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Ann Thorac Surg 2004;78:1109-1118
© 2004 The Society of Thoracic Surgeons

Review

Apoptosis: Pathophysiology and therapeutic implications for the cardiac surgeon

Ali Khoynezhad, MDa,*, Ziba Jalali, MDb, Anthony J. Tortolani, MDa

a Department of Cardiothoracic Surgery, New York Presbyterian-Cornell Medical Center, New York, New York, USA
b Department of Medicine, New York University Medical Center, New York, New York, USA

* Address reprint requests to Dr Khoynezhad, Department of Cardiothoracic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th St, Bronx, NY 10467, USA
akhoy{at}lycos.com


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Comment
 References
 
Cardiomyocyte apoptosis has been associated with the pathogenesis of heart failure as well as ischemic and inflammatory myocardial conditions. The aim of this study is to give a critical synopsis of cardiomyocyte apoptosis and identify methods to prevent or attenuate apoptosis in patients undergoing cardiac surgery. Clinical conditions and agents associated with decreased apoptotic index are early repair or replacement of valvular pathology before deterioration of ventricular function, afterload reduction with medication or intraaortic balloon pulsation in patients with acute increase in afterload or in hemodynamically compromised patients, decreasing catecholamine-induced cardiotoxicity by using ß-blockers, phosphodiesterase inhibitors, or early insertion of intraaortic balloon pulsation or ventricular assist device. Prompt coronary revascularization, which reduces myocardial ischemia time, is the most effective antiapoptotic therapy. Reduction of myocardial apoptosis associated with cardiopulmonary bypass and aortic cross-clamping are other therapeutic targets. Some investigational therapies include ischemic preconditioning and use of antiapoptotic medication such as the caspase inhibitors, antioxidants, calcium-channel blockers, the insulin-like growth factor-1, and the poly-adenosine diphosphate-ribose-synthetase inhibitors. Most of the therapeutic implications in reducing cardiomyocyte apoptosis are still in the experimental phase. Some options are already incorporated in the clinical practice of the cardiovascular surgeon. New therapeutic considerations include avoiding sustained and long-term use of catecholamines and reducing or avoiding cardiopulmonary bypass—when clinically feasible. Noncatecholamine inotropes should be preferred for patients undergoing heart failure surgery and for patients with low output syndrome after open-heart surgery. The lessons learned from apoptosis research reinforce more liberal and early insertion of intraaortic balloon pulsation or ventricular assist device in clinical low output states.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Comment
 References
 
Apoptosis was introduced as a morphologically distinct mode of cell death in 1972 [1]. Cardiomyocyte apoptosis has been the topic of research in numerous studies. Within the plethora of these publications, a surgical group has contributed only to very few articles that are addressed to the cardiac surgeon.

Apoptosis contributes to the pathogenesis of various cardiac disease states. The therapeutic options could alter significantly the results of the surgical treatment of patients with ischemic, valvular heart disease and heart failure. Understanding the pathophysiology and its clinical implications are important for the cardiovascular surgeon, because the therapeutic options may improve the patient's outcome.

The aim of this study is to give a critical overview of cardiomyocyte apoptosis and its translational physiology as it relates to cardiovascular surgery: pathophysiology, diagnostic studies, etiology, and therapeutic implications for clinical practice.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Comment
 References
 
A search using "Ovid" resulted in more than 70,400 publications using the keyword "apoptosis." The search was subsequently limited to the English language and was focused on studies involving humans. The search engine resulted in 398 publications on heart failure and apoptosis and 591 on all ischemic myocardial conditions associated with apoptosis. The articles were assessed for their validity, importance, and applicability to the cardiovascular surgeon's practice. The methods used for detecting apoptosis were also critically reviewed for accuracy and completeness. The publications were analyzed, and clinically important data were collected and incorporated.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Comment
 References
 
Cell proliferation and cell death are in homeostasis. Physiologic cell death occurs primarily through an evolutionarily conserved form of cell suicide termed apoptosis. It originates from the Greek, and is translated as "falling of leaves from a tree or petals from a flower." The inducers of apoptosis may differ in diverse species, but the final common cell death pathway is identical and hardwired in all species including Homo sapiens. This process is also existent in terminally differentiated cells, including cardiac myocytes.

