Aberrant Deactivation-Induced Gain of Function in TRPM4 Mutant Is Associated with Human Cardiac Conduction Block

His-bundle electrocardiography was used to evaluate the effects of ethmozine on cardiac conduction in isolated perfused rabbit hearts electrically driven at cycle lengths of 320 and 250 ms. There was no significant change in conduction until high concentrations of ethmozine were reached. His-Purkinje and atrioventricular (AV) nodal conduction were slowed significantly at 0.1 μg/mL and atrial conduction at 1.0 μg/mL. Conduction block occurred at 10.0 μg/mL in all the hearts treated. Effects of the drug (0.1 and 0.01 μg/mL) on conduction of extrasystoles were also studied in hearts driven at a basic cycle length of 270 ms. No significant change was observed in atrial conduction of extrasystoles throughout the coupling intervals tested at both concentrations. Ethmozine (0.01 and 0.1 μg/mL) caused slowing of His-Purkinje conduction of extrasystoles but the effect of the drug did not change as a function of the coupling interval. An interval-dependent increase in AV-nodal conduction time was observed, with the maximum slowing of conduction occurring at coupling intervals close to the effective refractory period of the AV node. AV-nodal functional refractory period was increased significantly by ethmozine (0.01 and 0.1 μg/mL). The effective refractory period was significantly increased only at the higher concentration.

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THE STOCHASTIC NATURE OF CARDIAC PROPAGATION DUE TO THE DISCRETE CELLULAR STRUCTURE OF THE MYOCARDIUM

International Journal of Bifurcation and Chaos ◽

10.1142/s0218127496000990 ◽

1996 ◽

Vol 06 (09) ◽

pp. 1637-1656 ◽

Cited By ~ 8

Author(s):

MADISON S. SPACH

Keyword(s):

Gap Junctions ◽

Wave Front ◽

Cellular Structure ◽

Conduction Block ◽

Microscopic Level ◽

Cardiac Conduction ◽

Electrical Load ◽

Stochastic Nature ◽

Myocardial Architecture ◽

Front Movement

The object of this paper is to describe cardiac conduction phenomena caused by the discrete nature of cardiac cellular structure. Recent results show that the myocardial architecture creates inhomogeneities of electrical load at the microscopic level that cause cardiac propagation to be stochastic in nature. That is, the excitatory events during propagation are constantly changing and disorderly in the sense of varying intracellular events and delays between cells. A unique feature of the stochastic nature of cardiac propagation is that electrical boundaries produced by cellular myocardial architecture create inhomogeneities of electrical load that affect conduction inside individual cells and influence conduction delays across gap junctions, as well as at muscle bundle junctions. This process produces discontinuous propagation as a primary reflection of the nonuniformities of electrical load due to the irregular arrangement of the cellular borders and the associated nonuniform distribution of their electrical interconnections. A fundamental consequence of the stochastic nature of normal propagation at a microscopic level is that it provides a major protective effect against arrhythmias by re-establishing the general trend of wave front movement after small variations in excitation events occur. When the diversity at a very small size scale decreases throughout the tissue, such as occurs when there are regularly repeating relatively isolated groups of cells, larger fluctuations of load can develop and be distributed over more cells than occurs normally. The myocardial architecture may then fail to re-establish a smoothed wave front and re-entry can develop. These relatively new discontinuous conduction phenomena provide important theoretical and experimental challenges to synthesize a complete theory linking continuous and discontinuous media as applied to cardiac conduction. The results show that it will be important to distinguish differences in wave front movement and conduction block caused by mechanisms of continuous media versus wave front movement and block imposed by directional or localized changes in cellular connectivity; i.e., the topology of the electrical connections between cells (gap junctions).

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Dynamic changes of cardiac conduction during rapid pacing

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00784.2006 ◽

2007 ◽

Vol 292 (4) ◽

pp. H1796-H1811 ◽

Cited By ~ 26

Author(s):

Aleksandar A. Kondratyev ◽

Julien G. C. Ponard ◽

Adelina Munteanu ◽

Stephan Rohr ◽

Jan P. Kucera

Keyword(s):

