Diabetes mellitus attenuates the repolarization reserve in mammalian heart

Lengyel, Csaba; Virág, László; Bı́ró, Tamás; Jost, Norbert; Magyar, János; Biliczki, Péter; Kocsis, Erzsébet; Skoumal, Réka; Nánási, Péter P.; Tóth, Miklós; Kecskeméti, Valéria; Papp, Julius Gyula; Varró, András

doi:10.1016/j.cardiores.2006.11.010

Cited by 86 publications

(94 citation statements)

References 53 publications

(62 reference statements)

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“…This work is performed in an animal model (rat) which has only part of the cardiac K + repolarizing currents present in human heart (I to and IK 1 ). Different works carried out in different animal models showed that IK 1 is not affected by diabetes, IK s is slightly reduced, IK r is slightly or no reduced, and I to is reduced by half, being this last the main responsible for the action potential alterations found in diabetic hearts [2,14,40,41]. However, based on the results obtained with I to , we can expect that the intracellular regulation of the other channels would be impaired in diabetic hearts as well.…”

Section: Discussioncontrasting

confidence: 39%

Reduced Calmodulin Expression Accelerates Transient Outward Potassium Current Inactivation in Diabetic Rat Heart

Gallego

Ahyayauch

et al. 2008

Cell Physiol Biochem

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Background/Aims: In myocytes from diabetic hearts, the reduction in the amplitude of the transient outward potassium current (I_to) and the acceleration of its inactivation contribute to the action potential duration lengthening. Whereas the reduced amplitude is attributable to a reduced support of trophic factors, the mechanism underlying the acceleration of inactivation remains unknown. Ca²⁺/Calmodulin-dependent protein kinase II (CaMKII) modifies the inactivation kinetics of I_to. In this work we explored the role of CaMKII in the acceleration of I_to current inactivation observed in diabetic myocytes. Methods: We used patch-clamp and immunoblotting techniques in enzymatically-isolated myocytes from healthy and streptozotocin-induced diabetic rat hearts, and in blood samples from diabetic patients. Results: In control myocytes, inhibition of either calmodulin or CaMKII accelerated I_to current inactivation. However, in diabetic myocytes I_to inactivation was already accelerated, and did not respond to calmodulin or CaMKII inhibition. Calmodulin protein abundance was significantly reduced in diabetic myocytes. Incubation of diabetic myocytes with insulin recovered calmodulin expression to normal values. A similar pattern of calmodulin expression appears in the blood of diabetic patients. Insulin treatment also restored I_to current inactivation kinetics as well as the responsiveness to regulation by calmodulin. Conclusion: Diabetes-induced acceleration of I_to current inactivation is due to a reduced effect of CaMKII on I_to channels as a result of a diabetes-induced reduction in calmodulin protein expression. A correct follow up of the insulin treatment could prevent this alteration.

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Section: Discussioncontrasting

confidence: 39%

Reduced Calmodulin Expression Accelerates Transient Outward Potassium Current Inactivation in Diabetic Rat Heart

Gallego

Ahyayauch

et al. 2008

Cell Physiol Biochem

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“…However, the demonstration that genetic variants in NOS1AP reproducibly alter QT interval duration in families aggregating diabetes demonstrates that genetic effects are not swamped out by the strong effect of diabetes on repolarization. Rather, the opposite appears to be true: the reduced repolarization reserve of diabetes (35,36) shows a synergistic interaction with genetic variants that alter myocardial repolarization. It is thus notable that the strength of the effect of NOS1AP SNPs in EuropeanAmerican diabetic subjects in the current report, 11.3-to 13.9-ms differences between alternate homozygotes, is much greater than that observed in the previous reports by Arking et al (11) Of additional interest, 34% (n ϭ 264) of all European-American diabetic subjects (n ϭ 778) in the Diabetes Heart Study is using a QT-altering medication (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study

