Continued depression of maximal oxygen consumption and mitochondrial proteomic expression despite successful coronary artery bypass grafting in a swine model of hibernation

Kelly, Rosemary F.; Cabrera, Jesús A.; Ziemba, Elizabeth A.; Crampton, Melanie; Anderson, Lorraine; McFalls, Edward O.; Ward, Herbert B.

doi:10.1016/j.jtcvs.2010.08.061

Cited by 38 publications

(58 citation statements)

References 26 publications

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“…This study is to our knowledge the first to report such data in paired biopsies from human heart, and the results are in agreement with previous observations of decreased OXPHOS capacity in chronic cardiac ischemia in animal models (4,12,16,17). The composition of the present substrate-inhibitor protocol was done with a stepwise addition of substrates: first for complex I linked respiration and then for combined complex-I and -II respiration, followed by inhibition of complex I, leaving only complex II-linked respiration, and finally inhibition of the entire respiratory chain respiration by antimycin A inhibition of complex III.…”

Section: Discussionsupporting

confidence: 92%

“…However, one study reported a preserved OXPHOS capacity but decreased respiratory control ratio (RCR) interpreted as mild uncoupling of the mitochondria (21). Chronic ischemia is thought to produce regions of viable "hibernating" cardiac myocytes with the potential to regain some degree of mitochondrial and contractile function upon reestablishment of sufficient oxygen provision, i.e., via coronary angioplasty bypass grafting (17). In two of the animal studies mentioned above, a protective "chronic preconditioning effect" was reported.…”

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confidence: 99%

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Impaired mitochondrial function in chronically ischemic human heart

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Hey-Mogensen

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Chronic ischemic heart disease is associated with myocardial hypoperfusion. The resulting hypoxia potentially inflicts damage upon the mitochondria, leading to a compromised energetic state. Furthermore, ischemic damage may cause excessive production of reactive oxygen species (ROS), producing mitochondrial damage, hereby reinforcing a vicious circle. Ischemic preconditioning has been proven protective in acute ischemia, but the subject of chronic ischemic preconditioning has not been explored in humans. We hypothesized that mitochondrial respiratory capacity would be diminished in chronic ischemic regions of human myocardium but that these mitochondria would be more resistant to ex vivo ischemia and, second, that ROS generation would be higher in ischemic myocardium. The aim of this study was to test mitochondrial respiratory capacity during hyperoxia and hypoxia, to investigate ROS production, and finally to assess myocardial antioxidant levels. Mitochondrial respiration in biopsies from ischemic and nonischemic regions from the left ventricle of the same heart was compared in nine human subjects. Maximal oxidative phosphorylation capacity in fresh muscle fibers was lower in ischemic compared with nonischemic myocardium (P Ͻ 0.05), but the degree of coupling (respiratory control ratio) did not differ (P Ͼ 0.05). The presence of ex vivo hypoxia did not reveal any chronic ischemic preconditioning of the ischemic myocardial regions (P Ͼ 0.05). ROS production was higher in ischemic myocardium (P Ͻ 0.05), and the levels of antioxidant protein expression was lower. Diminished mitochondrial respiration capacity and excessive ROS production demonstrate an impaired mitochondrial function in ischemic human heart muscle. No chronic ischemic preconditioning effect was found. mitochondrial respiration; reactive oxygen species; left ventricle CHRONIC ISCHEMIC HEART DISEASE (IHD) is caused by progressive atherosclerosis of the coronary arteries, leading to regional hypoperfusion of the myocardium. This results in local hypoxia that potentially limits ATP production from the processes of oxidative phosphorylation (OXPHOS) in mitochondria (4,8,12). Furthermore, acute ischemia and reperfusion causes mitochondrial dysfunction and subsequent excessive production of reactive oxygen species (ROS) by the electron transport chain (ETC) (23). Blockade of complex I or III in the ETC decreases ROS production during episodes of ischemia and helps protect the mitochondria against ischemic damage (2, 9), whereas blockade at a step distal of complex III [site of cytochrome c oxidase (COX)] has been shown to increase ROS generation (9). Traditionally (5), complexes I and III are regarded as the primary sources of ROS (within the ETC), but recently complex II has also been shown to produce ROS, at least in skeletal muscle (31). The deleterious actions of ROS include damage to the mitochondrial membrane constituents (lipids and proteins) and mtDNA (28), opening of mitochondrial permeability transition pores, resulting in mitochondrial depolari...