Ventricular Myocytes ◽

Conduction Block ◽

Pump Current ◽

Neonatal Rat ◽

Cardiac Conduction ◽

Dynamic Changes ◽

Abrupt Decrease ◽

Rate Dependent ◽

Ionic Mechanisms ◽

Inward Currents

Slow conduction and unidirectional conduction block (UCB) are key mechanisms of reentry. Following abrupt changes in heart rate, dynamic changes of conduction velocity (CV) and structurally determined UCB may critically influence arrhythmogenesis. Using patterned cultures of neonatal rat ventricular myocytes grown on microelectrode arrays, we investigated the dynamics of CV in linear strands and the behavior of UCB in tissue expansions following an abrupt decrease in pacing cycle length (CL). Ionic mechanisms underlying rate-dependent conduction changes were investigated using the Pandit-Clark-Giles-Demir model. In linear strands, CV gradually decreased upon a reduction of CL from 500 ms to 230–300 ms. In contrast, at very short CLs (110–220 ms), CV first decreased before increasing again. The simulations suggested that the initial conduction slowing resulted from gradually increasing action potential duration (APD), decreasing diastolic intervals, and increasing postrepolarization refractoriness, which impaired Na+ current ( INa) recovery. Only at very short CLs did APD subsequently shorten again due to increasing Na+/K+ pump current secondary to intracellular Na+ accumulation, which caused recovery of CV. Across tissue expansions, the degree of UCB gradually increased at CLs of 250–390 ms, whereas at CLs of 180–240 ms, it first increased and subsequently decreased. In the simulations, reduction of inward currents caused by increasing intracellular Na+ and Ca2+ concentrations contributed to UCB progression, which was reversed by increasing Na+/K+ pump activity. In conclusion, CV and UCB follow intricate dynamics upon an abrupt decrease in CL that are determined by the interplay among INa recovery, postrepolarization refractoriness, APD changes, ion accumulation, and Na+/K+ pump function.

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Effects of insulin on the reversal of myocardial contractility after bupivacaine-induced cardiac asystole in vitro

10.21203/rs.2.11217/v3 ◽

2019 ◽

Author(s):

Hyun Joo Kim ◽

Ja Rang Jung ◽

Carl Lynch III ◽

Wyun Kon Park

Keyword(s):

Conduction Block ◽

Metabolic Energy ◽

Cardiac Conduction ◽

Control Group ◽

Na Channel ◽

Tyrode Solution ◽

Contractile Responses ◽

Glucose Treatment

Abstract Background: Insulin-glucose treatment effectively reverses severe bupivacaine (BPV)-induced myocardial depression or cardiovascular collapse in in vivo. However, the mechanisms for the recovery are poorly defined. Methods: Using the guinea pig myocardium, cumulative concentration-responses on contractile forces for insulin or insulin combined with 33 mM glucose (insulin/glucose) were measured. After achieving asystole by 500 µM BPV, different concentrations of insulin or insulin/glucose were applied to determine the recovery of stimulated contractile responses and contractions in either recirculating or non-recirculating (washout) condition. Because we did not observe any recovery from asystole with insulin treatment in the recirculating condition, further experiments were performed whether intermittent contractile responses (conduction block) could be reversed by insulin. In the washout condition, after achieving asystole, the muscles were washed with the Tyrode solution containing insulin or insulin/glucose for 60 minutes. After achieving asystole, BPV concentrations in the Tyrode solution in the presence or absence of insulin for 60 minutes were measured. Results: There were similar concentration-dependent decreases in contractility in both the insulin and insulin/glucose groups. Neither insulin nor insulin/glucose restored the stimulated contractile responses from conduction disturbance or asystole induced by BPV in the continued presence of BPV. In the BPV-washout condition, while superfusion with a control (plain Tyrode) solution for 60 minutes after achieving asystole by BPV restored contractility to approximately 60% of the baseline, time-dependent complete recovery was observed in the insulin- and insulin/glucose-treated groups. At each time period from asystole to 60 minutes, the BPV concentrations in the insulin-treated group were slightly lower than those in the control group. Conclusions: Neither insulin nor insulin/glucose treatment does not rescue Na+ channel function to reverse BPV-induced cardiac conduction block or asystole regardless of improved cardiac performance, possibly due to improved myocardial energetics in isolated in vitro animal myocardium model. These findings suggest that treatment with insulin or insulin/glucose is desirable for metabolic energy supply to the myocardium in cases of BPV-induced cardiac collapse. However, considering the importance of decreased BPV concentrations in cardiac tissues, insulin or insulin/glucose may not achieve satisfactory outcomes.

