring as a dramatic event. It can be the consequence of a ventricular tachycardia/fibrillation (VT/VF), a common and life-threatening arrhythmia. The underlying mechanisms of this catastrophic arrhythmia are poorly known. In fact, it can occur in the presence of a structural heart condition which itself generates the suitable substrate for this arrhythmia. Nevertheless, a VF may cause SCD also in young and otherwise healthy individuals, without overt structural abnormalities, generating difficulties in the screening and prevention of these patients. The implantable cardioverter-defibrillator represents the only therapy to contrast SCD by treating a VT/VF; however, it cannot prevent the occurrence of such arrhythmias. Catheter ablation is emerging as an essential therapeutic tool in the management of patients experiencing ventricular arrhythmias.

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.

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.

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

Objectives The aim of this study was to identify the pattern of exercise left atrial (LA) dynamics, its gas exchange correlates, and prognosis in mitral regurgitation (MR) of primary and secondary origin. Background The adaptive response and clinical significance of LA function during exercise in MR is undefined. Methods A total of 196 patients with MR (81 with primary MR, 115 with secondary MR) and 54 control subjects underwent exercise stress echocardiography and cardiopulmonary exercise testing with LA function assessment. Patients with MR were divided into 4 groups according to etiology and severity using a cutoff of 3+. Results LA dynamics was studied using speckle-tracking echocardiography. Compared with control subjects, patients with MR had a lower LA strain and strain rate at rest. Exercise LA strain and LA strain rate progressively worsened from primary MR 3+ (25.5; IQR: 23.4 to 29.0); and those with secondary MR Conclusions In MR of any origin, exercise LA reservoir and pump function are impaired. For similar MR extent, secondary MR exhibits worse atrial function, resulting in the lowest exercise performance, limited cardiac output increase, impaired right ventricular–to–pulmonary circulation coupling, and the highest event rate.

Background: Brugada syndrome (BrS) is considered a purely electrical disease with variable electrical substrates. Variable rates of mechanical abnormalities have been also reported. Whether exists a link between electrical and mechanical abnormalities has never been previously explored. This investigational physiopathological study aimed to determine the relationship between the substrate size/location, as exposed by ajmaline provocation, and the severity of mechanical abnormalities, as assessed by cardiac magnetic resonance in patients with BrS. Methods: Twenty-four consecutive high-risk patients with BrS (mean age, 38±11 years, 17 males), presenting with malignant syncope and documented polymorphic ventricular tachycardia/ventricular fibrillation, and candidate to implantable cardioverter defibrillator implantation, underwent cardiac magnetic resonance and electroanatomic maps. During each examination, ajmaline test (1 mg/kg over 5 minutes) was performed. Cardiac magnetic resonance findings were compared with 24 age, sex, and body surface area-matched controls. In patients with BrS, the correlation between the electrical substrate extent and right ventricular regional mechanical abnormalities before/after ajmaline challenge was analyzed. Results: After ajmaline, patients with BrS showed a reduction of right ventricular (RV) ejection fraction ( P P P P P 2 to 14.2±7.3 cm 2 ( P r =−0.830, P Conclusions: BrS is a dynamic RV electromechanical disease, where functional abnormalities correlate with the maximal extent of the substrate size. These findings open new lights on the physiopathology of the disease. Registration: URL: https://clinicaltrial.gov ; Unique identifier: NCT03524079.

Brugada syndrome (BrS) is a hereditary disorder, characterized by a specific electrocardiogram pattern and highly related to an increased risk of sudden cardiac death. BrS has been associated with other cardiac and non-cardiac pathologies, probably because of protein expression shared by the heart and other tissue types. In fact, the most commonly found mutated gene in BrS, SCN5A, is expressed throughout nearly the entire body. Consistent with this, large meals and alcohol consumption can trigger arrhythmic events in patients with BrS, suggesting a role for organs involved in the digestive and metabolic pathways. Ajmaline, a drug used to diagnose BrS, can have side effects on non-cardiac tissues, such as the liver, further supporting the idea of a role for organs involved in the digestive and metabolic pathways in BrS. The BrS electrocardiogram (ECG) sign has been associated with neural, digestive, and metabolic pathways, and potential biomarkers for BrS have been found in the serum or plasma. Here, we review the known associations between BrS and various organ systems, and demonstrate support for the hypothesis that BrS is not only a cardiac disorder, but rather a systemic one that affects virtually the whole body. Any time that the BrS ECG sign is found, it should be considered not a single disease, but rather the final step in any number of pathways that ultimately threaten the patient's life. A multi-omics approach would be appropriate to study this syndrome, including genetics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and glycomics, resulting eventually in a biomarker for BrS and the ability to diagnose this syndrome using a minimally invasive blood test, avoiding the risk associated with ajmaline testing.

