Low Serum Calcium Levels Linked to Sudden Cardiac Death.

Low Serum Calcium Levels Linked to Sudden Cardiac Death, Says Shocking Cedars-Sinai Study; Calcium Conundrum Continues.

Recently, researchers at the renowned Cedars-Sinai Heart Institute published a study^[1] suggesting that even patients who came in at the lower end of the normal range for serum calcium levels (according to the FDA normal range is 9-11 mg/dL^[2]) in their lab tests were at a much higher risk for sudden cardiac arrest (SCA). Sudden cardiac arrest doesn’t always mean a heart attack, by the way. It simply refers to a stoppage of the heart—in this case, electrically mediated), ultimately resulting in death.  This study compared cases of SCA with matched controls from another large, population-based study. So, by matched controls, we mean that they also had a generally “matching” diagnosis: in this study, coronary artery disease (CAD), as opposed to a healthy control group. 

The data revealed that, in blood drawn within 90 days of the sudden cardiac arrest, blood calcium levels lower than 8.95 mg/dL were associated with a 2.3-fold increase in odds of SCA as compared with levels higher than 9.55 mg/dL. And for every 1-unit change, a 1.6-fold increase.

Scary. What is remarkable here are a few things:

1. 8.95 mg/dL is not a dangerously low calcium level.

I wouldn’t ordinarily have called you in the middle of dinner—well, at least not before this study came out —to tell you to go to the ER. I would have only done that if your serum calcium had been at, maybe, an 8.6 or lower. And you probably would have felt all tingly and numb in your fingers and toes—and perhaps around your mouth. This funny feeling is called “paresthesia.” And trying to say the word “paresthesia” correctly ten times fast makes it feel even stranger! I might not have even told you to start taking any calcium supplements.  NOTE: I think a notable drawback to the study was that they relied on serum calcium levels only, not ionized, or “free,” calcium levels:  Much as the name implies, ionized calcium is a measure of the amount of  calcium in free, ionized form, as opposed to total, serum calcium. It is thought to be a much more accurate measure of biologically active calcium, and is particularly important when assessing for hypocalcemia, for example.

2.  This study shows low-normal blood calcium is an independent risk factor for SCA.

Both the study and control groups had coronary artery disease (CAD), but there were differences between them. The study group was more likely to have diabetes, be African-American, have chronic kidney disease, high blood pressure, and chronic obstructive pulmonary disease (COPD) than the control group members while still having CAD. How did these factors affect the results, if at all?

----------------------------

Let’s stop for a second. I would like to talk to you a little bit about electrolytes and the heart. Yes, I know. The last time you heard the word “electrolytes,” was probably in a “Gatorade” commercial.  But the fine makers of Gatorade were trying to tell you something: electrolytes, those ions like potassium, calcium, sodium, and magnesium, are important to strong muscles, and muscle endurance. Well, the heart is a muscle!               

Potassium is a big player: KCl (potassium chloride) is part of the lethal injection mix, so you definitely don’t want too much of it, because an excess of it can causes sudden cardiac death (SCD); but if you are on dialysis, for example, such as in ESRD (end-stage renal disease), your nephrologist will also prescribe KCl, to shore up flagging potassium levels!  But either way, too much potassium (often prescribed under the brand names Klor-Con or Kay-Ciel, or simply potassium supplements) is not a good idea. Excess potassium, or hyperkalemia, can be fatal. We often talk about “potassium-sparing” diuretics—diuretics that conserve potassium in your body. In this case potassium levels remain too low, and hypokalemia can result. Too little potassium can be fatal. If you consider that potassium and sodium are required for the action potentials of synapses (remember those “voltage-gated ion channels” from physiology or biology class?) it kind of makes sense. 

Now, what is the analogue of potassium? Sodium! But, funny thing, too little sodium (hyponatremia) can land you in the hospital, but it cannot cause sudden cardiac death; neither can hypernatremia (too much sodium).  

Magnesium is a mineral that can have major effects on the heart: it serves as a “counterbalance” of sorts to calcium. Too much magnesium or too little magnesium—either condition can cause arrhythmias that can result in sudden cardiac death. 

Let me tell you how calcium fits in. Calcium is an important molecular signal in muscle cells. And remember, kids, the heart is a muscle. So, there are calcium channels in the heart that create action potentials. We know that intracellular calcium is under very tight control, and overload of it causes arrhythmia, which in turn can cause SCD.  This control is lost with most of the cardiomyopathies and congestive heart failure. And there are also “calcium channel blockers,” (remember hearing about those from your doctor?) like verapamil, which prevent the uncoordinated, willy-nilly firing of those channels, and therefore, prevent arrhythmias in that fashion. So, here is a mechanism suggesting that overly high intracellular calcium levels cause arrhythmia and SCD. But the study reports that too-low calcium levels are the problem.

Hypocalcemia has been previously associated with heart failure, prolonged QT intervals on EKG, and life-threatening cardiac arrhythmias^[3] . 

