Editorial: The Role of Calcium Handling in Heart Failure and Heart Failure Associated Arrhythmias

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.

Key points: The dyadic cleft, where coupled ryanodine receptors (RyRs) reside, is thought to serve as a microdomain for local signalling, as supported by distinct modulation of coupled RyRs dependent on Ca²⁺/calmodulin‐dependent kinase II (CaMKII) activation during high‐frequency stimulation. Sympathetic stimulation through β‐adrenergic receptors activates an integrated signalling cascade, enhancing Ca²⁺ cycling and is at least partially mediated through CaMKII. Here we report that CaMKII activation during β‐adrenergic signalling is restricted to the dyadic cleft, where it enhances activity of coupled RyRs thereby contributing to the increase in diastolic events. Nitric oxide synthase 1 equally participates in the local modulation of coupled RyRs. In contrast, the increase in the Ca²⁺ content of the sarcoplasmic reticulum and related increase in the amplitude of the Ca²⁺ transient are primarily protein kinase A‐dependent. The present data extend the concept of microdomain signalling in the dyadic cleft and give perspectives for selective modulation of RyR subpopulations and diastolic events. In cardiac myocytes, β‐adrenergic stimulation enhances Ca²⁺ cycling through an integrated signalling cascade modulating L‐type Ca²⁺ channels (LTCCs), phospholamban and ryanodine receptors (RyRs). Ca²⁺/calmodulin‐dependent kinase II (CaMKII) and nitric oxide synthase 1 (NOS1) are proposed as prime mediators for increasing RyR open probability. We investigate whether this pathway is confined to the high Ca²⁺ microdomain of the dyadic cleft and thus to coupled RyRs. Pig ventricular myocytes are studied under whole‐cell voltage‐clamp and confocal line‐scan imaging with Fluo‐4 as a [Ca²⁺]_i indicator. Following conditioning depolarizing pulses, spontaneous RyR activity is recorded as Ca²⁺ sparks, which are assigned to coupled and non‐coupled RyR clusters. Isoproterenol (ISO) (10 nm) increases Ca²⁺ spark frequency in both populations of RyRs. However, CaMKII inhibition reduces spark frequency in coupled RyRs only; NOS1 inhibition mimics the effect of CaMKII inhibition. Moreover, ISO induces the repetitive activation of coupled RyR clusters through CaMKII activation. Immunostaining shows high levels of CaMKII phosphorylation at the dyadic cleft. CaMKII inhibition reduces I_CaL and local Ca²⁺ transients during depolarizing steps but has only modest effects on amplitude or relaxation of the global Ca²⁺ transient. In contrast, protein kinase A (PKA) inhibition reduces spark frequency in all RyRs concurrently with a reduction of sarcoplasmic reticulum Ca²⁺ content, Ca²⁺ transient amplitude and relaxation. In conclusion, CaMKII activation during β‐adrenergic stimulation is restricted to the dyadic cleft microdomain, enhancing LTCC‐triggered local Ca²⁺ release as well as spontaneous diastolic Ca²⁺ release whilst PKA is the major pathway increasing global Ca²⁺ cycling. Selective CaMKII inhibition may reduce potentially arrhythmogenic release without negative inotropy.

Candidate patients for cardiac surgery procedures with a history of malignancies and antitumour therapy or with an active cancer and on antineoplastic treatment are increasingly common in daily practice. Oncological therapy can lead to cardiovascular injury and, therefore, has the potential for impacting operative risks and surgical strategies. This means that a number of considerations are essential to take into account prior to cardiac surgery. These include the type of cancer, previous cardiotoxicity or concomitant antitumour therapy, reversibility or irreversibility of such complications, the interaction between cancer disease course and extracorporeal circulation, the need for associated surgery and the impact of cancer on early and long-term outcomes. Adequate preoperative evaluation of cardiovascular abnormalities potentially related to antineoplastic therapy and proper diagnostic workup of other conditions linked to the type of cancer (e.g. haematological disorders and lung dysfunction) are therefore of paramount importance for appropriate surgical decision-making. Careful evaluation of the association of cardiovascular disease to be treated and the prognosis of remitted or active cancer should be established to enhance the prediction of early, medium and long-term outcomes and for a more correctly informed patient. Furthermore, if the prognosis of operated patients appears unfavourable, then alternative therapeutic strategies can be applied without significant delay. The aim of this review is to give an overview of factors that should be considered in adult patients who are undergoing, or have undergone, treatment for oncological indications who are candidates for cardiac surgery.

