A Novel DLG1 Variant in a Family with Brugada Syndrome: Clinical Characteristics and In Silico Analysis.

BACKGROUND: Brugada syndrome (BrS) is an inherited primary channelopathy syndrome associated to sudden cardiac death. Overall, variants have been identified in eighteen genes encoding for ion channel subunits and seven genes for regulatory proteins. Recently, a missense variant in DLG1 has been found within a BrS phenotype-positive patient. DLG1 encodes for synapse associated protein 97 (SAP97), a protein characterized by the presence of multiple domains for protein-protein interactions including PDZ domains. In cardiomyocytes, SAP97 interacts with Nav1.5, a PDZ binding motif of SCN5A and others potassium channel subunits. AIM OF THE STUDY: To characterize the phenotype of an Italian family with BrS syndrome carrying a DLG1 variant. METHODS: Clinical and genetic investigations were performed. Genetic testing was performed with whole-exome sequencing (WES) using the Illumina platform. According to the standard protocol, a variant found by WES was confirmed in all members of the family by bi-directional capillary Sanger resequencing. The effect of the variant was investigated by using in silico prediction of pathogenicity. RESULTS: The index case was a 74-year-old man with spontaneous type 1 BrS ECG pattern that experienced syncope and underwent ICD implantation. WES of the index case, performed assuming a dominant mode of inheritance, identified a heterozygous variant, c.1556G>A (p.R519H), in the exon 15 of the DLG1 gene. In the pedigree investigation, 6 out of 12 family members had the variant. Carriers of the gene variant all had BrS ECG type 1 drug induced and showed heterogeneous cardiac phenotypes with two patients experiencing syncope during exercise and fever, respectively. The amino acid residue #519 lies near a PDZ domain and in silico analysis suggested a causal role for the variant. Modelling of the resulting protein structure predicted that the variant disrupts an H-bond and a likelihood of being pathogenic. As a consequence, it is likely that a conformational change affects protein functionality and the modulating role on ion channels. CONCLUSIONS: A DLG1 gene variant identified was associated with BrS. The variant could modify the formation of multichannel protein complexes, affecting ion channels to specific compartments in cardiomyocytes.

Effectiveness and safety of implantable loop recorder and clinical utility of remote monitoring in patients with unexplained, recurrent, traumatic syncope.

BACKGROUND: Implantable loop recorder (ILR) is still underutilized in clinical practice, especially in the setting of elderly patients with recurrent, traumatic, unexplained syncope. Data on the actual risk of traumatic syncopal recurrence during ILR monitoring in this specific patient setting are lacking. RESEARCH DESIGN AND METHODS: Prospective, multicentre registry enrolling consecutive patients undergoing ILR insertion for unexplained, recurrent, traumatic syncope. In a proportion of enrolled patients, remote monitoring (RM) was used for device follow-up. The risk of traumatic and non-traumatic syncopal recurrences during ILR observation were prospectively assessed. RESULTS: A total of 483 consecutive patients (68±14 years, 59% male) were enrolled. During a median follow-up of 18 months, a final diagnosis was reached in 270 patients (55.9%). The risk of syncopal and traumatic syncopal recurrence was of 26.5 and 9.3%, respectively. RM significantly reduced the time to diagnosis (19.7±10.3 vs. 22.1±10.8 months; p=0.015) and was associated with a significant reduction in the risk of syncope recurrence of 48% (p<0.001), and of traumatic syncope recurrence of 49% (p=0.018). CONCLUSIONS: ILR monitoring is effective and safe in patients with unexplained, recurrent, traumatic syncope. RM reduces the time to diagnosis and significantly reduces the risk of traumatic and non-traumatic syncopal relapses.

Near zero vascular complications using echo-guided puncture during catheter ablation of arrhythmias: A retrospective study and literature review.

