Induction of ventricular fibrillation during programmed ventricular stimulation in a patient with CASQ2 heterozygous mutation.

INTRODUCTION: We report the case of a 37-year-old male athlete, who developed during exercise atrial and ventricular arrhythmias. No structural heart disease. RESULTS: Invasive programmed ventricular stimulation induced ventricular fibrillation. A heterozygous mutation in the CASQ2 gene (c.775G>T, p.E259X) was found. CONCLUSIONS: The findings in our patient may suggest some increased ventricular excitability using programmed ventricular stimulation in CASQ2 polymorphic ventricular tachycardia patients.

A Clinical Diagnostic Test for Calcium Release Deficiency Syndrome.

Importance: Sudden death and cardiac arrest frequently occur without explanation, even after a thorough clinical evaluation. Calcium release deficiency syndrome (CRDS), a life-threatening genetic arrhythmia syndrome, is undetectable with standard testing and leads to unexplained cardiac arrest. Objective: To explore the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS. Design, Setting, and Participants: An international, multicenter, case-control study including individual cases of CRDS, 3 patient control groups (individuals with suspected supraventricular tachycardia; survivors of unexplained cardiac arrest [UCA]; and individuals with genotype-positive catecholaminergic polymorphic ventricular tachycardia [CPVT]), and genetic mouse models (CRDS, wild type, and CPVT were used to define the cellular mechanism) conducted at 10 centers in 7 countries. Patient tracings were recorded between June 2005 and December 2023, and the analyses were performed from April 2023 to December 2023. Intervention: Brief tachycardia and a subsequent pause (either spontaneous or mediated through cardiac pacing). Main Outcomes and Measures: Change in QT interval and change in T-wave amplitude (defined as the difference between their absolute values on the postpause sinus beat and the last beat prior to tachycardia). Results: Among 10 case patients with CRDS, 45 control patients with suspected supraventricular tachycardia, 10 control patients who experienced UCA, and 3 control patients with genotype-positive CPVT, the median change in T-wave amplitude on the postpause sinus beat (after brief ventricular tachycardia at ≥150 beats/min) was higher in patients with CRDS (P < .001). The smallest change in T-wave amplitude was 0.250 mV for a CRDS case patient compared with the largest change in T-wave amplitude of 0.160 mV for a control patient, indicating 100% discrimination. Although the median change in QT interval was longer in CRDS cases (P = .002), an overlap between the cases and controls was present. The genetic mouse models recapitulated the findings observed in humans and suggested the repolarization response was secondary to a pathologically large systolic release of calcium from the sarcoplasmic reticulum. Conclusions and Relevance: There is a unique repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause in CRDS cases and mouse models, which is absent from the controls. If these findings are confirmed in larger studies, this easy to perform maneuver may serve as an effective clinical diagnostic test for CRDS and become an important part of the evaluation of cardiac arrest.

Transmural APD heterogeneity determines ventricular arrhythmogenesis in LQT8 syndrome: Insights from Bidomain computational modeling.

Long QT Syndrome type 8 (LQT8) is a cardiac arrhythmic disorder associated with Timothy Syndrome, stemming from mutations in the CACNA1C gene, particularly the G406R mutation. While prior studies hint at CACNA1C mutations' role in ventricular arrhythmia genesis, the mechanisms, especially in G406R presence, are not fully understood. This computational study explores how the G406R mutation, causing increased transmural dispersion of repolarization, induces and sustains reentrant ventricular arrhythmias. Using three-dimensional numerical simulations on an idealized left-ventricular model, integrating the Bidomain equations with the ten Tusscher-Panfilov ionic model, we observe that G406R mutation with 11% and 50% heterozygosis significantly increases transmural dispersion of repolarization. During S1-S4 stimulation protocols, these gradients facilitate conduction blocks, triggering reentrant ventricular tachycardia. Sustained reentry pathways occur only with G406R mutation at 50% heterozygosis, while neglecting transmural heterogeneities of action potential duration prevents stable reentry, regardless of G406R mutation presence.

Characterization and natural history of patients with LMNA-related dilated cardiomyopathy in the phase 3 REALM-DCM trial.

