The link between abnormal calcium handling and electrical instability in acquired long QT syndrome – Does calcium precipitate arrhythmic storms?

https://doi.org/10.1016/j.pbiomolbio.2015.11.003Get rights and content

Abstract

Release of Ca2+ ions from sarcoplasmic reticulum (SR) into myocyte cytoplasm and their binding to troponin C is the final signal form myocardial contraction. Synchronous contraction of ventricular myocytes is necessary for efficient cardiac pumping function. This requires both shuttling of Ca2+ between SR and cytoplasm in individual myocytes, and organ-level synchronization of this process by means of electrical coupling among ventricular myocytes. Abnormal Ca2+ release from SR causes arrhythmias in the setting of CPVT (catecholaminergic polymorphic ventricular tachycardia) and digoxin toxicity.

Recent optical mapping data indicate that abnormal Ca2+ handling causes arrhythmias in models of both repolarization impairment and profound bradycardia. The mechanisms involve dynamic spatial heterogeneity of myocardial Ca2+ handling preceding arrhythmia onset, cell-synchronous systolic secondary Ca2+ elevation (SSCE), as well as more complex abnormalities of intracellular Ca2+ handling detected by subcellular optical mapping in Langendorff-perfused hearts. The regional heterogeneities in Ca2+ handling cause action potential (AP) heterogeneities through sodium–calcium exchange (NCX) activation and eventually overwhelm electrical coupling of the tissue.

Divergent Ca2+ dynamics among different myocardial regions leads to temporal instability of AP duration and – on the patient level – in T wave lability. Although T-wave alternans has been linked to cardiac arrhythmias, non-alternans lability is observed in pre-clinical models of the long QT syndrome (LQTS) and CPVT, and in LQTS patients. Analysis of T wave lability may provide a real-time window on the abnormal Ca2+ dynamics causing specific arrhythmias such as Torsade de Pointes (TdP).

Section snippets

Background

From a molecular perspective, the force generated during cardiac contraction is developed by the interaction between actin and myosin proteins and cross-bridge cycling in thousands of sarcomeres in each cardiomyocyte. For the heart to maintain blood circulation, individual sarcomeres have to contract in a synchronized pattern. Loss of temporal organization of this process results in circulatory arrest, as exemplified by the early phase of ventricular fibrillation, when the contractility of

Calcium handling and triggered activity

Triggered activity refers to abnormal generation of an AP, which is initiated (“triggered”) by the preceding (normal or abnormal) AP. In contrast to reentry, it does not require spatially extended tissue and can be observed in single cardiomyocytes. Most clinically relevant arrhythmias may involve more than one mechanism – reentry around a scar initiated by a triggered ectopic beat being an obvious example. However, study of arrhythmia models involving mostly triggered activity offer important

Dual optical mapping data

The dual wavelength optical mapping technique has been used by our team and others to study the mechanisms of arrhythmogenesis in the setting of repolarization delay. This technique allows simultaneous recording of Vm and Cai signals with excellent spatial and temporal resolution. Moreover, it can be naturally applied to study perfused heart at physiological temperature, and can thus provide insights that cannot be readily obtained from isolated cell experiments (Choi and Salama, 2000).

Spatial heteogeneity of calcium transients

When the EAD model described above is studied at better spatial resolution (100 × 100 pixels, 150 μm per pixel), a striking spatial heterogeneity of the normalized CaT signal is easily appreciated (Kim et al., 2015). This is largely absent at baseline, when spatial the amplitude of both CaT and AP is relatively even across the epicardial surface at all times, but increases dramatically with the appearance of Ca oscillations. Intriguingly, the areas of high calcium oscillation amplitude are

Sex-differences explain spatial heteogeneities of CaTs and location of EADs

An examination of the distribution of the sites that fired the first EADs produced a striking pattern. EADs could not be associated with specific anatomical features but were initiated around the base of the adult female rabbit heart (Sims et al., 2008). In contrast, the same LQT model failed to elicit EADs and TdP in adult male rabbit hearts. This sex difference in arrhythmia phenotype was reversed in pre-pubertal rabbits where IKr blockade elicited EADs and TdP in pre-pubertal males but not

Subcellular Ca2+ dynamics

Clearly, the study of subcellular Ca2+ dynamics underlying EAD generation in the beating heart may fundamentally improve the understanding of the arrhythmogenic mechanisms. If SR Ca2+ release is indeed responsible for EADs, does it occur in the form of propagated Ca2+ waves as observed in the DAD models?

The subcellular Ca2+ dynamics in the beating heart has been studied with confocal microscopy by several research teams (Aistrup et al., 2006, Aistrup et al., 2009, Atiga et al., 1998, Kaab

Discussion

The results of the optical mapping experiments described above lead us to suspect that the mechanisms of EAD generation share many similarities with that of DAD generation and DAD-related arrhythmogenesis, namely cellular Ca2+ overload, SOICR and depolarization mediated by NCX activity. In contrast to situations associated with DADs, repolarization delay has not been firmly linked to SR overload. However, there are good reasons to believe that repolarization delay increases SR Ca2+ load, since

Translational aspects

How do these findings fit into the clinical picture of TdP treatment, and what are the implications for arrhythmia management and SCD risk stratification in general? First, the model we propose predicts the protective effect of rapid pacing (∼90 beats per minute), recommended in patients with runs of TdP. Regular and frequent “unloading” of jSR through the normal CICR mechanism expected during relatively rapid pacing may minimize the chance that jSR will fill over the SOICR threshold. On the

Conclusion

Normal cardiac function involves propagation of electrical signals through the cardiac chambers; local action potential leads to Ca2+ entry into the cell and release from SR in individual cardiomyocytes, resulting in synchronized contraction. The main mechanism of Ca2+ removal from myocytes is the electrogenic NCX exchanger. Therefore, disturbance of myocyte Ca2+ handling can in turn affect membrane potential via changes in NCX current and cause arrhythmia. This appears to be the case in long

Editors' note

Please see also related communications in this issue by Zile and Trayanova (2016) and Lee et al. (2016).

Funding sources

Supported in part by NHLBI HL-70722 and HL-093074 to GS and AHA to JK.

Conflict of interest disclosures

None.

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    1

    JN and JJK contributed equally to this work.

    2

    Current address: RSS Center, Advanced Medical Device Research Division, Korea Electrotechnology Research Institute, Seoul, 121-912, South Korea.

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