Hyperpolarized / Polarized arrest as an alternative to Depolarized arrest Guo Wei Zhejiang University School of Medicine

 Elective cardiac arrest can be achieved by inducing depolarization, polarization, hyperpolrization or influencing calcium mechanisms

Depolarized arrest Depolarized arrest: induced by elevating the extracellular potassium concentration, is currently the most commonly used technique. Hyperkalemia: usually within 15 to 40 mmol/L.

Depolarized arrest  Hyperkalemia leads to a depolarization of the membrane potential (Em) from about - 80 mv to around - 50 mv in cardiac tissue

 At this depolarized potential, the fast Na + channels are inactivated (since the threshold is - 70 to - 65 mv, resulting in diastolic arrest  However,The reversal potential of the Na + – Ca 2+ exchanger also occurs at - 50 mv

Depolarized arrest  Moreover, higher potassium concentrations, which depolarize the membrane further (to around -40 mv), would tend to activate the slow calcium channel and cause calcium influx into the myocyte  Other ionic mechanisms also exist (such as Na – H exchange)

hyperkalemia disadvantages  Other ionic currents remain active  Energy-dependent transmembrane pumps remain active in an attempt to correct these abnormal ionic gradients, depleting critical energy supplies  High potassium-induced endothelial injury

 A potentially beneficial alternative to hyperkalemic cardioplegia is to arrest the heart in a hyperpolarized or polarized state, which maintains the membrane potential of the arrested myocardium at or near to the resting membrane potential

Polarized /hyperpolarized arrest hyperpolarized/ Polarized arrest: induced by sodium-channel blockers or by agents that activate potassium channels

Polarized /hyperpolarized arrest advantages : ionic movement (particularly Na + and Ca 2+ ) reduced, because the threshold potential for activation of the ion channels will not be reached and window currents will not be activated. This reduction in ionic imbalance should, in turn, reduce myocardial energy utilization

Polarized /hyperpolarized arrest Polarized arrest can be achieved in a number of ways  Sodium-channel blockade [ Procaine and TTX ]  Na/H exchange inhibitor [HOE 694]  Na/K/2Cl cotransport inhibitor [furosemide])  influencing Ca 2+ desensitization [BDM]

Polarized /hyperpolarized arrest  Adenosine or potassium channel openers (KCOs), which are thought to induce hyperpolarized arrest have demonstrated improved protection when compared to hyperkalemic (depolarized) arrest

Adenosine  Adenosine can induce arrest through a hyperpolarization effect, particularly on myocardial conductive tissue, and was shown to provide good myocardial protection when used alone (at a concentration of 10 mmol/L) as a cardioplegic agent or as an additive (1 mmol/L) to K + cardioplegia

Adenosine  Some studys showed that the adenosine plus hyperkalemic solution induced an initial transient hyperpolarization before depolarization; this initial hyperpolarization was thought to arrest SA node conduction before myocyte contractility arrest

ATP-sensitive potassium channel  ATP-sensitive potassium-channel activation myocardial resting Em (around -80 mv) is close to the equilibrium potential of K + (about -94 mv).

ATP-sensitive potassium channel  Hyperpolarization with KCOs has been demonstrated in isolated guinea pig and human ventricular myocytes  KCOs have also been used as additives to hyperkalemic cardioplegic solutions and have been shown to enhance postischemic recovery of function

ATP-sensitive potassium channel  The improved protection compared to the K + cardioplegic solution may be related to its ability to maintain minimal metabolic activity, thereby maintaining transmembrane ionic gradients

Calcium antagonists  Hypocalcemia The absence of extracellular Ca 2+ induces cardiac arrest in diastole  High concentrations of calcium antagonists prevent Ca 2 + -induced Ca 2 + release and induce arrest by inhibiting excitation-contraction coupling, thus exerting a protective effect on cardiac arrest

Calcium antagonists  But the membrane binding property of these drugs may result in slow recovery.  The absence of Ca 2+ increased the risk of a "calcium paradox"

 In conclusion, myocardial protection during cardiac surgery or cardiac transplantation has relied on hyperkalemic solutions for many years. However, hyperkalemic solutions have a number of problems

 Hyperpolarization or polarization should avoid or reduce some of the damaging effects associated with depolarization  Considerable additional studies are required