Novel therapeutic approaches for heart failure by normalizing calcium cycling

Key Points

  • Heart failure (HF) is the leading cause of death in the Western world.

  • Abnormal intracellular Ca2+ handling is crucial to the pathogenesis of heart failure, and is an important contributor to a decrease in ventricular contractile function.

  • Hyperactivity of the sympathetic nervous system is important role in sustaining abnormal intracellular Ca2+ release.

  • Protein kinase A (PKA) hyperphosphorylation of the cardiac ryanodine receptor (RyR2) leads to dissociation of the channel-stabilizing protein calstabin2, which is associated with diastolic Ca2+ leak and a reduction in cardiac contractility.

  • β-adrenoceptor blockers are one class of the few drugs that reduce mortality in CHF patients. Beta-blockers reverse PKA-hyperphosphorylation of RyR2 and increase calstabin2 binding, which might contribute to increased contractility in patients with CHF.

  • Specific inhibitors for G-protein-coupled receptor kinase (GRK) or protein kinase C (PKC-α) are promising therapeutic targets to normalize intracellular signalling in the failing heart.

  • New drugs designed to increase sarcoplasmic reticulum Ca2+ loading in CHF could potentially induce cardiac arrhythmias.

  • The 1,4-benzothiazepine JTV519 increases calstabin2 binding to RyR2 in failing hearts. By preventing intracellular Ca2+ leak, JTV519 increases cardiac contractility and decreases the propensity to cardiac arrhythmias in CHF.


Congestive heart failure is the leading cause of death in the Western world. Abnormal intracellular calcium (Ca2+) handling is central to the pathogenesis of heart failure because it contributes to a decrease in ventricular contractile function. Chronic hyperactivity of the sympathetic nervous system causes increased phosphorylation of the ryanodine receptor intracellular Ca2+-release channel, a key Ca2+-handling protein in the heart, by protein kinase A. Alteration of the structure and function of ryanodine receptors contributes to defective intracellular Ca2+ handling and an increased propensity for cardiac arrhythmias in failing hearts. Novel therapeutic strategies are now being evaluated to specifically correct defective Ca2+-handling in heart failure.

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Figure 1: Excitation–contraction coupling in the heart.
Figure 2: Regulation of intracellular Ca2+ signalling in the heart.
Figure 3: Ryanodine receptor-2 is a macromolecular complex.
Figure 4: Action of β-adrenoceptor blockers and JTV519 on ryanodine receptor-2 in heart failure.


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Correspondence to Andrew R. Marks.

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The authors are employed by Columbia University, which has filed patents based on some of the authors' findings described in this article.

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Muscle cells that contract rhythmically in the heart.


The phase of the cardiac cycle during which the ventricles contract.


The phase of the cardiac cycle during which the ventricles are relaxed.


An invagination of the plasma membrane that contains ion channels and ion transporters that are in a close spatial relationship with ion channels on the sarcoplasmic reticulum (to enable efficient excitation–contraction coupling).


Hormones (for example, adrenaline and noradrenaline) that affect the sympathetic nervous system, produced in the medulla of the adrenal gland. Catecholamines are derivatives of the steroid catechol, which is derived from the amino acid tyrosine.


The ability of Ca2+ influx through voltage-gated L-type Ca2+ channels to trigger Ca2+ release from the sarcoplasmic reticulum.


An evolutionarily conserved mechanism which allows for the rapid enhancement of cardiac contractility and cardiac output during exercise or sudden stress. This stress response is mediated by the activation of the sympathetic nervous system, which leads to phosphorylation of an array of intracellular proteins in the heart, including ryanodine receptor-2, by protein kinase A.


Structures containing two proteins essential to EC coupling: the L-type Ca2+ channels (LTCC) on the plasma membrane and the ryanodine receptors (RyR2) on the sarcoplasmic reticulum. The LTCC–RyR2 complexes are organized in to lattices which allow a large population of receptors to be simultaneously switched on, or off, by a very small change in ligand concentration.

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Wehrens, X., Marks, A. Novel therapeutic approaches for heart failure by normalizing calcium cycling. Nat Rev Drug Discov 3, 565–574 (2004) doi:10.1038/nrd1440

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