LAUSR

In Europe, more than 15 million people are diagnosed with heart failure (HF), and this number continues to increase, representing a major cause of hospitalization and death. About half of the HF patient population presents with reduced ejection fraction (HFrEF).1 The most common forms of death or hospitalization of HFrEF patients are pump failure and arrhythmias,2,3 and for both conditions, alterations of cardiac myocyte calcium (Ca2+) handling play an important role. Cardiac myocytes tightly control their Ca2+ homeostasis in a process coined excitation–contraction (EC) coupling. Upon membrane depolarization during the cardiac action potential, Ca2+ enters myocytes via L-type Ca2+ channels. This Ca2+ influx triggers a much larger intracellular Ca2+ release from the Ca2+ store, the sarcoplasmic reticulum (SR)4 (Figure 1). This Ca2+ activates the myofilament machinery to contract during systole. During diastole, Ca2+ diffuses from the myofilaments and is taken back up into the SR (∼70%) by the SR Ca2+ ATPase (SERCA), or exported by the Na+/Ca2+ exchanger, and the ensuing decrease of intracellular Ca2+ initiates relaxation (Figure 1). The energy for these processes comes from mitochondria, which turn over the cellular ATP pool in less than a minute. The spatiotemporal control of Ca2+ homeostasis is governed by protein phosphorylation through kinases, increasing and accelerating contractility (inotropy), relaxation (lusitropy), and heart rate (chronotropy). Noradrenaline-induced activation of β-adrenoceptors (β-AR) stimulates cyclic adenosine monophosphate (cAMP) production, followed by protein kinase A (PKA) activation (Figure 1). Phosphorylation by PKA activates Ca2+ channels to increase Ca2+ influx, promotes Ca2+ release from the SR via ryanodine receptors, accelerates Ca2+ uptake by SERCA and reduces myofilament Ca2+ affinity (Figure 1, right).4 Activation of Epac (exchange protein directly activated by cAMP) additionally activates the Ca2+/calmodulin-dependent protein