Although the operating theater may appear daunting given the number of personnel, environmental factors, and pieces of equipment needed to successfully manage a patient through cardiac surgery, it is, in many ways, an ideal place to perform research. Duration of ischemia is known, electrolytes and glucose concentrations are meticulously regulated, and hemodynamics can be followed throughout the procedure, including the pre- and post-operative phases. Furthermore, local drug delivery, as opposed to systemic therapy, can be administered reliably via the cannulated coronary circulation.
The cornerstone of cardioprotection in cardiac surgery has been the cardioplegia solution. These solutions typically contain potassium, mannitol, and glucose. By arresting and cooling the heart, the metabolic demands of the myocardium are minimized. However, despite decades of experience with cardioplegia, there has been surprisingly little change in these formulations except for, perhaps, the adoption of blood cardioplegia. And despite the use of cardioplegia, I/R injury still occurs.
There are some small studies supporting the use of metabolic additives, such as pyruvate91
The goal of such metabolic supplementation is to provide the arrested myocardium with energy substrates with favorable characteristics (e.g., avoidance of fatty acid oxidation), and to replete the cell with anaplerotic substrates. However, evidence to date supporting the use of these agents have not been sufficiently convincing to lead to widespread clinical use.
The concept of ischemic preconditioning has also been applied during cardiac surgery. Either before or just following establishment of cardiopulmonary bypass, the aorta is cross-clamped for several minutes, released for several minutes and then once again cross-clamped for cardioplegia. Several groups have utilized this technique, and some benefit has been seen in small studies. A recent meta-analysis concluded that this form of pre-conditioning decreased post-operative ventricular arrhythmias and inotrope use and translated into shorter ICU stays94
. These suggestive findings await prospective testing in patients.
Given the association of immune system activation with I/R injury, together with the marked systemic inflammation elicited by surgery and by exposure to the bypass circuit, a number of investigators have focused their attention on modulating immune responses. Leukocyte filters,95-97
and specific volatile anesthetics101-103
have all been tested in small studies with no clear signal of benefit. Initial data on the anti-C5a antibody, pexelizumab, appeared promising and prompted two large randomized clinical trials. PRIMO-CABG104
demonstrated a strong trend toward decreasing death or MI, but these results were not confirmed in the larger follow-up PRIMO-CABG II study.105
Finally, aprotinin, an antifibrinolytic protein with anti-inflammatory properties, was documented to have favorable effects on myocardial I/R in human and animal studies, but was later taken off the market because of clear evidence for harm associated with its use.106-108
In aggregate, results of inhibiting the inflammatory response occurring in cardiac surgery have been disappointing.
The naturally occurring pyridoxine metabolite and purinergic receptor antagonist, pyridoxal-5′-phosphate (MC-1), was studied in two large CABG clinical studies. MC-1 was found to prevent intracellular Ca2+
overload and appeared promising for mitigating I/R injury.109
Indeed, phase II data from the MEND-CABG I study suggested lower post-procedural infarct sizes.110
Based on this result, a larger phase III study was undertaken. Disappointingly, however, MEND-CABG II failed to find any difference in infarct size and reported a slight early increase in mortality with MC-1 (1.0% vs 0.3%, P
Another strategy to prevent intracellular Ca2+
overload is antagonism of the sodium-hydrogen exchanger. Cariporide, a potent inhibitor of this transporter, was first evaluated in the GUARDIAN trial, a catch-all study of patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) or planned elective revascularization with either percutaneous coronary intervention (PCI) or CABG.112
An efficacy signal was noted for the CABG subset,113
and the drug was subjected to a larger trial dedicated to CABG.114
The primary endpoint in EXPEDITION (death or MI) was lower in the cariporide arm as compared with placebo (16.6% vs 20.3%, P
=0.0002), the first time a phase III clinical study of myocardial protection had met its primary endpoint. However, whereas the composite endpoint was driven by a significant reduction in perioperative MI (18.9% vs 14.4%, P
<0.0001), there was a paradoxical increase in overall mortality (2.2% vs 1.5%, P
=0.02), which appeared to be driven by an increase in cerebrovascular events. Indeed, there was a significant increase in stroke and altered mental status associated with the drug.
Perhaps the most thoroughly studied drug in surgical ischemia-reperfusion is acadesine, a purine analog that increases tissue adenosine levels in energy-deprived tissues.115,116
A potent cardioprotective role has been ascribed to stimulation of adenosine receptors in I/R via modulation of mPTP opening.68,117
Acadesine, given as an additive in cardioplegia solution, has been investigated in a number of smaller studies,118-120
as well in as the ~2,700 patient phase III Acadesine 1024 Trial.121
Although the largest study failed to show a statistically significant difference in the primary outcome of peri-procedural MI (3.4% vs 4.0%, P
=0.24 in favor of acadesine), a subsequent meta-analysis of all available data on acadesine suggested a 27% reduction in MI (3.6% vs 4.9%, P
=0.02) and a 26% decrease in the combined outcome of stroke/MI/cardiac death (7.6% vs 4.6%, P
Acadesine is currently undergoing study in the Reduction in cardiovascular Events by acaDesine in subjects undergoing CABG (RED-CABG) trial, which plans to enroll 7,500 high-risk subjects.123