RESUMEN
The voltage-gated potassium ion channel KV11.1 plays a critical role in cardiac repolarization. Genetic variants that render Kv11.1 dysfunctional cause long QT syndrome (LQTS), which is associated with fatal arrhythmias. Approximately 90% of LQTS-associated variants cause intracellular protein transport (trafficking) dysfunction, which pharmacological chaperones like E-4031 can rescue. Protein folding and trafficking decisions are regulated by chaperones, protein quality control factors, and trafficking machinery comprising the cellular proteostasis network. Here, we test whether trafficking dysfunction is associated with alterations in the proteostasis network of pathogenic Kv11.1 variants and whether pharmacological chaperones can normalize the proteostasis network of responsive variants. We used affinity-purification coupled with tandem mass tag-based quantitative mass spectrometry to assess protein interaction changes of WT KV11.1 or trafficking-deficient channel variants in the presence or absence of E-4031. We identified 572 core KV11.1 protein interactors. Trafficking-deficient variants KV11.1-G601S and KV11.1-G601S-G965∗ had significantly increased interactions with proteins responsible for folding, trafficking, and degradation compared to WT. We confirmed previous findings that the proteasome is critical for KV11.1 degradation. Our report provides the first comprehensive characterization of protein quality control mechanisms of KV11.1. We find extensive interactome remodeling associated with trafficking-deficient KV11.1 variants and with pharmacological chaperone rescue of KV11.1 cell surface expression. The identified protein interactions could be targeted therapeutically to improve KV11.1 trafficking and treat LQTS.
Asunto(s)
Síndrome de QT Prolongado , Transporte de Proteínas , Proteostasis , Humanos , Síndrome de QT Prolongado/metabolismo , Síndrome de QT Prolongado/genética , Células HEK293 , Canales de Potasio Éter-A-Go-Go/metabolismo , Canales de Potasio Éter-A-Go-Go/genética , Canal de Potasio ERG1/metabolismo , Canal de Potasio ERG1/genética , AnimalesRESUMEN
BACKGROUND: Drug-induced QT prolongation (diLQT) is a feared side effect that could expose susceptible individuals to fatal arrhythmias. The occurrence of diLQT is primarily attributed to unintended drug interactions with cardiac ion channels, notably the hERG (human ether-a-go-go-related gene) channels that generate the delayed-rectifier potassium current (IKr) and thereby regulate the late repolarization phase. There is an important interindividual susceptibility to develop diLQT, which is of unknown origin but can be reproduced in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs). We aimed to investigate the dynamics of hERG channels in response to sotalol and to identify regulators of the susceptibility to developing diLQT. METHODS: We measured electrophysiological activity and cellular distribution of hERG channels after hERG blocker treatment in iPS-CMs derived from patients with highest sensitivity (HS) or lowest sensitivity (LS) to sotalol administration in vivo (ie, on the basis of the measure of the maximal change in QT interval 3 hours after administration). Specific small interfering RNAs and CAVIN1-T2A-GFP adenovirus were used to manipulate CAVIN1 expression. RESULTS: Whereas HS and LS iPS-CMs showed similar electrophysiological characteristics at baseline, the late repolarization phase was prolonged and IKr significantly decreased after exposure of HS iPS-CMs to low sotalol concentrations. IKr reduction was caused by a rapid translocation of hERG channel from the membrane to the cytoskeleton-associated fractions upon sotalol application. CAVIN1, essential for caveolae biogenesis, was 2× more highly expressed in HS iPS-CMs, and its knockdown by small interfering RNA reduced their sensitivity to sotalol. CAVIN1 overexpression in LS iPS-CMs using adenovirus showed reciprocal effects. We found that treatment with sotalol promoted translocation of the hERG channel from the plasma membrane to the cytoskeleton fractions in a process dependent on CAVIN1 (caveolae associated protein 1) expression. CAVIN1 silencing reduced the number of caveolae at the membrane and abrogated the translocation of hERG channel in sotalol-treated HS iPS-CMs. CAVIN1 also controlled cardiomyocyte responses to other hERG blockers, such as E4031, vandetanib, and clarithromycin. CONCLUSIONS: Our study identifies unbridled turnover of the potassium channel hERG as a mechanism supporting the interindividual susceptibility underlying diLQT development and demonstrates how this phenomenon is finely tuned by CAVIN1.
