Jong J. Kim - Academia.edu (original) (raw)

Papers by Jong J. Kim

American Journal of Physiology-Heart and Circulatory Physiology, 2008

Endocardial mapping has suggested that Purkinje fibers may play a role in the maintenance of long... more Endocardial mapping has suggested that Purkinje fibers may play a role in the maintenance of long-duration ventricular fibrillation (LDVF). To determine the influence of Purkinje fibers on LDVF, we chemically ablated the Purkinje system with Lugol solution and recorded endocardial and transmural activation during LDVF. Dog hearts were isolated and perfused, and the ventricular endocardium was exposed and treated with Lugol solution ( n = 6) or normal Tyrode solution as a control ( n = 6). The left anterior papillary muscle endocardium was mapped with a 504-electrode (21 × 24) plaque with electrodes spaced 1 mm apart. Transmural activation was recorded with a six-electrode plunge needle on each side of the plaque. Ventricular fibrillation (VF) was induced, and perfusion was halted. LDVF spontaneously terminated sooner in Lugol-ablated hearts than in control hearts (4.9 ± 1.5 vs. 9.2 ± 3.2 min, P = 0.01). After termination of VF, both the control and Lugol hearts were typically excita...

Progress in biophysics and molecular biology, Jan 26, 2015

Release of Ca(2+) ions from sarcoplasmic reticulum (SR) into myocyte cytoplasm and their binding ... more Release of Ca(2+) 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 Ca(2+) between SR and cytoplasm in individual myocytes, and organ-level synchronization of this process by means of electrical coupling among ventricular myocytes. Abnormal Ca(2+) release from SR causes arrhythmias in the setting of CPVT (catecholaminergic polymorphic ventricular tachycardia) and digoxin toxicity. Recent optical mapping data indicate that abnormal Ca(2+) handling causes arrhythmias in models of both repolarization impairment and profound bradycardia. The mechanisms involve dynamic spatial heterogeneity of myocardial Ca(2+) handling preceding arrhythmia onset, cell-synchronous systolic secondary Ca(2+) elevation (SSCE), as well as more complex abnormalities of intracellular Ca(2+...

Journal of the American College of Cardiology, 2010

Background: Action potential (AP) prolongation results in TdP in clinical and experimental LQT2, ... more Background: Action potential (AP) prolongation results in TdP in clinical and experimental LQT2, but the exact mechanism remains uncertain. T-Wave alternans has been proposed as a marker of arrhythmic risk and is elicited by APD and Ca2+ alternans. However, non-alternans TWL has been associated with TdP in LQT syndrome. We hypothesized that TWL at constant heart rate precedes TdP in a LQT2 model and that it is caused by abnormal Cai dynamics. Methods: Female rabbit hearts were perfused, AV node was ablated and ventricles paced at 50 beats per minute. Epicardial ECG was recorded during optical mapping (RH 237 and Rhod-2 AM) of AP and Cai. LQT2 was mimicked by Dofetilide (D; 500 nM/L) and decrease in [K+]o and [Mg2+] o. TWL was calculated as logarithm of root-mean-square of differences between T wave amplitude from subsequent beats. Results: D prolonged AP durations and induced TdP (n=8/8). Baseline Ca transient (CaT) was usually monophasic. Occasionally, a small secondary peak was observed. The number of CaT peaks per AP during paced rhythm increased upon D addition and prior to VT onset compared to baseline in all cases (Number of CaT per AP: 1.33±0.39 vs 2.32±0.47, p<0.002). This was accompanied by increased TWL (-4.06±0.94 vs-2.89±0.95, p<0.002). Conclusions: TWL precedes TdP in rabbit LQT2 model. Complex Ca dynamics (>1 CaT peak per AP) occurs during prolonged AP, promoting TWL and TdP. Possible mechanisms include secondary Ca2+ release from an overloaded sarcoplasmic reticulum and enhanced Na/Ca exchange current.

American Journal of Physiology-Heart and Circulatory Physiology, 2013

Bradycardia prolongs action potential (AP) durations (APD adaptation), enhances dispersion of rep... more 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. Ca2+transients and APs were measured optically from Langendorff rabbit hearts at high (150 × 150 μm2) or low (1.5 × 1.5 cm2) 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 τf→s= 48 ± 9.2 s) and caused a secondary Ca2+release (SCR) from the sarcoplasmic reticulum during AP plateaus, occurring at the base on average of 184.4 ± 9.7 ms after the Ca2+transient upstroke. In subcellular imaging, SCRs were temporally synchronous and spatially homogeneous within myocytes. In diastole, SHR elicited variable ...

