Abstract
IntroductionFrequency-dependent acceleration of relaxation (FDAR) ensures appropriate ventricular filling at high heart rates and results from accelerated sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) activity independent of calcium removal from the cell. Because lipopolysaccharide (LPS) challenge may induce aberrations in calcium trafficking and protein phosphorylation, we tested whether LPS would abolish FDAR in rats.MethodsFollowing LPS injection, changes in force-frequency relationship and FDAR were studied in cardiomyocytes, isolated hearts and in vivo by echocardiography. Calcium uptake and phosphatase activities were studied in sarcoplasmic reticulum (SR) vesicle preparations. Western blots of phospholamban and calcium/calmodulin-dependent protein kinase II, and serine/threonine phosphatase activity were studied in heart preparations.ResultsIn cardiomyocytes and isolated heart preparations, reductions in time constant of relaxation (τ) and time to 50% relaxation at increasing rate of pacing were blunted in LPS-treated rats compared with controls. Early diastolic velocity of the mitral annulus (Ea), a relaxation parameter which correlates in vivo with τ, was reduced in LPS rats compared with control rats. LPS impaired SR calcium uptake, reduced phospholamban phosphorylation and increased serine/threonine protein phosphatase activity. In vivo inhibition of phosphatase activity partially restored FDAR, reduced phosphatase activity and prevented phospholamban dephosphorylation in LPS rat hearts.ConclusionsLPS impaired phospholamban phosphorylation, cardiac force-frequency relationship and FDAR. Disruption of frequency-dependent acceleration of LV relaxation, which normally participates in optimal heart cavity filling, may be detrimental in sepsis, which is typically associated with elevated heart rates and preload dependency.
Highlights
Frequency-dependent acceleration of relaxation (FDAR) ensures appropriate ventricular filling at high heart rates and results from accelerated sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) activity independent of calcium removal from the cell
Disruption of frequency-dependent acceleration of left ventricle (LV) relaxation, which normally participates in optimal heart cavity filling, may be detrimental in sepsis, which is typically associated with elevated heart rates and preload dependency
Loss of this fundamental adaptive mechanism that ensures optimal LV filling was accompanied by reduced sarcoplasmic reticulum (SR) calcium uptake, dephosphorylation of phospholamban and serine/threonine phosphatase activity increases
Summary
Frequency-dependent acceleration of relaxation (FDAR) ensures appropriate ventricular filling at high heart rates and results from accelerated sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) activity independent of calcium removal from the cell. Does the heart generally beat stronger when it is stimulated to contract faster, the kinetic of contraction is accelerated, that is, the frequency-dependent acceleration of relaxation (FDAR) [1,2]. Only a limited number of studies have evaluated the frequency-dependent gain in contractility in the septic myocardium. In these studies, inotropic responsiveness to changes in frequency of stimulation from lipopolysaccharide (LPS)
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