I) pathophysiology of cardiomyocyte apoptosis
Pure apoptotic cell death is significantly different from necrosis. However, there are cell death pathways that are similar to both. Apoptosis is an energy-requiring and precisely regulated process, which is directed by a genetic program [2]. Apoptotic cell initiates its own death process by activating endogenous proteases. Alternatively, necrosis occurs secondary to an external inducer. Figure 1 is a schematic representation of the differences between cardiomyocyte apoptosis and necrosis.



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  		Fig 1. Cell shrinkage and aggregation of chromosomal DNA into small masses and preparation for exocytosis are microscopic hallmarks of early stages of apoptosis. These apoptotic bodies are membrane bounded and are subsequently phagocytosed by macrophages and neutrophils. Necrosis, on the other hand, is associated with loss of transmembrane ion gradient and membrane disruption secondary to depletion of intracellular adenosine triphosphate causing an inflammatory reaction in surrounding tissue. The specific DNA fragmentation is a hallmark of apoptosis, and it is utilized as a detection method in the "DNA laddering."

 
Activation and regulation of apoptosis
Apoptotic cell death is activated through the caspase (cystein aspartic acid-specific protease) cascade. At least 10 different members of these intracellular proteases that cleave substrate proteins behind aspartate residues are known [3]. Once the so-called downstream caspases (caspase-3, -6, -7) are activated, cell death appears to be inevitable; this occurs several hours before the morphologic appearance of apoptosis [4].

Two major molecular pathways in caspase activation are recognized in myocardial cells (Fig 2). The main pathway is initiated by the release of a mitochondrial respiratory chain protein—the cytochrome c—from mitochondrial intermembranous space [5]. The cytochrome-c–mediated activation of apoptosis has been demonstrated in animal and human models of heart failure [6, 7]. Cytochrome c in conjunction of apoptosis protease-activating factor (Apaf-1) and dextro-adenosine triphosphate (dATP) allow the autocatalytic activation of the most upstream caspase on the mitochondrial pathway (procaspase-9) [8]. This cytosolic complex is orchestrated in response to certain stimuli such as apoptosis-inducing factor (AIF), aberrant oncogene expression, p-53, cytotoxic agents, and DNA damage [9].



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  		Fig 2. A simplified presentation of the two main pathways of caspase activation leading to myocardial apoptosis. (Apaf-1 = apoptosis protease-activating factor-1; AIF = apoptosis inducing factor; Bcl-2 = B-cell lymphoma-2 protein; CASH = caspase homologue; dATP = dextro-adenosine triphosphate; FADD = Fas-associated death domain protein; FLAME-1 = FADD-like antiapoptotic molecule-1; FLIP = FLICE-inhibitory protein; IAP = inhibitor of apoptosis proteins; I-FLICE = inhibitor of FADD-like interleukin-1ß-converting enzyme.)

 
The mitochondrial pathway is regulated through at least two classes of proteins. The first class is antiapoptotic intracellular proteins (such as the proto-oncogene Bcl-2 family proteins) and proapoptotic proteins (such as Bax) [5]. The ratio between Bcl-2 and Bax in cardiac myocytes has been shown in human and animal studies to be related to an increased apoptosis rate [10]. Regulation of Bcl-2 is studied in various apoptogenic cardiac conditions in humans and rats. Increased levels of Bcl-2 are detected soon after acute coronary occlusion in human and rat hearts [11, 12]. However, in chronic heart failure secondary to pressure overload, the levels of Bcl-2 are underexpressed in a rat model [13]. The second group of regulatory proteins is the inhibitor of apoptosis proteins (IAP) family [14]. The antiapoptotic characteristics of inhibitor of apoptosis proteins are due to direct inhibition of different steps of signal transduction in cytochrome-c–dependent or death-receptor–mediated apoptosis.

