Mechanically-Induced Ventricular Arrhythmias during Acute Regional Ischemia

Baumeister, Peter; Lawen, Tarek; Rafferty, Sara A.; Taeb, Behzad; Uzelac, Ilija; Fenton, Flavio H.; Quinn, T. Alexander

doi:10.1016/j.yjmcc.2018.07.021

Cited by 6 publications

(16 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1b), resulting in a significant increase in the VP (Fig. 1c) that was similar to that measured previously in the whole heart during acute ischemia 18,19 . These changes stabilised after 5 min, as no further change in APD, CaTD, or the VP were observed, nor was there a change under physiologic conditions over time (Fig.…”

Section: / 35supporting

confidence: 88%

“…uncoupling of voltage-Ca 2+ dynamics due to relative differences in action potential and Ca 2+transient shortening by ATP-sensitive potassium (KATP) channel activation 18 . This creates a vulnerable period (VP) for Ca 2+ -driven arrhythmias during late repolarisation, as Ca 2+ remains high in repolarizing cells 19 (this has also been shown to occur during beta-adrenergic stimulation in failing human hearts 20 ).…”

Section: / 35mentioning

confidence: 99%

See 1 more Smart Citation

The cardiac TRPA1 channel drives calcium-mediated mechano-arrhythmogenesis

Cameron

Stoyek

Bak

et al. 2020

Preprint

View full text Add to dashboard Cite

SUMMARY PARAGRAPHPhysiological systems require feedback to maintain normal function. In the heart, electrical excitation causes mechanical contraction1, with feedback of mechanics to electrics occurring through ‘mechano-electric coupling’ processes2. In diseases that affect cardiac mechanics, this feedback can result in deadly mechanically-induced arrythmias (‘mechano-arrhythmogenicity’)3. However, the molecular identity of the specific factor(s) driving mechano-arrhythmogenicity are unknown4. Here we show that mechano-sensitive5–10 transient receptor potential kinase ankyrin 1 (TRPA1) channels11 are a source of cardiac mechano-arrhythmogenicity through a calcium (Ca2+)-driven mechanism. Using a cell-level approach involving stretch of single ventricular myocytes combined with simultaneous voltage-Ca2+ imaging, we found that activation of TRPA1 channels resulted in an increase in diastolic Ca2+ load and the appearance of stretch-induced arrhythmias, which were driven by trans-sarcolemmal fluxes and intracellular oscillations of Ca2+, and prevented by pharmacological TRPA1 channel block or Ca2+ buffering. Our results demonstrate that TRPA1 channels act as a trigger for stretch-induced excitation (via Ca2+-influx) and create a substrate for complex arrhythmic activity (via Ca2+-overload), and thus may represent a novel anti-arrhythmic target in cardiac diseases in which TRPA1 channel expression and activity are augmented12–16.

show abstract

Section: / 35supporting

confidence: 88%

Section: / 35mentioning

confidence: 99%

The cardiac TRPA1 channel drives calcium-mediated mechano-arrhythmogenesis

Cameron

Stoyek

Bak

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The patterns of systolic stretch used in our simulations are similar to those described in regions of myocardial mechanical heterogeneity. Experimental studies of acute ischemia (Baumeister et al, 2018) revealed that ischemic tissue shows a similar stretches as stretch pattern P used in for this computational study. Late diastolic stretches, such as stretch pattern S, have been observed in various pathological conditions such as ischemia or heart failure (Neves et al, 2016) and isometric conditions are often used in experimental set-ups FIGURE 6 | Maximal calcium wave amplitude and calcium wave velocity for simulations of three coupled cardiomyocytes.…”

Section: Sub-cellular Structure and Calcium Handlingmentioning

confidence: 93%

Mechano-Electric Coupling and Arrhythmogenic Current Generation in a Computational Model of Coupled Myocytes

Timmermann

McCulloch

2020

Front. Physiol.

View full text Add to dashboard Cite

A wide range of arrhythmogenic phenotypes have been associated with heterogeneous mechanical dyskinesis. Pro-arrhythmic effects are often associated with dysregulated intra-cellular calcium handling, especially via the development of intra- and inter-cellular calcium waves. Experimental evidence suggests that mechanical strain can contribute to the generation and maintenance of these calcium waves via a variety of mechano-electric coupling mechanisms. Most model studies of mechano-electric coupling mechanisms have been focused on mechano-sensitive ion channels, even though experimental studies have shown that intra- and inter-cellular calcium waves triggered by mechanical perturbations are likely to be more prevalent pro-arrhythmic mechanisms in the diseased heart. A one-dimensional strongly coupled computational model of electromechanics in rabbit ventricular cardiomyocytes showed that specific myocyte stretch sequences can modulate the susceptibility threshold for delayed after-depolarizations. In simulations of mechanically-triggered calcium waves in cardiomyocytes coupled to fibroblasts, susceptibility to calcium wave propagation was reduced as the current through the gap junction caused current drain from the myocytes. In 1D multi-cellular arrays coupled via gap junctions, mechanically-induced waves may contribute to synchronizing arrhythmogenic calcium waves and after-depolarizations.

