Hibernating Myocardium: A Review

Heusch, Gerd; Schulz, Rainer

doi:10.1007/978-3-642-72134-2_2

Cited by 11 publications

(14 citation statements)

References 65 publications

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“…Although peripheral and coronary arteries both perfuse muscle tissue, a unique feature of the heart muscle is its permanent contractile activity that requires continuous oxygen supply. A chronic decrease in oxygen supply alters the cellular composition of viable cardiomyocytes in the ischaemic area, resulting in a regional loss of contractile force called hibernating myocardium 30,31 . Inside cardiomyocytes, hallmarks of hibernating myocardium are reduced myofilaments 32 and mitochondria content as well as an increased glycogen content 33 .…”

Section: Role Of Mrtfs In Thymosin ß4-induced Neovascularizationmentioning

confidence: 99%

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

et al. 2014

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Gradual occlusion of coronary arteries may result in reversible loss of cardiomyocyte function (hibernating myocardium), which is amenable to therapeutic neovascularization. The role of myocardin-related transcription factors (MRTFs) co-activating serum response factor (SRF) in this process is largely unknown. Here we show that forced MRTF-A expression induces CCN1 and CCN2 to promote capillary proliferation and pericyte recruitment, respectively. We demonstrate that, upon G-actin binding, thymosin 4 (T 4), induces MRTF translocation to the nucleus, SRF-activation and CCN1/2 transcription. In a murine ischaemic hindlimb model, MRTF-A or T 4 promotes neovascularization, whereas loss of MRTF-A/B or CCN1-function abrogates the T 4 effect. We further show that, in ischaemic rabbit hindlimbs, MRTF-A as well as T 4 induce functional neovascularization, and that this process is inhibited by angiopoietin-2, which antagonizes pericyte recruitment. Moreover, MRTF-A improves contractile function of chronic hibernating myocardium of pigs to a level comparable to that of transgenic pigs overexpressing T 4 (T 4tg). We conclude that MRTF-A promotes microvessel growth (via CCN1) and maturation (via CCN2), thereby enabling functional improvement of ischaemic muscle tissue.

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Section: Role Of Mrtfs In Thymosin ß4-induced Neovascularizationmentioning

confidence: 99%

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

et al. 2014

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“…Although hypoxia is an obligatory consequence of ischemia, it rarely exists alone. Hibernating myocardium may represent a condition of chronic hypoxia (Heusch and Schulz, 1996) but in most other conditions of moderate to severe ischemia, hypoxia is accompanied by or precedes energy depletion, acidosis and/or reoxygenation. Each of these latter conditions involves cell and tissue loss, and the pathways of cell death in each case are unique.…”

Section: Ischemiamentioning

confidence: 99%

“…It has been described in multiple regions of the myocardium during infarction, hibernation (Heusch and Schulz, 1996) and during both ischemia and subsequent reperfusion (Chen et al, 1997;Fliss and Gattinger, 1996). Death pathways involving necrosis, apoptosis and oncosis have been described (reviewed in Kajstura et al, 1996;Ohno et al, 1998).…”