et al. 2008

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OBJECTIVES—Prolongation of the electrocardiographic QT interval is a risk factor for sudden cardiac death (SCD). Diabetic individuals are at increased risk for prolonged QT interval and SCD. We sought to replicate the finding that genetic variants in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene are associated with QT interval duration in a type 2 diabetes–enriched sample of European ancestry. RESEARCH DESIGN AND METHODS—Two single nucleotide polymorphisms (SNPs) in NOS1AP were genotyped in 624 European Americans and 127 African Americans from 400 pedigrees enriched for type 2 diabetes. An additive genetic model was tested for each SNP in ancestry-specific analyses in the total sample and the diabetic subset (European Americans, n = 514; African Americans, n = 115), excluding from the analyses individuals taking QT-altering medications. RESULTS—In European Americans, rs10494366 minor homozygotes had a 9.3-ms-longer QT interval compared with major homozygotes (P = 5.7 × 10−5); rs10918594 minor homozygotes had a 12.5-ms-longer QT interval compared with major homozygotes (P = 1.5 × 10−6). Restricting analyses to the diabetic European Americans strengthened the effect despite the reduction in sample size (11.3-ms difference, P = 5.1 × 10−5; 13.9-ms difference, P = 1.6 × 10−6, respectively). No association between the NOS1AP SNPs and QT interval duration was observed in the limited number of African Americans. CONCLUSIONS—Two NOS1AP SNPs are strongly associated with QT interval duration in a predominately diabetic European-American sample. Stronger effects of NOS1AP variants in diabetic individuals suggest that this patient subset may be particularly susceptible to genetic variants that influence myocardial depolarization and repolarization as manifest in the QT interval.

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“…Diabetes is known to induce marked remodelling in the set of cardiac ion currents in all mammalian species studied, including dogs (Lengyel et al, 2007), rabbits (Lengyel et al, 2008) and rats (Magyar et al, 1992). In addition, differences in the effects of both rosiglitazone and troglitazone were observed when compared between healthy and diabetic rats (Arikawa et al, 2002;Kavak et al, 2008).…”

Section: Limitations Of the Studymentioning

confidence: 95%

Effects of rosiglitazone on the configuration of action potentials and ion currents in canine ventricular cells

Szentandrássy

Harmati

Bárándi

et al. 2011

British J Pharmacology

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In spite of its widespread clinical application, there is little information on the cellular cardiac effects of the antidiabetic drug rosiglitazone in larger experimental animals. In the present study therefore concentration-dependent effects of rosiglitazone on action potential morphology and the underlying ion currents were studied in dog hearts. EXPERIMENTAL APPROACHStandard microelectrode techniques, conventional whole cell patch clamp and action potential voltage clamp techniques were applied in enzymatically dispersed ventricular cells from dog hearts. KEY RESULTSAt concentrations Ն10 mM rosiglitazone decreased the amplitude of phase-1 repolarization, reduced the maximum velocity of depolarization and caused depression of the plateau potential. These effects developed rapidly and were readily reversible upon washout. Rosiglitazone suppressed several transmembrane ion currents, concentration-dependently, under conventional voltage clamp conditions and altered their kinetic properties. The EC50 value for this inhibition was 25.2 Ϯ 2.7 mM for the transient outward K + current (Ito), 72.3 Ϯ 9.3 mM for the rapid delayed rectifier K + current (IKr) and 82.5 Ϯ 9.4 mM for the L-type Ca 2+ current (ICa) with Hill coefficients close to unity. The inward rectifier K + current (IK1) was not affected by rosiglitazone up to concentrations of 100 mM. Suppression of Ito, IKr, and ICa was confirmed also under action potential voltage clamp conditions. CONCLUSIONS AND IMPLICATIONSAlterations in the densities and kinetic properties of ion currents may carry serious pro-arrhythmic risk in case of overdose with rosiglitazone, especially in patients having multiple cardiovascular risk factors, like elderly diabetic patients. LINKED ARTICLE

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Diabetes mellitus attenuates the repolarization reserve in mammalian heart

Abstract: It is concluded that type 1 diabetes mellitus, although only moderately, lengthens ventricular repolarization, attenuates the repolarization reserve by decreasing I(to) and I(Ks) currents, and thereby may markedly enhance the risk of sudden cardiac death.

Cited by 86 publications

References 53 publications

Reduced Calmodulin Expression Accelerates Transient Outward Potassium Current Inactivation in Diabetic Rat Heart

Reduced Calmodulin Expression Accelerates Transient Outward Potassium Current Inactivation in Diabetic Rat Heart

Association of NOS1AP Genetic Variants With QT Interval Duration in Families From the Diabetes Heart Study

Effects of rosiglitazone on the configuration of action potentials and ion currents in canine ventricular cells

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