The role of late sodium current in the inherited and acquired cardiac arrhythmias: from the biophysics properties to new therapeutic targets

• Grant number: 14/09861-1
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: February 01, 2015
• End date: January 31, 2020
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Danilo Roman Campos
• Grantee: Danilo Roman Campos
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Alexandre da Costa Pereira ; Jader dos Santos Cruz ; José Eduardo Krieger ; Monica Levy Andersen
• Associated research grant(s): 21/05584-7 - Assessment of acute and chronic toxicity of the heart and brain exposed to pesticides found in potable water in Brazil, AP.JP2; 18/08208-3 - Structure and function studies of sodium channel to the development of green pesticides, AP.R SPRINT

Abstract

The control of cardiac rhythm is dictated by the shape of the action potential (AP), which relays on the distinct class of ion currents, among them sodium current (INa), whichever has two components, a fast and a slow inactivating current. The latter is known as late sodium current (INaL). INaL has an important role in the repolarization phase of the AP in cardiac cells and under pathophysiological conditions it may be augmented, which is an important arrhythmogenic substrate. INaL may be up-regulated by means of: (1) point mutations in the SCN5A gene, the one responsible for most of the INa in cardiac cells. Sometimes the point mutation leads to Long QT type 3 syndrome; (2) intracellular signaling triggered by heart remodeling, precipitating changes in the biophysical properties of the gene product of the SCN5A gene. It is postulated that the heart remodeling observed in the Chagas' disease (CD) may conduct to an increased INaL. Depend upon the trigger to increased INaL, the pharmacological responsiveness to class I antiarrhythmic drugs, such as Lidocaine (1b) and Flecainide (Ic) are changed. Thus, it is necessary to understand the relationship between etiology x pharmacology of INaL and its pharmacological implication. Along these lines, the present project has two main objectives: (1) study the point mutation linked to SCN5A and long QT type 3 syndrome and its impact on the biophysical and pharmacological properties of INaL; (2) to understand whether INaL triggers arrhythmias during CD and if class I anti-arrhythmic drugs are therapeutics agents to treat arrhythmias in CD. The proposed project intents to be the corner stone to initiate a laboratory to study inherited and acquired cardiac arrhythmias due to changes in the biophysical properties of ion channels. (AU)

Scientific publications

(13)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SANTOS, MICHEL SANTANA; OLIVEIRA, EVALEIDE DINIZ; SANTOS-MIRANDA, ARTUR; CRUZ, JADER SANTOS; SANTANA GONDIM, ANTONIO NEI; RODRIGUES MENEZES-FILHO, JOSE EVALDO; SOUZA, DIEGO SANTOS; PINHO-DA-SILVA, LEIDIANE; GUEDES JESUS, ITAMAR COUTO; ROMAN-CAMPOS, DANILO; et al. Dissection of the Effects of Quercetin on Mouse Myocardium. BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, v. 120, n. 6, p. 550-559, JUN 2017. (14/09861-1)

CRUZ, JADER SANTOS; SANTOS-MIRANDA, ARTUR; SALES-JUNIOR, POLICARPO ADEMAR; MONTI-ROCHA, RENATA; CAMPOS, PAULA PEIXOTO; MACHADO, FABIANA SIMAO; ROMAN-CAMPOS, DANILO. Altered Cardiomyocyte Function and Trypanosoma cruzi Persistence in Chagas Disease. American Journal of Tropical Medicine and Hygiene, v. 94, n. 5, p. 1028-1033, 2016. (14/09861-1)

CRUZ, JADER SANTOS; MACHADO, FABIANA SIMAO; ROPERT, CATHERINE; ROMAN-CAMPOS, DANILO. Molecular mechanisms of cardiac electromechanical remodeling during Chagas disease: Role of TNF and TGF-beta. TRENDS IN CARDIOVASCULAR MEDICINE, v. 27, n. 2, p. 81-91, FEB 2017. (14/09861-1)

JOVIANO-SANTOS, V, J.; SANTOS-MIRANDA, A.; NERI, E. A.; FONSECA-ALANIZ, M. H.; KRIEGER, J. E.; PEREIRA, A. C.; ROMAN-CAMPOS, D.. SCN5A compound heterozygosity mutation in Brugada syndrome: Functional consequences and the implication for pharmacological treatment. Life Sciences, v. 278, AUG 1 2021. (19/21304-4, 14/09861-1, 18/20777-3)

