The link between abnormal calcium handling and electrical instability in acquired long QT syndrome – Does calcium precipitate arrhythmic storms?
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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Cited by (33)
Dual loss of regulator of G protein signaling 2 and 5 exacerbates ventricular myocyte arrhythmias and disrupts the fine-tuning of G<inf>i/o</inf> signaling
2022, Journal of Molecular and Cellular CardiologyCitation Excerpt :These data together indicated that increased Gi/o activity due to the dual absence of RGS2 and 5 is involved in receptor and non-receptor-dependent arrhythmia development in ventricular cardiomyocytes. Abnormal cytoplasmic Ca2+ handling has been implicated in ventricular myocyte arrhythmogenesis [27–31]. Because EFS-induced arrhythmias in cardiomyocytes from Rgs2/5 dbKO male mice was accompanied by elevated cytoplasmic Ca2+, we determined whether the dual absence of RGS2 and 5 affected the pathways involved in Ca2+ handling during excitation-contraction coupling.
Mechanisms of torsades de pointes
2022, Torsades de PointesCombining an in silico proarrhythmic risk assay with a tPKPD model to predict QTc interval prolongation in the anesthetized uinea pig assay
2020, Toxicology and Applied PharmacologyCitation Excerpt :However, it has been well documented that: 1) hERG inhibition on its own does not always translate to the occurrence of TdP, 2) action potential duration (APD) prolongation in vitro is not always associated with the clinical prolongation of the QTc interval and, 3) a prolonged QTc interval does not always linearly correlate to the occurrence of TdP. The generally accepted explanation for these discrepancies is that although the inhibition of IKr plays a critical role in delaying repolarization, activation of inward late sodium (late INa) and/or calcium currents (ICa) have been shown to be needed to generate a proarrhythmic response (Nemec et al., 2016). As such, drugs that inhibit both inward (late INa and ICa) and outward (IK) cardiac currents (e.g. ranolazine, verapamil) tend to prolong the QTc interval, but are not associated with the generation of TdP due to the blockade of inward currents (Fermini and Fossa, 2003; Fermini et al., 1995).
Estradiol up-regulates L-type Ca<sup>2+</sup> channels via membrane-bound estrogen receptor/phosphoinositide-3-kinase/Akt/cAMP response element-binding protein signaling pathway
2018, Heart RhythmCitation Excerpt :For example, E2 (1 nM) up-regulates the L-type Ca2+ channel (Ca,L) and ICa,L in myocytes isolated from the base of the epicardium in female rabbit hearts but not myocytes from the endocardium or apex.19,20 During repolarization delay or prolonged action potential durations, as in bradycardia and LQT2, the higher ICa,L in female epicardium results in Ca2+ overload and spontaneous Ca2+ release from the sarcoplasmic reticulum (SR), producing an increase in the forward mode of the Na–Ca exchange current INCX, a depolarizing current that reactivates ICa,L and results in the genesis of EADs and TdP.19–25 The latter studies emphasized apex–base heterogeneities of ICa,L. Others reported endo–epi heterogeneities of ICa,L at the base of female but not male rabbit and dog hearts.14,19,20
- 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.