Secreted protein acidic and rich in cysteine (SPARC) is a non-structural extracellular matrix protein that regulates interactions between the matrix and neighboring cells. In the cardiovascular system, it is expressed by cardiac fibroblasts, endothelial cells, and at lower levels by ventricular cardiomyocytes. SPARC expression levels are increased upon myocardial injury and also during hypertrophy and fibrosis. We have previously shown that SPARC improves cardiac function after myocardial infarction by regulating post-synthetic procollagen processing, however whether SPARC directly affects cardiomyocyte contraction is still unknown. In this study we demonstrate a novel inotropic function for extracellular SPARC in the healthy heart as well as in the diseased state after myocarditis-induced cardiac dysfunction. We demonstrate SPARC presence on the cardiomyocyte membrane where it is co-localized with the integrin-beta1 and the integrin-linked kinase. Moreover, extracellular SPARC directly increases cardiomyocyte cell shortening ex vivo and cardiac function in vivo, both in healthy myocardium and during coxsackie virus-induced cardiac dysfunction. In conclusion, we demonstrate a novel inotropic function for SPARC in the heart, with a potential therapeutic application when myocyte contractile function is diminished such as that caused by a myocarditis-related cardiac injury.

Key points: Ventricular arrhythmias are a major complication after myocardial infarction (MI), associated with sympathetic activation. The structurally heterogeneous peri‐infarct zone is a known substrate, but the functional role of the myocytes is less well known. Recordings of monophasic action potentials in vivo reveal that the peri‐infarct zone is a source of delayed afterdepolarizations (DADs) and has a high beat‐to‐beat variability of repolarization (BVR) during adrenergic stimulation (isoproterenol, ISO). Myocytes isolated from the peri‐infarct region have more DADs and spontaneous action potentials, with spontaneous Ca²⁺ release, under ISO. These myocytes also have reduced repolarization reserve and increased BVR. Other properties of post‐MI remodelling are present in both peri‐infarct and remote myocytes. These data highlight the importance of altered myocyte adrenergic responses in the peri‐infarct region as source and substrate of post‐MI arrhythmias. Ventricular arrhythmias are a major early complication after myocardial infarction (MI). The heterogeneous peri‐infarct zone forms a substrate for re‐entry while arrhythmia initiation is often associated with sympathetic activation. We studied the mechanisms triggering these post‐MI arrhythmias in vivo and their relation to regional myocyte remodelling. In pigs with chronic MI (6 weeks), in vivo monophasic action potentials were simultaneously recorded in the peri‐infarct and remote regions during adrenergic stimulation with isoproterenol (isoprenaline; ISO). Sham animals served as controls. During infusion of ISO in vivo, the incidence of delayed afterdepolarizations (DADs) and beat‐to‐beat variability of repolarization (BVR) was higher in the peri‐infarct than in the remote region. Myocytes isolated from the peri‐infarct region, in comparison to myocytes from the remote region, had more DADs, associated with spontaneous Ca²⁺ release, and a higher incidence of spontaneous action potentials (APs) when exposed to ISO (9.99 ± 4.2 vs. 0.16 ± 0.05 APs/min, p = 0.004); these were suppressed by CaMKII inhibition. Peri‐infarct myocytes also had reduced repolarization reserve and increased BVR (26 ± 10 ms vs. 9 ± 7 ms, P < 0.001), correlating with DAD activity. In contrast to these regional distinctions under ISO, alterations in Ca²⁺ handling at baseline and myocyte hypertrophy were present throughout the left ventricle (LV). Expression of some of the related genes was, however, different between the regions. In conclusion, altered myocyte adrenergic responses in the peri‐infarct but not the remote region provide a source of triggered activity in vivo and of repolarization instability amplifying the substrate for re‐entry. These findings stimulate further exploration of region‐specific therapies targeting myocytes and autonomic modulation.