The alternative pathway for activation of apoptosis is called the death receptor pathway. This pathway is best studied in the literature, but is thought to play only a secondary role in initiation of cardiomyocyte apoptosis [15]. The activation of the most upstream caspase (procaspase-8) involves the binding of extracellular death signal proteins (eg, Fas-ligand) to their cognate death receptor on the cell surface, such as Fas-associated death domain protein (FADD) [16]. The cytoplasmatic domain has a characteristic amino acid residue that is essential for the proapoptotic activity. This domain is specific for each death receptor.

At least two different regulatory proteins for inhibition of death receptor pathway are described. The first group is the inhibitors of receptor-mediated caspase activation such as FADD-like interleukin-1ß-converting enzyme (FLICE)-inhibitory protein (FLIP), inhibitor of FADD-like interleukin-1ß-converting enzyme (I-FLICE), caspase homologue (CASH), and FADD-like antiapoptotic molecule-1 (FLAME-1) [17]. This class of proteins inhibits competitively the receptor-induced activation of upstream caspase. The second group is the inhibitor of the apoptosis protein family that was discussed earlier.

Diagnostic tools
A few methods are available for identifying the prevalence of apoptotic cells in a tissue sample (Fig 3). The most convincing proof of apoptosis is the visualization of nuclear-stained cells. This method is limited owing to the difficulty of finding a few cells that remain only 6 to 24 hours [1].



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  		Fig 3. Most common and valid methods used for detection of apoptosis. (TUNEL = terminal deoxynucleotidyl-transferase mediated dUTP nick end-labeling.)

 
Other techniques that utilize electrophoresis of nuclear fragments (DNA-laddering) [18] or the histochemical staining of the fragmented DNA—the so-called TUNEL (terminal deoxynucleotidyl-transferase mediated dUTP nick end-labeling) — and its modifications such as comet assay [19] or in-situ end-labeling are limited by the inability to specify cell type and the fact that DNA fragmentation can occur during damage or repair.

II) apoptosis as therapeutic target in cardiovascular disease
Various conditions and agents can induce cardiomyocyte apoptosis (Fig 4). Prevalence of programmed cell death has been documented in ischemic and dilated cardiomyopathies [20], acute myocardial infarction [21], atherosclerosis [22], myocarditis [23], cardiac allograft rejection [24], and dysrythmic cardiac disease [25]. Antiapoptotic strategies that have been developed and studied in these myocardial conditions will be discussed below.



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  		Fig 4. The most relevant myocardial conditions and agents that induce cardiomyocyte apoptosis are listed (right side). These can potentially lead to other clinical entities (left side). (ANF = antinuclear factor; TNF = tumor necrosis factor.)

 
Ischemic myocardial conditions
Ischemic heart conditions are the leading inducers of cardiac apoptosis. Myocyte loss during the acute stage of myocardial infarction due to apoptotic cell death is well established in animal and human studies. Increased apoptotic index (percent of apoptotic cells in ratio to all cells) was demonstrated as early as 3 hours and as long as 1 month after coronary occlusion in rat hearts [26]. Apoptotic human cardiomyocytes were predominantly in the hypoperfused border zone between the central infarct area and nonischemic cardiac tissue [21]. Olivetti and associates [21] demonstrated 12% apoptotic cell death in the infarct border zone and 1% in noncompromised myocytes distant from the infarct zone.

Broad-spectrum caspase inhibitors such as zVAD.fmk and IDN-6734 have been used successfully as antiapoptotic agent in a rat model of acute myocardial infarction [27, 28]. The inhibitor ZVAD.fmk has decreased infarction size with improved hemodynamics and has attenuated apoptosis compared with controls [27]. Armstrong and coworkers [28] found that IDN-6734 reduces the size of myocardial infarction in rats, if the polycaspase inhibitor is given before (47% reduction) or 1 hour after (45% reduction) reperfusion of the left anterior descending artery. Potentially, these polycaspase inhibitors could be given to patients after an acute myocardial infarction or before apoptogenic conditions such as cardiopulmonary bypass and the cardioplegic/reperfused heart to reduce the amount of cell death.