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Effects of insulin on the reversal of myocardial contractility after bupivacaine-induced cardiac asystole in vitro

10.21203/rs.2.11217/v1 ◽

2019 ◽

Author(s):

Hyun Joo Kim ◽

Ja Rang Jung ◽

Carl Lynch III ◽

Wyun Kon Park

Keyword(s):

Conduction Block ◽

Metabolic Energy ◽

Cardiac Conduction ◽

Control Group ◽

Na Channel ◽

Tyrode Solution ◽

Contractile Responses ◽

Glucose Treatment

Abstract Background: Insulin-glucose treatment effectively reverses severe bupivacaine (BPV)-induced myocardial depression or cardiovascular collapse in in vivo. However, the mechanisms for the recovery are poorly defined. Methods: Using the guinea pig myocardium, cumulative concentration-responses on contractile forces for insulin or insulin combined with 33 mM glucose (insulin/glucose) were measured. After achieving asystole by 500 µM BPV, different concentrations of insulin or insulin/glucose were applied to determine the recovery of stimulated contractile responses and contractions in either recirculating or non-recirculating (washout) condition. Because we did not observe any recovery from asystole with insulin treatment in the recirculating condition, further experiments were performed whether intermittent contractile responses (conduction block) could be reversed by insulin. In the washout condition, after achieving asystole, the muscles were washed with the Tyrode solution containing insulin or insulin/glucose for 60 minutes. After achieving asystole, BPV concentrations in the Tyrode solution in the presence or absence of insulin for 60 minutes were measured. Results: There were similar concentration-dependent decreases in contractility in both the insulin and insulin/glucose groups. Neither insulin nor insulin/glucose restored the stimulated contractile responses from conduction disturbance or asystole induced by BPV in the continued presence of BPV. In the BPV-washout condition, while superfusion with a control (plain Tyrode) solution for 60 minutes after achieving asystole by BPV restored contractility to approximately 60% of the baseline, time-dependent complete recovery was observed in the insulin- and insulin/glucose-treated groups. At each time period from asystole to 60 minutes, the BPV concentrations in the insulin-treated group were slightly lower than those in the control group. Conclusions: Neither insulin nor insulin/glucose treatment does not rescue Na+ channel function to reverse BPV-induced cardiac conduction block or asystole regardless of improved cardiac performance, possibly due to improved myocardial energetics in isolated in vitro animal myocardium model. These findings suggest that treatment with insulin or insulin/glucose is desirable for metabolic energy supply to the myocardium in cases of BPV-induced cardiac collapse. However, considering the importance of decreased BPV concentrations in cardiac tissues, insulin or insulin/glucose may not achieve satisfactory outcomes.

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NONMMUT140591.1 may serve as a ceRNA to regulate Gata5 in UT-B knockout-induced cardiac conduction block

Open Life Sciences ◽

10.1515/biol-2021-0106 ◽

2021 ◽

Vol 16 (1) ◽

pp. 1240-1251

Author(s):

Xuejiao Lv ◽

Yuxin Sun ◽

Wenxi Tan ◽

Yang Liu ◽

Naiyan Wen ◽

...

Keyword(s):

Molecular Mechanisms ◽

Function Analysis ◽

Conduction Block ◽

Cardiac Conduction ◽

Sequencing Analysis ◽

Sequencing Data ◽

Aberrant Expression ◽

Cerna Network ◽

And Control ◽

Transcriptome Level

Abstract We intended to explore the potential molecular mechanisms underlying the cardiac conduction block inducted by urea transporter (UT)-B deletion at the transcriptome level. The heart tissues were harvested from UT-B null mice and age-matched wild-type mice for lncRNA sequencing analysis. Based on the sequencing data, the differentially expressed mRNAs (DEMs) and lncRNAs (DELs) between UT-B knockout and control groups were identified, followed by function analysis and mRNA–lncRNA co-expression analysis. The miRNAs were predicted, and then the competing endogenous RNA (ceRNA) network was constructed. UT-B deletion results in the aberrant expression of 588 lncRNAs and 194 mRNAs. These DEMs were significantly enriched in the inflammation-related pathway. A lncRNA–mRNA co-expression network and a ceRNA network were constructed on the basis of the DEMs and DELs. The complement 7 (C7)–NONMMUT137216.1 co-expression pair had the highest correlation coefficient in the co-expression network. NONMMUT140591.1 had the highest degree in the ceRNA network and was involved in the ceRNA of NONMMUT140591.1-mmu-miR-298-5p-Gata5 (GATA binding protein 5). UT-B deletion may promote cardiac conduction block via inflammatory process. The ceRNA NONMMUT140591.1-mmu-miR-298-5p-Gata5 may be a potential molecular mechanism of UT-B knockout-induced cardiac conduction block.

