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1. Molecular mechanisms underlying the beneficial effects of exercise and dietary interventions in the prevention of cardiometabolic diseases.

Author

Forte M, Rodolico D, Ameri P, Catalucci D, Chimenti C, Crotti L, Schirone L, Pingitore A, Torella D, Iacovone G, Valenti V, Schiattarella GG, Perrino C, and Sciarretta S

Subjects
Animals, Humans, Exercise, Caloric Restriction, Life Style, Cardiovascular System, Cardiovascular Diseases prevention & control
Abstract

Cardiometabolic diseases still represent a major cause of mortality worldwide. In addition to pharmacological approaches, lifestyle interventions can also be adopted for the prevention of these morbid conditions. Lifestyle changes include exercise and dietary restriction protocols, such as calorie restriction and intermittent fasting, which were shown to delay cardiovascular ageing and elicit health-promoting effects in preclinical models of cardiometabolic diseases. Beneficial effects are mediated by the restoration of multiple molecular mechanisms in heart and vessels that are compromised by metabolic stress. Exercise and dietary restriction rescue mitochondrial dysfunction, oxidative stress and inflammation. They also improve autophagy. The result of these effects is a marked improvement of vascular and heart function. In this review, we provide a comprehensive overview of the molecular mechanisms involved in the beneficial effects of exercise and dietary restriction in models of diabetes and obesity. We also discuss clinical studies and gap in animal-to-human translation., (Copyright © 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Published
2023
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2. The role of mitochondrial dynamics in cardiovascular diseases.

Author

Forte M, Schirone L, Ameri P, Basso C, Catalucci D, Modica J, Chimenti C, Crotti L, Frati G, Rubattu S, Schiattarella GG, Torella D, Perrino C, Indolfi C, and Sciarretta S

Subjects
Humans, Mitochondrial Dynamics, Myocardium, Brain Ischemia, Cardiovascular Diseases, Stroke
Abstract

The process of mitochondrial dynamics is emerging as a core player in cardiovascular homeostasis. This process refers to the co-ordinated cycles of biogenesis, fusion, fission and degradation to which mitochondria constantly undergo to maintain their integrity, distribution and size. These mechanisms represent an early response to mitochondrial stress, confining organelle portions that are irreversibly damaged and preserving mitochondrial function. Accumulating evidence demonstrates that impairment in mitochondrial dynamics leads to myocardial damage and cardiac disease progression in a variety of disease models, including pressure overload, ischaemia/reperfusion and metabolic disturbance. These findings suggest that modulation of mitochondrial dynamics may be considered as a valid therapeutic strategy in cardiovascular diseases. In this review, we discuss the current evidence about the role of mitochondrial dynamics in cardiac pathophysiology, with a particular focus on the mechanisms underlying the development of cardiac hypertrophy and heart failure, metabolic and genetic cardiomyopathies, ischaemia/reperfusion injury, atherosclerosis and ischaemic stroke. LINKED ARTICLES: This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc., (© 2020 The British Pharmacological Society.)

Published
2021
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3. Sex-Related Differences in Cardiac Channelopathies: Implications for Clinical Practice.

Author

Asatryan B, Yee L, Ben-Haim Y, Dobner S, Servatius H, Roten L, Tanner H, Crotti L, Skinner JR, Remme CA, Chevalier P, Medeiros-Domingo A, Behr ER, Reichlin T, Odening KE, and Krahn AD

Subjects
Female, Humans, Male, Sex Factors, Cardiovascular Diseases genetics, Channelopathies genetics
Abstract

Sex-related differences in prevalence, clinical presentation, and outcome of cardiac channelopathies are increasingly recognized, despite their autosomal transmission and hence equal genetic predisposition among sexes. In congenital long-QT syndrome, adult women carry a greater risk for Torsades de pointes and sudden cardiac death than do men. In contrast, Brugada syndrome is observed predominantly in adult men, with a considerably higher risk of arrhythmic sudden cardiac death in adult men than in women. In both conditions, the risk for arrhythmias varies with age. Sex-associated differences appear less evident in other cardiac channelopathies, likely a reflection of their rare(r) occurrence and our limited knowledge. In several cardiac channelopathies, sex-specific predictors of outcome have been identified. Together with genetic and environmental factors, sex hormones contribute to the sex-related disparities in cardiac channelopathies through modulation of the expression and function of cardiac ion channels. Despite these insights, essential knowledge gaps exist in the mechanistic understanding of these differences, warranting further investigation. Precise application of the available knowledge may improve the individualized care of patients with cardiac channelopathies. Promoting the reporting of sex-related phenotype and outcome parameters in clinical and experimental studies and advancing research on cardiac channelopathy animal models should translate into improved patient outcomes. This review provides a critical digest of the current evidence for sex-related differences in cardiac channelopathies and emphasizes their clinical implications and remaining gaps requiring further research.

Published
2021
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4. Executive Attentional Dyscontrol as a Core Cognitive and Behavioral Feature of Individuals with Obesity and Cardiovascular Disease: A Cross-Sectional Investigation.

Author

Pietrabissa, Giada, Cammisuli, Davide Maria, Scarpina, Federica, Volpi, Clarissa, Crotti, Lia, Mauro, Alessandro, Gondoni, Luca Alessandro, and Castelnuovo, Gianluca

Subjects
ANXIETY sensitivity, CARDIOVASCULAR diseases, EXECUTIVE function, COGNITIVE interference, BODY mass index, CARDIAC rehabilitation
Abstract

Executive attention as a frontal domain ability that is effective in potentially blocking distracting information, reconciling conflicts among simultaneous attentional demands, and regulating impulsive behavior may be impaired in individuals with obesity and cardiovascular disease (CVD). This study aimed (i) to explore the presence of selected cognitive (global cognitive impairment, sensitivity to interference, and attention) and psychological (quality of life, depression, anxiety, and impulsivity) dimensions and (ii) to examine the interactive relationship between attentional dyscontrol—both as a psychological and as a cognitive measure—and the above-mentioned variables in a sample of patients with CVD attending a cardiac rehabilitation program across different body mass index (BMI) levels. Clinical information of 104 patients with CVD was retrospectively collected. Participants were classified into three groups according to their BMI as follows: normal weight (NW = 30), overweight (OW = 19), and obese (OB = 55). Individuals with CVD and a higher BMI showed problems in controlling executive attention—through both neuropsychological and behavioral measures. Specifically, OB patients demonstrated reduced sensitivity to cognitive interference, lower capabilities in divided attention during visual-tracking tasks, and greater impulsivity compared to NW patients. This behavioral characteristic was also found to be correlated with higher levels of anxiety and depression and a lower quality of life. Implications for cognitive rehabilitation were discussed to offer directions for better management of patients with CVD and obesity. [ABSTRACT FROM AUTHOR]