Background: Catheter ablation (CA) is routinely used for the treatment of arrhythmias. Vascular complications are the most common complications during these procedures. Previous data reported that ultrasound (US)-guided puncture is a useful method to avoid vascular complications. We reported our experience using US-guided puncture in patients undergoing CA for arrhythmias. Methods: A total of 273 patients (mean age 57 ± 17 years; 58% male) were referred to our center for CA of arrhythmias from January 2016 to December 2019. All procedures were performed by expert operators, and US-guided vascular access was performed on all patients. Doppler sonography was performed the day after the procedure on all patients. Results: Eighty-four patients (31%) underwent atrioventricular nodal reentrant tachycardia ablation, 49 patients (18%) atrioventricular reentrant tachycardia ablation, 14 patients (5%) atrial tachycardia ablation, 25 patients (9%) atrial flutter ablation, 63 patients (23%) atrial fibrillation ablation, and 38 patients (14%) ventricular tachycardia ablation. Vascular pseudo-aneurysms and arteriovenous fistula were defined as major complications; furthermore, venous thrombosis and inguinal hematomas were as defined minor complications. The percentage of major vascular complications was 0.3% (1 arteriovenous fistula) and the percentage of minor vascular complications was 0.3% (1 venous thrombosis). Discussion: Ultrasound-guided vascular puncture in patients undergoing CA is useful to improve procedural success and reduce complications.

Management of older patients with unexplained, recurrent, traumatic syncope and bifascicular block: Implantable loop recorder versus empiric pacemaker implantation-Results of a propensity-matched analysis.

BACKGROUND: In patients with unexplained syncope and bifascicular block (BFB), syncope may be caused by intermittent atrioventricular (AV) block. When a correlation between syncope and bradyarrhythmia is not documented in these patients, 2 alternative management strategies can be adopted: (1) empiric pacemaker (PM) implantation or (2) long-term continuous electrocardiographic monitoring by implantable loop recorder (ILR). OBJECTIVE: The purpose of this study was to compare the risk of syncope recurrence associated with empiric PM implantation or ILR monitoring. METHODS: A prospective, multicenter, observational study enrolled consecutive patients with unexplained, recurrent, traumatic syncope and BFB who underwent ILR monitoring or empiric PM implantation. The risk and causes of syncope recurrence were assessed and compared between the 2 groups. Individual 1:1 propensity matching of baseline characteristics was performed. RESULTS: A total of 309 consecutive patients (age 77.2 ± 12.2 years; 60.8% male) were enrolled. Propensity matching yielded 89 matched pairs. After median follow-up of 33 months, empiric PM implantation was associated with a significantly lower risk of syncope recurrence than ILR monitoring (19.1 vs 46.1%; P <.001). A total of 35 patients (39.3%) who underwent ILR monitoring developed bradyarrhythmias (68.6% paroxysmal AV block) requiring PM implantation during follow-up. Excluding bradyarrhythmic syncope, the most frequent causes of syncope recurrence in both study groups were reflex syncope and orthostatic hypotension. CONCLUSION: In patients with unexplained, recurrent, traumatic syncope and BFB, empiric PM implantation significantly reduced the risk of syncope recurrence in comparison with ILR monitoring. A high rate of patients who underwent ILR monitoring developed bradyarrhythmias requiring PM implantation.

Fever following Covid-19 vaccination in subjects with Brugada syndrome: Incidence and management.

BACKGROUND: Fever is a potential side effect of the Covid-19 vaccination. Patients with Brugada syndrome (BrS) have an increased risk of life-threatening arrhythmias when experiencing fever. Prompt treatment with antipyretic drugs is suggested in these patients. AIM OF THE STUDY: To evaluate the incidence and management of fever within 48 h from Covid-19 vaccination among BrS patients. METHODS: One hundred sixty-three consecutive patients were enrolled in a prospective registry involving five European hospitals with a dedicated inherited disease ambulatory. RESULTS: The mean age was 50 ± 14 years and 121 (75%) patients were male. Prevalence of Brugada electrocardiogram (ECG) pattern type-1, -2, and -3 was 32%, 44%, and 24%, respectively. Twenty-eight (17%) patients had an implantable cardioverter-defibrillator (ICD). Fever occurred in 32 (19%) BrS patients after 16 ± 10 h from vaccination, with a peak of body temperature of 37.9° ± 0.5°. Patients with fever were younger (39 ± 13 vs. 48 ± 13 years, p = .04). No additional differences in terms of sex and cardiovascular risk factors were found between patients with fever and not. Twenty-seven (84%) out of 32 patients experienced mild fever and five (16%) moderate fever. Pharmacological treatment with antipyretic drugs was required in 18 (56%) out of 32 patients and was associated with the resolution of symptoms. No patient required hospital admission and no arrhythmic episode was recorded in patients with ICD within 48 h after vaccination. No induced type 1 BrS ECG pattern and new ECG features were found among patients with moderate fever. CONCLUSION: Fever is a common side effect in BrS patients after the Covid-19 vaccination. Careful evaluation of body temperature and prompt treatment with antipyretic drugs may be needed.