AIMS: LMNA-related dilated cardiomyopathy (DCM) is a rare disease with an incompletely defined phenotype. The phase 3 REALM-DCM trial evaluated a potential disease-modifying therapy for LMNA-related DCM but was terminated due to futility without safety concern. This study utilized pooled data from REALM-DCM to descriptively characterize the phenotype and progression of LMNA-related DCM in a contemporary cohort of patients using common heart failure (HF) measures. METHODS: REALM-DCM enrolled patients with stable LMNA-related DCM, an implanted cardioverter defibrillator or cardiac resynchronization therapy defibrillator, and New York Heart Association (NYHA) Class II/III HF symptoms. RESULTS: Between 2018 and 2022, 77 patients took part in REALM-DCM. The median patient age was 53 years (range: 23-72), and 57% were male. Overall, 88% of patients had a pathogenic or likely pathogenic LMNA variant, and 12% had a variant of uncertain significance with a concordant phenotype. Among patients with confirmed sequencing, 55% had a missense variant. Atrial fibrillation was present in 60% of patients; 79% of all patients had NYHA Class II and 21% had NYHA Class III HF symptoms at baseline. Median (range) left ventricular ejection fraction (LVEF), 6 min walk test (6MWT) distance, Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score and N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration at baseline were 42% (23-62), 403 m (173-481), 67 (18-97) and 866 pg/mL (57-5248), respectively. LVEF, 6MWT distance and KCCQ-OS score were numerically lower in patients who had NYHA Class III versus II symptoms at baseline (LVEF: 38% vs. 43%; 6MWT distance: 326 vs. 413 m; and KCCQ-OS score: 43 vs. 70), whereas NT-proBNP concentration was higher (1216 vs. 799 pg/mL). Median follow-up was 73 weeks (range: 0.4-218; 73 in NYHA Class II and 75 in NYHA Class III). Patients displayed variable change from baseline in 6MWT, KCCQ-OS and NT-proBNP values during follow-up. Overall, 25% of patients experienced ventricular tachycardia, and 8% had ventricular fibrillation. Ten (13%) patients met the composite endpoint of worsening HF (adjudicated HF-related hospitalization or urgent care visit) or all-cause death; six had NYHA Class II and four had NYHA Class III at baseline. All-cause mortality occurred in 6 (8%) patients; three had NYHA Class II and three had NYHA Class III symptoms at baseline. CONCLUSIONS: Findings confirm the significant morbidity and mortality associated with LMNA-related DCM despite the standard of care management. Typical measures of HF, including 6MWT distance, KCCQ-OS score and NT-proBNP concentration, were variable but correlated with NYHA class. An unmet treatment need remains among patients with LMNA-related DCM. NCT03439514.

Real-world candidacy to mavacamten in a contemporary hypertrophic obstructive cardiomyopathy population.

AIMS: In the EXPLORER-HCM trial, mavacamten reduced left ventricular outflow tract obstruction (LVOTO) and improved functional capacity of symptomatic hypertrophic obstructive cardiomyopathy (HOCM) patients. We sought to define the potential use of mavacamten by comparing real-world HOCM patients with those enrolled in EXPLORER-HCM and assessing their eligibility to treatment. METHODS AND RESULTS: We collected information on HOCM patients followed up at 25 Italian HCM outpatient clinics and with significant LVOTO (i.e. gradient ≥30 mmHg at rest or ≥50 mmHg after Valsalva manoeuvre or exercise) despite pharmacological or non-pharmacological therapy. Pharmacological or non-pharmacological therapy resolved LVOTO in 1044 (61.2%) of the 1706 HOCM patients under active follow-up, whereas 662 patients (38.8%) had persistent LVOTO. Compared to the EXPLORER-HCM trial population, these real-world HOCM patients were older (62.1 ± 14.3 vs. 58.5 ± 12.2 years, p = 0.02), had a lower body mass index (26.8 ± 5.3 vs. 29.7 ± 4.9 kg/m2 , p < 0.0001) and a more frequent history of atrial fibrillation (21.5% vs. 9.8%, p = 0.027). At echocardiography, they had lower left ventricular ejection fraction (LVEF, 66 ± 7% vs. 74 ± 6%, p < 0.0001), higher left ventricular outflow tract gradients at rest (60 ± 27 vs. 52 ± 29 mmHg, p = 0.003), and larger left atrial volume index (49 ± 16 vs. 40 ± 12 ml/m2 , p < 0.0001). Overall, 324 (48.9%) would have been eligible for enrolment in the EXPLORER-HCM trial and 339 (51.2%) for treatment with mavacamten according to European guidelines. CONCLUSIONS: Real-world HOCM patients differ from the EXPLORER-HCM population for their older age, lower LVEF and larger atrial volume, potentially reflecting a more advanced stage of the disease. About half of real-world HOCM patients were found eligible to mavacamten.

The Structural-Functional Crosstalk of the Calsequestrin System: Insights and Pathological Implications.

