Dataset Information

Bradycardia alters Ca(2+) dynamics enhancing dispersion of repolarization and arrhythmia risk.

ABSTRACT: Bradycardia prolongs action potential (AP) durations (APD adaptation), enhances dispersion of repolarization (DOR), and promotes tachyarrhythmias. Yet, the mechanisms responsible for enhanced DOR and tachyarrhythmias remain largely unexplored. Ca(2+) transients and APs were measured optically from Langendorff rabbit hearts at high (150 × 150 ?m(2)) or low (1.5 × 1.5 cm(2)) magnification while pacing at a physiological (120 beats/min) or a slow heart rate (SHR = 50 beats/min). Western blots and pharmacological interventions were used to elucidate the regional effects of bradycardia. As a result, bradycardia (SHR 50 beats/min) increased APDs gradually (time constant ?f?s = 48 ± 9.2 s) and caused a secondary Ca(2+) release (SCR) from the sarcoplasmic reticulum during AP plateaus, occurring at the base on average of 184.4 ± 9.7 ms after the Ca(2+) transient upstroke. In subcellular imaging, SCRs were temporally synchronous and spatially homogeneous within myocytes. In diastole, SHR elicited variable asynchronous sarcoplasmic reticulum Ca(2+) release events leading to subcellular Ca(2+) waves, detectable only at high magnification. SCR was regionally heterogeneous, correlated with APD prolongation (P < 0.01, n = 5), enhanced DOR (r = 0.9277 ± 0.03, n = 7), and was gradually reversed by pacing at 120 beats/min along with APD shortening (P < 0.05, n = 5). A stabilizer of leaky ryanodine receptors (RyR2), 3-(4-benzylcyclohexyl)-1-(7-methoxy-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)propan-1-one (K201; 1 ?M), suppressed SCR and reduced APD at the base, thereby reducing DOR (P < 0.02, n = 5). Ventricular ectopy induced by bradycardia (n = 5/15) was suppressed by K201. Western blot analysis revealed spatial differences of voltage-gated L-type Ca(2+) channel protein (Cav1.2?), Na(+)-Ca(2+) exchange (NCX1), voltage-gated Na(+) channel (Nav1.5), and rabbit ether-a-go-go-related (rERG) protein [but not RyR2 or sarcoplasmic reticulum Ca(2+) ATPase 2a] that correlate with the SCR distribution and explain the molecular basis for SCR heterogeneities. In conclusion, acute bradycardia elicits synchronized subcellular SCRs of sufficient magnitude to overcome the source-sink mismatch and to promote afterdepolarizations.

SUBMITTER: Kim JJ

PROVIDER: S-EPMC3602772 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Bradycardia alters Ca(2+) dynamics enhancing dispersion of repolarization and arrhythmia risk.

Kim Jong J JJ Němec Jan J Papp Rita R Strongin Robert R Abramson Jonathan J JJ Salama Guy G

American journal of physiology. Heart and circulatory physiology 20130111 6

Bradycardia prolongs action potential (AP) durations (APD adaptation), enhances dispersion of repolarization (DOR), and promotes tachyarrhythmias. Yet, the mechanisms responsible for enhanced DOR and tachyarrhythmias remain largely unexplored. Ca(2+) transients and APs were measured optically from Langendorff rabbit hearts at high (150 × 150 μm(2)) or low (1.5 × 1.5 cm(2)) magnification while pacing at a physiological (120 beats/min) or a slow heart rate (SHR = 50 beats/min). Western blots and p ...[more]

PMID: 23316064

Similar Datasets

Project description:BACKGROUND: Brugada syndrome (BrS) is an inherited arrhythmia syndrome caused by loss-of-function variants in the cardiac sodium channel gene SCN5A (sodium voltage-gated channel alpha subunit 5) in ≈20% of subjects. We identified a family with 4 individuals diagnosed with BrS harboring the rare G145R missense variant in the cardiac transcription factor TBX5 (T-box transcription factor 5) and no SCN5A variant. METHODS: We generated induced pluripotent stem cells (iPSCs) from 2 members of a family carrying TBX5-G145R and diagnosed with Brugada syndrome. After differentiation to iPSC-derived cardiomyocytes (iPSC-CMs), electrophysiologic characteristics were assessed by voltage- and current-clamp experiments (n=9 to 21 cells per group) and transcriptional differences by RNA sequencing (n=3 samples per group), and compared with iPSC-CMs in which G145R was corrected by CRISPR/Cas9 approaches. The role of platelet-derived growth factor (PDGF)/phosphoinositide 3-kinase (PI3K) pathway was elucidated by small molecule perturbation. The rate-corrected QT (QTc) interval association with serum PDGF was tested in the Framingham Heart Study cohort (n=1893 individuals). RESULTS: TBX5-G145R reduced transcriptional activity and caused multiple electrophysiologic abnormalities, including decreased peak and enhanced “late” cardiac sodium current (INa), which were entirely corrected by editing G145R to wildtype. Transcriptional profiling and functional assays in genome-unedited and -edited iPSC-CMs showed direct SCN5A downregulation caused decreased peak INa, and that reduced PDGF receptor (PDGFRA [platelet-derived growth factor receptor α]) expression and blunted signal transduction to PI3K was implicated in enhanced late INa. Tbx5 regulation of the PDGF axis and increased arrhythmia risk with disruption of PDGF sigaling were both conserved in murine model systems. PDGF receptor blockade markedly prolonged normal iPSC-CM action potentials and plasma levels of PDGF in the Framingham Heart Study were inversely correlated with the QTc interval (P

