br Relationship among ICD shocks substrate and mortality

Relationship among ICD shocks, substrate, and mortality There is a strong correlation between ICD-shocked spontaneous VTAs and subsequent mortality [5,6]. Patients who receive inappropriate shocks are also at an increased risk of mortality, although the magnitude of this increase is smaller [5,6]. These findings, together with the fact that the electrical shock may cause myocardial damage and dysfunction, suggest that the ICD shock itself is harmful, adversely affecting prognosis. However, this is uncertain because the significant correlation between shocks and prognosis was not proved in subsequent clinical studies [15,16]. Whether shocks play an independent causal role or whether this correlation is due solely to the underlying disease and arrhythmia is strongly debated [17–19]. Recently, a retrospective study enrolling a large number of ICD recipients, which was expected to resolve this conflict, has been published. The ALTITUDE Survival by Rhythm Study [20] demonstrated that patients who received shocks for VTAs and atrial fibrillation had an increased risk of death and that there was no increased risk of mortality for those with inappropriate shocks for sinus tachycardia or lead noise/artifact/oversensing. This indicated that the adverse outcomes after ICD shocks are more closely related to the underlying disease and arrhythmia than to a harmful effect from the shock. Conversely, the importance of shocks on the prognosis has been suggested by another pivotal clinical trial. The MADIT-RIT study demonstrated that the programming of ICD therapies for VTAs of a high rate or those with a prolonged delay in therapy was associated with reductions in inappropriate therapy and mortality [21]. Reductions in the number of inappropriate shocks and the associated reductions in total shock energy contributed in part to the mortality benefit in the high rate and delayed therapy group. The potential roles of shocks and VTAs in HF progression, based on currently available information obtained in clinical and experimental studies, are discussed in the following sections.
Calcium signaling in an experimental model of VF storm Intracellular Ca2+-cycling is controlled by ion crth2 antagonist and transporters, including L-type Ca2+ channel, sarcoplasmic reticulum (SR) Ca2+-release channel ryanodine receptor (RyR2), SR Ca2+-pump (SERCA2a), its regulatory protein phospholamban (PLB), and Na+–Ca2+ exchanger (NCX). Protein phosphorylation is a major regulatory mechanism for contractility and relaxation (Fig. 1). Phosphorylating mediators include PKA, CaMKII, and protein kinase Cα (PKCα). Under physiological conditions, CaMKII is activated by a fast heart rate and CaMKII-mediated phosphorylation of these Ca2+-handling proteins increases Ca2+ influx and SR Ca2+-storage, leading to increased intracellular systolic Ca2+ and increased contractility. PKA is activated by β-adrenergic receptor agonists and catalyzes phosphorylation of the same Ca2+-handling proteins modified by CaMKII, but at different amino acids. PKCα is activated downstream to a variety of G-protein-coupled receptors such as angiotensin II receptor, α-adrenoreceptor and endothelin receptor, and is activated by increased intracellular Ca2+ concentrations ([Ca2+]i). PKCα activation leads to decreased activity of SERCA2a by phosphorylating inhibitor-1 (I-1). PKCα -mediated phosphorylation of I-1 leads to PLB dephosphorylation, resulting in reduced SR Ca2+ load and Ca2+ release, causing reduced contractility [38]. While cardiac function is regulated by these protein kinases, excess activity of PKA [32], CaMKII [39–41], and PKCα [42] and the resulting hyperphosphorylation of these Ca2+-handling proteins are linked to mechanical dysfunction and arrhythmias. We examined the alterations in Ca2+-signals and protein phosphorylation in a rabbit model of VF storm (Fig. 2) [14]. This animal model was developed from a rabbit model of chronic complete atrioventricular block (CAVB). CAVB rabbits show biventricular hypertrophy and electrophysiological features similar to long QT syndrome including torsades de pointes-like arrhythmia, VF, and sudden death [43,44]. CAVB rabbits equipped with ICDs followed up for ~80 days all showed cardiac hypertrophy, long QT, and ICD-detected VF-episodes, followed by VF storm (defined as ≥3 VF episodes per 24-h), which developed in approximately 50% of CAVB rabbits. VF storm rabbits showed left-ventricular function deterioration, along with striking activation of CaMKII and enhanced expression of protein phosphatase. These alterations were associated with notable changes: hyperphosphorylation of L-type Ca2+ channel and RyR2 and dephosphorylation of PLB, a phosphorylation pattern similar to findings in failing human and animal hearts [45]. These prominent changes in VF storm rabbits were attributed in part to the direct effects of repeated VF and defibrillation. Indeed, VF induction and defibrillation 10 times over 1h in baseline rabbits reproduced the changes observed in CaMKII activation and PLB phosphorylation in VF storm rabbits, but 10 shock pulses without VF induction did not. PKAα catalytic subunit was decreased similarly in VF storm and non-storm rabbits. PKA-dependent phosphorylation of myosin-binding protein C and troponin I did reduce, but there was no difference between the VF storm and non-storm rabbit groups. Neither PKCα catalytic subunit expression nor PKCα activity were altered. These results suggest that CaMKII, but not PKA or PKCα, plays a central pathophysiological role in left ventricular dysfunction associated with VF storm in this animal model.