Atrial fibrillation ablation: is common practice far from guidelines' world? The Italian experience from a national survey.

PURPOSE: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, occurring in 1-2% of the general population. Catheter ablation has become an important treatment modality for patients with symptomatic drug-refractory AF. We report data regarding the AF ablation approaches and modalities in the Italian "real world." METHODS: The survey was set-up to collect data on ablation procedure across Italy. All centers performing AF ablation were invited, regardless of the number of annual procedures, to complete a questionnaire regarding their ablation approaches. All centers reported data regarding procedures performed during the year 2017. RESULTS: A total of 3260 procedures were reported from 49 participating hospitals. Most of Italian regions were included in the study. The majority of the centers performed "Always" pulmonary vein isolation (PVI) in paroxysmal and persistent AF catheter ablation, while adjunctive lesions in persistent AF ablation were planned in most of them but not all, and 16% never performed lesions other than PVI. During ablation procedure, vitamin k inhibitors were uninterrupted in 55% of centers, while direct oral anticoagulant in 44% of centers was used uninterruptedly. No relationship was observed between patient data and the number of procedures performed at each center. CONCLUSIONS: This survey suggests that the adherence of Italian centers to the most recent European Society of Cardiology guidelines for AF ablation is reasonably high.

Effect of SAcubitril/Valsartan on left vEntricular ejection fraction and on the potential indication for Implantable Cardioverter Defibrillator in primary prevention: the SAVE-ICD study.

PURPOSE: Sacubitril/valsartan has been associated with a positive reverse left ventricular remodelling in patients with heart failure with reduced ejection fraction (HFrEF). These patients may also benefit from an ICD implant. We aimed to assess EF improvement after 6 months of treatment with sacubitril/valsartan, evaluating when ICD as primary prevention was no longer indicated. METHODS: Multicentre, observational, prospective study enrolling all consecutive patients with HFrEF and EF ≤ 35% with an ICD as primary prevention and starting treatment with sacubitril/valsartan (NCT03935087). Resynchronization therapy and patients experiencing appropriate ICD therapies before sacubitril/valsartan were excluded. RESULTS: Two-hundred-and-thirty patients were enrolled (73.9% males, mean age 64.3 ± 12.1 years) After 6 months of treatment, a reduction in left ventricular end-diastolic and end-systolic volumes was noted and LVEF increased from 28.3 ± 5.6% to 32.2 ± 6.5% (p < 0.001). At 6 months, a non-ischemic aetiology of cardiomyopathy and a final dose of sacubitril/valsartan > 24/26 mg twice daily were associated with a higher probability of an absolute increase of > 5% in LVEF. A total of 5.3% of primary prevention patients still had an arrhythmic event in the first 6 months after treatment with sacubitril/valsartan started. CONCLUSIONS: Sacubitril/valsartan improves systolic function in HFrEF, mainly due to reverse left ventricular remodelling. Improvement in EF after 6 months of treatment could help prevent ICD implantation in nearly one out of four patients, with important clinical and economic implications. However, the risk of sudden cardiac death in this recovered HFrEF population has not been thoroughly studied, and the present data should be interpreted only as hypothesis-generating.

Causes of syncopal recurrences in patients treated with permanent pacing for bradyarrhythmic syncope: Findings from the SYNCOPACED registry.

