Hibernating Myocardium
2008; Lippincott Williams & Wilkins; Volume: 102; Issue: 1 Linguagem: Inglês
10.1161/circresaha.107.168278
ISSN1524-4571
AutoresRosemary F. Kelly, Wim J. Sluiter, Edward O. McFalls,
Tópico(s)Mitochondrial Function and Pathology
ResumoHomeCirculation ResearchVol. 102, No. 1Hibernating Myocardium Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBHibernating MyocardiumIs the Program to Survive a Pathway to Failure? Rosemary F. Kelly, Wim Sluiter and Edward O. McFalls Rosemary F. KellyRosemary F. Kelly From Cardiac Surgery (R.F.K.) and Cardiology (E.O.M.), Veterans Affairs Medical Center, University of Minnesota, Minneapolis; and the Mitochondrial Research Unit (W.S.), Erasmus Medical Center, Rotterdam, The Netherlands. , Wim SluiterWim Sluiter From Cardiac Surgery (R.F.K.) and Cardiology (E.O.M.), Veterans Affairs Medical Center, University of Minnesota, Minneapolis; and the Mitochondrial Research Unit (W.S.), Erasmus Medical Center, Rotterdam, The Netherlands. and Edward O. McFallsEdward O. McFalls From Cardiac Surgery (R.F.K.) and Cardiology (E.O.M.), Veterans Affairs Medical Center, University of Minnesota, Minneapolis; and the Mitochondrial Research Unit (W.S.), Erasmus Medical Center, Rotterdam, The Netherlands. Originally published4 Jan 2008https://doi.org/10.1161/CIRCRESAHA.107.168278Circulation Research. 2008;102:3–5Winter hibernation carries the promise of rejuvenation in the spring. In a similar fashion, myocardial "hibernation" describes a clinical phenomenon in which patients with ischemic left ventricular dysfunction demonstrate improved cardiac function following bypass surgery.1 The signature of myocardial hibernation is decreased blood flow with preserved glucose uptake, as demonstrated by positron emission tomography imaging, and identifies individuals with ischemic cardiomyopathy who may benefit from revascularization.2 In experimental models of hibernating myocardium, oxygen consumption is reduced in the absence of active ischemia.3,4 This implies that hibernation is a coordinated response to balance myocardial energy utilization with energy production capacity.5 However, within hibernating myocardium, several morphological and functional changes have been observed that can identify regions in which complete revascularization may not result in normalization of contraction.6–10 In fact, those myocardial regions with the greatest metabolic abnormalities in the hibernating tissue demonstrate the longest delay in recovery.11In the current issue, Page et al12 demonstrate that the process of hibernation is associated with altered expression of mitochondrial proteins. Using 2D differential-in-gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry in a swine model of hibernation, they have found that key mitochondrial proteins associated with the electron transport chain are reduced. The functional importance of the decreased protein expression is documented by reduced activity measurements of the pyruvate dehydrogenase complex, cytochrome c oxidase, and citrate synthase. The parallel reductions in mitochondrial proteins and contractile function 5 months after placement of the coronary artery constrictor suggest that the "downregulation" of electron transport proteins is related to the reduced oxygen consumption. In fact, the reductions in ATPase correlate with the reduction in subendocardial blood flows in the hibernating myocardium. In addition, "upregulation" of several cytosolic proteins has been observed, including the antioxidant enzyme superoxide dismutase 1, highlighting a potential role for repetitive ischemia–reoxygenation in the stress response. Interestingly, the temporal increase in the antioxidant proteins coincides with the time that apoptosis is diminished in this model.13 A logical hypothesis is that superoxide production stimulates a stress response, including superoxide dismutase 1 expression, which, in turn, reduces subsequent reactive oxygen species (ROS) production and thus promotes a survival pathway within the mitochondria.14 Although the findings are novel, a causal relationship between the observed decreased expression of mitochondrial proteins and persistent reductions in oxygen consumption and contractile function remains speculative. Clearly, more studies are needed to identify whether interventions that restore blood flow to the hibernating tissue will reprogram mitochondria to a normal expression of key proteins.Mitochondrial Adaptations to Brief Myocardial Ischemia (Preconditioning)It