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Section: Discussionsupporting

confidence: 92%

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confidence: 99%

Impaired mitochondrial function in chronically ischemic human heart

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Larsen

Hey-Mogensen

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…It is conceivable that mitochondrial measurements under basal conditions do not represent in vivo conditions at higher work states, which might unmask a propensity for a state of energetic failure. We have observed that within hibernating hearts, contractile reserve in response to a catecholamine infusion remains submaximal, despite successful revascularization with a left internal mammary graft and the inability to enhance oxygen consumption maximally may relate to the observed reduction in key ETC proteins [26]. Several lines of evidence suggest that the mitochondrial proteome retains plasticity with strategies that might improve heart failure, as supported by an observed increase in the expression of mitochondrial ETC proteins following resynchronization of dogs with heart failure [27].…”

Section: Discussionmentioning

confidence: 94%

Reduced expression of mitochondrial electron transport chain proteins from hibernating hearts relative to ischemic preconditioned hearts in the second window of protection

Cabrera

Butterick

Long

et al. 2013

Journal of Molecular and Cellular Cardiology

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“…Although somewhat controversial [54], the study results suggest that more novel therapies other than revascularization need to be considered in order to improve contractile function and reduce heart failure. In our swine model of hibernating myocardium hibernation, we subjected the pigs to off-pump revascularization with a LIMA graft and at 4-weeks post-CABG showed that the increase in regional blood flow in response to high-dose infusion of catecholamine was sub-maximal, despite the presence of a widely patent graft [55]. In addition, the mitochondrial proteome remains abnormal at this time, as manifested by reduced expression of electron transport proteins and increased uncoupling protein-2 [56].…”

Section: Management Of Patients With Hibernating Hearts and Ischemic mentioning

confidence: 99%

The Recovery of Hibernating Hearts Lies on a Spectrum: from Bears in Nature to Patients with Coronary Artery Disease

Colbert

Holley

Stone

et al. 2015

J. of Cardiovasc. Trans. Res.

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Clinicians often use the term "hibernating myocardium" in reference to patients with ischemic heart disease and decreased function within viable myocardial regions. Because the term is a descriptor of nature's process of torpor, we provide a comparison of the adaptations observed in both conditions. In nature, hearts from hibernating animals undergo a shift in substrate preference in favor of fatty acids, while preserving glucose uptake and glycogen. Expression of electron transport chain proteins in mitochondria is decreased while antioxidant proteins including uncoupling protein-2 are increased. Similarly, hibernating hearts from patients have a comparable metabolic signature, with increased glucose uptake and glycogen accumulation and decreased oxygen consumption. In contrast to nature however, patients with hibernating hearts are at increased risk for arrhythmias, and contractility does not fully recover following revascularization. Clearly, additional interventions need to be advanced in patients with coronary artery disease and hibernating myocardium to prevent refractory heart failure.

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Continued depression of maximal oxygen consumption and mitochondrial proteomic expression despite successful coronary artery bypass grafting in a swine model of hibernation

Cited by 38 publications

References 26 publications

Impaired mitochondrial function in chronically ischemic human heart

Impaired mitochondrial function in chronically ischemic human heart

Reduced expression of mitochondrial electron transport chain proteins from hibernating hearts relative to ischemic preconditioned hearts in the second window of protection

The Recovery of Hibernating Hearts Lies on a Spectrum: from Bears in Nature to Patients with Coronary Artery Disease

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