Background: Cardiac resynchronization therapy (CRT) involves stimulation of both right ventricle (RV) and left ventricle (LV). LV pacing from the sites of delayed electrical activation improves CRT response. The RV-LV conduction is typically measured in intrinsic rhythm. The differences in RV-LV conduction patterns and timing between intrinsic rhythm and during paced RV activation, these differences are not fully understood. Methods: Enrolled patients were implanted with a de novo CRT device and quadripolar LV lead, with lead implant locations at the implanting physician's discretion. QRS duration and conduction delay between the RV lead and each of the four LV electrodes (D1, M2, M3, and P4) were measured during intrinsic conduction and RV pacing. Results: Conduction measurements were collected from 275 patients across 14 international centers (68 ± 13 years of age, 73% male, 45% ischemic, 158 ± 22ms QRS duration). Mean RV-LV conduction time was shorter during intrinsic conduction versus RV pacing by 59.6ms (106.5 ± 36.5versus 166.1 ± 32.1ms, p&nbsp

Brugada syndrome (BrS) represents an inherited disorder associated with risk of sudden cardiac death due to VF in patients without structural heart disease. Currently, BrS is diagnosed by typical cove-shaped ST-segment elevation >2 mm in >1 RV precordial lead V1, V2 occurring spontaneously or after a sodium-channel blocker provocation test without any further evidence of malignant arrhythmias. An ICD should always be implanted in symptomatic BrS patients to prevent sudden death, despite high rates of complications with these devices. In asymptomatic people, an electrophysiological study should be performed to evaluate the need for an ICD. The recent discovery of a functional substrate has revolutionised our approach to the pathophysiology and management of BrS. Promising new therapeutic options have emerged in the last 3 years. Ajmaline is able to determine the extension of the substrate by prolonging the duration and fragmentation of abnormal epicardial electrograms. Substrate ablation results in the disappearance of both coved-type ECG and ventricular tachycardia/VF inducibility. These findings are clinically relevant, suggesting that epicardial ablation guided by ajmaline infusion may be an effective therapeutic option in BrS, potentially removing the need for ICD implantation.

ObjectivesThe association between obesity and atrial fibrillation (AF) is well-established. We aimed to evaluate the impact of index body mass index (BMI) on AF recurrence at 12 months following catheter ablation using propensity-weighted analysis. In addition, periprocedural complications and fluoroscopy details were examined to assess overall safety in relationship to increasing BMI ranges.MethodsBaseline, periprocedural and follow-up data were collected on consecutive patients scheduled for AF ablation. There were no specific exclusion criteria. Patients were categorised according to baseline BMI in order to assess the outcomes for each category.ResultsAmong 3333 patients, 728 (21.8%) were classified as normal (BMI 2), 1537 (46.1%) as overweight (BMI 25.5–29.0 kg/m2) and 1068 (32.0%) as obese (BMI ≥30.0 kg/m2). Procedural duration and radiation dose were higher for overweight and obese patients compared with those with a normal BMI (p=0.002 and p2led to a 1.2-fold increased likelihood of experiencing recurrent AF at 12-months follow-up as compared with overweight patients (HR 1.223; 95% CI 1.047 to 1.429; p=0.011), while no significant correlation was found between overweight and normal BMI groups (HR 0.954; 95% CI 0.798 to 1.140; p=0.605) and obese versus normal BMI (HR 1.16; 95% CI 0.965 to 1.412; p=0.112).ConclusionsPatients with a baseline BMI ≥30 kg/m2have a higher recurrence rate of AF following catheter ablation and therefore lifestyle modification to target obesity preprocedure should be considered in these patients.

A healthy regime is fundamental for the prevention of cardiovascular diseases (CVD). In inherited channelopathies, such as Brugada syndrome (BrS) and Long QT syndrome (LQTS), unfortunately, sudden cardiac death could be the first sign for patients affected by these syndromes. Several known factors are used to stratify the risk of developing cardiac arrhythmias, although none are determinative. The risk factors can be affected by adjusting lifestyle habits, such as a particular diet, impacting the risk of arrhythmogenic events and mortality. To date, the importance of understanding the relationship between diet and inherited channelopathies has been underrated. Therefore, we describe herein the effects of dietary factors on the development of arrhythmia in patients affected by BrS and LQTS. Modifying the diet might not be enough to fully prevent arrhythmias, but it can help lower the risk.