Apoptosis plays an important role in remodeling of viable myocardium after myocardial infarction [21, 29]. Apoptotic inhibition by insulin-like growth factor-1 (IGF-1) in a transgenic mouse model resulted in decreased ventricular dilatation a week after an acute myocardial infarction [30]. Other therapeutic benefits may be derived from the use of the antioxidants probucol and pyrrolidine dithiocarbamate after myocardial infarction. A randomized controlled study demonstrated a decrease of cardiomyocyte apoptosis in rats treated with antioxidants after induction of myocardial infarction [31].

Antioxidants have been also implicated in ischemia-reperfusion injury [32]. This is per explicans the damage to the myocardium after coronary flow restoration after a critical period of ischemia. This concept plays a significant role for patients undergoing coronary revascularization and open-heart surgery. Induction of apoptosis has been demonstrated during ischemia-reperfusion in animal models [33]. Myocardial ischemia-reperfusion is known to be associated with an acute rise in reactive oxygen radicals, causing contractile dysfunction, myocardial infarction, and arrhythmias [34]. A potential therapeutic benefit may be the use of antioxidants such as superoxide dismutase, catalase, gluthathione peroxidase, vitamin C and E in cardioplegic solutions, or as an adjunct to the cardiopulmonary bypass circuit. However, there is no level-1 evidence promoting use of antioxidants in ischemic cardiac disease including acute myocardial infarction.

Another pharmacologic approach to treating ischemia-reperfusion injury is inhibition of poly-adenosine diphosphate (ADP)-ribose-synthetase. Poly-ADP-ribose-synthetase is a DNA repair enzyme, which is released by caspase-3 and which causes cellular energy depletion and cell death [35]. Inhibition of poly-ADP-ribose-synthetase reduced infarct size and improved left ventricular performance in reperfused rabbit hearts [36].

Another apodictic strategy in attenuation of ischemia-reperfusion injury is ischemic preconditioning [37]. This is defined as a reduction in the amount of cardiomyocyte death when a critical ischemic episode is preceded by a brief, nonlethal period of ischemia and reperfusion. Ischemic preconditioning reduces infarct size, decreases postperfusion arrhythmias, attenuates platelet-mediated thrombosis, and slows the rate of cellular ATP depletion [38]. Although the mechanism of ischemic preconditioning is not fully understood, there are experimental studies linking it with upregulation of the antiapoptotic Bcl-2 protein and underexpression of the proapoptotic Bax [39]. Reactive oxygen radicals released by the ischemia-reperfusion process activates the Bcl-2 gene by stimulating a specific nuclear transcription factor (NF{kappa}B), which in turn reduces apoptosis [40].

Jenkins and coworkers [41] demonstrated evidence of ischemic preconditioning in patients undergoing coronary artery bypass grafting. Performing two episodes of 3-minute aortic cross-clamping antecedent to the planned ischemia resulted in decreased troponin T and preserved ATP storages compared with the control group [41]. However, there is a contradicting paper revealing increased creatine kinase release in 10 patients after ischemic preconditioning [42]. Randomized controlled studies are required to establish the potential benefits and clinical efficacy of ischemic preconditioning in patients undergoing coronary bypass or open-heart surgery.

Myocardial stunning represents viable but nonfunctional myocytes with normal coronary reserve. It is an ischemic injury causing postreperfusion myocardial dysfunction despite the absence of necrosis [43]. Myocardial stunning is common after unstable angina, acute myocardial infarction with early reperfusion, and after interventional procedures on the heart and after open-heart surgery [44]. Open-heart surgery is the most "controlled" scenario for myocardial stunning, and has been the subject of multiple translational research projects. Transient postoperative left and right ventricular dysfunction attributable to stunning has been clearly demonstrated after aortic cross-clamping and subsequent reperfusion in patients undergoing coronary artery bypass grafting [45–47]. It reaches a nadir at approximately 4 hours after surgery and is usually completely recovered within the first 2 postoperative days. However, repetitive stunning may be an unrecognized cause of chronic left ventricular dysfunction and dilated cardiomyopathy [44]. Myocardial stunning has been also proposed after cardiac transplantation and in survivors of cardiac arrest [48, 49].

