Papers by Raffaella Bloise
Circulation, Nov 8, 2022
Introduction: Patients with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) may expe... more Introduction: Patients with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) may experience life-threatening arrhythmic events (LAE) despite standard-of-care treatment with beta-blockers (BB), but risk stratification is not well defined. Hypothesis: Both clinical and genetic risk factors predispose to BB failure, including the class of BBs (β1-selective vs. non-selective). Methods: LAE was defined as the composite of sudden cardiac death, aborted cardiac arrest, or hemodynamically non-tolerated ventricular tachycardia. We fitted a Cox proportional hazards regression model with multiple events during BB treatment only with the following explanatory covariates: 1) LAE before diagnosis, 2) unexplained syncope before diagnosis, 3) genotype, and 4) type of BB (as time-dependent variable). Results: We included n=238 CPVT patients: n=135 (57%) probands, n=134 (56%) females, n=216 (91%) RYR2, n=10 (4%) CASQ2, n=5 (2%) RYR2-Loss-of-Function, n=4 (2%) TRDN and n=3 (1%) TECRL. Before the diagnosis, 48/238 (20%) patients experienced an LAE, while 110/238 (46%) patients experienced an unexplained syncope. During a mean follow-up of 9.7±7.6 years of treatment with BB only, 35/238 (15%) patients experienced one or more LAEs (annual rate 4.0%, 95% CI: 3.1%-5.0%), with a mean of 2.1±2.4 LAEs per patient. Multivariable analysis with multiple events at follow-up showed that LAE before diagnosis (HR 3.9; 95%CI: 2.3-6.8; p<0.001), syncope before diagnosis (HR 2.7; 95%CI: 1.5-5.0; p=0.001), TRDN mutations (HR 10.9; 95%CI: 4.2-28.0; p<0.001) and use of β1-selective BBs (HR 3.0; 95%CI: 1.7-5.3; p<0.001) were significantly associated with the occurrence of LAE (Figure). Conclusions: In patients with CPVT, history of LAE and/or unexplained syncope before diagnosis, TRDN mutations and the use of selective BBs are independent risk factors for the occurrence of multiple LAEs at follow-up during BB treatment.
Circulation, Oct 16, 2007
The conclusive diagnosis of Brugada Syndrome (BrS) is established in patients (pts) with spontane... more The conclusive diagnosis of Brugada Syndrome (BrS) is established in patients (pts) with spontaneous type 1 ECG or in carriers of a loss of function SCN5A mutation. We carried out a systematic analysis of ECG recordings in BrS pts to test the hypothesis that the presence of intraventricular (Intra-Ven) and atrioventricular (A-Ven) conduction delay is the distinguishing common feature of pts with SCN5A mutations (Mut+) and in pts with a spontaneous type 1 ECG pattern (spont-ECG). We assessed the following 5 ECG parameters: late potentials (quantified as RMS at 40 Hz), aVR sign (relative size of the R and q waves in aVR), QRS complex fragmentation (defined as an additional R′ or notching of the of S wave), PQ and QRS duration. We studied 200 consecutive BrS pts to define whether the prevalence of ECG markers correlate with 1) the presence of a SCN5A mutation (Mut+) or 2) the presence of a spontaneous type 1 pattern ECG (spont-ECG). Results are summarized in the table . Interestingly, Mut+ not only presented prolonged PQ (p<0.003 vs Mut÷) as previously reported but more significantly they showed the presence of abnormal markers of intraventricular conduction (QRS duration, aVR sign and late potentials). Similarly, also the presence of a spont-ECG was associated with prolonged PQ and QRS intervals and with late potentials. Based on our ECG analysis we propose that Brugada syndrome is a disease characterized by impairment of A-Ven and Intra-Ven conduction, the presence of a mutation in the SCN5A gene and, the presence of a spontaneous type 1 ECG identify patients with accentuated conduction defects. These findings suggest that the presence of interventricular conduction delay is a landmark of BrS and should be considered as diagnostic markers in BrS.
Circulation, Nov 8, 2022
Introduction: The effectiveness of implantable cardioverter-defibrillators (ICDs) in reducing mor... more Introduction: The effectiveness of implantable cardioverter-defibrillators (ICDs) in reducing mortality in patients with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is debated.Hypothesis. The ICD confers survival benefit in patients with CPVT. Methods: We included n=238 genotype-proven CPVT patients, of whom 91 (38%) had an ICD implanted. All patients were treated with beta-blocker (BB) monotherapy. Survival probability at the occurrence of a first Life-threatening Arrhythmic Event (LAE, defined as: sudden cardiac death, aborted cardiac arrest or hemodynamically non-tolerated ventricular tachycardia) was compared between ICD carriers and non-ICD carriers. In ICD carriers, the benefit-to-harm ratio (rate of appropriate shocks on LAE over rate of major complications) was investigated. Results: During 1,643 person-years of follow-up, 35/238 (15%) patients experienced a first LAE on BB monotherapy (annual LAE rate 2.1%, 95%CI: 1.5-3.0%). Of the 35 individuals who experienced an LAE, 23 patients had an ICD when the LAE occurred, and all survived after ICD shock. Of the remaining 12 patients who were not carriers of an ICD, 4/12 (33%) died suddenly, 2/12 (17%) survived but suffered anoxic brain injury, while 6/12 (50%) survived without consequences. The probability of dying at the occurrence of a first LAE was 25-fold higher (OR: 24.9, 95% CI: 1.2-513.0; p=0.037) in patients without an ICD, as compared to patients with an ICD. Major complications occurred in 17/91 (19%) patients with an ICD (2.6% per year, 95%CI: 1.5%-4.1%). Comparing the rate of major complication to the rate of appropriate ICD shocks on LAE (LAE rate 5.2% per year, 95%CI: 3.5-7.4%), the benefit-to-harm ratio was 2, favoring the benefit of ICD therapy. Conclusion: The ICD conferred a significant survival benefit in terms of arrhythmic mortality at the occurrence of the first LAE in BB monotherapy.