Adverse drug reactions (ADRs) are an important and frequent cause of morbidity and mortality. ADR can be related to a variety of drugs, including anticonvulsants, anaesthetics, antibiotics, antiretroviral, anticancer, and antiarrhythmics, and can involve every organ or apparatus. The causes of ADRs are still poorly understood due to their clinical heterogeneity and complexity. In this scenario, genetic predisposition toward ADRs is an emerging issue, not only in anticancer chemotherapy, but also in many other fields of medicine, including hemolytic anemia due to glucose-6-phosphate dehydrogenase (G6PD) deficiency, aplastic anemia, porphyria, malignant hyperthermia, epidermal tissue necrosis (Lyell’s Syndrome and Stevens-Johnson Syndrome), epilepsy, thyroid diseases, diabetes, Long QT and Brugada Syndromes. The role of genetic mutations in the ADRs pathogenesis has been shown either for dose-dependent or for dose-independent reactions. In this review, we present an update of the genetic background of ADRs, with phenotypic manifestations involving blood, muscles, heart, thyroid, liver, and skin disorders. This review aims to illustrate the growing usefulness of genetics both to prevent ADRs and to optimize the safe therapeutic use of many common drugs. In this prospective, ADRs could become an untoward “stress test,” leading to new diagnosis of genetic-determined diseases. Thus, the wider use of pharmacogenetic testing in the work-up of ADRs will lead to new clinical diagnosis of previously unsuspected diseases and to improved safety and efficacy of therapies. Improving the genotype-phenotype correlation through new lab techniques and implementation of artificial intelligence in the future may lead to personalized medicine, able to predict ADR and consequently to choose the appropriate compound and dosage for each patient.

Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the SCN5A gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the SCN5A novel variant in vitro. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T&gt, A (p.Val1667Asp) in the SCN5A gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants.

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.

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.

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 ± 12.1years, 67% male, 37% ischemic, EF 26.4 ± 6.5%, PR 190.3 ± 39.1ms). Relative to intrinsic conduction (QRSd of 165 ± 16ms), BiV reduced QRSd by 11.9% to 145 ± 18ms (P < 0.001 vs intrinsic), and MPP reduced QRSd by 13.3% to 142 ± 19ms (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 ± 13ms (P < 0.001 vs BiV), while MPP + SyncAV reduced QRSd further by 25.6% to 122 ± 14ms (P < 0.05 vs BiV + SyncAV). Conclusion: SyncAV can significantly improve acute electrical synchrony beyond conventional CRT, with further improvement achieved by superimposing MPP.

Patients with COVID-19 frequently have non-typical ECG changes in the QRS and T-wave morphology. The novel CineECG uses using the mean temporal spatial isochrones (mTSI) to relate the activation and recovery pathway to the cardiac anatomy. The aim of this feasib ility study is to use the novel CineECG to separate normal from abnormal ECGs. The ECGs of 100 normal controls were used to obtain the normal mTSI paths values for the QRS, ST segment and T-wave. These normal CineECG values were used to classify the COVID-19 ECGs as either as normal or abnormal of 107 patients being treatedfor COVID-19 in the University Medical Center Utrecht. The CineECG was able to classify 98% of the normal ECG correctly and 94% of the abnormal ECG in comparison to expert ECG classifications. The ability of the CineECG to relate the ECG to the cardiac anatomy supports the detection of abnormal ECGs. The CineECG might be a novel ECG screening tool to detect potential cardiac involvement of the COVID-19 disease for non-ECG experts.

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.

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.

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.

Funding Acknowledgements Abbott Introduction SyncAV has been shown to improve electrical synchronization by automatically adjusting atrioventricular delay (AVD) according to the intrinsic atrioventricular conduction time. Additional incremental electrical synchronization may be gained by the addition of second left ventricular (LV) pulse with MultiPoint Pacing (MPP). While the electrical synchronization benefits of SyncAV have been previously explored, there has been no assessment of the acute hemodynamic impact of SyncAV with or without MPP. Objective Evaluate the acute LV hemodynamic impact of SyncAV with and without MPP. Methods Heart failure patients with LBBB and QRS duration (QRSd) > 140 ms undergoing CRT-P/D implant with a quadripolar LV lead were enrolled in this prospective study. A guidewire or catheter with pressure transducer was placed in the LV chamber and the maximum pressure change (dP/dtmax) was recorded during the following pacing modes: intrinsic conduction, conventional biventricular pacing with SyncAV (BiV + SyncAV), and MPP with SyncAV (MPP + SyncAV). Twelve-lead surface ECG was used to determine the patient-tailored SyncAV offset that minimized QRSd. Results Twenty-seven patients (67% male, 44% ischemic, 30 ± 7% ejection fraction) completed the acute recordings. Relative to the intrinsic QRSd of 163 ms, BiV + SyncAV reduced QRSd by 21.5% to 124 ms (p Conclusion SyncAV may significantly improve acute LV hemodynamics in addition to electrical synchrony in LBBB patients. Further incremental improvement was achieved by combining SyncAV with MPP. Abstract Figure.