Calsequestrin (CASQ) is a key intra-sarcoplasmic reticulum Ca2+-handling protein that plays a pivotal role in the contraction of cardiac and skeletal muscles. Its Ca2+-dependent polymerization dynamics shape the translation of electric excitation signals to the Ca2+-induced contraction of the actin-myosin architecture. Mutations in CASQ are linked to life-threatening pathological conditions, including tubular aggregate myopathy, malignant hyperthermia, and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The variability in the penetrance of these phenotypes and the lack of a clear understanding of the disease mechanisms associated with CASQ mutations pose a major challenge to the development of effective therapeutic strategies. In vitro studies have mainly focused on the polymerization and Ca2+-buffering properties of CASQ but have provided little insight into the complex interplay of structural and functional changes that underlie disease. In this review, the biochemical and structural natures of CASQ are explored in-depth, while emphasizing their direct and indirect consequences for muscle Ca2+ physiology. We propose a novel functional classification of CASQ pathological missense mutations based on the structural stability of the monomer, dimer, or linear polymer conformation. We also highlight emerging similarities between polymeric CASQ and polyelectrolyte systems, emphasizing the potential for the use of this paradigm to guide further research.

Unexpected impairment of INa underpins reentrant arrhythmias in a knock-in swine model of Timothy syndrome.

Timothy syndrome 1 (TS1) is a multi-organ form of long QT syndrome associated with life-threatening cardiac arrhythmias, the organ-level dynamics of which remain unclear. In this study, we developed and characterized a novel porcine model of TS1 carrying the causative p.Gly406Arg mutation in CACNA1C, known to impair CaV1.2 channel inactivation. Our model fully recapitulated the human disease with prolonged QT interval and arrhythmic mortality. Electroanatomical mapping revealed the presence of a functional substrate vulnerable to reentry, stemming from an unforeseen constitutional slowing of cardiac activation. This signature substrate of TS1 was reliably identified using the reentry vulnerability index, which, we further demonstrate, can be used as a benchmark for assessing treatment efficacy, as shown by testing of multiple clinical and preclinical anti-arrhythmic compounds. Notably, in vitro experiments showed that TS1 cardiomyocytes display Ca2+ overload and decreased peak INa current, providing a rationale for the arrhythmogenic slowing of impulse propagation in vivo.

Diagnóstico del síndrome de QT largo: valor del ortostatismo / Diagnosis of long QT syndrome: time to stand up

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Impact of the Bolsa Família Program on energy, macronutrient, and micronutrient intakes: Study of the Northeast and Southeast / Impacto do Programa Bolsa Família no consumo de energia, macro e micronutrientes: estudo das regiões Nordeste e Sudeste

ABSTRACT Objective: To assess the impact of the Bolsa Família Program on the energy and nutrient intakes of beneficiaries from the Brazilian Northeast and Southeast regions. Methods: The study used data from the 2008-2009 Pesquisa de Orçamento Famíliar, which assessed individual food intake on two nonconsecutive days of individuals aged more than 10 years. Based the personal information booklet, food intake values were transformed into nutritional values (energy and nutrients). Analysis of the impact measure was preceded by propensity score matching, a technique that matches some socioeconomic characteristics of beneficiaries and nonbeneficiaries. Once the score was calculated, the impact of the Bolsa Família Program was estimated by nearest neighbor matching. Results: The program increased energy and macronutrient intakes and decreased calcium and vitamin A, D, E, and C intakes of adolescent beneficiaries in both regions. Adult beneficiaries from the Southeast region increased their fiber, iron, and selenium intakes, and those from the Northeast region decreased their energy, lipid, added sugar, sodium, zinc, vitamin E, and pyridoxine intakes. Conclusion: The results show a positive impact of the program on the energy and macronutrient intakes, and a negative impact on the intakes of most study micronutrients, especially in adolescents, which reinforce the importance of implementing intersectoral actions to improve the nutritional quality of the Bolsa Família Program beneficiaries' diet.

RESUMO Objetivo: Avaliar o impacto do Programa Bolsa Família no consumo de energia e nutrientes de beneficiários das regiões Nordeste e Sudeste do Brasil. Métodos: Utilizou-se dados da Pesquisa de Orçamento Famíliar realizada em 2008-2009, que avaliou o consumo alimentar individual de dois dias não consecutivos de indivíduos acima de 10 anos. Com base nas informações da caderneta pessoal, transformou-se os valores de consumo de alimentos em valores nutricionais (energia e nutrientes). A análise da medida de impacto foi precedida de técnica propensity score que assemelhou os indivíduos beneficiários e os não beneficiários em relação ao conjunto de características socioeconômicas. Após o cálculo do escore, estimou-se o impacto do Programa Bolsa Família por meio do algoritmo de pareamento do vizinho mais próximo. Resultados: O impacto do programa traduziu-se no maior consumo de energia e macronutrientes e no menor consumo de cálcio e vitaminas A, D, E e C entre adolescentes beneficiários em ambas as regiões. Em relação aos adultos, observou-se maior consumo de fibra, ferro e selênio na região Sudeste e menor consumo de energia, lipídeos, açúcar de adição, sódio, zinco, vitamina E e piridoxina no Nordeste. Conclusão: Os resultados retratam impacto positivo do programa sobre o consumo de energia e macronutrientes e impacto negativo sobre o consumo da maioria dos micronutrientes analisados, especialmente em relação aos adolescentes, o que reforça a importância da adoção de ações intersetoriais para melhoria da qualidade nutricional da alimentação dos participantes do programa.