Myocardial stunning appears to be a form of ischemia-reperfusion and is associated with apoptosis. Although the mechanism is not fully understood, two plausible hypotheses are generation of reactive oxygen radicals and cellular calcium overload. Both of these agents are known to be potent inducers of apoptosis [50, 51]. The first clinical application of therapies for cardiac apoptosis associated with stunning will be in open-heart surgery, because it is a perfect model of myocardial stunning. The timing and duration of ischemia, as well as the degree of coronary flow reduction, are anticipated and orchestrated. And contrary to other clinical settings associated with myocardial stunning, preoperative, intraoperative, and postoperative ventricular performance is evaluated.

Implied therapeutic interventions include the use of antioxidants (such as vitamin E analogues) and calcium antagonists (such as nisoldipine) in cardioplegic solution or as adjunct to cardiopulmonary bypass circuit. All these therapies have demonstrated attenuation of myocardial stunning in experimental studies [52, 53]. However, there are currently no controlled clinical data on the efficacy of these medications.

Stunning must be distinguished from chronic hibernating myocardium. Both involve reversible myocardial dysfunction. However, coronary reserve in chronic hibernating myocardium is reduced whereas it is normal or near normal in stunned myocardium. Additionally, chronic hibernating myocardium may be associated with de-differentiation of myocytes associated with the expression of fetal DNA. Positron emission tomography is the most accurate test to differentiate between these clinical entities [43]. Chronic hibernating myocardium represents the characteristic status of dysfunctional but viable cardiac myocardium, which will recover after coronary artery bypass grafting [54]. Although apoptosis has been detected in chronic hibernating myocardium, there is no evidence that increased apoptosis occurs in chronic hibernating myocardium [55].

Inflammatory myocardial conditions
Apoptosis has been demonstrated in inflammatory conditions of the myocardium including myocarditis [23] and cardiac allograft rejection [24]. Proinflammatory cytokines such as tumor necrosis factor-{alpha} and interleukin-1 has been shown to act as negative inotropic and induce cardiomyocyte apoptosis [19]. Tumor necrosis factor receptor-1 and Fas-receptor have a similar sacroplasmatic assembly complex known as the death domain. Tumor necrosis factor-{alpha} can induce and enhance apoptosis through Fas-receptor and tumor necrosis factor receptor-1 [16]. Clinical trials are currently under way to examine the benefit of long-term inhibition of tumor necrosis factor-{alpha}.

Cardiotrophin-1 is a cytokine from the interleukin-6 family. It is antiapoptotic and has hypertrophic effects on isolated myocytes [56]. Cardiotrophin-1 increases survival of cardiomyocytes kept under serum-deprived conditions [56]. However, use of cardiotrophin-1 as an antiapoptotic agent remains investigational.

Dilative and hypertrophic myocardial conditions
Both dilative and hypertrophic changes of myocardium are associated with necrosis and apoptosis [57–59]. Aortic and mitral valve regurgitation causes dilation of the left ventricle secondary to volume overload; increasing left ventricular end-diastolic pressure and the isometric stretch of cardiomyocytes. Cheng and coauthors [59] verified a 21-fold higher incidence of apoptosis in a rat model when the papillary muscle was exposed to 50 mN/mm2 isometric tension compared with 7–8 mN/mm2. This evidence supports that acute volume overload is associated with myocardial apoptosis.

