Tox and Hound – Sneaking into the Party

by Sarah Shafer

How does a heart break? In the case of beta-blocker (BB) and calcium-channel blocker (CCB) overdose, it’s a lack of calcium. Calcium is essential to muscle contraction, allowing actin and myosin to interact so that the cell shortens. Without calcium, the myosin and actin are blocked from interacting, and the cell stays floppy. In skeletal muscle, this leads to paralysis, in the peripheral vasculature it leads to dilation, and in the heart, it leads to death.

The cardiac myocyte relies on a process called “calcium-induced calcium release” (CICR) to contract. What this means is that a little bit of calcium comes into the cell, interacts with the ryanodine receptor, and triggers the release of a lot of intracellular calcium. The release of the large internal stores of calcium is what is necessary to promote the interaction between actin and myosin. This whole process starts via L-type calcium channels, which open up to allow extracellular calcium to come in and get the process started. With a BB overdose, the signaling cascade that activates the L-type calcium channels gets blocked. With a CCB overdose, these L-type calcium channels get directly blocked.

No calcium means hypotension and bradycardia. So what’s a broken heart to do? This is where high-dose insulin steps in to save the day. High-dose insulin infusion is the treatment for symptomatic BB and CCB overdose. It is given as a 1 unit/kg bolus followed by a 1 unit/kg/hour infusion. This is ten times the standard dose of insulin for the treatment of diabetic ketoacidosis and can be titrated up to effect, with doses >20 units/kg/hr reported in the literature.^​1​

So how does high-dose insulin work? It seems like a funny therapy for a poisoning that causes cardiotoxicity, not glucose dysregulation. Wait, you say, CCBs can cause hyperglycemia by blocking the calcium-channels associated with insulin release. True, but the benefits of insulin infusion have nothing to do with correcting hyperglycemia. The “official” explanation for why high-dose insulin works goes like this:

We know that cardiac myocytes generally prefer free fatty acids as a metabolic substrate, but when they get stressed, they start to utilize more and more glucose. Insulin promotes glucose uptake and metabolism in the cardiac myocyte, leading to improved cardiac function.^​2​ It also causes vasodilation, which is thought to improve local microcirculation of the heart.^​2​ When the heart is working really hard, it needs a lot of fresh blood to deliver oxygen and nutrients in order to help keep it going, but when it’s working too hard, it doesn’t pump effectively. By causing local vasodilation, insulin helps deliver fresh blood to the starving muscle. Together, these effects lead to increased inotropy and improved cardiac function in the setting of BB and CCB overdose.^​1​

This explanation for why high-dose insulin works is given in countless toxicology lectures as we try to explain away a therapy that we don’t understand. We’ve all stated some variation of, “We’re not quite sure why high-dose insulin works, but maybe it has to do with…” And while the official story remains, I’ve always found it hand-wavy. BB/CCB overdose is a really dangerous cardiac poisoning and to say that high-dose insulin works because it helps a stressed-out heart eats the carbs that it wants doesn’t satisfy my simple brain. If BB and CCB overdose cause poisoning by keeping calcium from entering the myocyte, doesn’t it make more sense that high-dose insulin is an effective antidote because it sneaks calcium into the party? Turns out there’s evidence that this is what happens.

When insulin binds with a cardiac myocyte, it triggers a signaling cascade that causes glucose transporters (GLUT) to show up at the cell membrane ready to suck up a bunch of glucose into the cell.^​3​ It does this by increasing intracellular levels of calcium via the sarcoplasmic reticulum, triggering the movement of GLUT.^​3​ The first is through stimulation of L-type calcium channels, which cause calcium-induced calcium release through the ryanodine receptor.^​3​ Does this sound familiar? It should because this is the same pathway necessary for contraction, which ends up getting blocked by BB and CCB. The second mechanism involves a completely separate messenger system that triggers calcium release from the sarcoplasmic reticulum through inositol triphosphate (IP3).^​3,4​ This second mechanism is slower and directly leads to the activation of GLUT. In addition to influencing calcium release from intracellular sarcoplasmic reticulum stores, insulin is also involved with phosphatidylinositide 3-kinase (PI3K), which is found to promote calcium entry into the cell without needing L-type calcium channels.^​5​

So what does all this nerdy gobbledygook really mean? It means that in a poisoning that causes cardiotoxicity by disrupting the normal movements of calcium, we have an effective antidote that we didn’t really understand, but it turns out that our antidote, high-dose insulin, may work by fixing the calcium disruption. In BB overdose, the L-type calcium channels don’t get properly activated, rendering them ineffective. Insulin stimulates L-type calcium channels, making up for the loss of beta-adrenergic mediated activation. In CCB overdose, the L-type calcium channels are blocked, so calcium can’t even get in. However, insulin provides a solution through two different means. It can sneak calcium into the party through another door, via PI3K-mediated calcium efflux. It also stimulates IP3 to slowly release calcium from the sarcoplasmic reticulum. Once calcium is out into the cytoplasm, it is then able to trigger calcium-induced calcium release through the ryanodine receptor.

While insulin’s effects on calcium get mentioned in passing, it makes more sense to me that this mechanism is what makes high-dose insulin an effective therapy in BB/CCB overdose. Sure, substrate utilization is important, and the vasodilatory effects may provide some benefit. However, if you want to un-break a heart, you have to have calcium at the party.