Asunto(s)
Canal de Potasio ERG1 , Células Madre Pluripotentes Inducidas , Síndrome de QT Prolongado , Miocitos Cardíacos , Sotalol , Humanos , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/metabolismo , Síndrome de QT Prolongado/genética , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Canal de Potasio ERG1/genética , Canal de Potasio ERG1/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Sotalol/farmacología , Potenciales de Acción/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/metabolismo , Canales de Potasio Éter-A-Go-Go/genética , MasculinoRESUMEN
Genetic variants of gene SCN5A encoding the alpha-subunit of cardiac voltage-gated sodium channel Nav1.5 are associated with various diseases, including long QT syndrome (LQT3), Brugada syndrome (BrS1), and progressive cardiac conduction disease (PCCD). In the last decades, the great progress in understanding molecular and biophysical mechanisms of these diseases has been achieved. The LQT3 syndrome is associated with gain-of-function of sodium channels Nav1.5 due to impaired inactivation, enhanced activation, accelerated recovery from inactivation or the late current appearance. In contrast, BrS1 and PCCD are associated with the Nav1.5 loss-of-function, which in electrophysiological experiments can be manifested as reduced current density, enhanced fast or slow inactivation, impaired activation, or decelerated recovery from inactivation. Genetic variants associated with congenital arrhythmias can also disturb interactions of the Nav1.5 channel with different proteins or drugs and cause unexpected reactions to drug administration. Furthermore, mutations can affect post-translational modifications of the channels and their sensitivity to pH and temperature. Here we briefly review the current knowledge on biophysical mechanisms of LQT3, BrS1 and PCCD. We focus on limitations of studies that use heterologous expression systems and induced pluripotent stem cells (iPSC) derived cardiac myocytes and summarize our understanding of genotype-phenotype relations of SCN5A mutations.
Asunto(s)
Canalopatías , Canal de Sodio Activado por Voltaje NAV1.5 , Humanos , Animales , Canalopatías/genética , Canalopatías/metabolismo , Canal de Sodio Activado por Voltaje NAV1.5/genética , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Miocardio/metabolismo , Síndrome de Brugada/genética , Síndrome de Brugada/metabolismo , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/metabolismo , Síndrome de QT Prolongado/fisiopatologíaRESUMEN
Here, we characterized the p.Arg583His (R583H) Kv7.1 mutation, identified in two unrelated families suffered from LQT syndrome. This mutation is located in the HС-HD linker of the cytoplasmic portion of the Kv7.1 channel. This linker, together with HD helix are responsible for binding the A-kinase anchoring protein 9 (AKAP9), Yotiao. We studied the electrophysiological characteristics of the mutated channel expressed in CHO-K1 along with KCNE1 subunit and Yotiao protein, using the whole-cell patch-clamp technique. We found that R583H mutation, even at the heterozygous state, impedes IKs activation. Molecular modeling showed that HС and HD helixes of the C-terminal part of Kv7.1 channel are swapped along the C-terminus length of the channel and that R583 position is exposed to the outer surface of HC-HD tandem coiled-coil. Interestingly, the adenylate cyclase activator, forskolin had a smaller effect on the mutant channel comparing with the WT protein, suggesting that R583H mutation may disrupt the interaction of the channel with the adaptor protein Yotiao and, therefore, may impair phosphorylation of the KCNQ1 channel.