SANTOS-MIRANDA, ARTUR; JOVIANO-SANTOS, JULLIANE V.; SARMENTO, JAQUELINE O.; COSTA, ALEXANDRE D.; SOARES, ALLYSSON T. C.; MACHADO, FABIANA S.; CRUZ, JADER S.; ROMAN-CAMPOS, DANILO. A novel substrate for arrhythmias in Chagas disease. PLoS Neglected Tropical Diseases, v. 15, n. 6, JUN 2021. (19/21304-4, 14/09861-1, 18/20777-3, 18/22830-9, 20/09403-4)

DA SILVA, AGATHA RIBEIRO; NERI, ELIDE A.; TURACA, LAURO THIAGO; DARIOLLI, RAFAEL; FONSECA-ALANIZ, MIRIAM H.; SANTOS-MIRANDA, ARTUR; ROMAN-CAMPOS, DANILO; VENTURINI, GABRIELA; KRIEGER, JOSE E.. NOTCH1 is critical for fibroblast-mediated induction of cardiomyocyte specialization into ventricular conduction system-like cells in vitro. SCIENTIFIC REPORTS, v. 10, n. 1, p. 18-pg., 2020-09-30. (19/21304-4, 14/24577-8, 18/22830-9, 15/50216-5, 17/05829-4, 13/17368-0, 14/09861-1)

ROMAN-CAMPOS, DANILO; SALES-JUNIOR, POLICARPO; SANTOS-MIRANDA, ARTUR; JOVIANO-SANTOS, V, JULLIANE; ROPERT, CATHERINE; CRUZ, JADER S.. Deletion of inducible nitric oxide synthase delays the onset of cardiomyocyte electrical remodeling in experimental Chagas disease. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v. 1866, n. 12, DEC 1 2020. (14/09861-1, 19/21304-4, 18/22830-9, 18/20777-3)

LEISIANE PEREIRA MARQUES; SAMUEL SANTOS BESERRA; DANILO ROMAN-CAMPOS; ANTONIO NEI SANTANA GONDIM. Efeito Cardiodepressor do Acetato de Eugenil em Coração de Roedor. Arquivos Brasileiros de Cardiologia, v. 115, n. 5, p. 967-970, 2020-12-07. (14/09861-1)

SANTOS-MIRANDA, ARTUR; JOVIANO-SANTOS, JULLIANE VASCONCELOS; RIBEIRO, GRAZIELLE ALVES; BOTELHO, ANA FLAVIA M.; ROCHA, PETER; VIEIRA, LEDA QUERCIA; CRUZ, JADER SANTOS; ROMAN-CAMPOS, DANILO. Reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental Chagas disease. PLOS PATHOGENS, v. 16, n. 3, MAR 2020. (18/20777-3, 14/09861-1, 18/22830-9)

JOVIANO-SANTOS, JULLIANE VASCONCELOS; SANTOS-MIRANDA, ARTUR; ROMAN-CAMPOS, DANILO. Cardiac electrical remodeling and neurodegenerative diseases association. Life Sciences, v. 267, FEB 15 2021. (19/21304-4, 18/22830-9, 18/20777-3, 14/09861-1)

VICTOR MARTINS MIRANDA; SAMUEL SANTOS BESERRA; DANILO ROMAN-CAMPOS. Ações Transmurais Inotrópicas e Antiarrítmicas da Ranolazina em um Modelo Celular da Síndrome do QT Longo Tipo 3. Arquivos Brasileiros de Cardiologia, v. 114, n. 4, p. 732-735, 2020-05-29. (14/09861-1)

SANTANA GONDIM, ANTONIO NEI; LARA, ALINE; SANTOS-MIRANDA, ARTUR; ROMAN-CAMPOS, DANILO; LAUTON-SANTOS, SANDRA; RODRIGUES MENEZES-FILHO, JOSE EVALDO; LINS DE VASCONCELOS, CARLA MARIA; CONDE-GARCIA, EDUARDO ANTONIO; GUATIMOSIM, SILVIA; CRUZ, JADER S.. (-)-Terpinen-4-ol changes intracellular Ca2+ handling and induces pacing disturbance in rat hearts. European Journal of Pharmacology, v. 807, p. 56-63, JUL 15 2017. (14/09861-1)

S. BESERRA, SAMUEL; ROMAN-CAMPOS, DANILO. Impact of pacing frequency in amiodarone interaction with cardiomyocytes near physiological temperature in health and disease conditions. BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, v. 128, n. 4, NOV 2020. (14/09861-1, 19/21304-4)