Effect of heptanol and ethanol on excitation wave propagation in a neonatal rat ventricular myocyte monolayer

Podgurskaya, A.D.; Tsvelaya, V. A.; Frolova, Sheida; Kalita, I. Y.; Kudryashova, Nina; Agladze, Konstantin

doi:10.1016/j.tiv.2018.05.009

Cited by 7 publications

(10 citation statements)

References 39 publications

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“…In these CMs application of heptanol also induced a prolongation of the APD, suggesting they were also coupled to MyoFbs. In 4 cells that were classified as not connected and had a baseline APD between 150 and 290 ms, there was no prolongation and in contrast APD was reduced in these cells, in line with previously reported effects of heptanol on AP properties 22 and the reduction of Ca current by heptanol 23 .…”

Section: Resultssupporting

confidence: 90%

Myofibroblast modulation of cardiac myocyte structure and function

Nagaraju

Dries

Gilbert

et al. 2019

Sci Rep

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After myocardial infarction, resident fibroblasts (Fb) differentiate towards myofibroblasts (MyoFb), generating the scar tissue and the interstitial fibrosis seen in the adjacent myocardium. Fb and MyoFb have the potential to interact with cardiac myocytes (CMs) but insight into the phenotype-specific role and mode of interaction is still incomplete. Our objectives are to further define the modulation of CMs by MyoFbs compared to Fbs, as well as the role of direct contact through gap junctions vs. soluble mediators, using Fbs and CMs from pig left ventricle. Fbs were treated to maintain an undifferentiated state (SD-208) or to attain full differentiation to MyoFb (TGF-β1). Fbs and MyoFbs were co-cultured with CMs, with the possibility of direct contact or separated by a Thincert membrane. Only in direct co-culture, both Fbs and MyoFbs were able to decrease CM viability after 2 days. Only MyoFbs induced significant distal spreading of CMs in both direct and indirect co-culture. MyoFbs, but not Fbs, readily made connections with CMs in direct co-culture and connexin 43 expression in MyoFb was higher than in Fb. When coupled to CMs, MyoFbs reduced the CM action potential duration and hyperpolarized the CM resting membrane potential. Uncoupling reversed these effects. In conclusion, MyoFbs, but not Fbs, alter the CM structural phenotype. MyoFbs, but not Fbs, are likely to electrically connect to CMs and thereby modulate the CM membrane potential. These data provide further support for an active role of MyoFbs in the arrhythmogenic substrate after cardiac remodelling.

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Section: Resultssupporting

confidence: 90%

Myofibroblast modulation of cardiac myocyte structure and function

Nagaraju

Dries

Gilbert

et al. 2019

Sci Rep

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“…of NRVMs, preparation of samples were performed as previously described in Materials and methods section in Ref. 16 . In brief, isolation and seeding of NRVMs were performed according to the Worthington protocol (http://www.worth ingto n-bioch em.com/NCIS/defau lt.html).…”

Section: Preparation Of Neonatal Rat Ventricular Cardiomyocytes Prepmentioning

confidence: 99%

“…Data processing and statistics. Data processing was performed as previously described 16 . All videos from optical mapping and images from the confocal microscope were processed in the ImageJ.…”

Section: Patch-clampmentioning

confidence: 99%

Cyclophosphamide arrhythmogenicitytesting using human-induced pluripotent stem cell-derived cardiomyocytes

Podgurskaya

Slotvitsky

Tsvelaya

et al. 2021

Sci Rep

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Cyclophosphamide (CP) is an anticancer drug, an alkylating agent. Cardiotoxicity of CP is associated with one of its metabolites, acrolein, and clinical cardiotoxicity manifestations are described for cases of taking CP in high doses. Nevertheless, modern arrhythmogenicity prediction assays in vitro include evaluation of beat rhythm and rate as well as suppression of cardiac late markers after acute exposure to CP, but not its metabolites. The mechanism of CP side effects when taken at low doses (i.e., < 100 mg/kg), especially at the cellular level, remains unclear. In this study conduction properties and cytoskeleton structure of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) obtained from a healthy donor under CP were evaluated. Arrhythmogenicity testing including characterization of 3 values: conduction velocity, maximum capture rate (MCR) measurements and number of occasions of re-entry on a standard linear obstacle was conducted and revealed MCR decrease of 25% ± 7% under CP. Also, conductivity area reduced by 34 ± 15%. No effect of CP on voltage-gated ion channels was found. Conduction changes (MCR and conductivity area decrease) are caused by exposure time-dependent alpha-actinin disruption detected both in hiPSC-CMs and neonatal ventricular cardiomyocytes in vitro. Deviation from the external stimulus frequency and appearance of non-conductive areas in cardiac tissue under CP is potentially arrhythmogenic and could develop arrhythmic effects in vivo.