Apoptosis is also well established in hypertrophied myocardium regardless of etiology [57, 58]. Ventricular hypertrophy results from conditions such as acutely increased afterload, long-lasting hypertension, and aortic or pulmonary stenosis. Isolated adult cardiomyocytes treated with angiotensin II revealed increased apoptotic index in a human model [60]. Angiotensin-converting enzyme inhibitors prevented apoptotic cell death in the same study. Angiotensin II activates proapoptotic p-53 transcription, which is a transactivator protein involved in cell cycle control and DNA repair [61]. It also induces apoptogenic genes such as c-myc, c-fos, c-jun, and upregulation of the transcription of genes encoding for proapoptotic atrial natriuretic factor [62]. Angiotensin-II blockers and angiotensin-converting enzyme inhibitors can inhibit this effect, and reduce the apoptotic cell death.

Teiger and coworkers [58] reproduced an acute increase in afterload and compensatory ventricular hypertrophy by aortic banding in rats. Apoptosis was significantly higher in banded rats in comparison with the control group. Peak apoptotic index was on the fourth day after aortic banding, and it was suggested that apoptosis might be important in the transition between compensatory hypertrophy and heart failure. Therapeutic ramifications for the cardiac surgeon include prompt repair/replacement of valvular pathology before deterioration of left ventricular function, liberal use of an afterload-reducing agent, or early insertion of intraaortic balloon pulsation in patients with acute myocardial infarction or ischemic mitral regurgitation with hemodynamic compromise.

Congestive heart failure
Apoptosis in heart failure has been established in animal and human studies [20, 63]. The number of apoptotic cells is significantly lower than in ischemic myocardial conditions, making the investigation of cardiomyocyte apoptosis in congestive heart failure a difficult task. Apoptosis contributes significantly to progressive left ventricular dysfunction by ongoing apoptotic cell death. Compensatory mechanisms such as left ventricular hypertrophy, left ventricular dilation, enhanced and sustained activity of sympathetic nervous system, the renin-angiotensin-aldosterone system, and altered intracellular calcium homeostasis are closely associated with heart failure. These mechanisms are also considered as potent inducers of apoptosis and are responsible for remodeling and progression of heart failure [60, 64].

Increased sympathetic nerve activity is a hallmark of congestive heart failure, and is associated with direct toxic and proapoptotic effects on cardiomyocytes [64]. In two studies, the direct toxic and proapoptotic effects of norepinephrine were abolished by a ß-adrenoreceptor antagonist but not by an {alpha}-antagonist [64]. The antiapoptotic effects of ß-blockers on norepinephrine-induced apoptosis have been demonstrated for atenolol and carvedilol [65, 66]. The latter have been proven to be more effective, probably because of additional antioxidant effects and inhibition of mitochondrial cytochrome c release. The ß-antagonists have become a mainstay in the treatment of heart failure patients. Gradual escalation of the dose of orally administered ß-adrenoreceptor blockers has been shown in randomized controlled studies to significantly reduce overall mortality and to decrease heart-failure–related hospitalization in patients with left ventricular dysfunction [67, 68]. Alternatively, sustained and high-dose use of catecholamines should be avoided in patients after cardiogenic shock, acute myocardial infarction, or other low-output syndromes associated with long pump runs. Noncatecholamine inotropes such as phosphodiesterase inhibitors may be preferred in such cases. Prompt insertion of intra-aortic balloon pulsation or ventricular assist devices to limit the use of catecholamine-based rescue should be an integral part of the armamentarium of the cardiac surgeon.

Low-output cardiac states are characterized by elevated serum and tissue concentration of angiotensin II secondary to renin-angiotensin-aldosterone system activation [69]. Angiotensin II increases afterload, causes ventricular remodeling, and promotes cardiomyocyte and endothelial necrosis and apoptosis as well as diastolic ventricular dysfunction secondary to fibroblast proliferation and collagen deposition in the left ventricular wall [60]. Angiotensin II promotes apoptosis, and angiotensin-converting enzyme inhibitors and angiotensin-II blockers have demonstrated an attenuation of this effect [60, 61, 70]. There is level-1 evidence supporting the use of angiotensin-converting enzyme inhibitors or angiotensin-II blockers in patients with congestive heart failure [71, 72]. The use of angiotensin-converting enzyme inhibitors or angiotensin-II blockers after surgery in patients with poorly functioning or dilated ventricles is clearly beneficial.