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. Methods 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 3452 ± 26.4 vs Group 2436.3 ± 28.4 vs Group 1424.4 ± 24.3 ms, respectively; p, Highlights • Only the use of HCQ in combination with AZT causes a significant increase of QT interval. • Older patients are at higher risk of prolonged QT when treated with HCQ with/without AZT. • The use of HCQ alone or in combination with AZT might be considered as safe relating to arrhythmic risk in the treatment of COVID-19 patients.

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.

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

Supraventricular premature beats (SVPBs) are atrial contractions arising in ectopic foci rather than in the sinoatrial node. SVPBs are found in healthy individuals or in patients with underlying heart disease and can be asymptomatic or felt as palpitations. External triggers (alcohol, caffeine, smoking, stress) and several disease conditions (arterial hypertension, chronic obstructive pulmonary disease, obstructive sleep apnea syndrome, thyroid malfunction, electrolyte imbalances, or drug toxicity) may favor SVPB occurrence. SVPBs increase with age and are slightly more common in males than in females. SVPBs are generally a benign condition; however, frequent SVPBs may beget prolonged repolarization, atrial fibrillation, or even ventricular tachycardia and, rarely, ventricular fibrillation. Asymptomatic SVPBs without underlying structural heart defects generally do not require treatment, while the concomitant disease conditions should be treated, and potential external triggers should be avoided. β-Blockers, calcium antagonists, class 1c antiarrhythmic drugs or amiodarone, or radiofrequency catheter ablation can be used in selected patients with persistent symptoms.

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

Atrial Fibrillation (AF) is the most commonly described cardiac arrhythmia found in the general population and can lead to adverse outcomes. Its onset and maintenance requires the presence of an arrhythmogenic substrate that predisposes the patient for risk of these types of arrhythmias and the occurrence of a trigger event. A major characteristic of AF-related structural remodelling is atrial fibrosis, a process closely related to inflammation. Autoimmune rheumatic diseases constitute systemic inflammatory disorders that can also present with cardiovascular manifestations, including a high incidence of AF, thus supporting the idea of a link between AF and inflammation. A vicious cycle exists in which inflammation leads to a higher prevalence of structural cardiovascular disease, which in turn leads to more inflammation and AF; in fact, inflammation is known to affect signalling pathways that lead to the development of AF. Therapy must first target systemic inflammation, since decreasing the inflammatory burden has consistently shown to positively ameliorate the prognosis. When this approach is not sufficient, rhythm or, when not feasible, rate control is indicated in addition to anticoagulant therapy. As far as the rhythm control strategy is concerned, antiarrhythmic drugs and/or catheter ablation should be considered. New mapping techniques allowing the characterization of the arrhythmic substrate have opened new perspectives and may help in the treatment of AF in these patients, since atrial tissue is the target of inflammation-induced arrhythmic alterations. In cases where the natural history of the arrhythmia itself is more advanced, in order to minimize the impact of AF on cardiac function as well as quality of life, a device-based therapy, including an "ablate and pace" approach could be adopted.

Objectives This study investigates the electrocardiographic-electrophysiological effects of administration of anesthetic drugs for general anesthesia (GA) in patients with BrS at high risk of sudden cardiac death (SCD). Background The safety of anesthetic agents in Brugada syndrome (BrS) is under debate. Methods All consecutive patients with spontaneous type 1 BrS electrocardiographic (ECG) patterns undergoing epicardial ablation of the arrhythmogenic substrate (AS) under GA were enrolled. Anesthesia was induced with single bolus of propofol and maintained with sevofluorane. ECG measurements were collected before, immediately after, and 20 min after induction of GA. Three-dimensional maps during GA and after ajmaline indicated the epicardial AS before ablation. Results Thirty-six patients with BrS (32 male, 88.9%; mean age 38.8 ± 12.0 years) with a spontaneous type 1 ECG pattern underwent GA. Induction was performed using propofol at mean dose of 1.6 to 2.6 mg/kg (2.1 ± 0.3 mg/kg). Twenty-eight (28 of 36, 77.8%) patients showed a reversion to a nondiagnostic pattern. ST-segment elevation (0.32 ± 0.01 mV vs. 0.19 ± 0.02 mV, p 2 vs. 20.3 ± 0.8 cm 2 ). No patient developed malignant arrhythmias during GA induction and maintenance. Conclusions This study shows that GA using single-bolus propofol and volatile anesthetics is safe in high-risk patients with BrS, and it may exert a modulating effect by reducing the manifestation of type 1 BrS pattern and AS in the form of epicardial abnormal ECGs. (Epicardial Ablation in Brugada Syndrome: An Extension Study of 200 BrS Patients; NCT03106701).