Published
2023
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5. A Primary Prevention Clinical Risk Score Model for Patients With Brugada Syndrome (BRUGADA-RISK)

Author

Gimeno-Blanes, Juan Ramón, Antonio, Pedro Silverio, Costa, Francisco Morosco, Sousa, Mario João, Honarbakhsh, Shohreh, Providencia, Rui, Garcia-Hernandez, Jorge, Martin, Claire, Hunter, Ross, Lim, Wei, Kirkby, Claire, Graham, Adam, Sharifzadehgan, Ardalan, Waldmann, Victor, Marijon, Eloi, Munoz-Esparza, Carmen, Lacunza, Javier, Gimeno-Blanes, Juan, Ankou, Benedicte, Chevalier, Philippe, Antonio, Nátalia, Elvas, Luís, Castelletti, Silvia, Crotti, Lia, Schwartz, Peter, Scanavacca, Mauricio, Darrieux, Francisco, Sacilotto, Luciana, Mueller-Leisse, Johanna, Veltmann, Christian, Vicentini, Alessandro, Demarchi, Andrea, Cortez-Dias, Nuno, Antonio, Pedro, de Sousa, João, Adragao, Pedro, Cavaco, Diogo, Costa, Francisco, Khoueiry, Ziad, Boveda, Serge, Sousa, Mario, Jebberi, Zeynab, Heck, Patrick, Mehta, Sarju, Conte, Giulio, Ozkartal, Tardu, Auricchio, Angelo, Lowe, Martin, Schilling, Richard, Prieto-Merino, David, Lambiase, Pier, Université de Paris (UP), Honarbakhsh, S, Providencia, R, Garcia-Hernandez, J, Martin, C, Hunter, R, Lim, W, Kirkby, C, Graham, A, Sharifzadehgan, A, Waldmann, V, Marijon, E, Munoz-Esparza, C, Lacunza, J, Gimeno-Blanes, J, Ankou, B, Chevalier, P, Antonio, N, Elvas, L, Castelletti, S, Crotti, L, Schwartz, P, Scanavacca, M, Darrieux, F, Sacilotto, L, Mueller-Leisse, J, Veltmann, C, Vicentini, A, Demarchi, A, Cortez-Dias, N, Antonio, P, de Sousa, J, Adragao, P, Cavaco, D, Costa, F, Khoueiry, Z, Boveda, S, Sousa, M, Jebberi, Z, Heck, P, Mehta, S, Conte, G, Ozkartal, T, Auricchio, A, Lowe, M, Schilling, R, Prieto-Merino, D, Lambiase, P, and Clinical sciences

Subjects
Adult, Male, medicine.medical_specialty, Benign early repolarization, [SDV]Life Sciences [q-bio], Population, 030204 cardiovascular system & hematology, Risk Assessment, sudden cardiac death, Sudden cardiac death, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Humans, Medicine, 030212 general & internal medicine, cardiovascular diseases, education, Death, Sudden, Cardiac/epidemiology, ventricular arrhythmia, Brugada Syndrome, Brugada syndrome, Brugada Syndrome/epidemiology, education.field_of_study, Framingham Risk Score, business.industry, Hazard ratio, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, Middle Aged, medicine.disease, Confidence interval, 3. Good health, Primary Prevention, inherited channelopathy, Death, Sudden, Cardiac, Cohort, Cardiology, Female, Cardiology and Cardiovascular Medicine, business
Abstract

Objectives: The goal of this study was to develop a risk score model for patients with Brugada syndrome (BrS). Background: Risk stratification in BrS is a significant challenge due to the low event rates and conflicting evidence. Methods: A multicenter international cohort of patients with BrS and no previous cardiac arrest was used to evaluate the role of 16 proposed clinical or electrocardiogram (ECG) markers in predicting ventricular arrhythmias (VAs)/sudden cardiac death (SCD) during follow-up. Predictive markers were incorporated into a risk score model, and this model was validated by using out-of-sample cross-validation. Results: A total of 1,110 patients with BrS from 16 centers in 8 countries were included (mean age 51.8 ± 13.6 years; 71.8% male). Median follow-up was 5.33 years; 114 patients had VA/SCD (10.3%) with an annual event rate of 1.5%. Of the 16 proposed risk factors, probable arrhythmia–related syncope (hazard ratio [HR]: 3.71; p < 0.001), spontaneous type 1 ECG (HR: 3.80; p < 0.001), early repolarization (HR: 3.42; p < 0.001), and a type 1 Brugada ECG pattern in peripheral leads (HR: 2.33; p < 0.001) were associated with a higher risk of VA/SCD. A risk score model incorporating these factors revealed a sensitivity of 71.2% (95% confidence interval: 61.5 to 84.6) and a specificity of 80.2% (95% confidence interval: 75.7 to 82.3) in predicting VA/SCD at 5 years. Calibration plots showed a mean prediction error of 1.2%. The model was effectively validated by using out-of-sample cross-validation according to country. Conclusions: This multicenter study identified 4 risk factors for VA/SCD in a primary prevention BrS population. A risk score model was generated to quantify risk of VA/SCD in BrS and inform implantable cardioverter-defibrillator prescription.

Published
2021

6. A Primary Prevention Clinical Risk Score Model for Patients With Brugada Syndrome (BRUGADA-RISK)

Author

Honarbakhsh, Shohreh, Providencia, Rui, Garcia-Hernandez, Jorge, Martin, Claire A, Hunter, Ross J, Lim, Wei Y, Kirkby, Claire, Graham, Adam J, Sharifzadehgan, Ardalan, Waldmann, Victor, Marijon, Eloi, Munoz-Esparza, Carmen, Lacunza, Javier, Gimeno-Blanes, Juan Ramón, Ankou, Benedicte, Chevalier, Philippe, Antonio, Nátalia, Elvas, Luís, Castelletti, Silvia, Crotti, Lia, Schwartz, Peter, Scanavacca, Mauricio, Darrieux, Francisco, Sacilotto, Luciana, Mueller-Leisse, Johanna, Veltmann, Christian, Vicentini, Alessandro, Demarchi, Andrea, Cortez-Dias, Nuno, Antonio, Pedro Silverio, de Sousa, João, Adragao, Pedro, Cavaco, Diogo, Costa, Francisco Morosco, Khoueiry, Ziad, Boveda, Serge, Sousa, Mario João, Jebberi, Zeynab, Heck, Patrick, Mehta, Sarju, Conte, Giulio, Ozkartal, Tardu, Auricchio, Angelo, Lowe, Martin D, Schilling, Richard J, Prieto-Merino, David, Lambiase, Pier D, and Brugada Syndrome Risk Investigators