Asunto(s)
Proteínas de Anclaje a la Quinasa A , Proteínas del Citoesqueleto , Canal de Potasio KCNQ1 , Síndrome de QT Prolongado , Animales , Femenino , Humanos , Masculino , Proteínas de Anclaje a la Quinasa A/metabolismo , Proteínas de Anclaje a la Quinasa A/genética , Proteínas de Anclaje a la Quinasa A/química , Células CHO , Cricetulus , Proteínas del Citoesqueleto/química , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Canal de Potasio KCNQ1/genética , Canal de Potasio KCNQ1/metabolismo , Canal de Potasio KCNQ1/química , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/metabolismo , Modelos Moleculares , Mutación , Canales de Potasio con Entrada de Voltaje/química , Canales de Potasio con Entrada de Voltaje/genética , Canales de Potasio con Entrada de Voltaje/metabolismo , Unión ProteicaRESUMEN
Drug withdrawal post-marketing due to cardiotoxicity is a major concern for drug developers, regulatory agencies, and patients. One common mechanism of cardiotoxicity is through inhibition of cardiac ion channels, leading to prolongation of the QT interval and sometimes fatal arrythmias. Recently, oxylipin signaling compounds have been shown to bind to and alter ion channel function, and disruption in their cardiac levels may contribute to QT prolongation. Cytochrome P450 2J2 (CYP2J2) is the predominant CYP isoform expressed in cardiomyocytes, where it oxidizes arachidonic acid to cardioprotective epoxyeicosatrienoic acids (EETs). In addition to roles in vasodilation and angiogenesis, EETs bind to and activate various ion channels. CYP2J2 inhibition can lower EET levels and decrease their ability to preserve cardiac rhythm. In this review, we investigated the ability of known CYP inhibitors to cause QT prolongation using Certara's Drug Interaction Database. We discovered that among the multiple CYP isozymes, CYP2J2 inhibitors were more likely to also be QT-prolonging drugs (by approximately 2-fold). We explored potential binding interactions between these inhibitors and CYP2J2 using molecular docking and identified four amino acid residues (Phe61, Ala223, Asn231, and Leu402) predicted to interact with QT-prolonging drugs. The four residues are located near the opening of egress channel 2, highlighting the potential importance of this channel in CYP2J2 binding and inhibition. These findings suggest that if a drug inhibits CYP2J2 and interacts with one of these four residues, then it may have a higher risk of QT prolongation and more preclinical studies are warranted to assess cardiovascular safety.
Asunto(s)
Citocromo P-450 CYP2J2 , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450 , Síndrome de QT Prolongado , Humanos , Sistema Enzimático del Citocromo P-450/metabolismo , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/metabolismo , Inhibidores Enzimáticos del Citocromo P-450/farmacología , AnimalesRESUMEN
Brugada syndrome (BrS) is an inherited disease characterized by right precordial ST-segment elevation in the right precordial leads on electrocardiograms (ECG), and high risk of life-threatening ventricular arrhythmia and sudden cardiac death (SCD). Mutations in the responsible genes have not been fully characterized in the BrS patients, except for the SCN5A gene. We identified a new genetic variant, c.1189C>T (p.R397C), in the KCNH2 gene in the asymptomatic male proband diagnosed with BrS and mild QTc shortening. We hypothesize that this variant could alter IKr-current and may be causative for the rare non-SCN5A-related form of BrS. To assess its pathogenicity, we performed patch-clamp analysis on IKr reconstituted with this KCNH2 mutation in the Chinese hamster ovary cells and compared the phenotype with the wild type. It appeared that the R397C mutation does not affect the IKr density, but facilitates activation, hampers inactivation of the hERG channels, and increases magnitude of the window current suggesting that the p.R397C is a gain-of-function mutation. In silico modeling demonstrated that this missense mutation potentially leads to the shortening of action potential in the heart.