is well recognized that the heart can favorably adapt to sustained reductions in oxygen availability. Since the seminal observation of ischemic myocardial preconditioning in the anesthetized canine model,15 evidence has emerged that the mitochondria can be primed into a "stress-resistant state," so that cell death is reduced following a subsequent period of ischemia and reperfusion.16 Although the signal transduction pathway is complex, mitochondria within preconditioned myocardium are altered so that the release of cytochrome c and proapoptotic factors and generation of ROS following ischemia are reduced.17 It has been proposed that the preconditioned mitochondrial phenotype is characterized by slight depolarization of the inner membrane of the mitochondria.18,19 As a consequence of this decrease in the membrane potential (ΔΨm), decreased ROS production is expected.20,21 One potential mechanism of depolarization of the inner membrane is a proton leak, from activation of adenine nucleotide translocation, the permeability transition pore, or uncoupling proteins.22 Uncoupling proteins are expressed and activated by superoxide23 (a potential feedback loop) and, along with their relationship with fatty acids,24 lead to a proton leak through the inner membrane into the matrix. Activation of these uncoupling proteins reduce ROS generation25 and exert a protective effect against oxidant damage during the second window of preconditioning.26Although the mechanisms that lead to myocardial hibernation are unclear, it is likely that ischemic preconditioning and hibernation share common signaling pathways that modify the severity of an energy supply/demand imbalance associated with limited blood flow. In a swine model of chronic hibernation, we have observed increased activation of p38 mitogen-activated protein kinase, enhanced GLUT4 translocation, and increased calcium-independent NO synthase activity,27 all of which have been observed in preconditioning. As demonstrated in preconditioned mitochondria, isolated mitochondria from hibernating tissue have acquired a stress-resistant phenotype that is characterized by preserved state 3 respiration following in vitro anoxia and reoxygenation.28 In this protected state of hibernation, isolated mitochondria demonstrate reduced superoxide generation, likely in part, because of increased expression of uncoupling proteins. The observations of Page et al12 provide additional evidence that mitochondria in hibernating tissue adapt in a way that reduces ROS production. A fundamental question is whether the mitochondria have acquired a program to reduce electron transport at the expense of limiting maximal oxygen consumption and possibly contraction.Mitochondrial Adaptations to Chronic Myocardial IschemiaIn response to chronic reductions in blood flow that result in myocardial hibernation, Page et al12 have found a reduction in proteins that contribute NADH equivalents to complex I, which would be expected to slow electron flow and reduce the generation of ROS during or following ischemia (Figure).29 They also show decreased expression of cytochrome bc1, which would have a similar effect on complex III–generated ROS, which are released toward the outer membrane. Finally, because of the potential for reversed proton flow through complex V, reduced expression of its ATPase activity may also act to limit ATP consumption during ischemia. The release of superoxide toward the cytoplasm can initiate a protective program that involves reducing expression of those proteins involved in electron transport. By slowing electron flow through complexes I, III, and IV, pumping of protons through the inner membrane is decreased and, along with the proton leak from activated uncoupling proteins, acts to reduce ΔΨm and minimize ROS production, as has been suggested in preconditioning.20,21 Although this paradigm would improve defenses against oxidant stress, it is unclear whether maximal electron transport and ATP formation can be sustained during high work states and, if not, whether these adaptations that protect against ROS provide a governor on maximal oxygen consumption and perpetuate heart failure.30Download figureDownload PowerPointHypothetical scheme that illustrates how altered mitochondrial proteins in the electron transport chain may alter electron transport and reduce ROS generation in hibernating myocardium. Within the hibernating tissue, key enzymes that contribute NADH equivalents into complex I, as well as proteins directly related