Subjects
cardiovascular diseases
Abstract

OBJECTIVES: The goal of this study was to develop a risk score model for patients with Brugada syndrome (BrS). BACKGROUND: Risk stratification in BrS is a significant challenge due to the low event rates and conflicting evidence. METHODS: A multicenter international cohort of patients with BrS and no previous cardiac arrest was used to evaluate the role of 16 proposed clinical or electrocardiogram (ECG) markers in predicting ventricular arrhythmias (VAs)/sudden cardiac death (SCD) during follow-up. Predictive markers were incorporated into a risk score model, and this model was validated by using out-of-sample cross-validation. RESULTS: A total of 1,110 patients with BrS from 16 centers in 8 countries were included (mean age 51.8 ± 13.6 years; 71.8% male). Median follow-up was 5.33 years; 114 patients had VA/SCD (10.3%) with an annual event rate of 1.5%. Of the 16 proposed risk factors, probable arrhythmia-related syncope (hazard ratio [HR]: 3.71; p

Published
2021

7. The Impact of Clinical and Genetic Findings on The Management of Young Brugada Syndrome Patients

Author

Andorin, Antoine, Behr, Elijah R., Denjoy, Isabelle, Crotti, Lia, Dagradi, Federica, Jesel, Laurence, Sacher, Frederic, Petit, Bertrand, Mabo, Philippe, Maltret, Alice, Wong, Leonie C. H., Degand, Bruno, Bertaux, Geraldine, Maury, Philippe, Dulac, Yves, Delasalle, Béatrice, Gourraud, Jean-Baptiste, Babuty, Dominique, Blom, Nico A., Schwartz, Peter J., Wilde, Arthur A., Probst, Vincent, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Strasbourg, IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Service de cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de cardiologie [CHU de Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de Cardiologie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Toulouse [Toulouse], Service pédiatrie-cardiologie, CHU Toulouse [Toulouse]-Hôpital des Enfants, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Cardiopathies et mort subite [ERL 3147], Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [APHP], Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Bordeaux [Bordeaux]-Université Bordeaux Segalen - Bordeaux 2, Service de cardiologie et maladies vasculaires, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes (UN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre de référence pour les maladies cardiaques héréditaires, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Laboratoire d'étude des textures et application aux matériaux ( LETAM ), Université Paul Verlaine - Metz ( UPVM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image ( LTSI ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Département de Cardiologie, Université de Poitiers, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), unité de recherche de l'institut du thorax UMR1087 UMR6291 ( ITX ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU de Tours, Cardiopathies et mort subite, Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Cardiologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)

Subjects
Death sudden, [ SDV ] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], Genetics, Brugada syndrome, cardiovascular diseases, Pediatrics, Arrhythmia
Abstract

International audience; Background - Brugada syndrome (BrS) is an arrhythmogenic disease associated with sudden cardiac death (SCD) that seldom manifests or is recognized in childhood. Objectives - The objectives of this study were to describe the clinical presentation of pediatric BrS to identify prognostic factors for risk stratification and to propose a data-based approach management. Methods - We studied 106 patients younger than 19 years at diagnosis of BrS enrolled from 16 European hospitals. Results - At diagnosis, BrS was spontaneous (n = 36, 34%) or drug-induced (n = 70, 66%). The mean age was 11.1 ± 5.7 years, and most patients were asymptomatic (family screening, (n = 67, 63%; incidental, n = 13, 12%), while 15 (14%) experienced syncope, 6(6%) aborted SCD or symptomatic ventricular tachycardia, and 5 (5%) other symptoms. During follow-up (median 54 months), 10 (9%) patients had life-threatening arrhythmias (LTA), including 3 (3%) deaths. Six (6%) experienced syncope and 4 (4%) supraventricular tachycardia. Fever triggered 27% of LTA events. An implantable cardioverter-defibrillator was implanted in 22 (21%), with major adverse events in 41%. Of the 11 (10%) patients treated with hydroquinidine, 8 remained asymptomatic. Genetic testing was performed in 75 (71%) patients, and SCN5A rare variants were identified in 58 (55%); 15 of 32 tested probands (47%) were genotype positive. Nine of 10 patients with LTA underwent genetic testing, and all were genotype positive, whereas the 17 SCN5A-negative patients remained asymptomatic. Spontaneous Brugada type 1 electrocardiographic (ECG) pattern (P = .005) and symptoms at diagnosis (P = .001) were predictors of LTA. Time to the first LTA event was shorter in patients with both symptoms at diagnosis and spontaneous Brugada type 1 ECG pattern (P = .006). Conclusion - Spontaneous Brugada type 1 ECG pattern and symptoms at diagnosis are predictors of LTA events in the young affected by BrS. The management of BrS should become age-specific, and prevention of SCD may involve genetic testing and aggressive use of antipyretics and quinidine, with risk-specific consideration for the implantable cardioverter-defibrillator.

Published
2016

9. Left Cardiac Sympathetic Denervation for Catecholaminergic Polymorphic Ventricular Tachycardia

Author

Wilde, Arthur A. M., Bhuiyan, Zahurul A., Crotti, Lia, Facchini, Mario, De Ferrari, Gaetano M., Paul, Thomas, Ferrandi, Chiara, Koolbergen, Dave R., Odero, Attilio, and Schwartz, Peter J.

Subjects
cardiovascular system, Cardiac Sympathetic Denervation, cardiovascular diseases
Abstract

Catecholaminergic polymorphic ventricular tachycardia is a potentially lethal disease characterized by adrenergically mediated ventricular arrhythmias manifested especially in children and teenagers. Beta-blockers are the cornerstone of therapy, but some patients do not have a complete response to this therapy and receive an implantable cardioverter–defibrillator (ICD). Given the nature of catecholaminergic polymorphic ventricular tachycardia, ICD shocks may trigger new arrhythmias, leading to the administration of multiple shocks. We describe the long-term efficacy of surgical left cardiac sympathetic denervation in three young adults with catecholaminergic polymorphic ventricular tachycardia, all of whom had symptoms before the procedure and were symptom-free afterward. peerReviewed

Published
2008

10. Multiscale Complexity Analysis of the Cardiac Control Identifies Asymptomatic and Symptomatic Patients in Long QT Syndrome Type 1.

