| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Ann Thorac Surg 2001;72:1454-1456
© 2001 The Society of Thoracic Surgeons
a MCP-Hahnemann University Medical School, Philadelphia, Pennsylvania, USA
b University of Michigan Health Systems, Ann Arbor, Michigan, USA
* Address reprint requests to Dr Narula, Hahnemann University Hospital, Broad & Vine, MS115-NT742, Philadelphia, PA 19102-1192, USA
e-mail: jagat.narula{at}drexel.edu
Open-heart surgery, particularly coronary artery bypass grafting (CABG) for coronary artery disease, is one of the great success stories in modern cardiovascular therapeutics, with more than 500,000 bypass procedures performed in the United States each year [1]. It not only improves survival but also relieves angina and improves exercise tolerance. This success story, however, has its trade-offs, including injury to the myocardium and central nervous system during circulatory arrest or low-flow bypass [2, 3]. Surgeons and researchers have grappled with different techniques to minimize neurologic dysfunction after open-heart surgery. The incidence of adverse cerebral outcomes after CABG ranges from 0.4% to approximately 80%. Perioperative cerebral injury has been divided into major deficits, which include focal neurologic deficits, coma, delirium and stupor; or relatively minor deficits, which include deterioration in short-term and long-term cognitive functions such as intellectual function and memory [1]. These cognitive changes may be subtle and may include problems with following directions, mental arithmetic, and planning complex actions [4]. In addition, family members and colleagues may observe that the patient is more prone to be short-tempered, is less able to withstand frustration, and has wider mood swings. The deterioration in cognitive function may demonstrate a biphasic temporal pattern with an immediate postoperative decline and then a late decline on long-term follow-up [5]. The pathogenesis of neurologic deficits after CABG has been ascribed to hypoxia, recurrent emboli, hemorrhage and metabolic abnormalities. The cellular and molecular mechanisms that result in neurologic deficits, particularly the decline in late cognitive function, continue to be defined. In a very elegant article in this issue of The Annals, Hagl and associates [6] have investigated the role of cell death in neurologic injury after hypothermic circulatory arrest. In addition to temporal characterization of cell death and significant revelations that lower temperatures (approximately 10°C) and use of antiapoptotic intervention (such as cyclosporin A) may lead to prevention of neuronal cell loss, the morphologic description of a spectrum of cell death provides a landmark observation. The types of cell death represented classic apoptosis, orthodox necrosis, and a state that most likely combines the features of both types (referred to as type 1 death). Because death by any means is a loss of functional tissue, should morphologic nuances in the type of cell death be at all important?
It is being increasingly recognized that the cells may defect from necrotic to apoptotic process and vice versa based on the available intracellular energy content [7]. This may be especially true during acute insults and particularly in terminally differentiated cells. The cells during the process of apoptosis may exhaust energy stores and die by necrosis. Unlike necrosis, apoptosis is an active energy requiring process and energy consumption increases enormously if repair of the apoptotic DNA is undertaken, such as by the help of poly-ADP-ribose polymerase (PARP) [8]. PARP utilizes NAD as a substrate to transfer ADP-ribose groups to nuclear proteins during DNA repair. On the other hand, the cells may be exposed to necrotogenic stimuli (such as during acute myocardial infarction), but interruption of injury (such as by reperfusion) may prevent the necrotic process and partially damaged cells may progress to death through the apoptotic cascade [9]. Similarly, milder necrotogenic stimuli may also induce cell death by apoptosis [10]. It is conceivable that the pendular process of cell death may produce various morphologic hybrids of the two cell death types. It may be logical to propose that interventions to abrogate any one process may produce preventative benefits that exceed expectations. The cell death, at least in terminally differentiated cells, may therefore allow multiple avenues of intervention.
The boundaries of apoptotic and necrotic cell death may be even hazier in chronic cardiac and neurologic disorders, such as CHF and Alzheimer’s disease. Studies of the apoptotic cascade in these disorders have been very informative. Activation of caspase 3 is a central step in apoptosis and eventually leads to cytoplasmic proteolysis and DNA fragmentation [11]. Activation of caspase 3 may result from two distinct (but not mutually exclusive) pathways (Fig 1). The pathway initiated by stress stimuli, such as ischemia, reactive oxygen radicals, and intracellular calcium overload, is mediated by cytochrome c release from mitochondria and its interaction with Apaf-1, caspase 9, and dATP [12]. The other pathway is cytokine based and cascades through activation of caspases 1 and 8 [13]. Processing of caspase 8 further amplifies the caspase 3 activation by mitochondrial release of cytochrome c via mitochondrial translocation of truncated Bid [14]. There are natural repressors of caspases, including IAPs for caspase 3 [15], ARC for caspase 8 [16], and ICEBERG for caspase 1 [17], which retard the apoptotic process. Similarly, BCl2 family proteins, including BCl2 and BClxL, prevent cytochrome c release and hence apoptosis [15]. Other BCl2 family members such as Bax potentiate apoptosis. Narula and associates [18] have demonstrated that cytochrome c is released from mitochondria in end-stage heart failure, and is associated with caspases 8, 9, and 3 upregulation and activation. Secondary to caspase 3 activation, cytoplasmic contents such as contractile proteins are cleaved to an extent [19], but the apoptosis is not completed and nuclei remain intact, leading to a state referred to as apoptosis interruptus [20]. The resistance to apoptosis is not clearly understood but is likely associated with loss of DNAses (unpublished observations), upregulation of antiapoptotic proteins, and downregulation of apoptotic factors [21]. Whereas loss of cytochrome c may contribute to systolic dysfunction, lack of completion of apoptosis maintains these cells in the state of suspended animation. The cells may exist until recovery or until depletion of energy allows them to die by necrosis. Because the interrupted apoptotic process leaves nuclear blue print intact, it may allow recovery of the cells with reconstitution of the cytoplasmic protein compartment. The revitalized cells have been termed as "zombie myocytes" [20]. The apoptotic process may therefore lead to death by necrosis or recovery of dysfunctional cells in chronic disease states. This is in contrast with acute diseases wherein proapoptotic proteins may overwhelm the protective response due to a shorter time for compensatory accumulation of antiapoptotic factors.
|
As various mechanisms by which cells are able to halt apoptosis "midstream" continue to unravel, our understanding of the pathogenesis of chronic conditions such as heart failure and chronic cognitive decline are only beginning to be understood. A growing understanding of cellular processes should eventually result in the development of more effective therapeutic strategies for management of cardiac and neurologic disorders, which were once considered invincible. Defining diverse cidal pathways in terminally differentiated cells, as described by Hagl and associates, is of paramount importance. And if these pathways are truly interrelated, we should be able to substantially minimize the tragedy of cell death.
References
This article has been cited by other articles:
|
|
 |
|
  Y. Chandrashekhar and J. Narula Death Hath a Thousand Doors To Let Out Life... Circ. Res., April 18, 2003; 92(7): 710 - 714. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