In numerous pathologies, spontaneous Ca 2+ release (SCR) emanating from the sarcoplasmic reticulu... more In numerous pathologies, spontaneous Ca 2+ release (SCR) emanating from the sarcoplasmic reticulum and occurring during the action potential (AP) plateau can drive voltage instability that initiates arrhythmias, but the direct interplay between SCRs and arrhythmogeneis has not been fully understood in bradycardia and in long QT type 2 (LQT2) models. Simultaneous optical measurement of intracellular Ca 2+ transient (Ca i T) and AP were performed in Langendorff-perfused rabbit hearts following AV node ablation. Bradycardia and/or LQT2 was/were induced and the spatial heterogeneity of intracellular Ca 2+ handling and its link to voltage dispersion were investigated. Upon switching from 120 to 50 beats/min, AP duration (APD) increased gradually with increasing occurrence of SCRs during the AP plateau (p<0.01, n=7). SCR was a) regionally heterogeneous, b) spatially correlated with APD prolongation, c) associated with enhanced dispersion of repolarization (DOR), d) reversed by pacing at 120 beats/min and e) suppressed with K201 (1µM) or flecainide (5µM), inhibitors of cardiac ryanodine receptors (RyR2) which reduced APD (p<0.01, n=5) and DOR (p<0.02, n=5). Western blots of Ca 2+ channels/transporters revealed intrinsic spatial distributions of Cav1.2α and NCX (but not RyR2, and SERCA2a) that correlate with the distribution of SCR and underlie the molecular mechanism responsible for SCRs.

Proceedings of the National Academy of Sciences, 2015

Significance Each heartbeat originates in the sinoatrial node (SAN), a collection of specialized ... more Significance Each heartbeat originates in the sinoatrial node (SAN), a collection of specialized cardiomyocytes (SANCs), which exhibit rhythmic action potentials and spontaneous Ca 2+ transients. We have found that the Ca 2+ sensor protein stromal interaction molecule 1 (STIM1) is enriched in the SANCs. Here we show that STIM1 Ca 2+ signaling is important in SANCs to maintain the Ca 2+ content of intracellular Ca 2+ stores and that this contributes to maintaining the regular sinus rhythm of the heart.

Circulation. Arrhythmia and electrophysiology, Jan 26, 2015

Background-Repolarization delay is a common clinical problem, which can promote ventricular arrhy... more Background-Repolarization delay is a common clinical problem, which can promote ventricular arrhythmias. In myocytes, abnormal sarcoplasmic reticulum Ca 2+-release is proposed as the mechanism that causes early afterdepolarizations, the cellular equivalent of ectopic-activity in drug-induced long-QT syndrome. A crucial missing link is how such a stochastic process can overcome the source-sink mismatch to depolarize sufficient ventricular tissue to initiate arrhythmias. Methods and Results-Optical maps of action potentials and Ca 2+-transients from Langendorff rabbit hearts were measured at low (150×150 μm 2 /pixel) and high (1.5×1.5 μm 2 /pixel) resolution before and during arrhythmias. Drug-induced long QT type 2, elicited with dofetilide inhibition of I Kr (the rapid component of rectifying K + current), produced spontaneous Ca 2+-elevations during diastole and systole, before the onset of arrhythmias. Diastolic Ca 2+waves appeared randomly, propagated within individual myocytes, were out-of-phase with adjacent myocytes, and often died-out. Systolic secondary Ca 2+elevations were synchronous within individual myocytes, appeared 188±30 ms after the action potential-upstroke, occurred during high cytosolic Ca 2+ (40%-60% of peak-Ca 2+-transients), appeared first in small islands (0.5×0.5 mm 2) that enlarged and spread throughout the epicardium. Synchronous systolic Ca 2+elevations preceded voltage-depolarizations (9.2±5 ms; n=5) and produced pronounced Spatial Heterogeneities of Ca 2+-transient-durations and action potentialdurations. Early afterdepolarizations originating from sites with the steepest gradients of membrane-potential propagated and initiated arrhythmias. Interestingly, more complex subcellular Ca 2+-dynamics (multiple chaotic Ca 2+-waves) occurred during arrhythmias. K201, a ryanodine receptor stabilizer, eliminated Ca 2+-elevations and arrhythmias. Conclusions-The results indicate that systolic and diastolic Ca 2+-elevations emanate from sarcoplasmic reticulum Ca 2+release and systolic Ca 2+-elevations are synchronous because of high cytosolic and luminal-sarcoplasmic reticulum Ca 2+ , which overcomes source-sink mismatch to trigger arrhythmias in intact hearts.