Author

Bari, Vlasta, Valencia, José F., Vallverdú, Montserrat, Girardengo, Giulia, Marchi, Andrea, Bassani, Tito, Caminal, Pere, Cerutti, Sergio, George Jr, Alfred L., Brink, Paul A., Crotti, Lia, Schwartz, Peter J., and Porta, Alberto

Subjects
MULTISCALE modeling, LONG QT syndrome, SINOATRIAL node, APPROXIMATION theory, ELECTROCARDIOGRAPHY, LIFE sciences
Abstract

The study assesses complexity of the cardiac control directed to the sinus node and to ventricles in long QT syndrome type 1 (LQT1) patients with KCNQ1-A341V mutation. Complexity was assessed via refined multiscale entropy (RMSE) computed over the beat-to-beat variability series of heart period (HP) and QT interval. HP and QT interval were approximated respectively as the temporal distance between two consecutive R-wave peaks and between the R-wave apex and T-wave end. Both measures were automatically taken from 24-hour electrocardiographic Holter traces recorded during daily activities in non mutation carriers (NMCs, n = 14) and mutation carriers (MCs, n = 34) belonging to a South African LQT1 founder population. The MC group was divided into asymptomatic (ASYMP, n = 11) and symptomatic (SYMP, n = 23) patients according to the symptom severity. Analyses were carried out during daytime (DAY, from 2PM to 6PM) and nighttime (NIGHT, from 12PM to 4AM) off and on beta-adrenergic blockade (BBoff and BBon). We found that the complexity of the HP variability at short time scale was under vagal control, being significantly increased during NIGHT and BBon both in ASYMP and SYMP groups, while the complexity of both HP and QT variability at long time scales was under sympathetic control, being smaller during NIGHT and BBon in SYMP subjects. Complexity indexes at long time scales in ASYMP individuals were smaller than those in SYMP ones regardless of therapy (i.e. BBoff or BBon), thus suggesting that a reduced complexity of the sympathetic regulation is protective in ASYMP individuals. RMSE analysis of HP and QT interval variability derived from routine 24-hour electrocardiographic Holter recordings might provide additional insights into the physiology of the cardiac control and might be fruitfully exploited to improve risk stratification in LQT1 population. [ABSTRACT FROM AUTHOR]

Published
2014
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11. Long-QT Syndrome.

Author

Schwartz, Peter J., Crotti, Lia, and Insolia, Roberto

Subjects
HEART diseases, ARRHYTHMIA, SUDDEN death, DISEASES in young adults, CARDIOVASCULAR diseases, MEDICAL genetics
Abstract

The article outlines the current knowledge about the genetics of the congenital long -QT syndrome (LQTS), a life-threatening cardiac arrhythmia syndrome that represents a leading cause of sudden death in the young. It looks at minor and major LQTS genes, the prevalence of LQTS, as well as the diagnosis and testing of LQTS. It also provides essential clinical data and describes an approach to the clinical management of LQTS patients.

Published
2012
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12. Spectrum and Prevalence of Mutations Involving BrS1- Through BrS12-Susceptibility Genes in a Cohort of Unrelated Patients Referred for Brugada Syndrome Genetic Testing Implications for Genetic Testing

Author

Crotti, Lia, Marcou, Cherisse A., Tester, David J., Castelletti, Silvia, Giudicessi, John R., Torchio, Margherita, Medeiros-Domingo, Argelia, Simone, Savastano, Will, Melissa L., Dagradi, Federica, Schwartz, Peter J., and Ackerman, Michael J.

Subjects
fungi, ventricular arrhythmias, Brugada syndrome, cardiovascular diseases, cardiac arrest, ST-segment elevation, genetic testing
Abstract

ObjectivesThe aim of this study was to provide the spectrum and prevalence of mutations in the 12 Brugada syndrome (BrS)–susceptibility genes discovered to date in a single large cohort of unrelated BrS patients.BackgroundBrS is a potentially lethal heritable arrhythmia syndrome diagnosed electrocardiographically by coved-type ST-segment elevation in the right precordial leads (V1 to V3; type 1 Brugada electrocardiographic [ECG] pattern) and the presence of a personal/family history of cardiac events.MethodsUsing polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, comprehensive mutational analysis of BrS1- through BrS12-susceptibility genes was performed in 129 unrelated patients with possible/probable BrS (46 with clinically diagnosed BrS [ECG pattern plus personal/family history of a cardiac event] and 83 with a type 1 BrS ECG pattern only).ResultsOverall, 27 patients (21%) had a putative pathogenic mutation, absent in 1,400 Caucasian reference alleles, including 21 patients with an SCN5A mutation, 2 with a CACNB2B mutation, and 1 each with a KCNJ8 mutation, a KCND3 mutation, an SCN1Bb mutation, and an HCN4 mutation. The overall mutation yield was 23% in the type 1 BrS ECG pattern-only patients versus 17% in the clinically diagnosed BrS patients and was significantly greater among young men

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13. Not All Beta-Blockers Are Equal in the Management of Long QT Syndrome Types 1 and 2 Higher Recurrence of Events Under Metoprolol

Author

Chockalingam, Priya, Crotti, Lia, Girardengo, Giulia, Johnson, Jonathan N., Harris, Katy M., van der Heijden, Jeroen F., Hauer, Richard N.W., Beckmann, Britt M., Spazzolini, Carla, Rordorf, Roberto, Rydberg, Annika, Clur, Sally-Ann B., Fischer, Markus, van den Heuvel, Freek, Kääb, Stefan, Blom, Nico A., Ackerman, Michael J., Schwartz, Peter J., and Wilde, Arthur A.M.

