Remodeling of calcium handling in human heart failure

Abstract

Heart failure (HF) is an increasing public health problem accelerated by a rapidly aging global population. Despite considerable progress in managing the disease, the development of new therapies for effective treatment of HF remains a challenge. To identify targets for early diagnosis and therapeutic intervention, it is essential to understand the molecular and cellular basis of calcium handling and the signaling pathways governing the functional remodeling associated with HF in humans. Calcium (Ca(2+)) cycling is an essential mediator of cardiac contractile function, and remodeling of calcium handling is thought to be one of the major factors contributing to the mechanical and electrical dysfunction observed in HF. Active research in this field aims to bridge the gap between basic research and effective clinical treatments of HF. This chapter reviews the most relevant studies of calcium remodeling in failing human hearts and discusses their connections to current and emerging clinical therapies for HF patients.

Figure 1

Intracellular Ca²⁺ cycling and regulation by signaling pathways. After the activation of sarcolemma (including T-tubules), Ca²⁺ enters cytoplasm through L-type Ca²⁺ channel. The entering Ca²⁺ then induces a much larger Ca²⁺ release from the sarcoplasmic reticulum (SR) via the ryanodine receptor (RyR). The released Ca²⁺ binds with Troponin-C to activate contraction. Relaxation starts when Ca²⁺ is returned by sarcoplasmic reticulum Ca²⁺ ATPase (SERCA) to SR and via the Na⁺/Ca²⁺ exchanger (NCX) to the extracellular domain. Some Ca²⁺ enters mitochondria to stimulate the production of ATP which is utilized for contraction and transcription. SERCA is inhibited by the dephosphorylated phospholamban (PLN). PLN can be phosphorylated by protein kinase A (PKA) and Ca²⁺/calmodulin-dependent kinase (CAMKII), both of which can be activated by β-adrenergic stimulation. PLN can be dephosphorylated by phosphotase 1 (PP1), which can be activated through Gαq-coupled receptors (angiotensin II receptor, endothelin 1 receptor, or α-adrenergic receptor). α, G-protein subunit α; β, G-protein subunit β; γ, G-protein subunit γ; AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate.

Figure 2

Region-dependent and cycle-length-dependent calcium transient duration (CaTD) in failing human heart. (A) CaTD was quantified at 80% relaxation (CaTD80). (B) CaTD80 at nonfailing human hearts (n=6) at subendocardium (sub-ENDO), midmyocardium (MID), and subepicardium (sub-EPI). (C) CaTD80 at failing human hearts (n=5). (D) The difference of CaTD80 between sub-ENDO and sub-EPI. It can be seen that this difference is significantly reduced in failing heart at faster heart rate (cycle length at 600ms). These data are obtained from Ca²⁺ transient measured using Rhod-2AM from the coronary-perfused wedge preparations from both failing and non-failing human hearts.

Figure 3

Morphological changes of calcium transient (CaT) and its relation to action potential (AP). (A) Simultaneous recordings of AP and CaT at one site at subendocardium from a failing human heart (F, top) and a nonfailing human heart (NF, bottom). (B) The two CaTs from panel A are overlapped for easy comparison. Compared to the CaT from NF, there is a distinct second rising component (labeled by “II”) in the CaT from failing human heart. Note that this second component was only observed at the sub-endocardium in 60% of the studied failing human hearts. (C) CaT duration at 80% relaxation (CaTD80) minus AP duration at 80% (APD80), summarized from five nonfailing hearts and five failing hearts (two ischemic cardiomyopathy and three idiopathic cardiomyopathy). It can be seen that this duration difference is significantly longer at the subendocardium in the failing human heart compared with the non-failing human heart, which is reflected in the example shown in panel A.

Figure 4

Protein expressions of sarcoplasmic reticulum Ca²⁺ ATPase 2a (SERCA2a) and phospholamban (PLN). Representative examples of Western blots (top) and normalized protein expression (bottom) are shown for SERCA2a (A) and PLN (B). NF (n=6) indicates the group of non-failing hearts; Isch-F (n=6), the group of failing hearts with ischemic cardiomyopathy; and Nonischemic-F (n=6), the group of failing hearts with nonischemic/idiopathic cardiomyopathy. ENDO indicates endocardium; EPI, epicardium.