Mathematical modelling of the calcium–left ventricular pressure relationship in the intact diabetic rat heart

Buijs, Jorn op den; Ligeti, L.; Ivanics, Tamás; Miklós, Zsuzsanna; Vusse, van der Gj Ger; Riel, van Naw Natal

doi:10.1111/j.1748-1716.2008.01831.x

Cited by 4 publications

(5 citation statements)

References 27 publications

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“…This result implies that the diastolic intracellular Ca 2+ at 6 Hz is greater in the diabetic trabeculae, and the decrease of sensitivity of myofilaments to Ca 2+ is more severe in the diabetic trabeculae. The latter implication is consistent with the findings of Zhang et al [ 12 ] and Op Den Buijs et al [ 58 ] showing a diabetes-induced decrease of Ca 2+ responsiveness.…”

Section: Discussionsupporting

confidence: 93%

Streptozotocin-induced diabetes prolongs twitch duration without affecting the energetics of isolated ventricular trabeculae

Han

Tran

Nielsen

et al. 2014

Cardiovasc Diabetol

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BackgroundDiabetes induces numerous electrical, ionic and biochemical defects in the heart. A general feature of diabetic myocardium is its low rate of activity, commonly characterised by prolonged twitch duration. This diabetes-induced mechanical change, however, seems to have no effect on contractile performance (i.e., force production) at the tissue level. Hence, we hypothesise that diabetes has no effect on either myocardial work output or heat production and, consequently, the dependence of myocardial efficiency on afterload of diabetic tissue is the same as that of healthy tissue.MethodsWe used isolated left ventricular trabeculae (streptozotocin-induced diabetes versus control) as our experimental tissue preparations. We measured a number of indices of mechanical (stress production, twitch duration, extent of shortening, shortening velocity, shortening power, stiffness, and work output) and energetic (heat production, change of enthalpy, and efficiency) performance. We calculated efficiency as the ratio of work output to change of enthalpy (the sum of work and heat).ResultsConsistent with literature results, we showed that peak twitch stress of diabetic tissue was normal despite suffering prolonged duration. We report, for the first time, the effect of diabetes on mechanoenergetic performance. We found that the indices of performance listed above were unaffected by diabetes. Hence, since neither work output nor change of enthalpy was affected, the efficiency-afterload relation of diabetic tissue was unaffected, as hypothesised.ConclusionsDiabetes prolongs twitch duration without having an effect on work output or heat production, and hence efficiency, of isolated ventricular trabeculae. Collectively, our results, arising from isolated trabeculae, reconcile the discrepancy between the mechanical performance of the whole heart and its tissues.

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Section: Discussionsupporting

confidence: 93%

Streptozotocin-induced diabetes prolongs twitch duration without affecting the energetics of isolated ventricular trabeculae

Han

Tran

Nielsen

et al. 2014

Cardiovasc Diabetol

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“…One study has proposed a model-based framework explicitly for assessing myofilament Ca 2+ sensitivity using a simple two-state, seven-parameter model ( Op Den Buijs et al, 2008 ). This model is highly simplified compared to others in the literature ( Rice et al, 2008 ) in an effort to improve identifiability.…”

Section: Model-based Assessmentmentioning

confidence: 99%

“…We first used an input Ca 2+ transient ( Figure 6A ) to simulate a control pressure response ( Figure 6B ; blue line). Model parameters are from Table 2 of Op Den Buijs et al (2008) . We then simulated two sets of inotropic responses by increasing the parameter governing the Ca 2+ affinity for TnC ( k 1 ) by 25% or 50%, which elicited greater pressure responses ( Figure 6B ; orange and green open circles).…”

Section: Model-based Assessmentmentioning

confidence: 99%

“… Model simulation of an increase in Ca 2+ myofilament sensitivity to test identifiability. The myofilament model ( Op Den Buijs et al, 2008 ) takes a Ca 2+ transient (A) as input and produces an LV pressure transient (B) as output; a parametric plot of these two variables produces a phase-loop (C) . The Ca 2+ transient function is defined by two decaying exponentials with parameters τ 1 = 80 ms, τ 2 = 40 ms, Ca dias = 0.12 µM, Ca amp = 0.3 µM, and t start = 50 ms (see Appendix of Rice et al (2008) ).…”

Section: Model-based Assessmentmentioning

confidence: 99%

“…The myofilament model was used to simulate two sets of positive inotropic responses corresponding to an increase in the Ca 2+ binding affinity by 25% (orange open circles) or 50% (green open circles) relative to control (blue line). The model parameters for the control model were taken from Table 2 of Op Den Buijs et al (2008) : k 1 = 38 s −1 , k 3 = 361 s −1 , α = 0.29 nM −2 s −1 , β = 658, k d = 212 s −1 , and Ca t = 117 nM. For generation of the simulation data, all parameters were kept the same except for k 1 , which was increased by either 25% or 50%.…”

Section: Model-based Assessmentmentioning

confidence: 99%

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Methods for assessing cardiac myofilament calcium sensitivity

Dowrick,

Taberner,

Han

et al. 2023

Front. Physiol.

