Ann Thorac Surg 1998;66:1335-1336
© 1998 The Society of Thoracic Surgeons
Original articles: cardiovascular
Invited commentary
Jakob Vinten-Johansen, PhDa
a Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center, Emory University School of Medicine, 550 Peachtree St, NE, Atlanta, GA 30365-2225, USA
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Invited commentary
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Adenosine has a host of physiologic effects ranging from bradycardia to attenuation of neutrophil activation [1]. The negative chronotropic and dromotropic effects of adenosine have been recognized for many years. More recent evidence has linked the negative electrophysiologic effects of adenosine to activation of the adenosine triphosphate-sensitive potassium channel, which, when activated by adenosine and other stimulators, induces membrane hyperpolarization. The adenosine triphosphate-sensitive potassium channel has also been linked to protection of the heart, most notably through preconditioning and adenosine-related pathways. Many investigators have reported that adenosine used as a pretreatment (whether or not cardioplegia was used as a modality of delivery) attenuates lethal injury (infarction), whereas equivocal effects on postischemic contractile function have been observed in nonlethal injury models (stunning). Hudspeth and associate, [2] reported in a surgical model that 400 µmol/L adenosine in blood cardioplegia significantly attenuated postischemic contractile dysfunction after normothermic global ischemia.
Based on these physiologic effects of adenosine, this study by Jayawant and associates set out to test the hypothesis that adenosine could enhance cardioplegia and myocardial protection compared with the adenosine triphosphate-sensitive potassium channel-opener pinacidil when given as a test solution before normothermic ischemia. Time to electrical and mechanical arrest and recovery of contractile effort were the key physiologic end points. The question is an important one in the ongoing search for a place for adenosine in the surgical cardioprotective armamentarium. In effect, Jayawant and associates tried to harness both the cardioplegic (arresting) and cardioprotective attributes of this autacoid.
The evidence presented that adenosine failed to achieve either (1) cardiac arrest or a significant decrease in time to electromechanical arrest or (2) significant improvement in postischemic contractile performance may not reflect a therapeutic limitation of adenosine, but may rather reflect an inability to exert or express these effects in this particular model. In this case, the model may have determined the outcome. First, the protocol for "cardioplegia" differs from conventional clinical use of cardioplegic solutions in that a single infusion of a crystalloid solution was made at 37°C. Therefore, this protocol represents more a pharmacologic pretreatment before normothermic global ischemia than conventional cardioplegia. Second, the 100 µmol/L adenosine used is two orders of magnitude lower than that found by others to initiate cardioplegia (quiescence) without adjunct arresting agents such as potassium. Therefore, it is not surprising that a 35% reduction in time to mechanical arrest was observed rather than total arrest (cardioplegia) relative to a control solution with no arresting agent. Third, the concentration of adenosine used by Jayawant and associates is well within the range used by numerous other investigators for its cardioprotective effects. However, the failure to enhance postischemic contractile recovery may be related more to the duration of persistent mechanical or electrical activity after ischemia than to a lack of cardioprotection per se. There was a loose correlation between the time to arrest and the extent of recovery of developed pressure, with longer durations of activity generally showing the poorest recovery. This raises the possibility that the functional outcome of the study was determined more by failure to arrest the heart than failure to protect the heart. The target of interest of the investigators is not entirely clear because the appropriate concentration of adenosine needed to induce arrest was not used. Finally, the role of membrane hyperpolarization was not assessed, and it is therefore difficult to speculate on the mechanism of action of adenosine or pinacidil, or to conclude that "the ineffectiveness of adenosine suggests that the cardioprotective properties of potassium-channel openers involve mechanisms other than the avoidance of membrane depolarization." At the very least a specific adenosine triphosphate-sensitive potassium channel antagonist like glibenclamide would have to be used in additional groups.
The role of adenosine in cardiac surgery is still unanswered. However, the purpose for which adenosine is intended (as an arresting agent, antiinflammatory agent, or metabolic agent) will determine its conditions of use in terms of time and concentration of delivery, and will influence the success or failure of adenosine-related therapy in surgical as well as nonsurgical applications. A distinct advantage of adenosine is its broad spectrum of effect, many targets of which participate in the inflammatory component of ischemic-reperfusion injury. Whether the cardioprotective effects and cardioplegic effects of adenosine can be be harnessed simultaneously in cardiac operations without troublesome side effects is an interesting question.
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References
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- Mullane K.M., Williams M. Adenosine and cardiovascular function. In: Williams M., ed. Adenosine and adenosine receptors. Totowa, NJ: Humana Press, 1990:289-333.
- Hudspeth D.A., Nakanishi K., Vinten-Johansen J., et al. Adenosine in blood cardioplegia prevents postischemic dysfunction in ischemically injured hearts. Ann Thorac Surg 1994;58:1637-1644.[Abstract/Free Full Text]
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Invited commentary
References