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New antiarrhythmic targets to control intracellular calcium handling.

Driessen HE, Bourgonje VJ, van Veen TA, Vos MA - Neth Heart J (2014)

Bottom Line: Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies.New targets include Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (I Na-Late ), all related to intracellular calcium (Ca(2+)) handling.These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, 3584 CM, Utrecht, the Netherlands, h.e.driessen@gmail.com.

ABSTRACT
Sudden cardiac death due to ventricular arrhythmias is a major problem. Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies. New targets include Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (I Na-Late ), all related to intracellular calcium (Ca(2+)) handling. In this review, drugs interfering with these targets (SEA-0400, K201, KN-93, W7, ranolazine, sophocarpine, and GS-967) are evaluated and their future as clinical compounds is considered. These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.

No MeSH data available.


Related in: MedlinePlus

a EAD and DAD formation. SR calcium overload leads to increased [Ca2+]i. This can lead to prolonged action potential duration creating a calcium window current potentially leading to EAD (3). Increased [Ca2+]i on the other hand can lead to spontaneous calcium release via CICR resulting in either EADs (4) or DADs (2) via NCX. Also, late Ina is able to increase [Ca]i via NCXr, hereby contributing to EAD formation. Numbers corresponding to black numbers in b. b 1; normal action potential and ICaL and INCX. 2; DAD occurring due to forward NCX activity (*). 3; EAD due to calcium window current via LTCC (**). 4; EAD due to forward NCX activity (***)
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Fig3: a EAD and DAD formation. SR calcium overload leads to increased [Ca2+]i. This can lead to prolonged action potential duration creating a calcium window current potentially leading to EAD (3). Increased [Ca2+]i on the other hand can lead to spontaneous calcium release via CICR resulting in either EADs (4) or DADs (2) via NCX. Also, late Ina is able to increase [Ca]i via NCXr, hereby contributing to EAD formation. Numbers corresponding to black numbers in b. b 1; normal action potential and ICaL and INCX. 2; DAD occurring due to forward NCX activity (*). 3; EAD due to calcium window current via LTCC (**). 4; EAD due to forward NCX activity (***)

Mentions: In hypertrophy and heart failure, Ca2+ handling is disturbed. As has been shown in several models, functional expression of SERCA is reduced whereas activity of the NCX is increased [5, 8]. Moreover, kinetics of RyR openings are also changed, leading to unanticipated Ca2+releases that can initiate EADs and DADs (Fig. 3). They are defined as: oscillations that attend (EADs) or follow (DADs) the cardiac AP and respond to preceding activation for their manifestation [9]. When the amplitude of the depolarisation reaches threshold, triggered activity in the form of ectopic beats occurs.Fig. 3


New antiarrhythmic targets to control intracellular calcium handling.

Driessen HE, Bourgonje VJ, van Veen TA, Vos MA - Neth Heart J (2014)

a EAD and DAD formation. SR calcium overload leads to increased [Ca2+]i. This can lead to prolonged action potential duration creating a calcium window current potentially leading to EAD (3). Increased [Ca2+]i on the other hand can lead to spontaneous calcium release via CICR resulting in either EADs (4) or DADs (2) via NCX. Also, late Ina is able to increase [Ca]i via NCXr, hereby contributing to EAD formation. Numbers corresponding to black numbers in b. b 1; normal action potential and ICaL and INCX. 2; DAD occurring due to forward NCX activity (*). 3; EAD due to calcium window current via LTCC (**). 4; EAD due to forward NCX activity (***)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig3: a EAD and DAD formation. SR calcium overload leads to increased [Ca2+]i. This can lead to prolonged action potential duration creating a calcium window current potentially leading to EAD (3). Increased [Ca2+]i on the other hand can lead to spontaneous calcium release via CICR resulting in either EADs (4) or DADs (2) via NCX. Also, late Ina is able to increase [Ca]i via NCXr, hereby contributing to EAD formation. Numbers corresponding to black numbers in b. b 1; normal action potential and ICaL and INCX. 2; DAD occurring due to forward NCX activity (*). 3; EAD due to calcium window current via LTCC (**). 4; EAD due to forward NCX activity (***)
Mentions: In hypertrophy and heart failure, Ca2+ handling is disturbed. As has been shown in several models, functional expression of SERCA is reduced whereas activity of the NCX is increased [5, 8]. Moreover, kinetics of RyR openings are also changed, leading to unanticipated Ca2+releases that can initiate EADs and DADs (Fig. 3). They are defined as: oscillations that attend (EADs) or follow (DADs) the cardiac AP and respond to preceding activation for their manifestation [9]. When the amplitude of the depolarisation reaches threshold, triggered activity in the form of ectopic beats occurs.Fig. 3

Bottom Line: Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies.New targets include Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (I Na-Late ), all related to intracellular calcium (Ca(2+)) handling.These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, 3584 CM, Utrecht, the Netherlands, h.e.driessen@gmail.com.

ABSTRACT
Sudden cardiac death due to ventricular arrhythmias is a major problem. Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies. New targets include Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (I Na-Late ), all related to intracellular calcium (Ca(2+)) handling. In this review, drugs interfering with these targets (SEA-0400, K201, KN-93, W7, ranolazine, sophocarpine, and GS-967) are evaluated and their future as clinical compounds is considered. These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.

No MeSH data available.


Related in: MedlinePlus