BACKGROUND: Few studies have examined the causes of syncope/collapse recurrences in patients with a previously implanted pacemaker for bradyarrhythmic syncope. OBJECTIVE: The purpose of this study was to assess the causes of syncope/collapse recurrences after pacemaker implantation for bradyarrhythmic syncope in a large patient population. METHODS: The SYNCOpal recurrences in patients treated with permanent PACing for bradyarrhythmic syncope (SYNCOPACED) registry was a prospective multicenter observational registry enrolling 1364 consecutive patients undergoing pacemaker implantation for bradyarrhythmic syncope. During follow-up, the time to the first syncope/collapse recurrence was recorded. Patients with syncope/collapse recurrences underwent a predefined diagnostic workup aimed at establishing the mechanism of syncope/collapse. RESULTS: During a median follow-up of 50 months, 213 patients (15.6%) reported at least 1 syncope/collapse recurrence. The risk of syncope/collapse recurrence was highest in patients who underwent implantation for cardioinhibitory vasovagal syncope (26.4%), followed by unexplained syncope and chronic bifascicular block (21.5%), cardioinhibitory carotid sinus syndrome (17.2%), atrial fibrillation needing pacing (15.5%), atrioventricular block (13.6%), and sinus node disease (12.5%) (P = .017). The most frequent cause of syncope/collapse recurrence was reflex syncope (27.7%), followed by orthostatic hypotension (26.3%), pacemaker or lead malfunction (5.6%), structural cardiac disease (5.2%), and atrial and ventricular tachyarrhythmias (4.7% and 3.8%, respectively). In 26.8% of cases, the mechanism of syncope/collapse remained unexplained. CONCLUSION: In patients receiving a pacemaker for bradyarrhythmic syncope, reflex syncope and orthostatic hypotension are the most frequent mechanisms of syncope/collapse recurrence after implantation. Pacing system malfunction, structural cardiac diseases, and tachyarrhythmias are rare mechanisms. The mechanism remains unexplained in >25% of patients.

Concealed structural heart disease discovered at cardiac magnetic resonance in patients with ventricular extrasystoles from ventricular outflow tract and apparently normal hearts.

BACKGROUND: Outflow tract (OT) premature ventricular contractions (PVCs) are commonly found in clinical practice; in most cases, PVCs are benign and observed in structurally normal hearts, not requiring any therapeutic intervention. In this study, we therefore sought to evaluate with cardiac magnetic resonance (CMR) patients with PVC and apparently normal heart at echocardiographic examination, in order to identify possible substrates linked with higher prevalence of arrhythmias or structural heart disease. METHODS: Thirty-three consecutive patients with frequent PVCs originating from the ventricular OT (right and left) were enrolled in the study and assessed by echocardiography and CMR. All patients had normal baseline electrocardiogram. RESULTS: CMR showed structural changes in 5 patients out of 33; in 3 cases, areas of fibrosis limited in one case to the middle basal segments of the interventricular septum and in two patients to the middle basal segments of the inferior-lateral wall were found. In 2 other cases, however, late gadolinium enhancement showed significant anomalies characterized in one patient by extensive areas of subepicardial fibrosis of the left ventricle, suitable with arrhythmogenic left dominant dysplasia; in another patient, a marked trabeculation of left ventricular medium apical segments suitable with non-compaction myocardium was present. CONCLUSIONS: CMR may identify cases of structural heart disease in subjects with OT PVCs and apparently normal electrocardiogram and echocardiogram examinations. A preliminary screening with CMR may be considered before any further invasive electrophysiology assessment and therapeutic planning.

Risk of syncopal recurrences in patients treated with permanent pacing for bradyarrhythmic syncope: role of correlation between symptoms and electrocardiogram findings.

AIMS: To evaluate the risk of syncopal recurrences after pacemaker implantation in a population of patients with syncope of suspected bradyarrhythmic aetiology. METHODS AND RESULTS: Prospective, multicentre, observational registry enrolling 1364 consecutive patients undergoing pacemaker implantation for syncope of bradyarrhythmic aetiology (proven or presumed). Before pacemaker implantation, all patients underwent a cardiac work-up in order to establish the bradyarrhythmic aetiology of syncope. According to the results of the diagnostic work-up, patients were divided into three groups: Group A, patients in whom a syncope-electrocardiogram (ECG) correlation was established (n = 329, 24.1%); Group B, those in whom clinically significant bradyarrhythmias were detected without a documented syncope-ECG correlation (n = 877, 64.3%); and Group C, those in whom bradyarrhythmias were not detected and the bradyarrhythmic origin of syncope remained presumptive (n = 158, 11.6%). During a median follow-up of 50 months, 213 patients (15.6%) reported at least one syncopal recurrence. Patients in Groups B and C showed a significantly higher risk of syncopal recurrences than those in Group A [hazard ratios (HRs): 1.60 and 2.66, respectively, P < 0.05]. Failure to establish a syncope-ECG correlation during diagnostic work-up before pacemaker implantation was an independent predictor of syncopal recurrence on multivariate analysis (HR: 1.90; P = 0.002). CONCLUSION: In selecting patients with syncope of suspected bradyarrhythmic aetiology for pacemaker implantation, establishing a correlation between syncope and bradyarrhythmias maximizes the efficacy of pacing and reduces the risk of syncopal recurrences.

