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Bradshaw et al. Vessel Plus 2023;7:35 https://dx.doi.org/10.20517/2574-1209.2023.121 Page 3 of 21

[45]
Some progress has been made in understanding the molecular identity of the mitoK channel , but the
ATP
quest to definitively characterize these channels continues. One of the challenges that has limited progress
towards better understanding mitoK channels has been that K channel openers and blockers are both
ATP
ATP
nonspecific; therefore, it is difficult to differentiate effects on sarcolemmal versus mitochondrial
channels [24,58] . The determination of the implicated subunits and the structural identification of a mitoK
ATP
channel would allow the prevention of undesirable side effects of nonspecific channel openers and
inhibitors and allow for directed cardiac targeting for clinical use. By utilizing the genetic deletion of known
sarcolemmal K channel subunits, it may be possible to indirectly identify subunits of a mitochondrial
ATP
K channel involved in cardioprotection or neuroprotection [41,45,59] .
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Novel mitochondrial proteins encoded by CCDC51 and ABCB8 genes, with unknown function, have been
[45]
implicated as proteins involved in a mitoK channel . Known potential sarcolemmal K channel
ATP
ATP
subunits (Kir6.1, Kir6.2, Kir1.1, SUR1) and non-K channel proteins (ROMK) have been systematically
ATP
evaluated using pharmacologic blockade, genetic deletion, or genetic alteration (gain of function) in
multiple mouse models to identify potential mitoK channel proteins involved in diazoxide
ATP
cardioprotection [41,59-66] . However, no subunit has thus far been definitively implicated in cardioprotection by
diazoxide. The characterization of the specific molecular profile of mitoK channels is a challenge that
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requires further research [36,67] .
K CHANNELS AND CARDIOPROTECTION
ATP
K channels provide endogenous myocardial protection via coupling of cell membrane potential to
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myocardial metabolism, since these channels are inhibited by ATP and open during times of metabolic
stress . Pharmacologic opening of K channels mimics ischemic preconditioning (IPC) in multiple
[44]
ATP
animal models [68-72] . Pharmacologic or non-pharmacologic opening of K channels with diazoxide affords
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protection to isolated myocytes when the channels are opened before the onset of stress, but not if
[73]
administered after the onset of stress . In an isolated heart model, opening K channels before ischemia
ATP
and during early ischemia but not upon reperfusion facilitated cardioprotection . The requirement that
[74]
these channels are targeted prior to stress is critical because it limits the usefulness of targeting these
channels for cardioprotection to situations such as cardiac surgery where a known subsequent ischemic
insult occurs . Diazoxide given throughout an ischemic episode led to maximal protection in human atrial
[75]
trabeculae, suggesting that diazoxide could be a helpful additive to cardioplegia .
[76]
Cardiac surgery is necessary to treat various cardiac diseases, but the surgery paradoxically causes injury to
myocardium that is often already compromised. Contributors to myocardial injury during cardiac surgery
include exposure to hypothermic hyperkalemic cardioplegia , an imposed global ischemic period, and an
[77]
already compromised myocardium. The clinical manifestation of the myocardial injury after cardiac surgery
is myocardial stunning (MS). Myocardial stunning is defined as myocardial dysfunction despite the
resumption of blood flow , similar to the clinical consequences following global ischemia for cardiac
[78]
surgery when flow is restored. MS is defined clinically as the need for inotropic support after surgery for
> 24 h but < 72 h, and it affects almost 70% of patients after cardiac surgery . This injury itself is reversible,
[79]
by definition, but it is associated with worse patient outcomes.

[80]
Early studies in canines demonstrated reduced myocardial function after brief myocardial ischemia ,
indicating that patients undergoing cardiac ischemia required for heart surgery would have a decrease in
myocardial function following reperfusion. The search for methods to protect the myocardium from such
insults has been ongoing since cardiac surgery began in the 1950s. Many pharmacologic and
nonpharmacologic methods have been identified with varying degrees of efficacy and clinical potential .
[81]