Background: Multipoint left ventricular (LV) pacing (MultiPoint™ Pacing [MPP], Abbott, Sylmar, CA, USA) improves the response rate to cardiac resynchronization therapy (CRT). We evaluated the feasibility of noninvasive radial artery tonometry (RAT) to characterize arterial pressure morphology changes (pre-ejection period [PEP] and ejection duration [ED]) between conventional CRT and MPP pacing interventions. Methods: Patients with a MPP-enabled CRT device (Quadra Assura MP™, Abbott) underwent noninvasive RAT assessment (SphygmoCor CVMS, AtCor Medical Inc., Itasca, IL, USA) at 3–6 months after implantation. A pacing protocol was performed in a randomized order including one optimized conventional biventricular CRT (CONV) configuration using the distal electrode and five MPP configurations. The PEP, ED, and PEP/ED ratio were determined for each intervention from the RAT pressure waveform and electrocardiogram. Results: Pressure waveforms were successfully recorded in 19 patients (89% male, QRS 147 ± 16ms, 63% ischemic). In 17/19 (89%) patients, at least one MPP intervention resulted in improved PEP, ED, and PEP/ED compared to CONV. The MPP intervention with greatest separation of LV cathodes and minimum intra-LV delay significantly improved PEP (mean PEP –15 ± 33%vs –8 ± 32% [CONV], P=0.04) and ED (mean ED +8 ± 8% [MPP] vs +4 ± 7% [CONV], P=0.02), and PEP/ED (–0.07 ± 0.14 [MPP] vs –0.04 ± 0.13 [CONV], P=0.02) compared with CONV. Conclusions: Noninvasive RAT efficiently characterizes changes in PEP and ED between CONV and MPP interventions. MPP configurations using the widest separation among LV cathodes and minimum intra-LV delay may significantly improve RAT-derived parameters as compared to conventional CRT.

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 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).

In this case report, we characterize a novel inherited frameshift mutation c.4700_4701del (p.Phe1567Cysfs*221) in a single copy of the SCN5A 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.

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.

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.

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.

Aims Clinical outcomes after radiofrequency catheter ablation (RFCA) remain suboptimal in the treatment of non-paroxysmal atrial fibrillation (AF). Electrophysiological mapping may improve understanding of the underlying mechanisms. To describe the arrhythmia substrate in patients with persistent (Pers) and long-standing persistent (LSPers) AF, undergoing RFCA, using an integrated mechanism mapping technique. Methods and results Patients underwent high-density electroanatomical mapping before and after catheter ablation. Integrated maps characterized electrogram (EGM) cycle length (CL) in regions with repetitive–regular (RR) activations, stable wavefront propagation, fragmentation, and peak-to-peak bipolar voltage. Among 83 patients (72% male, 60 ± 11 years old), RR activations were identified in 376 regions (mean CL 180 ± 31 ms). PersAF patients (n = 43) showed more RR sites per patient (5.3 ± 2.4 vs. 3.7 ± 2.1, P = 0.002) with faster CL (166 ± 29 vs. 190 ± 29 ms; P 75% of RR sites (Q4 82.6%, Q3 63.1%, Q2 35.1%, and Q1 0%; P Conclusion The integrated mapping technique allowed characterization of multiple arrhythmic substrates in non-paroxysmal AF patients. This technique might serve as tool for a substrate-targeted ablation approach.