Subjects
breakthrough cardiac events, nadolol, congenital long QT syndrome, cardiovascular diseases, propranolol, metoprolol, circulatory and respiratory physiology
Abstract

ObjectivesThe purpose of this study was to compare the efficacy of beta-blockers in congenital long QT syndrome (LQTS).BackgroundBeta-blockers are the mainstay in managing LQTS. Studies comparing the efficacy of commonly used beta-blockers are lacking, and clinicians generally assume they are equally effective.MethodsElectrocardiographic and clinical parameters of 382 LQT1/LQT2 patients initiated on propranolol (n = 134), metoprolol (n = 147), and nadolol (n = 101) were analyzed, excluding patients 480 ms. None of the asymptomatic patients had BCEs. Among symptomatic patients (n = 101), 15 had BCEs (all syncopes). The QTc shortening was significantly less pronounced among patients with BCEs. There was a greater risk of BCEs for symptomatic patients initiated on metoprolol compared to users of the other 2 beta-blockers combined, after adjustment for genotype (odds ratio: 3.95, 95% confidence interval: 1.2 to 13.1, p = 0.025). Kaplan-Meier analysis showed a significantly lower event-free survival for symptomatic patients receiving metoprolol compared to propranolol/nadolol.ConclusionsPropranolol has a significantly better QTc shortening effect compared to metoprolol and nadolol, especially in patients with prolonged QTc. Propranolol and nadolol are equally effective, whereas symptomatic patients started on metoprolol are at a significantly higher risk for BCEs. Metoprolol should not be used for symptomatic LQT1 and LQT2 patients.

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14. Adenosine and the Cardiovascular System: The Good and the Bad.

Author

Guieu, Régis, Deharo, Jean-Claude, Maille, Baptiste, Crotti, Lia, Torresani, Ermino, Brignole, Michele, and Parati, Gianfranco

Subjects
CARDIOVASCULAR system, ADENOSINES, PULMONARY blood vessels, CARDIOVASCULAR diseases, SLEEP apnea syndromes
Abstract

Adenosine is a nucleoside that impacts the cardiovascular system via the activation of its membrane receptors, named A1R, A2AR, A2BR and A3R. Adenosine is released during hypoxia, ischemia, beta-adrenergic stimulation or inflammation and impacts heart rhythm and produces strong vasodilation in the systemic, coronary or pulmonary vascular system. This review summarizes the main role of adenosine on the cardiovascular system in several diseases and conditions. Adenosine release participates directly in the pathophysiology of atrial fibrillation and neurohumoral syncope. Adenosine has a key role in the adaptive response in pulmonary hypertension and heart failure, with the most relevant effects being slowing of heart rhythm, coronary vasodilation and decreasing blood pressure. In other conditions, such as altitude or apnea-induced hypoxia, obstructive sleep apnea, or systemic hypertension, the adenosinergic system activation appears in a context of an adaptive response. Due to its short half-life, adenosine allows very rapid adaptation of the cardiovascular system. Finally, the effects of adenosine on the cardiovascular system are sometimes beneficial and other times harmful. Future research should aim to develop modulating agents of adenosine receptors to slow down or conversely amplify the adenosinergic response according to the occurrence of different pathologic conditions. [ABSTRACT FROM AUTHOR]

Published
2020
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15. The role of mitochondrial dynamics in cardiovascular diseases.

Author

Forte, Maurizio, Schirone, Leonardo, Ameri, Pietro, Basso, Cristina, Catalucci, Daniele, Modica, Jessica, Chimenti, Cristina, Crotti, Lia, Frati, Giacomo, Rubattu, Speranza, Schiattarella, Gabriele Giacomo, Torella, Daniele, Perrino, Cinzia, Indolfi, Ciro, Sciarretta, Sebastiano, Italian Society of Cardiology (SIC) Working group on Cellular and Molecular Biology of the Heart, and Italian Society of Cardiology Working group on Cellular and Molecular Biology of the Heart

Subjects
STROKE, MYOCARDIUM, CARDIOVASCULAR diseases, MITOCHONDRIA, CEREBRAL ischemia
Abstract

The process of mitochondrial dynamics is emerging as a core player in cardiovascular homeostasis. This process refers to the co-ordinated cycles of biogenesis, fusion, fission and degradation to which mitochondria constantly undergo to maintain their integrity, distribution and size. These mechanisms represent an early response to mitochondrial stress, confining organelle portions that are irreversibly damaged and preserving mitochondrial function. Accumulating evidence demonstrates that impairment in mitochondrial dynamics leads to myocardial damage and cardiac disease progression in a variety of disease models, including pressure overload, ischaemia/reperfusion and metabolic disturbance. These findings suggest that modulation of mitochondrial dynamics may be considered as a valid therapeutic strategy in cardiovascular diseases. In this review, we discuss the current evidence about the role of mitochondrial dynamics in cardiac pathophysiology, with a particular focus on the mechanisms underlying the development of cardiac hypertrophy and heart failure, metabolic and genetic cardiomyopathies, ischaemia/reperfusion injury, atherosclerosis and ischaemic stroke. LINKED ARTICLES: This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc. [ABSTRACT FROM AUTHOR]

Published
2020
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16. Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

Author

Lahrouchi, Najim, Tadros, Rafik, Crotti, Lia, Mizusawa, Yuka, Postema, Pieter G, Beekman, Leander, Walsh, Roddy, Hasegawa, Kanae, Barc, Julien, Ernsting, Marko, Turkowski, Kari L, Mazzanti, Andrea, Beckmann, Britt M, Shimamoto, Keiko, Diamant, Ulla-Britt, Wijeyeratne, Yanushi D, Kucho, Yu, Robyns, Tomas, Ishikawa, Taisuke, Arbelo, Elena, Christiansen, Michael, Winbo, Annika, Jabbari, Reza, Lubitz, Steven A, Steinfurt, Johannes, Rudic, Boris, Loeys, Bart, Shoemaker, M Ben, Weeke, Peter E, Pfeiffer, Ryan, Davies, Brianna, Andorin, Antoine, Hofman, Nynke, Dagradi, Federica, Pedrazzini, Matteo, Tester, David J, Bos, J Martijn, Sarquella-Brugada, Georgia, Campuzano, Óscar, Platonov, Pyotr G, Stallmeyer, Birgit, Zumhagen, Sven, Nannenberg, Eline A, Veldink, Jan H, Van Den Berg, Leonard H, Al-Chalabi, Ammar, Shaw, Christopher E, Shaw, Pamela J, Morrison, Karen E, Andersen, Peter M, Müller-Nurasyid, Martina, Cusi, Daniele, Barlassina, Cristina, Galan, Pilar, Lathrop, Mark, Munter, Markus, Werge, Thomas, Ribasés, Marta, Aung, Tin, Khor, Chiea C, Ozaki, Mineo, Lichtner, Peter, Meitinger, Thomas, Van Tintelen, J Peter, Hoedemaekers, Yvonne, Denjoy, Isabelle, Leenhardt, Antoine, Napolitano, Carlo, Shimizu, Wataru, Schott, Jean-Jacques, Gourraud, Jean-Baptiste, Makiyama, Takeru, Ohno, Seiko, Itoh, Hideki, Krahn, Andrew D, Antzelevitch, Charles, Roden, Dan M, Saenen, Johan, Borggrefe, Martin, Odening, Katja Elisabeth, Ellinor, Patrick T, Tfelt-Hansen, Jacob, Skinner, Jonathan R, Van Den Berg, Maarten P, Olesen, Morten Salling, Brugada, Josep, Brugada, Ramón, Makita, Naomasa, Breckpot, Jeroen, Yoshinaga, Masao, Behr, Elijah R, Rydberg, Annika, Aiba, Takeshi, Kääb, Stefan, Priori, Silvia G, Guicheney, Pascale, Tan, Hanno L, Newton-Cheh, Christopher, Ackerman, Michael J, Schwartz, Peter J, Schulze-Bahr, Eric, Probst, Vincent, Horie, Minoru, Wilde, Arthur A, Tanck, Michael W T, and Bezzina, Connie R