Section: Integration and Significance Of The Bnip3 Pathwaymentioning

confidence: 99%

A unique pathway of cardiac myocyte death caused by hypoxia–acidosis

Graham

Frazier

Thompson

et al. 2004

Journal of Experimental Biology

164

140

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SUMMARY Chronic hypoxia in the presence of high glucose leads to progressive acidosis of cardiac myocytes in culture. The condition parallels myocardial ischemia in vivo, where ischemic tissue becomes rapidly hypoxic and acidotic. Cardiac myocytes are resistant to chronic hypoxia at neutral pH but undergo extensive death when the extracellular pH (pH[o]) drops below 6.5. A microarray analysis of 20 000 genes (cDNAs and expressed sequence tags)screened with cDNAs from aerobic and hypoxic cardiac myocytes identified>100 genes that were induced by >2-fold and ∼20 genes that were induced by >5-fold. One of the most strongly induced transcripts was identified as the gene encoding the pro-apoptotic Bcl-2 family member BNIP3. Northern and western blot analyses confirmed that BNIP3 was induced by 12-fold(mRNA) and 6-fold (protein) during 24 h of hypoxia. BNIP3 protein, but not the mRNA, accumulated 3.5-fold more rapidly under hypoxia–acidosis. Cell fractionation experiments indicated that BNIP3 was loosely bound to mitochondria under conditions of neutral hypoxia but was translocated into the membrane when the myocytes were acidotic. Translocation of BNIP3 coincided with opening of the mitochondrial permeability pore (MPTP). Paradoxically,mitochondrial pore opening did not promote caspase activation, and broad-range caspase inhibitors do not block this cell death pathway. The pathway was blocked by antisense BNIP3 oligonucleotides and MPTP inhibitors. Therefore,cardiac myocyte death during hypoxia–acidosis involves two distinct steps: (1) hypoxia activates transcription of the death-promoting BNIP3 gene through a hypoxia-inducible factor-1 (HIF-1) site in the promoter and (2) acidosis activates BNIP3 by promoting membrane translocation. This is an atypical programmed death pathway involving a combination of the features of apoptosis and necrosis. In this article, we will review the evidence for this unique pathway of cell death and discuss its relevance to ischemic heart disease. The article also contains new evidence that chronic hypoxia at neutral pH does not promote apoptosis or activate caspases in neonatal cardiac myocytes.

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“…These species have a remarkable ability to fully recover cardiac function after a prolonged lack of oxygen (Gesser, 1977;Wasser et al, 1990Wasser et al, , 1992Hicks and Wang, 1998). This response contrasts with mammalian hearts, which generally succumb quickly during severe hypoxia and, in time, exhibit considerable myocardial necrosis (Allen et al, 1985;Heusch and Schulz, 1996). The pronounced anoxia tolerance of turtles and carp is linked to a marked depression of metabolic rate, which is further enhanced at low temperatures, so that anaerobic metabolism can balance energy consumption and reduce the rate of waste production (Jackson, 2000(Jackson, , 2002.…”

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confidence: 99%

Effects of temperature and anoxia upon the performance ofin situperfused trout hearts

Overgaard

Stecyk

Gesser

et al. 2004

Journal of Experimental Biology

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Rainbow trout (Oncorhynchus mykiss) are likely to experience acute changes in both temperature and oxygen availability and, like many other organisms, exhibit behavioural selection of low temperatures during hypoxia that acts to reduce metabolism and alleviate the demands on the heart. To investigate whether low temperature protects cardiac performance during anoxia, we studied the effects of an acute temperature change, from 10°C to either 5°C, 15°C or 18°C, upon the performance of in situ perfused trout hearts before, during and after exposure to 20·min of anoxia. Routine cardiac workload mimicked in vivo conditions at the given temperatures, and the effects of anoxia were evaluated as maximal cardiac performance before and after 20·min of anoxic perfusion. Functional data were related to maximal activities of glycolytic enzymes and energetic status of the heart at the termination of the experiment.At high oxygenation, maximum cardiac output and power output increased with temperature (Q 10 values of 1.8 and 2.1, respectively) as a result of increased heart rate. Hypoxia tolerance was inversely related to temperature. At 5°C, the hearts maintained routine cardiac output throughout the 20·min period of anoxia, and maximal cardiac performance was fully restored following reoxygenation. By contrast, cardiac function failed sooner during anoxia as temperature was increased and maximal performance after reoxygenation was reduced by 25%, 35% and 55% at 10°C, 15°C and 18°C, respectively. Increased functional impairment following anoxic exposure at elevated temperature occurred even though both cardiac glycolytic enzyme activity and the rate of lactate production were increased proportionally with cardiac work. Nonetheless, there was no indication of myocardial necrosis, as biochemical and energetic parameters were generally unaffected by anoxia.

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Hibernating Myocardium: A Review

Cited by 11 publications

References 65 publications

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

A unique pathway of cardiac myocyte death caused by hypoxia–acidosis

Effects of temperature and anoxia upon the performance ofin situperfused trout hearts

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