Background: Idiopathic ventricular fibrillation (IVF) in patients with normal baseline electrocardiograms (ECGs) is a rare disease. Little information is available on the clinical features and long-term follow-up of out-of-hospital cardiac arrest (OHCA) survivors presenting with "true" IVF and 12-lead ECGs that remain normal over time. Objective: To define the clinical and ECG characteristics, as well as long-term clinical outcomes of a large cohort of survivors of OHCA due to "true" IVF. Methods: OHCA survivors with VF as the presenting rhythm, normal baseline and follow-up ECGs with no signs of cardiac channelopathy including early repolarization or atrioventricular (AV) conduction abnormalities, and without structural heart disease were included in a registry. Results: A total of 245 OHCA survivors with IVF (median age: 38 years; males 59%) were recruited from 25 centres. All had normal baseline and follow-up ECGs, and no evidence of structural heart disease. 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 4 of them (1.6%) the lethal event was of cardiac origin. Patients treated with antiarrhythmic drugs (AADs) only had a higher rate of cardiovascular death compared to patients who received an ICD (16% vs. 0.4%, p=0.001). The ECG and echocardiogram of all patients remained unchanged over time. 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 (HR 0.41, 95% CI 0.18-0.92, p=0.03). Discussion: OHCA survivors of "true" IVF with normal baseline and follow-up 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. Funding: The study was supported by a grant of the Swiss Heart Foundation. Declaration of Interest: G.C. has received a research grant from the Swiss National Foundation. P.L. has received speaker fees and research grants from Boston Scientific, Abbott and Medtronic Research support from UCLH Biomedicine NIHR. F.L. is consultant and has received research support from Medtronic Plc, Abbott, Boston Scientific and Microport. S.B. has received speaker’s bureau from Medtronic and Microport. C.P. has received research grant from Biotronik and Biosense Webster. P.B. is consultant for Biotronik. A.A. is consultant to Abbott, Biosense Webster, Daiichi-Sankyo, Boston Scientific, Medtronic, Microport-CRM; and has received speaker fee from Daiichi-Sankyo, Boston Scientific, Medtronic, Microport-CRM Ethics Approval Statement: Data were collected in accordance with regulations set by the local Institutional Ethics Committee and/or Institutional Review Board.

Purpose: Cardiac resynchronization therapy (CRT) with multipoint left ventricular (LV) pacing (MultiPoint™ Pacing [MPP]) improves long-term LV reverse remodeling, though questions persist about how to program LV pacing vectors and delays. We evaluated if an empirical method of programming MPP vectors and delays between pacing pulses improved CRT response similar to pressure-volume loop (PVL) optimized MPP programming. Methods: Patients undergoing CRT implant (Quadra Assura MP™ CRT-D and Quartet™ LV lead) received MPP with programmed settings optimized either by PVL measurements at implant (PVL-OPT group) or empirically determined by maximizing the spatial separation between the two cathodes and minimal delays between the three ventricular pacing pulses (MAX-SEP group). CRT response was prospectively defined as a reduction in end-systolic volume (ESV) of ≥ 15% relative to baseline at 6months as determined by a blinded observer. Results: Patient characteristics at baseline (NYHA II–III, ejection fraction [EF] 27 ± 6%, QRS 151 ± 17ms) were not significantly different between the PVL-OPT (n = 27) and MAX-SEP (n = 26) groups. During the follow-up period, there were no differences in the number of patients requiring reprogramming due to phrenic nerve stimulation or a high threshold for PVL-OPT vs. MAX-SEP (5/27 [19%] vs. 7/26 [27%], p= 0.53). After 6months, ESV reduction, EF increase, and CRT response rate (RR) were similar for PVL-OPT vs. MAX-SEP (ESV − 20 ± 11 vs. − 22 ± 11%, p = 0.59; EF + 10 ± 4 vs. + 9 ± 7%, p = 0.53; RR 20/27 [74%] vs. 21/26 [81%], p = 0.74), while fewer patients in the PVL-OPT group experienced NYHA class reduction ≥ 2 (4/27 [15%] vs.15/26 [58%], p = 0.002). Conclusions: Both evaluated methods of MPP programming resulted in similar CRT outcomes. Empirical MPP programming by maximum spatial separation of LV cathodes may be an effective, simple, and non-invasive alternative to pressure-volume optimization.