Asunto(s)
Síndrome de Brugada , Canal de Potasio ERG1 , Mutación con Ganancia de Función , Adulto , Animales , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Brugada/genética , Síndrome de Brugada/metabolismo , Células CHO , Cricetulus , Electrocardiografía , Canal de Potasio ERG1/genética , Canal de Potasio ERG1/metabolismo , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/metabolismo , Mutación MissenseRESUMEN
Long QT Syndrome (LQTS) is a genetic heart disorder that can induce cardiac arrhythmias. The most prevalent subtype, LQT1, stems from rare variants in the KCNQ1 gene. Utilizing induced pluripotent stem cells (iPSCs) enables detailed cellular studies and personalized medicine approaches for this life-threatening condition. We generated two LQT1 iPSC lines with single nucleotide nonsense mutations, c.1031 C > T and c.1121 T > A in KCNQ1. Both lines exhibited typical iPSC morphology, expressed high levels of pluripotent markers, maintained normal karyotype, and possessed the capability to differentiate into three germ layers. These cell lines serve as important tools for investigating the biological mechanisms underlying LQT1 due to mutations in the KCNQ1 gene.
Asunto(s)
Células Madre Pluripotentes Inducidas , Canal de Potasio KCNQ1 , Síndrome de QT Prolongado , Humanos , Canal de Potasio KCNQ1/genética , Canal de Potasio KCNQ1/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/patología , Síndrome de QT Prolongado/metabolismo , Línea Celular , Heterocigoto , Mutación , Masculino , Femenino , Diferenciación CelularRESUMEN
KCNH2 (Potassium Voltage-Gated Channel Subfamily H Member) encodes a voltage-activated potassium channel role as rapidly activating-delayed rectifier potassium channel that plays an essential role in the final repolarization of the ventricular action potential. Mutations in this gene can cause long QT syndrome and short QT syndrome. Transcript variants encoding distinct isoforms were also identified. In this study, we generated induced pluripotent stem cells (iPSC) from a healthy individual by electroporation of peripheral blood mononuclear cells and generated a KCNH2 heterozygous knockout human iPSC line via CRISPR/Cas9 gene editing. The resulting iPSCs had a normal karyotype, were free of genomically integrated epitomal plasmids, expressed pluripotency markers, and maintained trilineage differentiation potential.
Asunto(s)
Canal de Potasio ERG1 , Heterocigoto , Células Madre Pluripotentes Inducidas , Síndrome de QT Prolongado , Células Madre Pluripotentes Inducidas/metabolismo , Humanos , Canal de Potasio ERG1/genética , Canal de Potasio ERG1/metabolismo , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/metabolismo , Síndrome de QT Prolongado/patología , Línea Celular , Sistemas CRISPR-Cas , Técnicas de Inactivación de Genes , Diferenciación Celular , Edición Génica , Arritmias CardíacasRESUMEN
The KCNQ1 gene encodes a voltage-gated potassium channel required for cardiac action potentials. Mutations in this gene have been associated with hereditary long QT syndrome 1, Jervell and Lange-Nielsen syndromes, and familial atrial fibrillation. The NM_000218.3(KCNQ1): c.604 + 2T > C mutation has been categorized as the causative variant leading to LQT1. In this study, we generated a KCNQ1 (c.644 + 2T > C) mutation human embryonic stem cell line WAe009-A-1L based on CRISPR base editing system. WAe009-A-1L cell has the potential to differentiate cardiomyocytes and would be used as an in vitro disease model for mechanism exploration and drug screening.