Temporary transvenous cardiac pacing: a survey on current practice.

BACKGROUND: Temporary transvenous cardiac pacing (TTCP) is a standard procedure in current practice, despite limited coverage in consensus guidelines. However, many authors reported several complications associated with TTCP, especially development of infections of cardiac implantable electronic devices (CIED). The aim of this survey was to provide a country-wide picture of current practice regarding TTCP. METHODS: Data were collected using an online survey that was administered to members of the Italian Association of Arrhythmology and Cardiac Pacing. RESULTS: We collected data from 102 physicians, working in 81 Italian hospitals from 17/21 regions. Our data evidenced that different strategies are adopted in case of acute bradycardia with a tendency to limit TTCP mainly to advanced atrioventricular block. However, some centers reported a greater use in elective procedures. TTCP is usually performed by electrophysiologists or interventional cardiologists and, differently from previous reports, mainly by a femoral approach and with nonfloating catheters. We found high inhomogeneity regarding prevention of infections and thromboembolic complications and in post-TTCP management, associated with different TTCP volumes and a strategy for management of acute bradyarrhythmias. CONCLUSION: This survey evidenced a high inhomogeneity in the approaches adopted by Italian cardiologists for TTCP. Further studies are needed to explore if these divergences are associated with different long-term outcomes, especially incidence of CIED-related infections.

Dynamic changes of QTc interval and prognostic significance in takotsubo (stress) cardiomyopathy.

BACKGROUND: Prolonged QT corrected (QTc) intervals are associated with adverse cardiovascular outcomes both in healthy and high-risk populations. Our objective was to evaluate the QTc intervals during a takotsubo cardiomyopathy (TTC) episodes and their potential prognostic role. HYPOTHESIS: Dynamic changes of QTc interval during hospitalization for TTC could be associated with outcome at follow-up. METHODS: Fifty-two consecutive patients hospitalized for TTC were enrolled. Twelve-lead electrocardiogram (ECG) was performed within 3 h after admission and repeated after 3, 5, and 7 days. Patients were classified in 2 groups: group 1 presented the maximal QTc interval length at admission and group 2 developed maximal QTc interval length after admission. RESULTS: Mean admission QTc interval was 493 ± 71 ms and mean QTc peak interval was 550 ± 76 ms (P < 0.001). Seventeen (33%) patients were included in group 1 and 35 (67%) patients in group 2. There were no differences for cardiovascular risk factors and in terms of ECG findings such as ST elevation, ST depression, and inverted T waves. Rates of adverse events during hospitalization among patients of group 1 and 2 were different although not significantly (20% vs 6%, P = 0.22). After 647 days follow-up, patients of group 1 presented higher risk of cardiovascular rehospitalization (31% vs 6%, P = 0.013; log-rank, P < 0.01). At multivariate analysis, including age and gender, a prolonged QTc interval at admission was significantly associated with higher risk of rehospitalization at follow-up (hazard ratio: 1.07 every 10 ms, 95% confidence interval: 1.003-1.14, P = 0.04). CONCLUSIONS: Prolonged QTc intervals at admission during a TTC episode could be associated with a higher risk of cardiovascular rehospitalization at follow-up. Dynamic increase of QTc intervals after admission are characterized by a trend toward a better prognosis.

Catecholaminergic polymorphic ventricular tachycardia associated with sinus node dysfunction and junctional rhythm: Case report and literature review.