Objectives Life expectancy of patients with repaired tetralogy of Fallot is normal until adulthood, when it becomes burdened by major complications such as cardiac arrhythmias and heart failure. Ventricular tachycardia (VT), associated with electrical conduction abnormalities in anatomical isthmuses, is the most common complication and is refractory to medical therapy. The arrhythmogenic sources can be surgically ablated during reoperations for pulmonary valve incompetence. The purpose of our study is to evaluate the safety and effectiveness of surgical radiofrequency ablation during PVR and its long-term impact on the occurrence of cardiac events. Methods A total of 118 patients with repaired tetralogy of Fallot underwent reoperation for pulmonary valve regurgitation in IRCCS-Policlinico San Donato between January 2002 and February 2016. Twenty patients with risk factors for ventricular arrhythmia underwent EP testing and were found positive. The mean QRS duration was 178 ms. Right ventricular dysfunction was present in all the patients, and 20% had associated tricuspid regurgitation. The cohort (N = 20), with positive EP study, underwent pulmonary valve replacement and concomitant intraoperative ventricular surgical radiofrequency ablation, targeting the slow conducting isthmuses identified during preoperative electroanatomical mapping. All patients were reviewed at 1 month, 3 months and 6 months with clinical evaluation, echocardiography, ECG and implantable cardioverter-defibrillator interrogation. At 6 months, a postoperative electrophysiological study was performed in all patients, and a cardioverter defibrillator was implanted as primary preventive measure in patients with residual inducible VT. Results Pulmonary valve replacement and surgical ventricular radiofrequency ablation were performed in all cases. One patient died while on V-V extracorporeal membrane oxygenation (ECMO) due to respiratory failure. There was no late mortality. Follow-up was complete with a median of 6.5 years. During the postoperative EPS study, inducible VT was found in 15.7% of patients who received an implantable cardioverter-defibrillator, whereas VT could no longer be induced in the remaining patients. No procedure-related complication was observed, and freedom from ventricular arrhythmia was 94% and 89.5% at 1 year and 5 years, respectively. Conclusions Pulmonary regurgitation and right ventricular dysfunction correlate with VT and SCD, but valve replacement alone does not reduce the risk of ventricular tachyarrhythmias. Intraoperative ventricular ablation during reoperation for pulmonary regurgitation prevents the occurrence of ventricular arrhythmias in the early and medium term. Accordingly, this technique may be proposed as a safe associated procedure in selected patients.

Brugada syndrome (BrS) and several cardiomyopathies, including dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, left ventricular non-compaction (LVNC), and hypertrophic cardiomyopathy (HCM), share common genetic mutations and are associated with an arrhythmogenic substrate (AS) and increased risk of sudden cardiac death (SCD) due to malignant ventricular arrhythmias. We report a family in which a SCN5A mutation was found in both a father and daughter who presented with different phenotypes: the father with LVNC and the daughter with BrS, suggesting SCN5A may be important in cases of overlap between BrS and these various other cardiomyopathies and arrhythmias. Additionally, we report a family in which a MYBPC3 mutation was found in a father, daughter, and son, but they also presented with different phenotypes: the father with HCM and the daughter and son with BrS, suggesting patients with cardiomyopathies or BrS exhibiting sarcomeric mutations may have common genetic pathways that ultimately diverge into different phenotypes. Generally, prevention of SCD may involve the use of an implantable cardioverter-defibrillator and/or pharmaceutical therapy. However, patients continue to experience difficulties with this treatment. Epicardial mapping together with ajmaline challenge used to identify the AS in BrS patients can be used to identify and ablate the AS in cardiomyopathy patients, thus preventing the recurrence of ventricular tachycardia/fibrillation and reducing or eliminating the need for shock or pharmacological therapy. Future studies and longer follow-up times are warranted to understand the fullest duration of the therapeutic potential of this ajmaline and map-guided ablation therapy.

Background Patient-specific programming of cardiac resynchronization therapy (CRT) is often neglected, despite significant nonresponse rates. The device-based SyncAV CRT algorithm dynamically adjusts atrioventricular delays to the intrinsic AV interval, reduced by a programmable offset, to accommodate each patient's changing needs. Objective The purpose of this study was to evaluate the acute effect of biventricular (BiV) pacing enhanced by SyncAV on electrical synchrony in a broad patient population. Methods Patients with existing CRT implants were prospectively evaluated at 5 international centers. Blinded 12-lead electrocardiographic QRS duration (QRSd) measurements were used to compare intrinsic conduction with nominal BiV pacing, BiV + SyncAV (default 50 ms offset), and BiV + SyncAV (optimized, patient-specific offset). BiV configurations were tested twice using the latest activating and earliest activating left ventricular (LV) electrodes as cathodes. Results Ninety patients (mean age 67.1 ± 9.5 years; 67 (74%) men; 55 (63%) with left bundle branch block; 37 (43%) with ischemic cardiomyopathy; LV ejection fraction 32% ± 9%) with intact atrioventricular conduction (PR interval 195 ± 45 ms) were enrolled. With BiV pacing from the latest activating LV electrode, the intrinsic QRSd of 155 ± 29 ms was reduced by 9% ± 20% to 138 ± 27 ms using traditional BiV pacing and by 13% ± 14% to 133 ± 25 ms using BiV + SyncAV (50 ms offset). The maximal QRSd reduction by 20% ± 10% to 123 ± 22 ms was achieved by BiV + SyncAV with an optimized offset. Similar QRSd reductions were observed with BiV pacing from the earliest activating LV electrode across all settings. Of all baseline characteristics, intrinsic QRSd was the only significant predictor of QRSd reduction magnitude. Conclusion SyncAV improved acute electrical synchrony beyond conventional CRT, particularly with patient-specific optimization. The degree of synchrony restored was contingent on intrinsic QRSd, but not limited by other baseline characteristics or by the LV pacing electrode used.