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, cardiovascular diseases, 610 Medicine & health, 3. Good health
Abstract

BACKGROUND Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. METHODS We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. RESULTS Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P

17. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Author

Yuki Bradford, Toshiko Tanaka, Jeffrey R. O'Connell, Florence Kyndt, Unnur Thorsteinsdottir, Ivana Kolcic, Xiaoyan Yin, Vincent Probst, Manolis Kellis, Christopher Newton-Cheh, Stefan Kääb, Argelia Medeiros-Domingo, Markus M. Nöthen, Paolo Gasparini, Jean-Jacques Schott, Ruth J. F. Loos, Thomas W. Mühleisen, Annukka Marjamaa, Morris Brown, Igor Rudan, Runjun D. Kumar, Peter J. Schwartz, Lars Lind, Martina Müller-Nurasyid, Xinchen Wang, Joshua C. Denny, Roberto Insolia, Soumya Raychaudhuri, Stephen W. Scherer, Bruno H. Stricker, Alexander Kluttig, Adamo Pio D'Adamo, Laurie A. Boyer, Moritz F. Sinner, Norbert Frey, Nour Eddine El Mokhtari, Thomas Meitinger, Jesper V. Olsen, Gerjan Navis, Steven R. Cummings, Richard W Morris, Nynke Hofman, Marcel den Hoed, Rudolf A. de Boer, Gonçalo R. Abecasis, Mark J. Daly, Dan M. Roden, Christian Gieger, Lyudmyla Kedenko, Marcus Dörr, Thomas P. Cappola, Afshin Parsa, Kari Stefansson, Markus Perola, Mark Eijgelsheim, Fredrik Nyberg, Robert M. Hamilton, Yalda Jamshidi, W. H. Linda Kao, Terho Lehtimäki, Annette Peters, David Schlessinger, Peter P. Pramstaller, James F. Wilson, Vilmundur Gudnason, Florian Kronenberg, Aroon D. Hingorani, Connie R. Bezzina, Abdennasser Bardai, Marylyn D. Ritchie, Andrew S. Plump, Johan Sundström, Daryl Waggott, Chrysoula Dalageorgou, Paul I.W. de Bakker, Uwe Völker, Aaron Isaacs, Oscar H. Franco, Yongmei Liu, Andrew N. Nicolaides, Lia Crotti, Cornelia M. van Duijn, Ben A. Oostra, Arne Pfeufer, Karl Werdan, Michael Morley, Jan A. Kors, Julien Barc, Lewin Eisele, Siegfried Perz, Stéphanie Chatel, Pieter A. van der Vleuten, Sara L. Pulit, Anna F. Dominiczak, Harry Campbell, Alice Ghidoni, Irene Mateo Leach, Nona Sotoodehnia, Nina Mononen, Henriette E. Meyer zu Schwabedissen, Alvaro Alonso, Fabiola Del Greco M, Dan E. Arking, Vera Adamkova, Mike A. Nalls, Valur Emilsson, Edward G. Lakatta, Kirill Tarasov, Alan F. Wright, Lenore J. Launer, Erik Ingelsson, Karin Halina Greiser, Ozren Polasek, Massimo Carella, Daniel F. Gudbjartsson, Bouwe P. Krijthe, Hanna Prucha, Per Hoffmann, Maura Griffin, Stefan Kiechl, Angel Carracedo, Ilja M. Nolte, Christine E. Moravec, Johann Willeit, Joshua C. Bis, Patricia B. Munroe, Marcello Ricardo Paulista Markus, Hailiang Huang, Mika Kähönen, Albert Hofman, Peter H. Whincup, Dirk J. van Veldhuisen, Michael Knoflach, Alicia Lundby, Serena Sanna, Hagen Kälsch, Bernhard Paulweber, Kamil Slowikowski, Luigi Ferrucci, Melanie Waldenberger, Marco Bobbo, Annukka M. Lahtinen, Ann-Christine Syvänen, J. Gustav Smith, Åsa Torinsson Naluai, Jaroslav A. Hubacek, Jeffrey Brandimarto, Wendy S. Post, Lude Franke, Mark J. Caulfield, Folkert W. Asselbergs, André G. Uitterlinden, Stefan Gustafsson, Pim van der Harst, David J. Tester, David S. Siscovick, David O. Arnar, Sarah H Wild, Elizabeth J. Rossin, Albert V. Smith, Bruce M. Psaty, Georg Ehret, Alan R. Shuldiner, Stephen Newhouse, Kimmo Kontula, Maria Brion, Andre Franke, Peter W. Macfarlane, Mika Kivimäki, Tamara B. Harris, Lasse Oikarinen, Tamara T. Koopmann, Kenneth B. Margulies, Aravinda Chakravarti, Gianfranco Sinagra, Maarten P. van den Berg, Veikko Salomaa, Karl-Heinz Jöckel, Daniel S. Evans, Caroline Hayward, Kimmo Porthan, Michael J. Ackerman, Jacqueline C.M. Witteman, Arthur A.M. Wilde, Martin G. Larson, Kasper Lage, Manuela Uda, Susan R. Heckbert, Joel S. Bader, Graham Watt, María Dolores Torres, Stephan B. Felix, Jerome I. Rotter, Pau Navarro, Meena Kumari, Johan Ärnlöv, Andrew D. Paterson, Antti Jula, Olli T. Raitakari, Raimund Erbel, Christopher J. O'Donnell, Britt M. Beckmann, Peter A. Noseworthy, Tim D. Spector, Wai K. Lee, Leopoldo Zelante, Nilesh J. Samani, John R. Giudicessi, Harold Snieder, Dag S. Thelle, David Ellinghaus, Eimo Martens, James B. Strait, Jorma S. A. Viikari, Andrew D. Johnson, Antonella Mulas, Hilma Holm, Johannes Haerting, Annamaria Iorio, Rebecca L. Zuvich, Sheila Ulivi, Andrew A. Hicks, Elijah R. Behr, Leo-Pekka Lyytikäinen, Bernhard Strohmer, Marco Orru, Claudia Lamina, Sandosh Padmanabhan, Christian Fuchsberger, Andrie G. Panayiotou, Ehret, Georg Benedikt, Internal Medicine, Public Health, Epidemiology, Rehabilitation Medicine, Medical Informatics, Clinical Genetics, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Ethical, Legal, Social Issues in Genetics (ELSI), Stem Cell Aging Leukemia and Lymphoma (SALL), Arking, D, Pulit, S, Crotti, L, van der Harst, P, Munroe, P, Koopmann, T, Sotoodehnia, N, Rossin, E, Morley, M, Wang, X, Johnson, A, Lundby, A, Gudbjartsson, D, Noseworthy, P, Eijgelsheim, M, Bradford, Y, Tarasov, K, Dörr, M, Müller-Nurasyid, M, Lahtinen, A, Nolte, I, Smith, A, Bis, J, Isaacs, A, Newhouse, S, Evans, D, Post, W, Waggott, D, Lyytikäinen, L, Hicks, A, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, D, Chatel, S, Gustafsson, S, Kumari, M, Morris, R, Naluai, A, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, A, Torres, M, Knoflach, M, Hubacek, J, Slowikowski, K, Raychaudhuri, S, Kumar, R, Harris, T, Launer, L, Shuldiner, A, Alonso, A, Bader, J, Ehret, G, Huang, H, Kao, W, Strait, J, Macfarlane, P, Brown, M, Caulfield, M, Samani, N, Kronenberg, F, Willeit, J, Smith, J, Greiser, K, Meyer Zu Schwabedissen, H, Werdan, K, Carella, M, Zelante, L, Heckbert, S, Psaty, B, Rotter, J, Kolcic, I, Polašek, O, Wright, A, Griffin, M, Daly, M, Arnar, D, Hólm, H, Thorsteinsdottir, U, Denny, J, Roden, D, Zuvich, R, Emilsson, V, Plump, A, Larson, M, O'Donnell, C, Yin, X, Bobbo, M, D'Adamo, A, Iorio, A, Sinagra, G, Carracedo, A, Cummings, S, Nalls, M, Jula, A, Kontula, K, Marjamaa, A, Oikarinen, L, Perola, M, Porthan, K, Erbel, R, Hoffmann, P, Jöckel, K, Kälsch, H, Nöthen, M, den