Elevated levels of angiotensin II and catecholamines in patients with congestive heart failure increase intracellular calcium ion in cardiomyocytes [60, 70, 73]. This cellular calcium overload can lead to apoptosis [51]. Sodium-hydrogen exchanger inhibitors can reduce cellular calcium by decreasing cellular sodium. Oral administration of sodium-hydrogen exchanger inhibitors has reduced mortality, arrhythmia, infarct size, apoptotic index and Bcl-2/bax ratio in an ischemic rat model [74]. However, no study has been performed on human models of heart failure. Calcium-channel blockers have been shown to decrease the direct toxicity of norepinephrine by decreasing intracellular calcium [73], but no studies have been undertaken that might show decreased apoptosis in heart failure models. Clinically, there is no level-1-evidence that channel blockers are of benefit in people with heart failure [75]. Calcium-channel blockers do not influence the structural cardiac remodeling process and fail to reduce overall mortality and hospitalization rates [76].


   Comment
Top
 Abstract
 Introduction
 Methods
 Results
 Comment
References
 
Evidence supports that apoptosis of cardiac myocytes is a feature of ischemic, inflammatory, dilative, and hypertrophic myocardial conditions as well as heart failure. The programmed cell death is precisely orchestrated and stimulated by a variety of conditions and agents. Accumulating data will widen the spectrum of therapeutic strategies for managing patients with cardiac conditions. Elucidation of antiapoptotic and proapoptotic interventions will translate into new treatment options in the field of cardiovascular surgery. However, there are as yet no level-1 clinical data on the efficacy of the strategies and management options that are discussed here.

A large variety of myocardial conditions and agents have been identified as inducers of cardiomyocyte apoptosis (Fig 4). The majority of antiapoptotic therapies are still investigational and without direct translation into the clinical praxis of cardiovascular surgery (Table 1). Some medical therapies such as use of ß-receptor antagonists, angiotensin-II blockers, and angiotensin-converting enzyme inhibitors have antiapoptotic effects. These medications are proven in randomized controlled studies to be of significant clinical benefit to patients with heart failure and in ischemic myocardial conditions. It remains unknown if the antiapoptotic characteristics of these medications are responsible for the associated survival benefit.


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  		Table 1. An Overview of Antiapoptotic Therapy

 
Myocardial ischemia, volume and pressure overload, and clinical conditions associated with sustained or acute increase in levels of catecholamines are clinically relevant stimuli of apoptosis that are pertinent to the cardiac surgeon. Therapeutic ramifications are in some cases already incorporated in the clinical praxis of cardiovascular surgery. These include reducing myocardial ischemia time with prompt coronary revascularization, early valvular repair or replacement before deterioration of ventricular function, and afterload reduction with intra-aortic balloon pulsation in compromised cardiac function after myocardial infarction or ischemic mitral regurgitation.

Understanding mechanisms of apoptosis helps to identify a new therapeutic target, which will change the surgeon's approach to certain clinical entities. Open-heart surgery and the use of cardiopulmonary bypass have been associated with increased apoptotic index. With off-pump coronary artery bypass, this apoptotic condition can be avoided. However, the majority of currently performed coronary operations and all other open-heart surgeries will require cardiopulmonary bypass. Thus, prevention and attenuation of the proinflammatory and apoptogenic state of cardiopulmonary bypass remain important therapeutic goals. Blood contact with foreign surface results in increased serum level of Fas and Fas-ligand in humans undergoing cardiopulmonary bypass [77]. This increases apoptotic cell death in the myocardium and other organs through the death receptor pathway. The evidence of postbypass syndrome including cerebral dysfunction and renal insufficiency may be secondary to apoptotic injury to other organs [78, 79]. Potential therapeutic implications are reduction of the foreign surface, shortening of bypass time, and addition of antiapoptotic medication to the priming solution in the cardiopulmonary bypass circuit. These can significantly impact the principles of myocardial protection performed in the routine clinical setting. A myocardial protection strategy based heavily on hypothermia will result in longer bypass times and increased apoptotic index. Alternately, surgeons using more normothermic techniques will have more prompt restoration of cardiac performance, decreased reperfusion time, and diminished use of catecholamines. All of these conditions have the benefit of reducing apoptotic rate.

