Key result
CaMKII inhibition reduces spontaneous Ca2+ release and contractions in cryoinjured rat myocardial slices.
Why the study?
Intrinsic transmural heterogeneities in Ca2+ handling and disease remodeling may differentially modulate spontaneous Ca2+ release across the LV wall and cause transmural differences in arrhythmia susceptibility.
Does CaMKII inhibition reduce arrhythmogenic Ca2+ events in cryoinjured rat living myocardial slices?
Does CaMKII inhibition reduce arrhythmogenic Ca2+ events in cryoinjured rat living myocardial slices?
CaMKII inhibition reduces arrhythmogenic spontaneous Ca2+ release specifically in the injured subendocardium, highlighting a potential mechanism for region-specific targeting in cardiac therapies.
Answers are grounded in this paper and cite their sources.
May support region-specific CaMKII inhibition after injury; leaves open translation from this animal model to clinical arrhythmia prevention.
Spontaneous Ca2+ release (SCR) can cause triggered activity and initiate arrhythmias. Intrinsic transmural heterogeneities in Ca2+ handling and their propensity to disease remodeling may differentially modulate SCR throughout the left ventricular (LV) wall and cause transmural differences in arrhythmia susceptibility. Here, we aimed to dissect the effect of cardiac injury on SCR in different regions in the intact LV myocardium using cryoinjury on rat living myocardial slices (LMS). We studied SCR under proarrhythmic conditions using a fluorescent Ca2+ indicator and high-resolution imaging in LMS from the subendocardium (ENDO) and subepicardium (EPI). Cryoinjury caused structural remodeling, with loss in T-tubule density and an increased time of Ca2+ transients to peak after injury. In ENDO LMS, the Ca2+ transient amplitude and decay phase were reduced, while these were not affected in EPI LMS after cryoinjury. The frequency of spontaneous whole-slice contractions increased in ENDO LMS without affecting EPI LMS after injury. Cryoinjury caused an increase in foci that generates SCR in both ENDO and EPI LMS. In ENDO LMS, SCRs were more closely distributed and had reduced latencies after cryoinjury, whereas this was not affected in EPI LMS. Inhibition of CaMKII reduced the number, distribution, and latencies of SCR, as well as whole-slice contractions in ENDO LMS, but not in EPI LMS after cryoinjury. Furthermore, CaMKII inhibition did not affect the excitation-contraction coupling in cryoinjured ENDO or EPI LMS. In conclusion, we demonstrate increased arrhythmogenic susceptibility in the injured ENDO. Our findings show involvement of CaMKII and highlight the need for region-specific targeting in cardiac therapies.
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Dries et al. (2021) studied Cardiac injury and arrhythmia susceptibility. CaMKII inhibition was evaluated on Spontaneous Ca2+ release and whole-slice contractions. CaMKII inhibition reduced the number, distribution, and latencies of spontaneous Ca2+ release and whole-slice contractions in cryoinjured subendocardial rat living myocardial slices.
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