Asunto(s)
Edición Génica , Células Madre Embrionarias Humanas , Canal de Potasio KCNQ1 , Mutación , Humanos , Células Madre Embrionarias Humanas/metabolismo , Células Madre Embrionarias Humanas/citología , Edición Génica/métodos , Canal de Potasio KCNQ1/genética , Canal de Potasio KCNQ1/metabolismo , Línea Celular , Sistemas CRISPR-Cas , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/citología , Diferenciación Celular , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genéticaRESUMEN
Potassium ion transport across myocardial cell membrane is essential for type 2 long QT syndrome (LQT2). However, the dysfunction of potassium ion transport due to genetic mutations limits the therapeutic effect in treating LQT2. Biomimetic ion channels that selectively and efficiently transport potassium ions across the cellular membranes are promising for the treatment of LQT2. To corroborate this, we synthesized a series of foldamer-based ion channels with different side chains, and found a biomimetic ion channel of K+ (BICK) with the highest transport activity among them. The selected BICK can restore potassium ion transport and increase transmembrane potassium ion current, thus shortening phase 3 of action potential (AP) repolarization and QT interval in LQT2. Moreover, BICK does not affect heart rate and cardiac rhythm in treating LQT2 model induced by E4031 in isolated heart as well as in guinea pigs. By restoring ion transmembrane transport tactic, biomimetic ion channels, such as BICK, will show great potential in treating diseases related to ion transport blockade. STATEMENT OF SIGNIFICANCE: Type 2 long QT syndrome (LQT2) is a disease caused by K+ transport disorder, which can cause malignant arrhythmia and even death. There is currently no radical cure, so it is critical to explore ways to improve K+ transmembrane transport. In this study, we report that a small-molecule biomimetic ion channel BICK can efficiently simulate natural K+ channel proteins on the cardiomyocyte and cure E4031-induced LQT2 in guinea pig by restoring K+ transport function for the first time. This study found that the potassium transmembrane transport by BICK significantly reduced the QT interval, which provides a conceptually new strategy for the treatment of LQT2 disease.
Asunto(s)
Síndrome de QT Prolongado , Potasio , Síndrome de QT Prolongado/metabolismo , Animales , Potasio/metabolismo , Cobayas , Humanos , Potenciales de Acción/efectos de los fármacos , Transporte Iónico/efectos de los fármacos , Masculino , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Canales de Potasio/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Frecuencia Cardíaca/efectos de los fármacosRESUMEN
BACKGROUND: CaM (calmodulin)-mediated long-QT syndrome is a genetic arrhythmia disorder (calmodulinopathies) characterized by a high prevalence of life-threatening ventricular arrhythmias occurring early in life. Three distinct genes (CALM1, CALM2, and CALM3) encode for the identical CaM protein. Conventional pharmacotherapies fail to adequately protect against potentially lethal cardiac events in patients with calmodulinopathy. METHODS: Five custom-designed CALM1-, CALM2-, and CALM3-targeting short hairpin RNAs (shRNAs) were tested for knockdown (KD) efficiency using TSA201 cells and reverse transcription-quantitative polymerase chain reaction. A dual-component suppression and replacement (SupRep) CALM gene therapy (CALM-SupRep) was created by cloning into a single construct CALM1-, CALM2-, and CALM3-specific shRNAs that produce KD (suppression) of each respective gene and a shRNA-immune CALM1 cDNA (replacement). CALM1-F142L, CALM2-D130G, and CALM3-D130G induced pluripotent stem cell-derived CMs were generated from patients with CaM-mediated long-QT syndrome. A voltage-sensing dye was used to measure action potential duration at 90% repolarization (APD90). RESULTS: Following shRNA KD efficiency testing, a candidate shRNA was identified for CALM1 (86% KD), CALM2 (71% KD), and CALM3 (94% KD). The APD90 was significantly prolonged in CALM2-D130G (647±9 ms) compared with CALM2-WT (359±12 ms; P<0.0001). Transfection with CALM-SupRep shortened the average APD90 of CALM2-D130G to 457±19 ms (66% attenuation; P<0.0001). Additionally, transfection with CALM-SupRep shortened the APD90 of CALM1-F142L (665±9 to 410±15 ms; P<0.0001) and CALM3-D130G (978±81 to 446±6 ms; P<0.001). CONCLUSIONS: We provide the first proof-of-principle suppression-replacement gene therapy for CaM-mediated long-QT syndrome. The CALM-SupRep gene therapy shortened the pathologically prolonged APD90 in CALM1-, CALM2-, and CALM3-variant CaM-mediated long-QT syndrome induced pluripotent stem cell-derived CM lines. The single CALM-SupRep construct may be able to treat all calmodulinopathies, regardless of which of the 3 CaM-encoding genes are affected.
