Neural mechanisms in remote ischaemic conditioning in the heart and brain: mechanistic and translational aspects

Basalay, Marina; Davidson, Sean M.; Gourine, AV; Yellon, Derek M.

doi:10.1007/s00395-018-0684-z

Cited by 63 publications

(52 citation statements)

References 153 publications

(229 reference statements)

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“…The mechanisms involved in this protective phenomenon might include multiple effectors, such as sympathetic/parasympathetic mechanisms, as bilateral vagotomy was previously shown to abolish cardioprotection induced by RIPC (Basalay et al. ). In addition, increased AKT activity stimulates Kv1.5 potassium channel protein expression at the cell surface (Warsi et al.…”

Section: Discussionmentioning

confidence: 99%

AKT and ERK1/2 activation via remote ischemic preconditioning prevents Kcne2 -dependent sudden cardiac death

Liu

Zhou

et al. 2019

Physiol Rep

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Sudden cardiac death (SCD) is the leading global cause of mortality. SCD often arises from cardiac ischemia reperfusion (IR) injury, pathologic sequence variants within ion channel genes, or a combination of the two. Alternative approaches are needed to prevent or ameliorate ventricular arrhythmias linked to SCD. Here, we investigated the efficacy of remote ischemic preconditioning (RIPC) of the limb versus the liver in reducing ventricular arrhythmias in a mouse model of SCD. Mice lacking the Kcne2 gene, which encodes a potassium channel β subunit associated with acquired Long QT syndrome were exposed to IR injury via coronary ligation. This resulted in ventricular arrhythmias in all mice (15/15) and SCD in 5/15 mice during reperfusion. Strikingly, prior RIPC (limb or liver) greatly reduced the incidence and severity of all ventricular arrhythmias and completely prevented SCD. Biochemical and pharmacological analysis demonstrated that RIPC cardioprotection required ERK1/2 and/or AKT phosphorylation. A lack of alteration in GSK‐3β phosphorylation suggested against conventional reperfusion injury salvage kinase (RISK) signaling pathway protection. If replicated in human studies, limb RIPC could represent a noninvasive, nonpharmacological approach to limit dangerous ventricular arrhythmias associated with ischemia and/or channelopathy‐linked SCD.

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Section: Discussionmentioning

confidence: 99%

AKT and ERK1/2 activation via remote ischemic preconditioning prevents Kcne2 -dependent sudden cardiac death

Liu

Zhou

et al. 2019

Physiol Rep

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“…Importantly, this effect was not due to altered blood flow into the ischaemic region [3,71]. The mechanism for this is not known but could potentially involve the parasympathetic nervous system, which is required to convey the signal of remote IPC, and is known to innervate the heart [6]. The shortcomings of ECG are that it does not allow accurate measurement of IS, especially in small animal species, and it probably reflects a combination of both the ischaemic AAR and IS.…”

Section: Measuring Infarct Size In Ischaemic Modelsmentioning

confidence: 99%

“…However, the recent CONDI-2/ERIC-PPCI multicentre trial of RIPC on IS in STEMI patients undergoing primary PCI showed no benefit [46]. Importantly, part of the "remote preconditioning reflex" of RIPC involves activation of the vagal nerve [6,78]. Consequently, vagal nerve stimulation (VNS) should be able to mimic the effects of RIPC.…”

Section: Fig 4 Redistribution Of Coronary Blood Flow Between Ischaemmentioning

confidence: 99%

“…Furthermore, even when recanalisation is successful, ischaemic regions of myocardium remain in up to 2/3 of patients due to microvascular obstruction (MVO), which is associated with a larger IS, a lower left ventricle (LV) ejection fraction, adverse LV remodelling, and worse clinical outcomes [47,53,56]. Experimentally, cardioprotective strategies can further limit IS, so long as they are applied prior to or close to the onset of reperfusion [6,47,55,56]. Ischaemic preconditioning (IPC) is considered the gold standard of cardioprotection.…”

Section: Introductionmentioning

confidence: 99%

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Targeting myocardial ischaemic injury in the absence of reperfusion

