What is the clinical evidence from this study?

Study design: Other. Population: Sepsis (LPS-induced). Intervention: Lipopolysaccharide (LPS) vs. Saline. Primary outcome: Ratio of early diastolic velocity of the mitral annulus (Ea) change to heart rate change (cm/sec/beat) (p=<0.05).

February 6, 2009Open Access

Cardiac force-frequency relationship and frequency-dependent acceleration of relaxation are impaired in LPS-treated rats

Q: What are the key findings of this study?

Lipopolysaccharide administration in rats impaired the cardiac force-frequency relationship and frequency-dependent acceleration of relaxation, reducing the ratio of Ea change to heart rate change.

Key Result

Lipopolysaccharide administration in rats impaired the cardiac force-frequency relationship and frequency-dependent acceleration of relaxation, reducing the ratio of Ea change to heart rate change.

PICO

Population

Sepsis (LPS-induced)

Intervention / Comparator

Lipopolysaccharide (LPS) vs Saline (10 mg/kg)

Primary Outcome

Ratio of early diastolic velocity of the mitral annulus (Ea) change to heart rate change (cm/sec/beat), p=<0.05

Main Result

Absolute Event Rate: 0.035% vs 0.054%

p-value: p=<0.05

Limitations

Use of an experimental LPS model of sepsis at frequencies well below the in vivo spectrum of the species studied
Heart frequency changes during echocardiography were achieved by increasing doses of volatile anaesthetics, which may alter calcium cycling and myocardial function
Immediate effects of heart rate increases on calcium handling were not evaluated
Calcium handling was studied exclusively in SR preparations, which may not reflect overall cardiac Ca2+ trafficking

Abstract

INTRODUCTION: 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. Because lipopolysaccharide (LPS) challenge may induce aberrations in calcium trafficking and protein phosphorylation, we tested whether LPS would abolish FDAR in rats. METHODS: Following 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. RESULTS: In cardiomyocytes and isolated heart preparations, reductions in time constant of relaxation (tau) 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 tau, 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. CONCLUSIONS: LPS 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.

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