Hoed, M, Loos, R, Thelle, D, Gieger, C, Meitinger, T, Perz, S, Peters, A, Prucha, H, Sinner, M, Waldenberger, M, de Boer, R, Franke, L, van der Vleuten, P, Beckmann, B, Martens, E, Bardai, A, Hofman, N, Wilde, A, Behr, E, Dalageorgou, C, Giudicessi, J, Medeiros-Domingo, A, Kyndt, F, Probst, V, Ghidoni, A, Insolia, R, Hamilton, R, Scherer, S, Brandimarto, J, Margulies, K, Moravec, C, Greco, M, Fuchsberger, C, O'Connell, J, Lee, W, Watt, G, Campbell, H, Wild, S, El Mokhtari, N, Frey, N, Asselbergs, F, Mateo Leach, I, Navis, G, van den Berg, M, van Veldhuisen, D, Kellis, M, Krijthe, B, Franco, O, Hofman, A, Kors, J, Uitterlinden, A, Witteman, J, Kedenko, L, Lamina, C, Oostra, B, Abecasis, G, Lakatta, E, Mulas, A, Orrú, M, Schlessinger, D, Uda, M, Markus, M, Völker, U, Snieder, H, Spector, T, Arnlöv, J, Lind, L, Sundström, J, Syvänen, A, Kivimaki, M, Kähönen, M, Mononen, N, Raitakari, O, Viikari, J, Adamkova, V, Kiechl, S, Brion, M, Nicolaides, A, Paulweber, B, Haerting, J, Dominiczak, A, Nyberg, F, Whincup, P, Hingorani, A, Schott, J, Bezzina, C, Ingelsson, E, Ferrucci, L, Gasparini, P, Wilson, J, Rudan, I, Franke, A, Mühleisen, T, Pramstaller, P, Lehtimäki, T, Paterson, A, Parsa, A, Liu, Y, van Duijn, C, Siscovick, D, Gudnason, V, Jamshidi, Y, Salomaa, V, Felix, S, Sanna, S, Ritchie, M, Stricker, B, Stefansson, K, Boyer, L, Cappola, T, Olsen, J, Lage, K, Schwartz, P, Kääb, S, Chakravarti, A, Ackerman, M, Pfeufer, A, de Bakker, P, Newton-Cheh, C, Arking, Dan E., Pulit, Sara L., Crotti, Lia, Van Der Harst, Pim, Munroe, Patricia B., Koopmann, Tamara T., Sotoodehnia, Nona, Rossin, Elizabeth J., Morley, Michael, Wang, Xinchen, Johnson, Andrew D., Lundby, Alicia, Gudbjartsson, Daníel F., Noseworthy, Peter A., Eijgelsheim, Mark, Bradford, Yuki, Tarasov, Kirill V., Dörr, Marcu, Müller Nurasyid, Martina, Lahtinen, Annukka M., Nolte, Ilja M., Smith, Albert Vernon, Bis, Joshua C., Isaacs, Aaron, Newhouse, Stephen J., Evans, Daniel S., Post, Wendy S., Waggott, Daryl, Lyytikäinen, Leo Pekka, Hicks, Andrew A., Eisele, Lewin, Ellinghaus, David, Hayward, Caroline, Navarro, Pau, Ulivi, Sheila, Tanaka, Toshiko, Tester, David J., Chatel, Stéphanie, Gustafsson, Stefan, Kumari, Meena, Morris, Richard W., Naluai, Asa T., Padmanabhan, Sandosh, Kluttig, Alexander, Strohmer, Bernhard, Panayiotou, Andrie G., Torres, Maria, Knoflach, Michael, Hubacek, Jaroslav A., Slowikowski, Kamil, Raychaudhuri, Soumya, Kumar, Runjun D., Harris, Tamara B., Launer, Lenore J., Shuldiner, Alan R., Alonso, Alvaro, Bader, Joel S., Ehret, Georg, Huang, Hailiang, Kao, W. H. Linda, Strait, James B., Macfarlane, Peter W., Brown, Morri, Caulfield, Mark J., Samani, Nilesh J., Kronenberg, Florian, Willeit, Johann, Smith, J. Gustav, Greiser, Karin H., Zu Schwabedissen, Henriette Meyer, Werdan, Karl, Carella, Massimo, Zelante, Leopoldo, Heckbert, Susan R., Psaty, Bruce M., Rotter, Jerome I., Kolcic, Ivana, Polašek, Ozren, Wright, Alan F., Griffin, Maura, Daly, Mark J., Arnar, David O., Hólm, Hilma, Thorsteinsdottir, Unnur, Denny, Joshua C., Roden, Dan M., Zuvich, Rebecca L., Emilsson, Valur, Plump, Andrew S., Larson, Martin G., O'Donnell, Christopher J., Yin, Xiaoyan, Bobbo, Marco, D'Adamo, ADAMO PIO, Iorio, Annamaria, Sinagra, Gianfranco, Carracedo, Angel, Cummings, Steven R., Nalls, Michael A., Jula, Antti, Kontula, Kimmo K., Marjamaa, Annukka, Oikarinen, Lasse, Perola, Marku, Porthan, Kimmo, Erbel, Raimund, Hoffmann, Per, Jöckel, Karl Heinz, Kälsch, Hagen, Nöthen, Markus M., Den Hoed, Marcel, Loos, Ruth J. F., Thelle, Dag S., Gieger, Christian, Meitinger, Thoma, Perz, Siegfried, Peters, Annette, Prucha, Hanna, Sinner, Moritz F., Waldenberger, Melanie, De Boer, Rudolf A., Franke, Lude, Van Der Vleuten, Pieter A., Beckmann, Britt Maria, Martens, Eimo, Bardai, Abdennasser, Hofman, Nynke, Wilde, Arthur A. M., Behr, Elijah R., Dalageorgou, Chrysoula, Giudicessi, John R., Medeiros Domingo, Argelia, Barc, Julien, Kyndt, Florence, Probst, Vincent, Ghidoni, Alice, Insolia, Roberto, Hamilton, Robert M., Scherer, Stephen W., Brandimarto, Jeffrey, Margulies, Kenneth, Moravec, Christine E., Del Greco M, Fabiola, Fuchsberger, Christian, O'Connell, Jeffrey R., Lee, Wai K., Watt, Graham C. M., Campbell, Harry, Wild, Sarah H., El Mokhtari, Nour E., Frey, Norbert, Asselbergs, Folkert W., Leach, Irene Mateo, Navis, Gerjan, Van Den Berg, Maarten P., Van Veldhuisen, Dirk J., Kellis, Manoli, Krijthe, Bouwe P., Franco, Oscar H., Hofman, Albert, Kors, Jan A., Uitterlinden, André G., Witteman, Jacqueline C. M., Kedenko, Lyudmyla, Lamina, Claudia, Oostra, Ben A., Abecasis, Gonçalo R., Lakatta, Edward G., Mulas, Antonella, Orrú, Marco, Schlessinger, David, Uda, Manuela, Markus, Marcello R. P., Völker, Uwe, Snieder, Harold, Spector, Timothy D., Ärnlöv, Johan, Lind, Lar, Sundström, Johan, Syvänen, Ann Christine, Kivimaki, Mika, Kähönen, Mika, Mononen, Nina, Raitakari, Olli T., Viikari, Jorma S., Adamkova, Vera, Kiechl, Stefan, Brion, Maria, Nicolaides, Andrew N., Paulweber, Bernhard, Haerting, Johanne, Dominiczak, Anna F., Nyberg, Fredrik, Whincup, Peter H., Hingorani, Aroon D., Schott, Jean Jacque, Bezzina, Connie R., Ingelsson, Erik, Ferrucci, Luigi, Gasparini, Paolo, Wilson, James F., Rudan, Igor, Franke, Andre, Mühleisen, Thomas W., Pramstaller, Peter P., Lehtimäki, Terho J., Paterson, Andrew D., Parsa, Afshin, Liu, Yongmei, Van Duijn, Cornelia M., Siscovick, David S., Gudnason, Vilmundur, Jamshidi, Yalda, Salomaa, Veikko, Felix, Stephan B., Sanna, Serena, Ritchie, Marylyn D., Stricker, Bruno H., Stefansson, Kari, Boyer, Laurie A., Cappola, Thomas P., Olsen, Jesper V., Lage, Kasper, Schwartz, Peter J., Kääb, Stefan, Chakravarti, Aravinda, Ackerman, Michael J., Pfeufer, Arne, De Bakker, Paul I. W., Newton Cheh, Christopher, Cardiology, ACS - Amsterdam Cardiovascular Sciences, and Human Genetics

