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  • 1
    Online Resource
    Online Resource
    Differentiating the effects of β-adrenergic stimulation and stretch on calcium and force dynamics using a novel electromechanical cardiomyocyte model
    American Physiological Society ; 2020
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 319, No. 3 ( 2020-09-01), p. H519-H530
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 319, No. 3 ( 2020-09-01), p. H519-H530
    Abstract: Cardiac electrophysiology and mechanics are strongly interconnected. Calcium is crucial in this complex interplay through its role in cellular electrophysiology and sarcomere contraction. We aim to differentiate the effects of acute β-adrenergic stimulation (β-ARS) and cardiomyocyte stretch (increased sarcomere length) on calcium-transient dynamics and force generation, using a novel computational model of cardiac electromechanics. We implemented a bidirectional coupling between the O’Hara-Rudy model of human ventricular electrophysiology and the MechChem model of sarcomere mechanics through the buffering of calcium by troponin. The coupled model was validated using experimental data from large mammals or human samples. Calcium transient and force were simulated for various degrees of β-ARS and initial sarcomere lengths. The model reproduced force-frequency, quick-release, and isotonic contraction experiments, validating the bidirectional electromechanical interactions. An increase in β-ARS increased the amplitudes of force (augmented inotropy) and calcium transient, and shortened both force and calcium-transient duration (lusitropy). An increase in sarcomere length increased force amplitude even more, but decreased calcium-transient amplitude and increased both force and calcium-transient duration. Finally, a gradient in relaxation along the thin filament may explain the nonmonotonic decay in cytosolic calcium observed with high tension. Using a novel coupled human electromechanical model, we identified differential effects of β-ARS and stretch on calcium and force. Stretch mostly contributed to increased force amplitude and β-ARS to the reduction of calcium and force duration. We showed that their combination, rather than individual contributions, is key to ensure force generation, rapid relaxation, and low diastolic calcium levels. NEW & NOTEWORTHY This work identifies the contribution of electrical and mechanical alterations to regulation of calcium and force under exercise-like conditions using a novel human electromechanical model integrating ventricular electrophysiology and sarcomere mechanics. By better understanding their individual and combined effects, this can uncover arrhythmogenic mechanisms in exercise-like situations. This publicly available model is a crucial step toward understanding the complex interplay between cardiac electrophysiology and mechanics to improve arrhythmia risk prediction and treatment. Listen to this article’s corresponding podcast at: https://ajpheart.podbean.com/e/behind-the-bench-episode-6-with-aurore-lyon/ .
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00275.2020
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2020
    detail.hit.zdb_id: 1477308-9
    SSG: 12
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    Impact of acute and enduring volume overload on mechanotransduction and cytoskeletal integrity of canine left ventricular myocardium
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 292, No. 5 ( 2007-05), p. H2324-H2332
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 292, No. 5 ( 2007-05), p. H2324-H2332
    Abstract: It is poorly understood how mechanical stimuli influence in vivo myocardial remodeling during chronic hemodynamic overload. Combined quantitation of ventricular mechanics and expression of key proteins involved in mechanotransduction can improve fundamental understanding. Adult anesthetized dogs ( n = 20) were studied at sinus rhythm (SR) and 0, 3, 10, and 35 days of complete atrioventricular block (AVB). Serial left ventricular (LV) myofiber mechanics were measured. Repeated LV biopsies were analyzed for mRNA and/or protein expression of β 1D -integrin, melusin, Akt, GSK3β, muscle LIM protein (MLP), four-and-a-half LIM protein 2 (fhl2), desmin, and calpain. Upon AVB, increased ejection strain (0.29 ± 0.01 vs. 0.13 ± 0.02, SR) and end-diastolic stress (4.8 ± 1.1 vs. 2.7 ± 0.4 kPa) dominated mechanical changes. Brain natriuretic peptide plasma levels were correspondingly high (33 ± 4 vs. 19 ± 1 pg/ml, SR). β 1D -Integrin protein expression increased chronically after AVB. Melusin was temporarily overexpressed (+33 ± 9%, 3 days AVB vs. SR), followed by elevated ratios of phosphorylated (P)-Akt to Akt and P-GSK3β to GSK3β (+26 ± 6% and +30 ± 8% at 10 days AVB vs. SR). These changes corresponded to peak hypertrophic growth at 3 to 10 days. MLP increased gradually to maxima at chronic AVB (+36 ± 7%). In contrast, fhl2 (−22 ± 3%, 3 days) and desmin (−30 ± 9%, 10 days AVB) transiently declined but recovered at chronic AVB. Calpain protein expression remained unaltered. In conclusion, volume overload after AVB causes a transient compromise of cytoskeletal integrity based, at least partly, on transcriptional downregulation. Subsequent cytoskeletal reorganization coincides with the upregulation of melusin, P-Akt, P-GSK3β, and MLP, indicating a strong drive to compensated hypertrophy.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00392.2006
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
    detail.hit.zdb_id: 1477308-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Mechanical properties of mesenteric arteries in diabetic rats: consequences of outward remodeling
    American Physiological Society ; 1999
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 276, No. 5 ( 1999-05-01), p. H1672-H1677
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 276, No. 5 ( 1999-05-01), p. H1672-H1677
    Abstract: Diabetes induces hemodynamic and biochemical changes that can influence mechanical properties of arteries. Structure and mechanics of mesenteric small arteries were investigated in rats with streptozotocin-induced diabetes (duration 7–9 wk). The external diameter of mesenteric artery branches was measured in control ( n = 9) and diabetic ( n = 7) Wistar Rp rats at baseline and during pressurization in situ (0–150 mmHg) under normal and passive smooth muscle conditions. Mean arterial pressure and mesenteric artery pressure were not significantly different. Baseline mesenteric artery diameter was larger in the diabetes-induced group (439 ± 12 vs. 388 ± 18 μm, P 〈 0.05). Media cross-sectional area of arteries from diabetic rats was not significantly increased (0.0149 ± 0.0015 vs. 0.0122 ± 0.0007 mm 2 ). Cross-sectional compliance was significantly increased in diabetic rats at intraluminal pressures ranging from 25 to 75 mmHg ( P 〈 0.005), whereas cross-sectional distensibility was not modified. Wall tension and circumferential wall stress were increased in diabetes. These results indicate that mesenteric small arteries of diabetic rats display eutrophic outward remodeling associated with increased wall tension and circumferential wall stress.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.1999.276.5.H1672
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1999
    detail.hit.zdb_id: 1477308-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
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