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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 RyR open probability, [Ca2+]SR, and sparks. Calcium sparks occur when [Ca2+]SR reaches RyR opening threshold. RyR opening threshold is influenced by the open probability of RyR. Higher open probability lowers the threshold. [Ca2+]SR is affected by total [Ca2+]in and SERCA. b In heart failure [Ca2+]SR is lowered but the RyR open threshold is lowered more extensively rendering [Ca2+]SR higher then threshold
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Fig4: a RyR open probability, [Ca2+]SR, and sparks. Calcium sparks occur when [Ca2+]SR reaches RyR opening threshold. RyR opening threshold is influenced by the open probability of RyR. Higher open probability lowers the threshold. [Ca2+]SR is affected by total [Ca2+]in and SERCA. b In heart failure [Ca2+]SR is lowered but the RyR open threshold is lowered more extensively rendering [Ca2+]SR higher then threshold

Mentions: DADs arise after full repolarisation of the myocyte. Ca2+ release from the SR is triggered when free SR [Ca2+], ([Ca2+]SR), reaches a certain threshold leading to opening of RyRs (Fig. 4) [10]. [Ca2+]SR is influenced by total [Ca2+]i and the activity of SERCA. Increased [Ca2+]SR load due to higher SERCA activity, for example via β-adrenergic stimulation, brings the [Ca2+]SR closer to the threshold for SR leak. Furthermore, the threshold is affected by the RyR open probability: if the open probability increases, the threshold lowers. The open probability of RyR is modulated by [Ca2+]SR, [Ca2+]i, AP, RyR phosphorylation and the stabilising protein FKBP12.6 (Calstabin) [11, 12]. RyR phosphorylation is among others executed by CaMKII, and this increases the open probability of RyR [13, 14]. Opening of multiple RyRs creates Ca2+ sparks, which can lead to DADs via creation of the transient inward current (Iti) by the NCX (Fig. 3) [15]. If the DADs reach threshold a new AP arises. In heart failure, [Ca2+]SR and threshold are both lowered (Fig. 4) yet threshold is affected more than [Ca2+]SR leading to a higher occurrence of triggered arrhythmias in these patients [16].Fig. 4


New antiarrhythmic targets to control intracellular calcium handling.

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

a RyR open probability, [Ca2+]SR, and sparks. Calcium sparks occur when [Ca2+]SR reaches RyR opening threshold. RyR opening threshold is influenced by the open probability of RyR. Higher open probability lowers the threshold. [Ca2+]SR is affected by total [Ca2+]in and SERCA. b In heart failure [Ca2+]SR is lowered but the RyR open threshold is lowered more extensively rendering [Ca2+]SR higher then threshold
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig4: a RyR open probability, [Ca2+]SR, and sparks. Calcium sparks occur when [Ca2+]SR reaches RyR opening threshold. RyR opening threshold is influenced by the open probability of RyR. Higher open probability lowers the threshold. [Ca2+]SR is affected by total [Ca2+]in and SERCA. b In heart failure [Ca2+]SR is lowered but the RyR open threshold is lowered more extensively rendering [Ca2+]SR higher then threshold
Mentions: DADs arise after full repolarisation of the myocyte. Ca2+ release from the SR is triggered when free SR [Ca2+], ([Ca2+]SR), reaches a certain threshold leading to opening of RyRs (Fig. 4) [10]. [Ca2+]SR is influenced by total [Ca2+]i and the activity of SERCA. Increased [Ca2+]SR load due to higher SERCA activity, for example via β-adrenergic stimulation, brings the [Ca2+]SR closer to the threshold for SR leak. Furthermore, the threshold is affected by the RyR open probability: if the open probability increases, the threshold lowers. The open probability of RyR is modulated by [Ca2+]SR, [Ca2+]i, AP, RyR phosphorylation and the stabilising protein FKBP12.6 (Calstabin) [11, 12]. RyR phosphorylation is among others executed by CaMKII, and this increases the open probability of RyR [13, 14]. Opening of multiple RyRs creates Ca2+ sparks, which can lead to DADs via creation of the transient inward current (Iti) by the NCX (Fig. 3) [15]. If the DADs reach threshold a new AP arises. In heart failure, [Ca2+]SR and threshold are both lowered (Fig. 4) yet threshold is affected more than [Ca2+]SR leading to a higher occurrence of triggered arrhythmias in these patients [16].Fig. 4

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