Mechanoenergetic inefficiency in the septic left ventricle is due to enhanced oxygen requirements for excitation?contraction coupling

Aghajani, Ebrahim; Nordhaug, Dag; Korvald, Christian; Steensrud, Tor; Husnes, Kjell Vidar; Ingebretsen, Ole C.; Revhaug, Arthur; Myrmel, Truls

doi:10.1016/j.cardiores.2004.04.019

Cited by 9 publications

(13 citation statements)

References 22 publications

(38 reference statements)

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“…For example, cardiac muscle mechano-energetic inefficiency is driven by increased energy and oxygen requirements for excitation-contraction-coupling during sepsis [67]. Ubiquitin-proteasome activation also contributes to ATPconsumption in critical illness.…”

Section: Metabolic Mechanisms Of Bioenergetic Failurementioning

confidence: 99%

Critical illness myopathy: what is happening?

Friedrich

2006

Current Opinion in Clinical Nutrition &Amp; Metabolic Care

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Section: Metabolic Mechanisms Of Bioenergetic Failurementioning

confidence: 99%

Critical illness myopathy: what is happening?

Friedrich

2006

Current Opinion in Clinical Nutrition &Amp; Metabolic Care

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“…Energy expenditure of the heart was determined as myocardial O 2 consumption (MV O2) and was calculated based on measurements using the difference in O2 content in the buffer entering and leaving the heart and the coronary flow (2,9,15). MV O2, stroke work [the area within the pressure-volume (P-V) loop], and P-V area (PVA; representing the total cardiac work) (18) was calculated at each work load.…”

Section: Animals Serca2mentioning

confidence: 99%

“…Work-independent MV O2 was measured in the retrograde perfused unloaded heart (MV O2 unloaded). By electrically arresting these hearts (elevation of extracellular K ϩ concentration), we could also measure the O2 cost of basal metabolism (MV O2 BM), and the difference between MV O2 unloaded and MV O2 BM was used to obtain the O2 cost of ECC (MV O2 ECC) (2,9,10,15).…”

Section: Animals Serca2mentioning

confidence: 99%

Impaired left ventricular mechanical and energetic function in mice after cardiomyocyte-specific excision of Serca2

Boardman

Aronsen

Louch

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Boardman NT, Aronsen JM, Louch WE, Sjaastad I, Willoch F, Christensen G, Sejersted O, Aasum E. Impaired left ventricular mechanical and energetic function in mice after cardiomyocyte-specific excision of Serca2. Am J Physiol Heart Circ Physiol 306: H1018 -H1024, 2014. First published January 31, 2014 doi:10.1152 doi:10. /ajpheart.00741.2013plasmic reticulum Ca 2ϩ -ATPase (SERCA)2 transports Ca 2ϩ from the cytosol into the sarcoplasmic reticulum of cardiomyocytes and is essential for maintaining myocardial Ca 2ϩ handling and thus the mechanical function of the heart. SERCA2 is a major ATP consumer in excitation-contraction coupling but is regarded to contribute to energetically efficient Ca 2ϩ handling in the cardiomyocyte. Previous studies using cardiomyocytespecific SERCA2 knockout (KO) mice have demonstrated that decreased SERCA2 activity reduces the Ca 2ϩ transient amplitude and induces compensatory Ca 2ϩ transport mechanisms that may lead to more inefficient Ca 2ϩ transport. In this study, we examined the relationship between left ventricular (LV) function and myocardial O2 consumption (MV O2) in ex vivo hearts from SERCA2 KO mice to directly measure how SERCA2 elimination influences mechanical and energetic features of the heart. Ex vivo hearts from SERCA2 KO hearts developed mechanical dysfunction at 4 wk and demonstrated virtually no working capacity at 7 wk. In accordance with the reported reduction in Ca 2ϩ transient amplitude in cardiomyocytes from SERCA2 KO mice, work-independent MV O2 was decreased due to a reduced energy cost of excitation-contraction coupling. As these hearts also showed a marked impairment in the efficiency of chemomechanical energy transduction (contractile efficiency, i.e, workdependent MV O2), hearts from SERCA2 KO mice were found to be mechanically inefficient. This ex vivo evaluation of mechanical and energetic function in hearts from SERCA2 KO mice brings together findings from previous experimental and mathematical modelingbased studies and demonstrates that reduced SERCA2 activity not only leads to mechanical dysfunction but also to energetic dysfunction. mechanical efficiency; myocardial oxygen consumption; contractile efficiency; pressure-volume area; mechanoenergetics RELAXATION OF THE MYOCARDIUM occurs as the cytosolic Ca 2ϩ concentration returns to its resting level primarily through Ca 2ϩ reuptake into the sarcoplasmic reticulum (SR) by sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA)2. Thus, SERCA2 is essential for maintaining myocardial Ca 2ϩ homeostasis and mechanical function of the heart. A reduction in the capacity or the absence of SERCA2 has been shown to lead to reduced force generation, delayed relaxation, and advanced onset of heart failure (3, 11, 27), whereas increased SERCA2 expression (transgenic mice and/or adenovirus-mediated overexpression) has been shown to increase cardiac function in the normal and failing heart (28, 39) as well as to protect against ischemiareperfusion (12, 31) and pressure overload (28,35).Myocardial SERCA2 activities are d...

