Nucleoside diphosphate kinase: a new player in heart failure?

21 See article by Lutz et al. [33] (pages 48 –55) in this Phosphorylation of these Ca handling proteins leads to issue. positive chronotropic, inotropic and lusitropic effects, which provide support for the failing heart. b-Adrenergic Despite considerable efforts, the incidence, prevalence stimulation, as the most potent natural cAMP generator and mortality of heart failure remain high in most inand the primary regulatory mechanism of cardiac function dustrialized countries [1,2]. This is partially due to the in the normal heart, was among the first choice of complex nature of the heart failure syndrome. As a final treatments for heart failure patients [6]. Another reason for outcome of many types of heart disease, the degree of b-adrenergic receptors as the target for heart failure heart failure varies from case to case depending on the treatments is that diminished cardiac response to b-adrenpathological history, genetic basis and environmental ergic stimulation (associated with a selective down regulabackground. However, the most common feature of the tion of b -adrenergic receptors, upregulation of b-ARK1 1 failing heart is diminished systolic and/or diastolic funcand an increase in G proteins) is well documented in heart i 21 tion, associated with disturbed intracellular Ca homeofailure. However, several clinical trials revealed that even stasis. Under physiological conditions, cardiac contraction though the hemodynamic symptoms were improved shortly 21 is initiated by Ca influx through sarcolemmal L-type after administration of b-adrenergic receptor agonists, 21 Ca channels, which subsequently triggers a large amount chronic administration increased mortality in treated pa21 of Ca release from the internal sarcoplasmic reticulum tients [7,8]. Similarly, other attempts aimed at improving (SR) stores via ryanodine receptors. The increased intracelcontractile function by raising intracellular cAMP level 21 lular Ca activates the contractile myofilaments, and then using cyclic nucleotide phosphodiesterase (PDE) inhibitors 21 is either recycled back into the SR by SR Ca pumps or results in increased mortality during chronic administration 1 21 extruded out of the cell via sarcolemmal Na –Ca in heart failure patients [9–11]. Furthermore, transgenic exchanger, resulting in cardiac muscle relaxation. Profound mice overexpressing b -adrenergic receptors [12] or G 1 sa 21 alterations in Ca handling proteins such as phospholam[13] also demonstrate an initial positive inotropic effect 21 1 21 ban, SR Ca pump, Na –Ca exchanger, contractile followed by subsequent cardiac hypertrophy and heart 21 myofilaments and coupling between L-type Ca channel failure. and ryanodine receptor have been shown in failing hearts Taken together, the above results seem to suggest that 21 [3–5]. Restoration of these Ca handling deficits is activation of b-adrenergic receptor /cAMP system may expected to have beneficial effects in patients with heart provide a short-term hemodynamic improvement, but failure. damages the failing heart in the long run. Thus, the The intracellular second messenger, cyclic adenosine reduced cardiac contractile response to b-adrenergic remonophosphate (cAMP), activates cAMP-dependent proceptor stimulation (attributed to selective downregulation tein kinase A, which subsequently phosphorylates many of of b1-adrenergic receptors, upregulation of b-ARK1 and the cardiac excitation–contraction components (including an increase in G proteins) might be considered to be a i 21 1 21 L-type Ca channel, ryanodine receptor, Na –Ca beneficial compensatory effect to the high plasma catecholexchanger, myofilament proteins and phospholamban). amine levels observed in patients with heart failure [14]. From this perspective, b-adrenergic receptor antagonists instead of agonists should be favorable for the chronic treatment of heart failure. Indeed, accumulating evidence *Corresponding author. Tel.: 11-212-263-5993; fax: 11-212-263indicates that b-adrenergic receptor blockers improve 5808. E-mail address: [email protected] (M. Artman). ventricular function and increase survival in heart failure