Genética y arritmias: aplicaciones diagnósticas y pronósticas / Genetics and arrhythmias: diagnostic and prognostic applications

En este artículo de revisión se comentan las bases genéticas de la parada cardiaca, prestando especial atención a las canalopatías cardiacas y la miocardiopatía ventricular derecha. Revisamos el uso apropiado de las pruebas genéticas para pacientes en quienes se sospecha de arritmias cardiacas hereditarias, subrayando la importancia de la mayoría de las correlaciones genotipo-fenotipo para la estratificación del riesgo. El artículo presenta también las opiniones más recientes sobre los criterios diagnósticos y los diagramas de flujo para el tratamiento de los pacientes con enfermedades arritmogénicas hereditarias (AU)

This review article discusses the genetic bases of cardiac arrest with a specific focus on cardiac channelopathies and right ventricular cardiomyopathy. We review the appropriate use of genetic testing in those patients suspected to have inherited cardiac arrhythmias, highlighting the importance of most genotype-phenotype correlations for risk stratification. The article also presents the most recent views on diagnostic criteria and flowcharts for treatment of patients with inherited arrhythmogenic diseases (AU)

Mutación de la proteína de Desmosoma Plakofilina-2 en una familia guanacasteca / Mutation of the protein Desmosoma plakofilina 2 in a family guanacasteca

Se reporta una mutación en la plakofilina-2, proteína del Desmosoma miocárdico, encontrada en dos pacientes de una misma familia procedente de Guanacaste, Costa Rica, portadores de Displasia/cardiomiopatía arritmogénica del ventrículo derecho sintomática (ARVC) y tratados con cariodesfibrilador implantable.

Nuevas perspectivas en el síndrome de QT largo / New insights into the long-QT syndrome

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Estrategias actuales para reducir el impacto de las enfermedades cardiovasculares en la mujer / Current strategies to diminish the impact of cardiovascular diseases in women

Recientemente, la European Society of Cardiology (ESC) ha promovido el programa «Women at Heart» con el objetivo de organizar iniciativas dirigidas a potenciar la investigación y la educación en el campo de las enfermedades cardiovasculares en la mujer. El análisis de los datos procedentes de los estudios Euro Heart Surveys proporciona comparaciones de las diferencias de sexo en las diferentes enfermedades y su tratamiento a través de Europa. Se ha organizado una conferencia de principios con el objetivo de sintetizar la información más actual desde una perspectiva europea, identificar las lagunas científicas y diseñar estrategias para modificar las ideas falsas relativas a las enfermedades cardiovasculares en mujeres. Además se pretende mejorar la estratificación del riesgo, el diagnóstico y el tratamiento desde una perspectiva del sexo, y aumentar la representación de las mujeres en los ensayos clínicos. En el European Heart Journal se ha publicado un documento de consenso de dicha conferencia de principios. Es preciso emprender actividades sinérgicas en el ámbito europeo con el apoyo de las sociedades científicas nacionales, las instituciones europeas, las autoridades nacionales de asistencia sanitaria, las asociaciones de pacientes y las fundaciones. El compromiso del comité de la ESC es que, a través de Europa, estas iniciativas contribuyan a una mayor concienciación de que las enfermedades cardiovasculares son la causa primaria de muerte en la mujer y mejoren los conocimientos sobre los factores de riesgo, la forma de presentación y el tratamiento de las enfermedades cardiovasculares en la mujer

The European Society of Cardiology (ESC) has recently promoted the "Women at Heart" program in order to organize initiatives targeted at promoting research and education in the field of cardiovascular diseases in women. Comparisons of the gender differences in specific disease and treatment trends across Europe are provided by analyzing data from the Euro Heart Surveys. A Policy Conference has been organized with the objective to summarize the state of the art from an European perspective, to identify the scientific gaps and to delineate the strategies for changing the misperception of cardiovascular diseases in women, improving risk stratification, diagnosis, and therapy from a gender perspective and increasing women representation in clinical trials. A Statement from the Policy Conference has been provided and published in the European Heart Journal. Synergic activities should be undertaken at European level with the support of national scientific societies, European institutions, national health care authorities, patients' associations, and foundations. The commitment of the Board of the ESC is that these initiatives contribute to increase the awareness across Europe that cardiovascular disease is the primary cause of death in women and to improve the knowledge of risk factors, presentation and treatment of cardiovascular diseases in women