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Effects of insulin on the reversal of myocardial contractility after bupivacaine-induced cardiac asystole in vitro

10.21203/rs.2.11217/v2 ◽

2019 ◽

Author(s):

Hyun Joo Kim ◽

Ja Rang Jung ◽

Carl Lynch III ◽

Wyun Kon Park

Keyword(s):

Conduction Block ◽

Metabolic Energy ◽

Cardiac Conduction ◽

Control Group ◽

Na Channel ◽

Tyrode Solution ◽

Contractile Responses ◽

Glucose Treatment

Abstract Background: Insulin-glucose treatment effectively reverses severe bupivacaine (BPV)-induced myocardial depression or cardiovascular collapse in in vivo. However, the mechanisms for the recovery are poorly defined. Methods: Using the guinea pig myocardium, cumulative concentration-responses on contractile forces for insulin or insulin combined with 33 mM glucose (insulin/glucose) were measured. After achieving asystole by 500 µM BPV, different concentrations of insulin or insulin/glucose were applied to determine the recovery of stimulated contractile responses and contractions in either recirculating or non-recirculating (washout) condition. Because we did not observe any recovery from asystole with insulin treatment in the recirculating condition, further experiments were performed whether intermittent contractile responses (conduction block) could be reversed by insulin. In the washout condition, after achieving asystole, the muscles were washed with the Tyrode solution containing insulin or insulin/glucose for 60 minutes. After achieving asystole, BPV concentrations in the Tyrode solution in the presence or absence of insulin for 60 minutes were measured. Results: There were similar concentration-dependent decreases in contractility in both the insulin and insulin/glucose groups. Neither insulin nor insulin/glucose restored the stimulated contractile responses from conduction disturbance or asystole induced by BPV in the continued presence of BPV. In the BPV-washout condition, while superfusion with a control (plain Tyrode) solution for 60 minutes after achieving asystole by BPV restored contractility to approximately 60% of the baseline, time-dependent complete recovery was observed in the insulin- and insulin/glucose-treated groups. At each time period from asystole to 60 minutes, the BPV concentrations in the insulin-treated group were slightly lower than those in the control group. Conclusions: Neither insulin nor insulin/glucose treatment does not rescue Na+ channel function to reverse BPV-induced cardiac conduction block or asystole regardless of improved cardiac performance, possibly due to improved myocardial energetics in isolated in vitro animal myocardium model. These findings suggest that treatment with insulin or insulin/glucose is desirable for metabolic energy supply to the myocardium in cases of BPV-induced cardiac collapse. However, considering the importance of decreased BPV concentrations in cardiac tissues, insulin or insulin/glucose may not achieve satisfactory outcomes.

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Ionic Mechanisms of Impulse Propagation Failure in the FHF2-Deficient Heart

Circulation Research ◽

10.1161/circresaha.120.317349 ◽

2020 ◽

Vol 127 (12) ◽

pp. 1536-1548 ◽

Cited By ~ 1

Author(s):

David S. Park ◽

Akshay Shekhar ◽

John Santucci ◽

Gabriel Redel-Traub ◽

Sergio Solinas ◽

...

Keyword(s):

Connexin 43 ◽

Sodium Current ◽

Conduction Block ◽

Tissue Level ◽

Axial Current ◽

Epileptic Encephalopathy ◽

Cardiac Conduction ◽

Impulse Propagation ◽

Ionic Mechanisms ◽

Gap Junctional

Rationale: FHFs (fibroblast growth factor homologous factors) are key regulators of sodium channel (Na V ) inactivation. Mutations in these critical proteins have been implicated in human diseases including Brugada syndrome, idiopathic ventricular arrhythmias, and epileptic encephalopathy. The underlying ionic mechanisms by which reduced Na v availability in Fhf2 knockout ( Fhf2 KO ) mice predisposes to abnormal excitability at the tissue level are not well defined. Objective: Using animal models and theoretical multicellular linear strands, we examined how FHF2 orchestrates the interdependency of sodium, calcium, and gap junctional conductances to safeguard cardiac conduction. Methods and Results: Fhf2 KO mice were challenged by reducing calcium conductance (gCa V ) using verapamil or by reducing gap junctional conductance (Gj) using carbenoxolone or by backcrossing into a cardiomyocyte-specific Cx43 (connexin 43) heterozygous background. All conditions produced conduction block in Fhf2 KO mice, with Fhf2 wild-type ( Fhf2 WT ) mice showing normal impulse propagation. To explore the ionic mechanisms of block in Fhf2 KO hearts, multicellular linear strand models incorporating FHF2-deficient Na v inactivation properties were constructed and faithfully recapitulated conduction abnormalities seen in mutant hearts. The mechanisms of conduction block in mutant strands with reduced gCa V or diminished Gj are very different. Enhanced Na v inactivation due to FHF2 deficiency shifts dependence onto calcium current (I Ca ) to sustain electrotonic driving force, axial current flow, and action potential (AP) generation from cell-to-cell. In the setting of diminished Gj, slower charging time from upstream cells conspires with accelerated Na v inactivation in mutant strands to prevent sufficient downstream cell charging for AP propagation. Conclusions: FHF2-dependent effects on Na v inactivation ensure adequate sodium current (I Na ) reserve to safeguard against numerous threats to reliable cardiac impulse propagation.

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