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Myofilament calcium (Ca2+) sensitivity is one of several mechanisms by which force production of cardiac muscle is modulated to meet the ever-changing demands placed on the heart. Compromised Ca2+ sensitivity is associated with pathologies, which makes it a parameter of interest for researchers. Ca2+ Sensitivity is the ratio of the association and dissociation rates between troponin C (TnC) and Ca2+. As it is not currently possible to measure these rates in tissue preparations directly, methods have been developed to infer myofilament sensitivity, typically using some combination of force and Ca2+ measurements. The current gold-standard approach constructs a steady-state force-Ca2+ relation by exposing permeabilised muscle samples to a range of Ca2+ concentrations and uses the half-maximal concentration as a proxy for sensitivity. While a valuable method for steady-state investigations, the permeabilisation process makes the method unsuitable when examining dynamic, i.e., twitch-to-twitch, changes in myofilament sensitivity. The ability of the heart to transiently adapt to changes in load is an important consideration when evaluating the impact of disease states. Alternative methods have been proffered, including force-Ca2+ phase loops, potassium contracture, hybrid experimental-modelling and conformation-based fluorophore approaches. This review provides an overview of the mechanisms underlying myofilament Ca2+ sensitivity, summarises existing methods, and explores, with modelling, whether any of them are suited to investigating dynamic changes in sensitivity. We conclude that a method that equips researchers to investigate the transient change of myofilament Ca2+ sensitivity is still needed. We propose that such a method will involve simultaneous measurements of cytosolic Ca2+ and TnC activation in actively twitching muscle and a biophysical model to interpret these data.

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Hearts of surviving MLP-KO mice show transient changes of intracellular calcium handling

et al. 2010

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The muscle Lim protein knock-out (MLP-KO) mouse model is extensively used for studying the pathophysiology of dilated cardiomyopathy. However, explanation is lacking for the observed long survival of the diseased mice which develop until adulthood despite the gene defect, which theoretically predestines them to early death due to heart failure. We hypothesized that adaptive changes of cardiac intracellular calcium (Ca(i)(2+)) handling might explain the phenomenon. In order to study the progression of changes in cardiac function and Ca(i)(2+) cycling, myocardial Ca(i)(2+)-transients recorded by Indo-1 surface fluorometry were assessed with concomitant measurement of hemodynamic performance in isolated Langendorff-perfused hearts of 3- and 9-month old MLP-KO animals. Hearts were challenged with beta-agonist isoproterenol and the sarcoplasmic reticular Ca(2+)-ATPase (SERCA2a) inhibitor cyclopiazonic acid (CPA). Cardiac mRNA content and levels of key Ca(2+) handling proteins were also measured. A decline in lusitropic function was observed in 3-month old, but not in 9-month old MLP-KO mice under unchallenged conditions. beta-adrenergic responses to isoproterenol were similar in all the studied groups. The CPA induced an increase in end-diastolic Ca(i)(2+)-level and a decrease in Ca(2+)-sequestration capacity in 3-month old MLP-KO mice compared to age-matched controls. This unfavorable condition was absent at 9 months of age. SERCA2a expression was lower in 3-month old MLP-KO than in the corresponding controls and in 9-month old MLP-KO hearts. Our results show time-related recovery of hemodynamic function and an age-dependent compensatory upregulation of Ca(i)(2+) handling in hearts of MLP-KO mice, which most likely involve the normalization of the expression of SERCA2a in the affected hearts.

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Mathematical modelling of the calcium–left ventricular pressure relationship in the intact diabetic rat heart

Abstract: We conclude from our modelling results that myocardial cross-bridge cycling is impaired at the early stage of diabetes.

Cited by 4 publications

References 27 publications

Streptozotocin-induced diabetes prolongs twitch duration without affecting the energetics of isolated ventricular trabeculae

Streptozotocin-induced diabetes prolongs twitch duration without affecting the energetics of isolated ventricular trabeculae

Methods for assessing cardiac myofilament calcium sensitivity

Hearts of surviving MLP-KO mice show transient changes of intracellular calcium handling

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