European Heart Journal, Oct 1, 2022
Giornale Italiano di Aritmologia e Cardiostimolazione, Apr 1, 2011
Circulation, Nov 8, 2022
Background: Based on the genetic background, Catecholaminergic Polymorphic Ventricular Tachycardi... more Background: Based on the genetic background, Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) has been recently classified in “typical” (RYR2 and CASQ2) and “atypical” (TRDN, TECRL, CALM1-3, RYR2 loss-of-function [RYR2-LoF]), but genotype-specific outcome is unknown.Hypothesis. We aimed to describe genotype-specific outcomes of patients with “typical” and “atypical” CPVT before treatment. Methods: Patients were classified in: 1) “Typical” CPVT (RYR2, CASQ2); 2) “Atypical” CPVT (TRDN, TECRL, CALM1-3 and RYR2-LoF). We assessed the occurrence of a first life-threatening arrhythmic event (LAE; sudden cardiac death, aborted cardiac arrest or hemodynamically non-tolerated ventricular tachycardia) before the initiation of therapy. We used the Kaplan-Meier life-table method and the log-rank test to compare the cumulative probability of experiencing a first LAE by the age of 40 years in the absence of treatment. Results: We included 238 patients (56% females, median age 14 years [IQR: 9-28 years]): 226/238 (95%) patients with “typical” CPVT (216 RYR2, 10 CASQ2), and 12/238 (5%) patients with “atypical” CPVT (5 RYR2-LoF, 4 TRDN, 3 TECRL). Interestingly, in 47% of probands the RYR2 variant was likely de novo. No patients experienced an LAE in the first year of age, but patients with atypical CPVT had an increased probability to experience a LAE by the age of 5 years (3/5, 60%), as compared with patients with typical CPVT (2/43, 5%; OR 30.8; p=0.003). In half of patients with LAE (23/48; 48%), the occurrence of LAE was the first clinical manifestation of CPVT. Overall, the probability to experience an LAE by the age of 40 years in the absence of treatment was higher in patients with atypical CPVT (100%), as compared to patients with typical CPVT (39%; p=0.003, Figure). Conclusions: Patients with atypical variants of CPVT are at increased risk to experience an LAE before treatment, especially during early childhood.
European Heart Journal, Oct 1, 2022
European Heart Journal, Oct 1, 2022
European Heart Journal, Nov 1, 2020
Background: Type 1 Long QT Syndrome (LQT1) is an arrhythmogenic disorder, caused by loss-of-funct... more Background: Type 1 Long QT Syndrome (LQT1) is an arrhythmogenic disorder, caused by loss-of-function mutations on KCNQ1 gene, coding for Kv7.1 potassium channel. Although LQT1 is described as the most benign form of LQTS, patients still experience arrhythmic events and there is an unmet need for personalized risk stratification. Attempts have been made to correlate the location of mutations with outcome, but the results are unequivocal. Purpose: We provide in the present study a new mutation site-specific risk profile obtained from a large cohort of LQT1 patients. Methods: We gathered data on 963 patients with the diagnosis of LQT1 and divided the Kv7.1 channel into 5 functional regions: the N-terminus (NT), the voltage sensor (VS, including transmembrane segments S1 to S4), the cytoplasmic loops (CL), the pore (PO, including the transmembrane segments S5, S6 and the S5-S6 extracellular linker), the C-terminus (CT). Results: We studied 963 LQT1 patients: 518 (54%) females; average age 20±17 years; mean QTc at baseline ECG 465±38ms. During a mean follow-up of 8±7 years, 172 (18%) patients experienced arrhythmic events:
Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases, Oct 1, 2011
potentials and twitch force were measured in muscle strips obtained from patients and controls. O... more potentials and twitch force were measured in muscle strips obtained from patients and controls. Of the 36 patients, 25 presented with chronic muscle weakness of varying degrees, up to wheelchair-dependence. The weakness was associated with intracellular Na + overload and edema. Older patients revealed a vacuolar myopathy or a progressive muscular dystrophy. Weakness , intracellular Na + overload and edema were increased and further raised by cooling and glucose/insulin, and almost completely normalized by 4 weeks of treatment with the carbonic anhydrase inhibitor acetazolamide (Jurkat-Rott et al., 2009). In vitro, the chronic weakness correlated to membrane depolariza-tion, and acetazolamide repolarized the membrane and restored force. We conclude that membrane depolarization associated with intracellular Na + overload and edema causes both episodic and permanent muscle weakness. The chronic weakness is reversible in muscles which show mild or only moderate fatty de-generation. Acetazolamide has direct and beneficial effects on weak muscle and can markedly improve both forms of weakness. In addition, we tested whether the edema in Duchenne muscular dystrophy (DMD) is caused by an osmotic effect due to increased myoplasmic Na + content or by inflammation. The muscle edema was quantified on STIR images using background noise as reference. Na
European Heart Journal, Nov 1, 2020
European Heart Journal, Nov 1, 2020
European Heart Journal, Aug 1, 2018
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Papers by Raffaella Bloise