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“…It then follows that drug-induced partial cellular uncoupling imparts non-symmetrical effects on the direction of impulse propagation in discontinuous cardiac tissue [43]. Aliphatic alcohols such as heptanol, [46] ethanol, [47] and palmitoleic acid [40] cause partial cellular uncoupling at low doses and complete uncoupling at higher doses, with ethanol being the least potent cellular uncoupler [47]. Low doses of aliphatic alcohols slightly slow conduction velocity due to partial uncoupling without affecting the source, i.e., fast Na current both in atria [46] and in ventricular tissue [48].…”

Section: Potential Mechanisms Of Vfmentioning

confidence: 99%

“…Low doses of aliphatic alcohols slightly slow conduction velocity due to partial uncoupling without affecting the source, i.e., fast Na current both in atria [46] and in ventricular tissue [48]. Wavebreaks with higher doses of ethanol promote the formation of multiple wavelets [47] simulating fibrillation-like state [49]. These experimental findings raise the hypothesis that low concentrations of alcohol, by inducing partial cellular uncoupling, eliminates UCB and protects the heart against reentrant VT/VF, while higher doses cause conduction block (wavebreaks) leading to VF.…”

Section: Potential Mechanisms Of Vfmentioning

confidence: 99%

Mechanisms of U-Shaped Association between Alcohol Intake and the Risk of Sudden Cardiac Death

Hs¹,

Demirdjian²

2019

J Hear Health

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Large cohort epidemiological studies have shown a U-shaped association between the relative risk of Sudden Cardiac Death (SCD) and the dose of alcohol consumed across both genders. The mechanisms of this relationship, i.e., too little or too high promoting SCD while moderate doses providing protection, remain elusive. In this brief review, we provide plausible electrophysiological and biochemical mechanisms of the U-shaped association of the dose of alcohol and the risk of SCD. At moderate doses alcohol causes partial cellular uncoupling "paradoxically" improves the conduction at narrow ventricular conducting pathways (source) that adjoins a large tissue mass (sink) eliminating preexisting Unidirectional Conduction (UCB) (from source-to-sink) and preventing re-entry formation. In contrast, higher doses of alcohol by further increasing cellular uncoupling cause conduction block at multiple ventricular sites (wavebreaks) in isolated tissues and patterned monolayers of cardiac myocytes leading to the formation of multiple reentrant and non-reentrant wave fronts simulating fibrillation-like state. In the absence of alcohol, the vulnerable narrow conducting pathways remain unchanged promoting UCB (i.e., conduction block from source-to-sink block) increasing the risk of reentry formation. Re-entry leads to Ventricular Fibrillation (VF), a major cause of SCD. Our hypothesis of U-shaped association between alcohol dose and SCD is based on the preponderance of clinical epidemiological data and on basic experimental studies using intact animal hearts and patterned monolayers of cardiac myocytes with vulnerable narrow strands of conducting pathways (source) abutting to a large tissue mass (sink).in 12 ounces of regular beer (~5% per volume alcohol), in five ounces of wine (~12% per volume alcohol) and 1.5 ounces of spirits (~40% alcohol). Therefore, up to 15 g/day is considered "light-to-moderate, " and greater than 30 g/day is considered "high" [3,4].The potential benefits of light-to-moderate doses of alcohol consumption, however, has not received universal acceptance. A recent systematic review of epidemiological data by The Global Burden of Disease Study by Alcohol Collaborators challenged the health benefits of light-to-moderate levels of alcohol consumption. This meta-analysis concluded that the level of alcohol consumption that minimized harm "across all health outcomes particularly the risk of cancer, was zero" [10]. This seeming controversy stems from the fact that certain diseases like Atrial Fibrillation (AF), stroke, [11] hypertension, heart failure, cardiomyopathy, cancer, and liver disease do not manifest any benefit from alcohol, [5,12,13] while other diseases do. The potential mechanisms of the observed benefits of low-to-moderate alcohol consumption in CAD and SCD remain undefined because the observed epidemiologic data are associative and not causative, providing no mechanistic insight by which alcohol causes it's beneficial or its ill effects. Since the questions that motivate

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Effect of heptanol and ethanol on excitation wave propagation in a neonatal rat ventricular myocyte monolayer

Cited by 7 publications

References 39 publications

Myofibroblast modulation of cardiac myocyte structure and function

Myofibroblast modulation of cardiac myocyte structure and function

Cyclophosphamide arrhythmogenicitytesting using human-induced pluripotent stem cell-derived cardiomyocytes

Mechanisms of U-Shaped Association between Alcohol Intake and the Risk of Sudden Cardiac Death

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