Asunto(s)
Calmodulina , Terapia Genética , Síndrome de QT Prolongado , Humanos , Calmodulina/genética , Calmodulina/metabolismo , Terapia Genética/métodos , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/terapia , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/metabolismo , Síndrome de QT Prolongado/diagnóstico , Miocitos Cardíacos/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Potenciales de Acción , Predisposición Genética a la Enfermedad , Mutación , Interferencia de ARN , Frecuencia Cardíaca/genéticaAsunto(s)
Potenciales de Acción , Células Madre Pluripotentes Inducidas , Síndrome de QT Prolongado , Miocitos Cardíacos , Humanos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Femenino , Estrógenos/farmacología , Estrógenos/metabolismo , Estradiol/farmacología , FenotipoRESUMEN
Visando avaliar o intervalo QTc e sua relação com variáveis clínicas, laboratoriais e com suscetibilidade da LDL à oxidação in vitro em pacientes com DM1, estudamos 40 diabéticos e 33 não diabéticos com idades de 24,83 ± 10,21 e 23,51 ± 7,28 anos, respectivamente, pareados por sexo, idade e índice de massa corporal (IMC). Avaliamos controle metabólico, apolipoproteínas A e B, coeficiente de oxidação da LDL por espectrofotometria e eletrocardiograma (ECG). O intervalo QTc foi calculado pela fórmula de Bazett. Não houve diferença no QTc entre os grupos dos DM1 e dos não diabéticos (394,43 ± 19,98 ms vs. 401,31 ± 17,83 ms; p = 0,2065). Cinco diabéticos apresentavam QTc aumentado (396,76 ± 14,63 ms vs. 429,75 ± 1,89 ms; p < 0,001) e menores níveis de apolipoproteína A que os demais diabéticos (74,60 ± 25,42 mg/dL vs. 113,64 ± 29,79 mg/dL; p = 0,011). Na amostra total, houve correlação entre QTc e IMC (rho = -0,288; p = 0,045), glicemia pós-prandial (rho = 0,357; p = 0,016) e coeficiente de oxidação 3 h (Cox3h) (r = -0,293; p = 0,039). Nos diabéticos, encontramos correlação entre QTc e triglicerídeos (rho = -0,420; p = 0,023) e Cox3h (r = -0,427; p = 0,021). Embora não tenhamos encontrado diferença entre o QTc dos diabéticos e não diabéticos estudados, houve correlação com marcadores de risco para a doença aterosclerótica. Entretanto, ainda são necessários mais estudos para estabelecer o real valor preditivo do QTc para esta doença nos pacientes com DM1.
To evaluate the QTc interval and its relation with clinical, laboratorial variables and LDL susceptibility to in vitro oxidation in patients with type 1 DM, we studied 40 diabetics and 33 non diabetics with 24.83 ± 10.21 and 23.51 ± 7.28 years old, respectively matched by sex, age and body mass index (BMI). We evaluated metabolic control, A and B apolipoproteins, LDL oxidation coefficient for spectrophotometry and electrocardiogram (ECG). Interval QTc was calculated by the Bazetts formula. There was no difference in QTc between diabetic and non diabetic groups (394.43 ± 19.98 ms versus 401.31 ± 17.83 ms; p = 0.2065). Five diabetics showed increased QTc (396.76 ± 14.63 ms versus 429.75 ± 1.89 ms; p < 0.001) and lesser A apolipoprotein levels than rest of diabetic group (74.60 ± 25.42 mg/dL versus 113.64 ± 29.79 mg/dL; p = 0,011). In pooled sample, there was correlation between QTc and BMI (rho = -0.288; p = 0.045), pot-prandial glycemia (rho = 0.357; p = 0.016) and 3 h oxidation coefficient (OxC3h) (r = -0.293; p = 0.039). In diabetics, there was correlation between QTc and triglycerides (rho = -0.420; p = 0.023) and OxC3h (r = -0.427; p = 0.021). Although there was no difference between QTc of diabetics and the non diabetics subjects studied, there was correlation with risk factors for the atherosclerotic disease. Further studies are necessary to establish the real predictive value of QTc for this type of disease in the patients with type 1 DM.