Subjects
Male, Candidate gene, Myocardium/metabolism, LOCI, Medizin, Heart electrophysiology, Genome-wide association study, Arrhythmias, Bioinformatics, Medical and Health Sciences, Heart Ventricle, Sudden cardiac death, Electrocardiography, PR INTERVAL, Arrhythmias, Cardiac/genetics, Death, Sudden, Cardiac/etiology, Genetics, ddc:616, Cardiac electrophysiology, Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Middle Aged, Myocardium, Polymorphism, Single Nucleotide, COMMON VARIANTS, Heart Ventricles/metabolism, Single Nucleotide, Long QT Syndrome/genetics, CHRONIC HEART-FAILURE, Death, Heart ventricle arrhythmia, genetic association study, gene, SNP, heart, Genome-Wide Association Study/methods, Long QT syndrome, QRS DURATION, Cardiac, Cardiac/etiology, Human, QT interval, congenital, hereditary, and neonatal diseases and abnormalities, Electrocardiography/methods, TRPM7, BIO/18 - GENETICA, Cardiac/genetics, Biology, Article, sudden cardiac death, QRS complex, CARDIAC REPOLARIZATION, medicine, Repolarization, cardiovascular diseases, GENOME-WIDE ASSOCIATION, Polymorphism, MED/01 - STATISTICA MEDICA, calcium, ta1184, Calcium signaling, Calcium Signaling/genetics, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, ta3121, Cardiovascular risk, medicine.disease, SARCOPLASMIC-RETICULUM, Sudden, MODEL, Genetic association, myocardial repolarization, Genetic variability, Gene expression, Clinical Medicine, genetic, Controlled study
Abstract

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain similar to 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

Published
2014

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