We report the case of a 38-year-old woman with history of syncope and polymorphic ventricular tachycardia; tachycardia was inducible at exercise stress test, not at electrophysiologic study. Phases of QT prolongation were found at ambulatory electrocardiogram monitoring. The woman came to our attention for periodic control of implantable loop recorder. Rest electrocardiogram at admission unexpectedly showed sinus bradycardia, junctional rhythm, and ventricular premature beats. Furthermore, loop recorder control revealed a short run of bidirectional tachycardia, not associated with syncope. Final diagnosis was catecholaminergic polymorphic ventricular tachycardia, and the patient was implanted with an ICD. We therefore report an unusual case of bidirectional ventricular tachycardia associated with sinus node dysfunction and junctional escape rhythm. We hypothesize that a diffuse dysfunction of cardiac conduction system, presumably based on diffuse disorder of calcium handling, may be responsible for both sinus node failure and ventricular tachycardia.

Left Atrial Appendage Closure Guided by 3D Printed Cardiac Reconstruction: Emerging Directions and Future Trends.

INTRODUCTION: Percutaneous left atrial appendage (LAA) occlusion has emerged as an alternative therapeutic approach to medical therapy for stroke prevention in patients with atrial fibrillation. 3D printing is a novel technology able to create a patient specific model of any given anatomical portion of the heart. RESULTS: Herein we report the first 2 cases of LAA occlusion procedure with 2 different systems, the Wave Crest device (Coherex Medical, Inc., USA) and the Amplatzer Amulet device (St. Jude Medical, St. Paul, MN, USA), in which a 3D printed LAA model (Care Tronik, Prato, Italy) was used in a rehearse phase. Both patients had history of paroxysmal AF and previous transient ischemic attack (TIA) occurred during oral anticoagulation with correct INR. In the first patient the occlusive device was positioned within the LAA after a rehearse occlusion using the 3D printed LAA plus a 27 mm Coherex Wavecrest device, demonstrating a good compression and sealing, particularly considering a proximal lobe of the appendage. In the second patient an attempt with the 27 mm Amulet device delivered within the 3D printed LAA, based on angiography and transesophageal echocardiographic (TEE), revealed insufficient covering of the proximal part of LAA vestibule; the device was released only after a second test with the 31 mm Amulet demonstrating a good sealing. CONCLUSION: These 2 cases demonstrated that 3D model could help in finding the correct position within LAA, sizing the device and guiding the choice of the closure device despite the measurements provided by angiography and TEE.

Early recurrence of atrial fibrillation after catheter ablation with left atrial fibrosis identified at cardiac magnetic resonance by late gadolinium enhancement.

In patients with atrial fibrillation (AF), extensive atrial tissue fibrosis identified by delayed enhancement magnetic resonance imaging has been associated with early recurrence of AF after catheter ablation. We present a case of a patient with extensive atrial fibrosis and AF recurrence.The study of late gadolinium enhancement with cardiac magnetic resonance imaging in patients with AF could be a valuable noninvasive tool for the selection of patients suitable for successful catheter ablation.

Clinical follow-up of atrial-fibrillation patients treated with novel oral anti-coagulants: A multi-disciplinary consensus from the Apulia section of the Italian Association of Hospital Cardiologists (ANMCO).

The clinical use of novel oral anti-coagulant (NOAC) drugs is actually regulated in Italy by bureaucratic restrictions; clinical prescription of NOACs preliminarily requires an online prescription plan which should be compiled on the Italian Drug Agency website. The prescription plan has 1-year validity and clinical condition of the patient treated with NOACs should be reassessed at 1-year prescription renewal. Only few specialists are presently allowed to prescribe NOACs: cardiologists, geriatricians, neurologists, hematologists and internists; general practitioners (GPs) are not currently allowed to prescribe NOACs, although they are the most in proximity with the patient. An even more complex issue is the pertinence of clinical follow-up of patients prescribed with NOACs (control of possible interactions with any new drug, periodical assessment of renal function, management of dose assumption mistakes or drug suspension for occurring surgery before hospitalization for any planned intervention). International statements partially indicate when and how periodical laboratory and clinical follow-up should be performed, but such statements do not often comply with local regulations and do not always take in due consideration the local criticalities and prescription limitations. In May 2015, the regional section of the Italian Association of Hospital Cardiologists of Apulia (ANMCO) therefore convened local representative champions of medical professionals potentially involved in prescription of NOACs, clinical management and follow-up of patients prescribed with NOACs. A final consensus conference formulated a possible shared diagnostic and therapeutic pathway for the clinical management and follow-up of patients assuming NOACs for atrial fibrillation.