show abstract

“…8 Yet, the molecular identity of the mechano-sensitive ion channels involved remains unknown. 9 Recent evidence from rabbit isolated heart studies suggests that ventricular mechanoarrhythmogenicity in regional ischemia is Ca 2+ -mediated, 10 and may relate to a VP in late repolarisation during which a temporal dissociation between the recovery of membrane potential and cytosolic Ca 2+ results in Ca 2+ remaining elevated as myocytes become re-excitable. 10,11 Further work showed that the mechano-sensitive, 12 Ca 2+ -permeable 13 transient receptor potential ankyrin 1 (TRPA1) channel 14 can act as a source for Ca 2+ -mediated mechano-arrhythmogenicity in ventricular myocytes by triggering premature excitation and creating a substrate for more complex arrhythmic activity.…”

Section: Introductionmentioning

confidence: 99%

“…9 Recent evidence from rabbit isolated heart studies suggests that ventricular mechanoarrhythmogenicity in regional ischemia is Ca 2+ -mediated, 10 and may relate to a VP in late repolarisation during which a temporal dissociation between the recovery of membrane potential and cytosolic Ca 2+ results in Ca 2+ remaining elevated as myocytes become re-excitable. 10,11 Further work showed that the mechano-sensitive, 12 Ca 2+ -permeable 13 transient receptor potential ankyrin 1 (TRPA1) channel 14 can act as a source for Ca 2+ -mediated mechano-arrhythmogenicity in ventricular myocytes by triggering premature excitation and creating a substrate for more complex arrhythmic activity. 15 Since the response of TRPA1 to mechanical stimulation is dependent on its baseline activity, 16 which is increased in ischemia 17 as it is agonised by multiple ischemic factors (e.g., increased cytosolic Ca 2+ and ROS), 18,19 TRPA1 may be involved in ischemic mechano-arrhythmogenicity.…”

Section: Introductionmentioning

confidence: 99%

Mechano-arrhythmogenicity is enhanced during late repolarisation in ischemia and driven by a TRPA1-, calcium-, and reactive oxygen species-dependent mechanism

Cameron

Quinn

2021

Preprint

View full text Add to dashboard Cite

BackgroundCardiac dyskinesis in regional ischemia results in arrhythmias through mechanically-induced changes in electrophysiology (‘mechano-arrhythmogenicity’) that involve ischemic alterations in voltage-calcium (Ca2+) dynamics, creating a vulnerable period (VP) in late repolarisation.ObjectiveTo determine cellular mechanisms of mechano-arrhythmogenicity in ischemia and define the importance of the VP.Methods and ResultsVoltage-Ca2+ dynamics were simultaneously monitored in rabbit ventricular myocytes by dual-fluorescence imaging to assess the VP in control and simulated ischemia (SI). The VP was longer in SI than in control (146±7 vs 54±8ms; p<0.0001) and was reduced by blocking KATP channels with glibenclamide (109±6ms; p<0.0001). Cells were rapidly stretched (10-18% increase in sarcomere length over 110-170ms) with carbon fibres during diastole or the VP. Mechano-arrhythmogenicity, associated with stretch and release in the VP, was greater in SI than control (7 vs 1% of stretches induced arrhythmias; p<0.005) but was similar in diastole. Arrhythmias during the VP were more complex than in diastole (100 vs 69% had sustained activity; p<0.05). In the VP, incidence was reduced with glibenclamide (2%; p<0.05), by chelating intracellular Ca2+ (BAPTA; 2%; p<0.05), blocking mechano-sensitive TRPA1 (HC-030031; 1%; p<0.005), or by scavenging (NAC; 1%; p<0.005) or blocking reactive oxygen species (ROS) production (DPI; 2%; p<0.05). Ratiometric Ca2+ imaging revealed that SI increased diastolic Ca2± (+9±1%, p<0.0001), which was not prevented by HC-030031 or NAC.ConclusionIn ischemia, mechano-arrhythmogenicity is enhanced specifically during the VP and is mediated by ROS, TRPA1, and Ca2+.

show abstract

Mechanically-Induced Ventricular Arrhythmias during Acute Regional Ischemia

Cited by 6 publications

References 0 publications

The cardiac TRPA1 channel drives calcium-mediated mechano-arrhythmogenesis

The cardiac TRPA1 channel drives calcium-mediated mechano-arrhythmogenesis

Mechano-Electric Coupling and Arrhythmogenic Current Generation in a Computational Model of Coupled Myocytes

Mechano-arrhythmogenicity is enhanced during late repolarisation in ischemia and driven by a TRPA1-, calcium-, and reactive oxygen species-dependent mechanism

Contact Info

Product

Resources

About