Arrhythmogenic Mechanisms in Heart Failure: Linking β-Adrenergic Stimulation, Stretch, and Calcium

Abstract

Heart failure (HF) is associated with elevated sympathetic tone and mechanical load. Both systems activate signaling transduction pathways that increase cardiac output, but eventually become part of the disease process itself leading to further worsening of cardiac function. These alterations can adversely contribute to electrical instability, at least in part due to the modulation of Ca²⁺ handling at the level of the single cardiac myocyte. The major aim of this review is to provide a definitive overview of the links and cross talk between β-adrenergic stimulation, mechanical load, and arrhythmogenesis in the setting of HF. We will initially review the role of Ca²⁺ in the induction of both early and delayed afterdepolarizations, the role that β-adrenergic stimulation plays in the initiation of these and how the propensity for these may be altered in HF. We will then go onto reviewing the current data with regards to the link between mechanical load and afterdepolarizations, the associated mechano-sensitivity of the ryanodine receptor and other stretch activated channels that may be associated with HF-associated arrhythmias. Furthermore, we will discuss how alterations in local Ca²⁺ microdomains during the remodeling process associated the HF may contribute to the increased disposition for β-adrenergic or stretch induced arrhythmogenic triggers. Finally, the potential mechanisms linking β-adrenergic stimulation and mechanical stretch will be clarified, with the aim of finding common modalities of arrhythmogenesis that could be targeted by novel therapeutic agents in the setting of HF.

Keywords: calcium; heart failure; microdomains; myocytes; ryanodine; stretch; sympathetic stimulation.

FIGURE 1

Stylized examples of afterdepolarizations occurring in the single canine myocyte. Figure shows both membrane potentials and contraction for each situation. (Left) DAD (^∗) induced by the β-adrenergic agonist isoproterenol (ISO); (Middle) illustrates an EAD (#) induced by augmentation of the late sodium current, using ATX-II; (Right) illustrates that under certain conditions both types of afterdepolarizations can be seen in the same action potential. In this particular example, blockade of the potassium current, I_Ks, together with β-adrenergic stimulation are the proarrhythmic treatment and it can be seen that an early aftercontraction initiates prior to the upstroke of the EAD.

FIGURE 2

Proposed pathways for inducing SR Ca²⁺ leak during β-adrenergic signaling and stretch in a ventricular cardiomyocyte. (A) β-AR raises cAMP levels via G_s-protein-dependent activation of AC that activates both PKA and Epac. PKA phosphorylates LTCC and PLB leading to more Ca²⁺ influx and faster uptake by SERCA into the SR. Epac activates nNOS and CaMKII via an PI3K and AkT signaling cascade promoting SR Ca²⁺ leak via RyR phosphorylation. The broken line indicates a cAMP and Epac-independent pathway for local activation of nNOS targeted to RyR in the dyad. RyR not coupled to LTCC in T-tubules are not modulated by CaMKII and nNOS. eNOS is localized to caveolae and exerts negative effects on LTCC during β-adrenergic stimulation. (B) Mechanotransduction involves ROS and NO for RyR activation. The ROS and NO pathway are independent and operate on different timescales via different mechanosensors. NOX2 produces ROS near RyR in the dyad increasing RyR activity possibly via oxidation of CaMKII. With a delay, nNOS is activated via an unknown mechanosensing mechanism. The enhanced SR Ca²⁺ leak promotes Ca²⁺ waves that activate a transient inward NCX current causing DAD. Caveolar eNOS is activated by stretch via PI3K-Akt and positively modulates EC coupling outside the dyad by mechanisms that are incompletely understood. See text for further details. AC, adenyl cyclase; β-AR, β-adrenergic receptor; cAMP, cyclic adenosine 3’,5’-monophosphate; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; EC, excitation contraction; DAD, delayed afterdepolarizations; eNOS, endothelial nitric oxide synthase; Epac, exchange protein activated by cAMP; LTCC, L-type Ca channel; NCX, Na⁺/Ca²⁺ exchanger; NO, nitric oxide; NOX2, NADPH oxidase type 2; nNOS, neuronal nitric oxide synthase; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; PLB, phospholamban; ROS, reactive oxygen species; RyR, ryanodine receptor; SERCA, SR Ca²⁺-ATPase; SR, sarcoplasmic reticulum.

FIGURE 3

Scheme of key events in β-adrenergic and stretch signaling for the induction of afterdepolarizations as potential targets for anti-arrhythmic therapy. The central event in the generation of afterdepolarizations is a Ca²⁺ wave that can produce DAD or EAD depending on the timing of NCX activation during the cardiac cycle (diastole or systole). Mechanical stretch and β-adrenergic agonists activate protein kinases (PKA, CaMKII) and free radicals (ROS, NO) that increase RyR activity and/or SR Ca²⁺ load to produce Ca²⁺ sparks and waves. Likewise, they increase the activity of late Na⁺ and Ca²⁺ currents promoting EADs, directly via phosphorylation and redox modification, or indirectly via modulation by increased SR Ca²⁺ release secondary to enhanced SR Ca²⁺ load. Stretch-activated ion channels further destabilize membrane potential during stretch. Anti-arrhythmic strategies include targeting of upstream stressors, downstream signaling components, and Ca handling proteins or currents. Specific examples under current investigation are indicated and further discussed in the text. DAD, delayed afterdepolarizations; EAD, early afterdepolarizations; LVAD, left ventricular assistant device; NCX, Na⁺/Ca²⁺ exchanger; NO, nitric oxide; NOX, NADPH oxidase type; nNOS, neuronal nitric oxide synthase; PKA, protein kinase A; ROS, reactive oxygen species; RyR, ryanodine receptor; SACNS, stretch-activated non-selective cation currents; SR, sarcoplasmic reticulum; SERCA, SR Ca²⁺-ATPase.