Dilated cardiomyopathy (DCM) is the leading indication for heart transplantation. TTN 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 TTN has been difficult to determine because of the sheer size of the protein for which TTN 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 TTN 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 TTN gene variants. Further studies are warranted to better understand this particular clinically-relevant variant.

Aims Continuous rhythm monitoring is valuable for adequate atrial fibrillation (AF) management in the clinical setting. Subcutaneous leadless implantable cardiac monitors (ICMs) yield an improved AF detection, overcoming the intrinsic limitations of the currently available external recording systems, thus resulting in a more accurate patient treatment. The study purpose was to assess the detection performance of a novel three-vector ICM device equipped with a dedicated AF algorithm. Methods and results Sixty-six patients (86.4% males; mean age 60.4 ± 9.4 years) at risk to present AF episodes, having undergone the novel ICM implant (BioMonitor, Biotronik SE&Co. KG, Berlin, Germany), were enrolled. External 48-h ECG Holter was performed 4 weeks after the device implantation. The automatic ICM AF classification was compared with the manual Holter arrhythmia recordings. Of the overall study population, 63/66 (95.5%) had analysable Holter data, 39/63 (62%) showed at least one true AF episode. All these patients had at least one AF episode stored in the ICM. On Holter monitoring, 24/63 (38%) patients did not show AF episodes, in 16 of them (16/24, 67%), the ICM confirmed the absence of AF. The AF detection sensitivity and positive predictive value for episodes' analysis were 95.4 and 76.3%, respectively. Conclusion Continuous monitoring using this novel device, equipped with a dedicated detection algorithm, yields an accurate and reliable detection of AF episodes. The ICM is a promising tool for tailoring individual AF patient management. Further long-term prospective studies are necessary to confirm these encouraging results.

Objectives The aim of this study was to perform a collaborative meta-analysis of published and unpublished quality-of-life, morbidity, and mortality data from randomized controlled trial comparisons of radiofrequency ablation (RFA) and antiarrhythmic drug therapy (AAD) in symptomatic atrial fibrillation. Background RFA is superior to AAD in decreasing recurrences of atrial fibrillation, but the effects on other clinical outcomes are not well established. Methods The primary investigators of eligible randomized controlled trials were invited to contribute standardized outcome data. Random-effects summary estimates were calculated as standardized mean differences and risk ratios with 95% confidence intervals for continuous and binary outcomes, respectively. Fixed effects were used in subgroup analyses. Results Twelve randomized controlled trials (n = 1,707 patients) were included. RFA led to greater improvements in 4 36-Item Short Form Health Survey areas and the symptom frequency score from baseline to 3 months. In all quality-of-life metrics, there was a trend toward diminution of the differences between the 2 approaches with follow-up. There were 7 of 866 (5 in a study using phased RFA) and 0 of 704 strokes in the RFA and AAD arms, respectively (p = 0.02, Fisher exact test). Bleeding and mortality events were not significantly different between the 2 arms. There was high heterogeneity for hospitalizations, with decreased hospitalization risk with RFA when it was not first-line therapy (risk ratio: 0.34; 95% confidence interval: 0.24 to 0.46) and increased risk as first-line therapy (risk ratio: 1.22; 95% confidence interval: 1.03 to 1.45). Conclusions RFA demonstrates an early but nonsustained superiority over AAD for the improvement of quality of life. There are no obvious differences in other clinical outcomes, and the periprocedural stroke risk is non-negligible.

Despite considerable improvements in the treatment of cardiovascular diseases, heart failure (HF) still represents one of the leading causes of death worldwide. Poor prognosis is mostly due to the limited regenerative capacity of the adult human heart, which ultimately leads to left ventricular dysfunction. As a consequence, heart transplantation is virtually the only alternative for many patients. Therefore, novel regenerative approaches are extremely needed, and several attempts have been performed to improve HF patients’ clinical conditions by promoting the replacement of the lost cardiomyocytes and by activating cardiac repair. In particular, cell-based therapies have been shown to possess a great potential for cardiac regeneration. Different cell types have been extensively tested in clinical trials, demonstrating consistent safety results. However, heterogeneous efficacy data have been reported, probably because precise end-points still need to be clearly defined. Moreover, the principal mechanism responsible for these beneficial effects seems to be the paracrine release of antiapoptotic and immunomodulatory molecules from the injected cells. This review covers past and state-of-the-art strategies in cell-based heart regeneration, highlighting the advantages, challenges, and limitations of each approach.