to subunits of the electron transport chain, are decreased, including cytochrome bc1 (complex III) and cytochrome c oxidase (complex IV). The overall effect may be to decrease the generation of superoxide (O2−) by decreasing (the reduced state of) the respiratory chain complexes. Decreasing complex V activity would also have an effect of preventing its ATPase activity elicited by the diminished membrane potential (Δψm). Together with increased expression and activation of uncoupling proteins (UCP), these effects could lead to slight depolarization in Δψm and reduced superoxide generation. It is unclear whether these mitochondrial adaptations occur in response to oxidant damage induced by repetitive supply/demand ischemia and, more importantly, whether the "downregulation" in mitochondrial proteins limits the maximal rate of oxygen expenditure available for contraction in hibernating myocardium. Altered proteins in hibernating myocardium are listed in gray, with red borders for decreased and blue borders for increased expression. The arrows with dotted lines indicate adaptations that would result in reduced oxidant damage. SOD1 indicates superoxide dismutase 1.A reduction in the capacity to produce energy to the contractile apparatus may exacerbate the depressed contractile function in hibernating myocardial tissue. A major unresolved question in cardiovascular physiology is which factors in the cascade of ATP production, transport, and utilization control the maximal performance of a normal heart or contribute to the dysfunction of a failing heart. The relationships between steady-state myocardial concentrations of ATP, ADP, free inorganic phosphate, creatine (Cr), and phosphocreatine (PCr) and the mitochondrial ATP production capacity also remain unclear, in part, because, in the normal heart, the in vivo maximal ATP synthetic capacity likely exceeds maximal ATP expenditure, as estimated by measurements of myocardial oxygen consumption. In patients with congestive heart failure, the PCr/ATP ratio, as determined by 31P-NMR spectroscopy, predicts the severity of left ventricular dysfunction and the risk of sudden death.31,32 Our swine model of hibernation with reduced blood flow and function indicates that the PCr/ATP ratio derived by 31P-NMR spectroscopy is normal at rest and remains normal during a 2-fold increase in the double product induced by an infusion of dobutamine, even in the presence of ATP-dependent potassium channel (KATP) blockade with glibenclamide.33 The finding of a normal PCr/ATP ratio during basal conditions and especially during a high cardiac work state supports the concept that the reduction in the blood flow in hibernating myocardial tissue is proportional to a reduction in energetic demands5 and that this occurs by a mechanism that is independent of KATP channel opening.34Clinical PerspectiveIn many individuals with ischemic cardiomyopathy, progressive heart failure may persist, despite successful revascularization. Several morphological and structural changes have been identified that may limit contraction within hibernating myocardium.6–10 It is also possible that alterations in the mitochondria that are initially programmed to reduce oxidant damage and prevent cell death in response to repetitive supply/demand ischemia, could act to limit maximal ATP production. Defining the factors that lead to this coordinated process to balance oxygen supply and expenditure, whether through mitochondrial adaptations or other signaling pathways, is critical for understanding the pathophysiology and advancing new therapies for hibernating myocardium and heart failure.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Sources of FundingThis work was supported in part by The Thoracic Surgery Foundation for Research and Education Nina Starr Braunwald Award (to R.F.K.).DisclosuresNone.FootnotesCorrespondence to Edward O. 