Basalay¹,

Yellon²,

Davidson³

2020

Basic Res Cardiol

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Sudden myocardial ischaemia causes an acute coronary syndrome. In the case of ST-elevation myocardial infarction (STEMI), this is usually caused by the acute rupture of atherosclerotic plaque and obstruction of a coronary artery. Timely restoration of blood flow can reduce infarct size, but ischaemic regions of myocardium remain in up to two-thirds of patients due to microvascular obstruction (MVO). Experimentally, cardioprotective strategies can limit infarct size, but these are primarily intended to target reperfusion injury. Here, we address the question of whether it is possible to specifically prevent ischaemic injury, for example in models of chronic coronary artery occlusion. Two main types of intervention are identified: those that preserve ATP levels by reducing myocardial oxygen consumption, (e.g. hypothermia; cardiac unloading; a reduction in heart rate or contractility; or ischaemic preconditioning), and those that increase myocardial oxygen/blood supply (e.g. collateral vessel dilation). An important consideration in these studies is the method used to assess infarct size, which is not straightforward in the absence of reperfusion. After several hours, most of the ischaemic area is likely to become infarcted, unless it is supplied by pre-formed collateral vessels. Therefore, therapies that stimulate the formation of new collaterals can potentially limit injury during subsequent exposure to ischaemia. After a prolonged period of ischaemia, the heart undergoes a remodelling process. Interventions, such as those targeting inflammation, may prevent adverse remodelling. Finally, harnessing of the endogenous process of myocardial regeneration has the potential to restore cardiomyocytes lost during infarction.

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“…Whether such spatial differences in the magnitude of cardioprotection also exist for more clinically relevant ischemic conditioning maneuvers such as ischemic postconditioning (Zhao et al ), or remote ischemic conditioning prior to (Heusch et al ) or during ischemia (Schmidt et al ) is currently not known. Cardioprotection by remote ischemic conditioning involves vagal nerves (Lieder et al ; Basalay et al ). Therefore, regional differences in cardiac innervation might impact on the magnitude of cardioprotection in septal and anterior free wall compartments.…”

Section: Introductionmentioning

confidence: 99%

Larger infarct size but equal protection by ischemic conditioning in septum and anterior free wall of pigs with LAD occlusion

et al. 2019

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The ischemic area at risk (AAR) is one major determinant of infarct size (IS). In patients, the largest AAR is seen with a proximal occlusion of the left anterior descending (LAD) coronary artery, which serves parts of the septum and of the anterior free wall. It is not clear, whether regional differences in the perfusion territories also impact on IS and the magnitude of cardioprotection by ischemic conditioning. We have retrospectively analyzed 132 experiments in pigs, which have a similar LAD perfusion territory as humans. The LAD was occluded for 60 min with subsequent 180 min reperfusion. Cardioprotection by either local ischemic pre‐ or postconditioning or remote ischemic pre‐ or perconditioning was induced in 93 pigs. The AAR was demarcated by blue dye staining, and IS was assessed by triphenyltetrazolium chloride (TTC) staining. Using digital planimetry, the AAR was separated into sections unequivocally located in the septum (AARS) or the anterior free wall (AARAFW). Relative IS was calculated for AARS or AARAFW. AARAFW was larger than AARS (51 ± 9% vs. 34 ± 8% of total AAR; mean ± SD, P < 0.001). Regional myocardial blood flow (microspheres) was not different between septum and anterior free wall. IS without ischemic conditioning tended to be larger in AARS than in AARAFW (50 ± 17% vs. 44 ± 19%; % of AARAWF or AARS, respectively; P = 0.075). Also, with robust IS reduction by ischemic conditioning, the difference in relative IS remained (AARS: 27 ± 16%; AARAFW: 21 ± 16%; P = 0.01). There is a somewhat greater susceptibility for infarction in septal than anterior free wall myocardium. However, ischemic conditioning still reduces IS in both septal and anterior free wall myocardium.

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Neural mechanisms in remote ischaemic conditioning in the heart and brain: mechanistic and translational aspects

Cited by 63 publications

References 153 publications

AKT and ERK1/2 activation via remote ischemic preconditioning prevents Kcne2 -dependent sudden cardiac death

AKT and ERK1/2 activation via remote ischemic preconditioning prevents Kcne2 -dependent sudden cardiac death

Targeting myocardial ischaemic injury in the absence of reperfusion

Larger infarct size but equal protection by ischemic conditioning in septum and anterior free wall of pigs with LAD occlusion

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