The reperfusion injury after a cardioplegic-induced myocardial arrest is another important topic. It will be an aimed target in the pool of antiapoptotic strategies. Antioxidants, poly-ADP-ribose-synthetase-inhibitors, and calcium-channel blockers may be useful in decreasing reactive oxygen radicals, reducing the neutrophil-mediated inflammatory cascade, and attenuating cellular calcium overload. All these agents are investigational, however, and may be available as an adjunct of cardioplegic solution or cardiopulmonary bypass circuit in near future.

Sustained and long-term use of catecholamines should be avoided, as it induces apoptosis and has direct toxic effects on the heart [64, 73]. In patients with low-output-syndrome after open-heart surgery, acute myocardial infarction, or other conditions associated with increased endogenous or exogenous catecholamine, the inotropic support of the heart should be done with alternative medications such as milrinone or amrinone. Experienced cardiac surgeons may consider being more liberal with the insertion of intraaortic balloon pulsations or ventricular assist devices in clinical low-output states as a bridge to recovery or as destination therapy. The Rematch trial has provided us level-1 evidence for the survival benefits associated with ventricular assist devices [80]. However, the optimal time for initiating circulatory assist has not been yet established. Late insertion of such devices after a prolonged trial of external catecholamine may produce a nonrecoverable cardiac failure state, which is "burned out" secondary to potent and prolonged induction of apoptotic cardiocyte death. Alternately, early insertion of ventricular assist devices may reduce the chronic apoptotic cell death associated with increased levels of serum angiotensin II and catecholamines. The early ventricular assistance will potentially increase the likelihood of myocardial recovery by limiting the proapoptotic stimuli and changing the strategy of destination therapy into a bridge to recovery.

There are significant limitations of our current knowledge about the cardiomyocyte apoptosis. It is unknown whether apoptosis is the primary event in pathologic cardiac conditions or the secondary. Also, further investigation is needed into whether inhibition of apoptosis will delay the disease progression in vivo and in translational human studies. Antiapoptotic medications have the highest potential to become clinically significant as a therapeutic option. These medications can be potentially administered preoperatively, as an adjunct to the priming solution of cardiopulmonary circuit or added to cardioplegic solution. However, the safety and long-term consequences of these therapies are not adequately investigated, and clinical integration of these strategies will require more studies. Such therapies potentially may result in an alternative mode of cell death, such as necrosis, or increase autoimmune and lymphoproliferative disorders.

Besides the limitation of knowledge, the inferiority of techniques used to detect apoptosis is of concern as well. The positive predictive value of terminal deoxynucleotidyl-transferase mediated dUTP nick end-labeling (TUNEL), which is the most commonly used method to detect apoptosis, is less than appropriate. For example, the apoptotic index of patients with end-stage cardiac failure has been reported to range from 0.2% to 30% in two different studies [20, 63]. The latter index is very high and does not appear clinically sound. It represents most probably a methodologic problem. The heterogeneity of examined tissue samples can reduce the accuracy of the DNA-laddering, because it cannot specify the cell type undergoing apoptosis in a tissue sample with multiple cell contents. The transience and brevity of apoptosis is another culprit for the low sensitivity rates of the diagnostic methods. More accurate tools are needed for the future studies and are being currently developed.

Apoptosis and its attenuation and inhibition will increasingly penetrate the field of cardiovascular surgery as a therapeutic target. It is imperative for the cardiac surgeon to understand the pathophysiology of apoptosis and to incorporate its surgical implications in the algorithms and armamentarium of cardiovascular surgery.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Comment
 References
 

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