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Gewirtz H and Dilsizian V (2017) Myocardial Viability, Circulation Research, 120:7, (1197-1212), Online publication date: 31-Mar-2017. Pasque M (2017) Not all that hibernates necessarily wakes up, The Journal of Thoracic and Cardiovascular Surgery, 10.1016/j.jtcvs.2016.10.044, 153:3, (591-592), Online publication date: 1-Mar-2017. Tiyantara M, Furqon M and Paramita S (2016) Pathological Q wave as an indicator of left ventricular ejection fraction in acute myocardial infarction, Medical Journal of Indonesia, 10.13181/mji.v25i2.1274, 25:2, (98-103) (2015) The Value of Using Pulsed Tissue Doppler Mitral Annulus Velocity during Dobutamine Stress Echocardiography for Assessment of Myocardial Viability in Patients with Coronary Artery Disease before Revasularization, Journal of Cardiology & Current Research, 10.15406/jccr.2015.03.00089, 3:1 Colbert R, Holley C, Stone L, Crampton M, Adabag S, Garcia S, Iaizzo P, Ward H, Kelly R and McFalls E (2015) The Recovery of Hibernating Hearts Lies on a Spectrum: from Bears in Nature to Patients with Coronary Artery Disease, Journal of Cardiovascular Translational Research, 10.1007/s12265-015-9625-5, 8:4, (244-252), Online publication date: 1-Jun-2015. Holley C, Long E, Butterick T, Duffy C, Lindsey M, Stone L, McFalls E and Kelly R (2015) Mitochondrial fusion proteins in revascularized hibernating hearts, Journal of Surgical Research, 10.1016/j.jss.2014.12.052, 195:1, (29-36), Online publication date: 1-May-2015. Voelkel N, Gomez-Arroyo J, Abbate A and Bogaard H (2015) The Pathobiology of Chronic Right Ventricular Failure The Right Ventricle in Health and Disease, 10.1007/978-1-4939-1065-6_13, (283-301), . Qu J, Young R, Page B, Shen X, Tata N, Li J, Duan X, Fallavollita J and Canty J (2014) Reproducible Ion-Current-Based Approach for 24-Plex Comparison of the Tissue Proteomes of Hibernating versus Normal Myocardium in Swine Models, Journal of Proteome Research, 10.1021/pr5000472, 13:5, (2571-2584), Online publication date: 2-May-2014. Galli G and Richards J (2014) Mitochondria from anoxia-tolerant animals reveal common strategies to survive without oxygen, Journal of Comparative Physiology B, 10.1007/s00360-014-0806-3, 184:3, (285-302), Online publication date: 1-Apr-2014. Galli G, Lau G and Richards J (2013) Beating oxygen: chronic anoxia exposure reduces mitochondrial F1FO-ATPase activity in turtle ( Trachemys scripta ) heart , Journal of Experimental Biology, 10.1242/jeb.087155, 216:17, (3283-3293), Online publication date: 1-Sep-2013. Cabrera J, Ziemba E, Colbert R, Kelly R, Kuskowski M, Arriaga E, Sluiter W, Duncker D, Ward H and McFalls E (2012) Uncoupling protein-2 expression and effects on mitochondrial membrane potential and oxidant stress in heart tissue, Translational Research, 10.1016/j.trsl.2011.11.001, 159:5, (383-390), Online publication date: 1-May-2012. Shabana A and El-Menyar A (2012) Myocardial Viability: What We Knew and What Is New, Cardiology Research and Practice, 10.1155/2012/607486, 2012, (1-13), . Antman E and Morrow D (2012) ST-Segment Elevation Myocardial Infarction Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 10.1016/B978-1-4377-0398-6.00055-X, (1111-1177), . Kelly R, Cabrera J and McFalls E (2011) Reply to the Editor, The Journal of Thoracic and Cardiovascular Surgery, 10.1016/j.jtcvs.2011.06.020, 142:4, (954-955), Online publication date: 1-Oct-2011. Li D, Pan D, Xia Y, Xu W and Qian W (2011) Use of an intracoronary Doppler guidewire for evaluation of coronary hemodynamics in the porcine model of acute hibernating myocardium during dobutamine stress tests, Journal of Clinical Ultrasound, 10.1002/jcu.20801, 39:6, (329-336), Online publication date: 1-Jul-2011. Kelly R, Cabrera J, Ziemba E, Crampton M, Anderson L, McFalls E and Ward H (2011) Continued depression of maximal oxygen consumption and mitochondrial proteomic expression despite successful coronary artery bypass grafting in a swine model of hibernation, The Journal of Thoracic and Cardiovascular Surgery, 10.1016/j.jtcvs.2010.08.061, 141:1, (261-268), Online publication date: 1-Jan-2011. Patterson B, Fields A and Shannon R (2009) New insights into myocardial glucose metabolism: surviving under stress, Current Opinion in Clinical Nutrition and Metabolic Care, 10.1097/MCO.0b013e32832c4167, 12:4, (424-430), Online publication date: 1-Jul-2009. Slezak J, Tribulova N, Okruhlicova L, Dhingra R, Bajaj A, Freed D and Singal P (2009) Hibernating myocardium: pathophysiology, diagnosis, and treatmentThis article is one of a selection of papers from the NATO Advanced Research Workshop on Translational Knowledge for Heart Health (published in part 2 of a 2-part Special Issue)., Canadian Journal of Physiology and Pharmacology, 10.1139/Y09-011, 87:4, (252-265), Online publication date: 1-Apr-2009. January 4, 2008Vol 102, Issue 1 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCRESAHA.107.168278PMID: 18174469 Originally publishedJanuary 4, 2008 Keywordsmyocardial hibernationheart failuresuperoxidepreconditioningmitochondriaPDF download Advertisement
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