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A Corrigendum on Long-term cultivation of human atrial myocardium by Klumm MJ, Heim C, Fiegle DJ, Weyand M, Volk T and Seidel T (2022). Front. Physiol. 13:839139. doi: 10.3389/fphys.2022.839139

Regional differences in ion channel activity in the heart control the sequence of repolarization and may contribute to differences in contraction. Corticosteroids such as aldosterone or corticosterone increase the L-type Ca2+ current (ICaL) in the heart via the mineralocorticoid receptor (MR). Here, we investigate the differential impact of corticosteroid-mediated increase in ICaL on action potentials (AP), ion currents, intracellular Ca2+ handling and contractility in endo- and epicardial myocytes of the rat left ventricle. Dexamethasone led to a similar increase in ICaL in endocardial and epicardial myocytes, while the K+ currents Ito and IK were unaffected. However, AP duration (APD) and AP-induced Ca2+ influx (QCa) significantly increased exclusively in epicardial myocytes, thus abrogating the normal differences between the groups. Dexamethasone increased Ca2+ transients, contractility and SERCA activity in both regions, the latter possibly due to a decrease in total phospholamban (PLB) and an increase PLBpThr17. These results suggest that corticosteroids are powerful modulators of ICaL, Ca2+ transients and contractility in both endo- and epicardial myocytes, while APD and QCa are increased in epicardial myocytes only. This indicates that increased ICaL and SERCA activity rather than QCa are the primary drivers of contractility by adrenocorticoids.

Chronic heart failure (HF) in adults causes remodeling of the cardiomyocyte transverse tubular system (t-system), which contributes to disease progression by impairing excitation-contraction (EC) coupling. However, it is unknown if t-system remodeling occurs in pediatric heart failure. This study investigated the t-system in pediatric viral myocarditis. The t-system and integrity of EC coupling junctions (co-localization of L-type Ca2+ channels with ryanodine receptors and junctophilin-2) were analyzed by 3D confocal microscopy in left-ventricular (LV) samples from 5 children with myocarditis (age 14 ± 3 months), undergoing ventricular assist device (VAD) implantation, and 5 children with atrioventricular septum defect (AVSD, age 17 ± 3 months), undergoing corrective surgery. LV ejection fraction (EF) was 58.4 ± 2.3% in AVSD and 12.2 ± 2.4% in acute myocarditis. Cardiomyocytes from myocarditis samples showed increased t-tubule distance (1.27 ± 0.05 μm, n = 34 cells) and dilation of t-tubules (volume-length ratio: 0.64 ± 0.02 μm2) when compared with AVSD (0.90 ± 0.02 μm, p < 0.001; 0.52 ± 0.02 μm2, n = 61, p < 0.01). Intriguingly, 4 out of 5 myocarditis samples exhibited sheet-like t-tubules (t-sheets), a characteristic feature of adult chronic heart failure. The fraction of extracellular matrix was slightly higher in myocarditis (26.6 ± 1.4%) than in AVSD samples (24.4 ± 0.8%, p < 0.05). In one case of myocarditis, a second biopsy was taken and analyzed at VAD explantation after extensive cardiac recovery (EF from 7 to 56%) and clinical remission. When compared with pre-VAD, t-tubule distance and density were unchanged, as well as volume-length ratio (0.67 ± 0.04 μm2 vs. 0.72 ± 0.05 μm2, p = 0.5), reflecting extant t-sheets. However, junctophilin-2 cluster density was considerably higher (0.12 ± 0.02 μm−3 vs. 0.05 ± 0.01 μm−3, n = 9/10, p < 0.001), approaching values of AVSD (0.13 ± 0.05 μm−3, n = 56), and the measure of intact EC coupling junctions showed a distinct increase (20.2 ± 5.0% vs. 6.8 ± 2.2%, p < 0.001). Severe t-system loss and remodeling to t-sheets can occur in acute HF in young children, resembling the structural changes of chronically failing adult hearts. T-system remodeling might contribute to cardiac dysfunction in viral myocarditis. Although t-system recovery remains elusive, recovery of EC coupling junctions may be possible and deserves further investigation.

The normally positive cardiac force-frequency relationship (FFR) becomes flat or negative in chronic heart failure (HF). Here we explored if remodeling of the cardiomyocyte transverse tubular system (t-system) is associated with alterations in FFR and contractile kinetics in failing human myocardium. Left-ventricular myocardial slices from 13 failing human hearts were mounted into a biomimetic culture setup. Maximum twitch force (F), 90% contraction duration (CD90), time to peak force (TTP) and time to relaxation (TTR) were determined at 37°C and 0.2–2 Hz pacing frequency. F1Hz/F0.5Hz and F2Hz/F0.5Hz served as measures of FFR, intracellular cardiomyocyte t-tubule distance (ΔTT) as measure of t-system remodeling. Protein levels of SERCA2, NCX1, and PLB were quantified by immunoblotting. F1Hz/F0.5Hz (R2 = 0.82) and F2Hz/F0.5Hz (R2 = 0.5) correlated negatively with ΔTT, i.e., samples with severe t-system loss exhibited a negative FFR and reduced myocardial wall tension at high pacing rates. PLB levels also predicted F1Hz/F0.5Hz, but to a lesser degree (R2 = 0.49), whereas NCX1 was not correlated (R2 = 0.02). CD90 correlated positively with ΔTT (R2 = 0.39) and negatively with SERCA2/PLB (R2 = 0.42), indicating that both the t-system and SERCA activity are important for contraction kinetics. Surprisingly, ΔTT was not associated with TTP (R2 = 0) but rather with TTR (R2 = 0.5). This became even more pronounced when interaction with NCX1 expression was added to the model (R2 = 0.79), suggesting that t-system loss impairs myocardial relaxation especially when NCX1 expression is low. The degree of t-system remodeling predicts FFR inversion and contraction slowing in failing human myocardium. Moreover, together with NCX, the t-system may be important for myocardial relaxation.