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“…Accordingly, MV O2 measured under this condition is defined as the oxygen cost of basal metabolism (MV O2BM). The calculated difference between the measured unloaded MV O2 obtained in unloaded retrograde mode (MV O2unloaded) and MV O2BM was used to obtain the oxygen cost of EC coupling (MV O2ECC) (2,7,19,20).…”

Section: Animalsmentioning

confidence: 99%

Chronic and acute exposure of mouse hearts to fatty acids increases oxygen cost of excitation-contraction coupling

Boardman

Larsen

Severson

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Boardman NT, Larsen TS, Severson DL, Essop MF, Aasum E. Chronic and acute exposure of mouse hearts to fatty acids increases oxygen cost of excitation-contraction coupling. Am J Physiol Heart Circ Physiol 300: H1631-H1636, 2011. First published February 18, 2011 doi:10.1152/ajpheart.01190.2010The aim of the present study was to evaluate the underlying processes involved in the oxygen wasting induced by inotropic drugs and acute and chronic elevation of fatty acid (FA) supply, using unloaded perfused mouse hearts from normal and type 2 diabetic (db/db) mice. We found that an acute elevation of the FA supply in normal hearts, as well as a chronic (in vivo) exposure to elevated FA as in db/db hearts, increased myocardial oxygen consumption (MV O2unloaded) due to increased oxygen cost for basal metabolism and for excitation-contraction (EC) coupling. Isoproterenol stimulation, on top of a high FA supply, led to an additive increase in MV O2unloaded, because of a further increase in oxygen cost for EC coupling. In db/db hearts, the acute elevation of FA did not further increase MV O2. Since the elevation in the FA supply is accompanied by increased rates of myocardial FA oxidation, the present study compared MV O2 following increased FA load versus FA oxidation rate by exposing normal hearts to normal and high FA concentration (NF and HF, respectively) and to compounds that either stimulate (GW-610742) or inhibit [dichloroacetate (DCA)] FA oxidation. While HF and NF ϩ GW-610742 increased FA oxidation to the same extent, only HF increased MV O2unloaded. Although DCA counteracted the HF-induced increase in FA oxidation, DCA did not reduce MV O2unloaded. Thus, in normal hearts, acute FA-induced oxygen waste is 1) due to an increase in the oxygen cost for both basal metabolism and EC coupling and 2) not dependent on the myocardial FA oxidation rate per se, but on processes initiated by the presence of FAs. In diabetic hearts, chronic exposure to elevated circulating FAs leads to adaptations that afford protection against the detrimental effect of an acute FA load, suggesting different underlying mechanisms behind the increased MV O2 following acute and chronic FA load. cardiac efficiency; myocardial oxygen consumption; fatty acid oxidation; basal metabolism; isoproterenol SEVERAL PHYSIOLOGICAL AND pathophysiological conditions (including fasting, diabetes/obesity, postoperatively) are associated with elevated levels of circulating catecholamines and fatty acid (FA). Both conditions are known to increase myocardial oxygen consumption (MV O 2 ) more than would be expected by changes in cardiac work, leading to oxygen waste and thus decreased cardiac efficiency (27,38,44,50).Following chronic elevation of circulating lipids such as in diabetes and obesity, FA becomes the predominant fuel for ATP generation in the heart both due to elevated supply and transcriptional changes increasing the expression of genes associated with FA utilization (1, 4, 5). Altered myocardial substrate supply and decreased cardiac efficiency have b...

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Mechanoenergetic inefficiency in the septic left ventricle is due to enhanced oxygen requirements for excitation?contraction coupling

Abstract: Basal MVO2 in the septic myocardium is not elevated, but an increased MVO2 for EC coupling is responsible for the energetic inefficiency.

Cited by 9 publications

References 22 publications

Critical illness myopathy: what is happening?

Critical illness myopathy: what is happening?

Impaired left ventricular mechanical and energetic function in mice after cardiomyocyte-specific excision of Serca2

Chronic and acute exposure of mouse hearts to fatty acids increases oxygen cost of excitation-contraction coupling

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