Project description:Background/aimDegenerative aortic valve stenosis (AS) is associated to ventricular arrhythmias and sudden cardiac death, as well as mental stress in specific patients. In such a context, substrate, autonomic imbalance as well as repolarization dispersion abnormalities play an undoubted role. Aim of the study was to evaluate the increase of premature ventricular contractions (PVC) and complex ventricular arrhythmias during mental stress in elderly patients candidate to the transcatheter aortic valve replacement (TAVR).MethodsIn eighty-one elderly patients with AS we calculated several short-period RR- and QT-derived variables at rest, during controlled breathing and during mild mental stress, the latter being represented by a mini-mental state evaluation (MMSE).ResultsAll the myocardial repolarization dispersion markers worsened during mental stress (p < 0.05). Furthermore, during MMSE, low frequency component of the RR variability increased significantly both as absolute power (LFRR) and normalized units (LFRRN U) (p < 0.05) as well as the low-high frequency ratio (LFRR/HFRR) (p < 0.05). Eventually, twenty-four (30%) and twelve (15%) patients increased significantly PVC and, respectively, complex ventricular arrhythmias during the MMSE administration. At multivariate logistic regression analysis, the standard deviation of QTend (QTesd), obtained at rest, was predictive of increased PVC (odd ratio: 1.54, 95% CI 1.14-2.08; p = 0.005) and complex ventricular arrhythmias (odd ratio: 2.31, 95% CI 1.40-3.83; p = 0.001) during MMSE. The QTesd showed the widest sensitive-specificity area under the curve for the increase of PVC (AUC: 0.699, 95% CI: 0.576-0.822, p < 0.05) and complex ventricular arrhythmias (AUC: 0.801, 95% CI: 0.648-0.954, p < 0.05).ConclusionIn elderly with AS ventricular arrhythmias worsened during a simple cognitive assessment, this events being a possible further burden on the outcome of TAVR. QTesd might be useful to identify those patients with the highest risk of ventricular arrhythmias. Whether the TAVR could led to a QTesd reduction and, hence, to a reduction of the arrhythmic burden in this setting of patients is worthy to be investigated.

Project description:BACKGROUND AND OBJECTIVES:Electrocardiographic (ECG) markers of the temporal dispersion of the myocardial repolarization phase have been shown able to identify chronic heart failure (CHF) patients at high mortality risk. The present prospective single-center study sought to investigate in a well-characterized cohort of decompensated heart failure (HF) patients the ability of short-term myocardial temporal dispersion ECG variables in predicting the 30-day mortality, as well as their relationship with N-terminal Pro Brain Natriuretic Peptide (NT-proBNP) plasmatic values. METHOD:One hundred and thirteen subjects (male: 59, 67.8%) with decompensated CHF underwent 5 min of ECG recording, via a mobile phone. We obtained QT end (QTe), QT peak (QTp) and T peak to T end (Te) and calculated the mean, standard deviation (SD), and normalized index (VN). RESULTS:Death occurred for 27 subjects (24%) within 30 days after admission. Most of the repolarization indexes (QTe mean (p < 0.05), QTeSD (p < 0.01), QTpSD (p < 0.05), mean Te (p < 0.05), TeSD (p < 0.001) QTeVN (p < 0.05) and TeVN (p < 0.01)) were significantly higher in those CHF patients with the highest NT-proBNP (>75th percentile). In all the ECG data, only TeSD was significantly and positively related to the NT-proBNP levels (r: 0.471; p < 0.001). In the receiver operating characteristic (ROC) analysis, the highest accuracy for 30-day mortality was found for QTeSD (area under curve, AUC: 0.705, p < 0.01) and mean Te (AUC: 0.680, p < 0.01), whereas for the NT-proBNP values higher than the 75th percentile, the highest accuracy was found for TeSD (AUC: 0.736, p < 0.001) and QTeSD (AUC: 0.696, p < 0.01). CONCLUSION:Both mean Te and TeSD could be considered as reliable markers of worsening HF and of 30-day mortality. Although larger and possibly interventional studies are needed to confirm our preliminary finding, these non-invasive and transmissible ECG parameters could be helpful in the remote monitoring of advanced HF patients and, possibly, in their clinical management. (ClinicalTrials.gov number, NCT04127162).

Dataset Information

Bradycardia alters Ca(2+) dynamics enhancing dispersion of repolarization and arrhythmia risk.

Publications

Bradycardia alters Ca(2+) dynamics enhancing dispersion of repolarization and arrhythmia risk.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets