The patient
Despite excellent cardioprotection using cold blood cardioplegia, significant peri-operative myocardial injury still occurs in patients undergoing CABG surgery ± valve surgery. The cause of this myocardial injury is multi-factorial being attributed to global ischemia–reperfusion injury, coronary embolization and prolonged aortic cross-clamp time. The extent of peri-operative myocardial injury can be assessed by measuring serum cardiac enzymes such as CK-MB, troponin-T and troponin-I, the elevation of which has been associated with worse clinical outcomes post-surgery [
9,
13,
29]. Surgeons are therefore continually seeking ways to minimise IRI, particularly as more high-risk patients are being operated upon and it is becoming increasingly clear that even mild to moderate elevations in CK-MB and troponin are associated with increased intermediate and long-term mortality.
Similar to the setting of a STEMI in which patients with a larger MI are most likely to benefit from a cardioprotective intervention, the same may apply to patients undergoing CABG surgery. Therefore, the patients most likely to benefit from a cardioprotective strategy during CABG surgery are those who are most at risk of sustaining significant peri-operative myocardial injury. This group includes patients undergoing 3-vessel CABG surgery with or without valve surgery, redo CABG surgery patients, patients with significant LVH or LV systolic dysfunction, patients with an additive Euroscore of ≥6 and diabetic patients. We believe that it is this group of higher-risk patients who should be selected for studies of novel cardioprotective strategies as they are more likely to experience a greater degree of myocardial IRI from the prolonged cross-clamp and cardio-pulmonary bypass times.
The intervention
A variety of cardioprotective strategies have been tried in the CABG surgery setting in the past. Although the majority of these were unsuccessful, one of the most potentially promising treatment strategies was cariporide, but unfortunately it had off-target cerebral side effects [
37]. In the setting of CABG surgery, the novel cardioprotective strategy can be applied either prior to myocardial ischemia (cross-clamping of the aorta), during myocardial ischemia in the cardioplegia solution or at the time of myocardial reperfusion (unclamping the aorta). As noted previously, the preclinical testing of the novel cardioprotective strategy in an animal IRI model which closely resembles the CABG setting should have been previously utilised to verify efficacy (see Table
1).
Which novel cardioprotective strategy should be pursued in the clinical setting?
There are a number of novel cardioprotective strategies which have shown promise in initial proof-of-concept clinical studies. The question is which of these should be taken forward into phase 2/3 clinical studies. Following discussion in the Workshop, it was agreed that the two most promising novel cardioprotective strategies were remote ischemic conditioning (RIC) and cyclosporine-A (CsA).
For RIC, in which cycles of brief ischemia and reperfusion applied to the upper or lower limb protect the myocardium from lethal IRI, there exist extensive preclinical data in a range of animal models including in vivo murine, rat, rabbit and porcine models of MI (reviewed in [
20,
56]). RIC is a non-invasive virtually cost-free cardioprotective strategy which has been shown to be effective when applied both prior to or during the index myocardial ischemia [
47] as well as at the onset of myocardial reperfusion [
2], lending itself to the clinical settings of CABG surgery [
18], planned PCI [
25], and STEMI patients receiving PCI [
8], settings in which initial proof-of-concept studies have already been successfully performed.
CsA has the advantage of targeting an end-effector of IRI, as opposed to the ever-expanding list of cardioprotective agents which tend to target G-protein coupled receptors and intracellular kinases and other mediators, which may be down-regulated or ineffective in the presence of co-morbidities. Because the main site of action of CsA is probably the mPTP, a purported mitochondrial channel which mediates cardiomyocyte death at the onset of myocardial reperfusion, most of the preclinical data in support of its role as a cardioprotective agent have been as an adjunct to myocardial reperfusion [
19,
22]. Similarly, there exist extensive preclinical data in a range of animal models including in vitro and in vivo models of MI, as well as in a rabbit model of post-cardiac arrest [
12]. However, the in vivo porcine MI model has produced mixed results with CsA for an unclear reason [
28,
35,
54]. CsA has also been demonstrated to be effective in human atrial tissue models of simulated IRI [
49]. Again, a preliminary proof-of-concept clinical study has demonstrated that a single intravenous bolus of CsA given prior to PCI can limit MI size in STEMI patients [
43].
Other potentially novel cardioprotective strategies for which there exist both preclinical data and initial proof-of-concept clinical studies are glucagon-like peptide 1 [
41], PKC-δ inhibition [
3], atrial natriuretic peptide [
32], and ischemic postconditioning [
60].
Clearly, for all these novel cardioprotective strategies preclinical studies are required to determine whether cardioprotection is maintained in the presence of certain confounding factors such as age, sex, diabetes, the metabolic syndrome, hyperlipidemia, hypertension and so forth. In this regard, a recent preclinical study suggests that CsA-mediated cardioprotection at the time of myocardial reperfusion was ineffective in Zucker obese rats [
26]. This intriguing finding requires confirmation and the mechanism underlying this observation needs further investigation.
In summary, for both CsA and RIC large multi-centred randomised controlled clinical trials are required to confirm their cardioprotective benefit in the clinical setting and investigate whether these interventions impact on clinical outcomes for patient benefit.