Journal of Molecular and Cellular Cardiology, 2015

Background and Objectives-The creation of cardiomyocytes derived from human induced pluripotent s... more Background and Objectives-The creation of cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs) has spawned broad excitement borne out of the prospects to diagnose and treat cardiovascular diseases based on personalized medicine. A common feature of hiPS-CMs is their spontaneous contractions but the mechanism(s) remain uncertain. Methods-Intrinsic activity was investigated by the voltage-clamp technique, optical mapping of action potentials (APs) and intracelular Ca 2+ (Ca i) transients (Ca i T) at subcellular-resolution and pharmacological interventions. Results-The frequency of spontaneous Ca i T (sCa i T) in monolayers of hiPS-CMs was not altered by ivabradine, an inhibitor of the pacemaker current, I f despite high levels of HCN transcripts (1-4). HiPS-CMs had negligible I f and I K1 (inwardly-rectifying K +-current) and a minimum diastolic potential of −59.1±3.3mV (n=18). APs upstrokes were preceded by a

Cardiac Electrophysiology: From Cell to Bedside, 2014

Heart Rhythm, 2010

Background-Alternans of intracellular Ca 2+ (Ca i) underlies T-wave alternans, a predictor of car... more Background-Alternans of intracellular Ca 2+ (Ca i) underlies T-wave alternans, a predictor of cardiac arrhythmias. A related phenomenon, T-Wave Lability (TWL), precedes Torsade de Pointes (TdP) in patients and animal models with impaired repolarization. However, the role of Ca i in TWL remains unexplored. Methods-Action potentials (APs) and Ca i transients, (CaTs) were mapped optically from paced Langendorff female rabbit hearts (n=8) at 1.2s cycle length, after AV node ablation. Hearts were perfused with normal Tyrode's solution then with dofetilide (0.5 μM) and reduced [K + ] (2 mM) and [Mg 2+ ] (0.5 mM) to elicit long QT type 2 (LQT2). Lability of EKG, voltage and Ca i signals were evaluated during regular paced rhythm, before and after dofetilide perfusion. Results-In LQT2, lability of Ca i , voltage and EKG signals increased during paced rhythm, before the appearance of early afterdepolarizations (EADs). LQT2 resulted in AP prolongation and multiple (1-3) additional Ca i upstrokes, while APs remained monophasic. When EADs appeared, Ca i rose before voltage upstrokes at the origins of propagating EADs. Interventions (i.e. ryanodine and thapsigargin, n=3 or low [Ca] o and nifedipine, n=4) that suppressed Ca i oscillations also abolished EADs. Conclusions-In LQT2, Ca i oscillations (Ca i O) precede EADs by minutes, indicating that they result from spontaneous sarcoplasmic reticulum Ca 2+ release rather than spontaneous I CaL reactivation. Ca i O likely produce oscillations of Na/Ca exchange current, I NCX. Depolarizing I NCX during the AP plateau contributes to the generation of EADs by reactivating Ca 2+-channels that have recovered from inactivation. TWL reflects CaTs and APs lability that occur before EADs and TdP.

Journal of the American College of Cardiology, 2011

Background: Enhanced dispersion of repolarization (DOR) in LQT2 and abnormalities of intracellula... more Background: Enhanced dispersion of repolarization (DOR) in LQT2 and abnormalities of intracellular Ca2+ (Cai) have been proposed as arrhythmogenic mechanism of Torsade de Pointes (TdP). However, the interplay and relative roles of DOR and SH of Cai is not understood. Methods: Simultaneous optical maps of membrane voltage (Vm) and Cai were recorded from the anterior surface of Langendorff rabbit hearts (n=7) paced at 50 bpm after AV node ablation. After perfusion with normal Tyrode (baseline; B), LQT2 was induced by adding dofetilide (0.5 μM) and reducing K+ (2 mM). Standard deviation of Vm and Cai signal amplitude was calculated in each 100x100 pixel frame and averaged over repolarization time-interval (from 100 ms after action potential upstroke to APD80). SH was calculated from paced beats as natural logarithm of this average at B and during LQT2. Results: Irregular regions of elevated Cai (~2x3 mm) appeared during phase 2 and 3 of action potential (Fig). During LQT2, SH of Cai exceeded SH of Vm in all hearts (-3.28±0.45 vs-3.55±0.41; p<0.01), although high Cai correlated with high Vm. At B, SH of Vm and Cai were similar and significantly lower than during LQT2. Conclusions: SH of Cai transient during LQT2 exceeds SH of Vm. Regions of elevated Cai exhibit complex oscillations on a mm scale. SH of Cai may reflect intrinsic regional differences of Cai handling mechanisms accentuated by repolarizationdelay of LQT2 rather than follow SH of Vm. Instead, SH of Cai appears to enhance SH of Vm, elevate DOR and facilitate TdP.