Altered myocardial force generation in end‐stage human heart failure

Papp, Zoltán; Velden, Jolanda van der; Borbély, Attila; Édes, István; Stienen, Ger J

doi:10.1002/ehf2.12020

Cited by 8 publications

(6 citation statements)

References 28 publications

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“…2D (square symbols). In line with several previous studies, Ca 2+ modulates kTR in same direction as force (26,28,30,32,(53)(54)(55)(56), i.e. in opposite direction to the Pi-modulated kTR-force relation.…”

Section: Dependence Of Force and K Tr On The [P I ]supporting

confidence: 92%

“…The rate constant kTR of this mechanically-induced force redevelopment represents the sum of apparent rate constants in the cross-bridge cycle limiting the transitions of cross-bridges between non-force-generating and force-generating states (26), reviewed in (2). There is consensus in several studies on slow and fast skeletal and cardiac muscles that Pi increases kTR whereas it decreases force (7,16,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). The opposing effects of Pi on kTR and force are in line with the reversibility of Pi release and the force-generating step in muscles contracting under mechanical load, i.e.…”

Section: Introductionmentioning

confidence: 99%

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Phosphate binding induced force-reversal occurs via slow backward cycling of cross-bridges

Stehle¹

2020

Preprint

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The release of inorganic phosphate (Pi) from the cross-bridge is a pivotal step in the cross-bridge ATPase cycle leading to force generation. It is well known that Pi release and the force-generating step are reversible, thus increase of [Pi] decreases isometric force by product inhibition and increases the rate constant kTR of mechanically-induced force redevelopment due to the reversible redistribution of cross-bridges among non-force-generating and force-generating states. The experiments on cardiac myofibrils from guinea pig presented here show that increasing [Pi] increases kTR almost reciprocally to force, i.e., kTR is proportional to 1/force. To elucidate which cross-bridge models can explain the reciprocal kTR-force relation, simulations were performed for models varying in sequence and kinetics of 1) the Pi release-rebinding equilibrium, 2) the force-generating step and its reversal, and 3) the transitions limiting forward and backward cycling of cross-bridges between non-force-generating and force-generating states. Models consisting of fast reversible force generation before/after rapid Pi release-rebinding fail to describe the kTR-force relation observed in experiments. Models consistent with the experimental kTR-force relation have in common that Pi binding and/or force-reversal are/is intrinsically slow, i.e., either Pi binding or force-reversal or both limit backward cycling of cross-bridges from force-generating to non-force-generating states.

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Section: Dependence Of Force and K Tr On The [P I ]supporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Phosphate binding induced force-reversal occurs via slow backward cycling of cross-bridges

Stehle¹

2020

Preprint

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“…In the failing heart changes in the SR calcium cycling and also in myofilament, mechanics are described . This could influence the adaption to mechanical load also.…”

Section: Introductionmentioning

confidence: 99%

The contractile adaption to preload depends on the amount of afterload

et al. 2017

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AimsThe Frank–Starling mechanism (rapid response (RR)) and the secondary slow response (SR) are known to contribute to increases contractile performance. The contractility of the heart muscle is influenced by pre‐load and after‐load. Because of the effect of pre‐load vs. after‐load on these mechanisms in not completely understood, we studied the effect in isolated muscle strips.Methods and resultsProgressive stretch lead to an increase in shortening/force development under isotonic (only pre‐load) and isometric conditions (pre‐ and after‐load). Muscle length with maximal function was reached earlier under isotonic (L max‐isotonic) compared with isometric conditions (L max‐isometric) in nonfailing rabbit, in human atrial and in failing ventricular muscles. Also, SR after stretch from slack to L max‐isotonic was comparable under isotonic and isometric conditions (human: isotonic 10 ± 4%, isometric 10 ± 4%). Moreover, a switch from isotonic to isometric conditions at L max‐isometric showed no SR proving independence of after‐load. To further analyse the degree of SR on the total contractile performance at higher pre‐load muscles were stretched from slack to 98% L max‐isometric under isotonic conditions. Thereby, the SR was 60 ± 9% in rabbit and 51 ± 14% in human muscle strips.ConclusionsThis work shows that the acute contractile response largely depends on the degree and type of mechanical load. Increased filling of the heart elevates pre‐load and prolongs the isotonic part of contraction. The reduction in shortening at higher levels of pre‐load is thereby partially compensated by the pre‐load‐induced SR. After‐load shifts the contractile curve to a better ‘myofilament function’ by probably influencing thin fibers and calcium sensitivity, but has no effect on the SR.

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“…The impact of heart failure on cells from the LV and RV is also unclear. Although numerous studies have shown that heart failure reduces maximum force and increases the calcium (Ca 2+ ) sensitivity of contraction of the permeabilized LV myocardium ( 4 , 5 , 6 , 7 , 8 , 9 , 10 ), few experiments have been performed using human RV samples. One recent study by Hsu et al.…”

mentioning

confidence: 99%