The delicate balance of extracellular calcium levels is a constant dance between how much calcium you take in through what you eat; how much is actually absorbed through your intestines; how much is excreted through your kidneys; and—a lot of people forget this one, but that’s why we all worry about calcium, right? — how much is turned over through bone remodeling. And that process is controlled by two main hormones: One of them, you probably know, Vitamin D3. Yes, boys and girls! Vitamin D is a hormone—even though it’s also all-natural, and comes from the sun. (Free-range, no antibiotics, and fair trade, too! And, did I mention, Vitamin D is also 100% gluten free?) The other hormone you probably are not as familiar with— parathyroid hormone (PTH, for short). PTH has nothing to do with your thyroid: it’s produced by the four parathyroid glands, tiny glands that look no bigger than grains of rice that sit nestled just under your thyroid gland. Barely visible, the powerful parathyroids and their PTH they produce pack one heck of a punch, exerting tyrannical control, in tandem with Vitamin D, over calcium levels throughout your body. If PTH levels go haywire, watch out—calcium levels go crazy.  The result?  Well, paresthesias, which we talked about before. (The needles and pins.) And then, there’s tetany. That means muscle cramps that stay cramped. Muscles that just freeze, Botox-style, but when you didn’t go looking for that Botox effect. Lockjaw is a good example of this. If it hits the diaphragm muscles, or the intercostal muscles (between the ribs), guess what, you can’t breathe! No bueno! 

AND NOW, BACK TO OUR REGULARLY SCHEDULED BLOGGING… I believe the study accounted for these possible “confounding factors” by adjusting for them statistically so that, according to the study’s accompanying editorial: "This is the first report to show that low serum calcium levels measured close in time to the index event [the SCA] are independently associated with an increased risk of SCA in the general population," observed Dr Hon-Chi Lee (Mayo Clinic, Rochester, MN) (Emphasis added.)

----------------------------

3.  The Mechanism By Which the Low Serum Calcium May Be Leading to SCD is Unclear; However, the Study Showed the Patients Who Died of SCA Also Were More Likely to Have a Prolonged QT Interval, Suggesting a  Causal Link Between the Two.  

The article points out that hypokalemia, hypomagnesemia, and hypocalcemia (low levels of potassium, magnesium, and calcium, respectively) are “all known to be associated with prolonged QT intervals, which have been shown to be an independent risk of sudden cardiac death in the general population.” Further, “[t]he effects of lower serum calcium levels on cardiac electrophysiology are multiple. For example, with a lower serum calcium concentration, calcium influx through the L-type calcium channel may be reduced, leading to reduced plateau depolarization and a shortened cardiac action potential.

However, a reduced calcium level may lead to slower L-type calcium channel inactivation, which may prolong the opening of calcium channels, sustaining the plateau of the cardiac action potential and leading to QT prolongation. QT prolongation may also arise because a low serum calcium level may result in a weaker outward current carried by the electrogenic sodium-calcium exchange in reverse mode during the plateau. [Dr. B’s note: If you don’t know what all that means, don’t worry about it—I’m gonna teach you ALL about it in the next few weeks—it’ll be cool!] In addition to its effects on cardiac electrophysiology, hypocalcemia may facilitate the development of cardiomyopathy and heart failure, which are related to increased mortality and cardiovascular events. These cellular and molecular effects of low serum calcium levels may contribute to the development of arrhythmia and SCA.”

4. But Dr. B., Didn’t You Say Calcium + Coronary Artery Disease  CAUSED Hardened Arteries? And Heart Attacks?  I Had a Coronary Calcium CT Scan! You’re Messing with My Mind!

We’re sorry. But that’s why it’s a conundrum. We’re always learning, too. You may have remembered a few years ago when everyone was panicking about taking too many calcium supplements because they thought coronary artery calcification might be the result. We even wrote about it in our newsletter. Whereas in 2013, it may have appeared that there was a 1:1 correlation between our taking even modest amounts of calcium supplements, and them being inevitably and irretrievably deposited on the walls of our arteries and rendering them into human White Cliffs of Dover (The famous White Cliffs of Dover, in Dover, England, are composed mainly of limestone, or calcium carbonate.^[4] ), through which blood may occasionally pass. (Especially if needed to forestall osteoporosis, for example, or even, let’s say, hypothetically at this point, to prevent SCA, in both of which cases, they may be better metabolized/absorbed). Since then, other studies came out showing that slightly higher levels of calcium do not pose any cardiac risk. Only if the calcium levels are kept very high and for a long time, then CV disease could develop. 

A good analogy may be this: Remember how for most of our lives, we were told to count milligrams of cholesterol, because if you eat high-cholesterol foods, then the cholesterol will immediately go straight to your arteries and stick to the arterial walls as plaque? And if you avoid high-cholesterol foods like eggs, or liver, you won’t have high cholesterol? Um, not so much. Not that simple! 

In my opinion, these results tell me we really need to re-evaluate what the lower bound of “normal” calcium is: Perhaps it may be closer to 8.8 -8.9 mg/dL than 8.6. (Don’t quote me on that: I don’t know yet.) We will still need to replicate these results through other studies. I would have preferred for this study to do ionized calcium tests, as I said, not just plain old serum calcium, but it also was an observational study, so that was impossible. Remember, we also did not know the cause of the low calcium level. If I had my way, I would design a study that could have also measured all subjects’ blood levels of Vitamin D, parathyroid hormone, and serum magnesium. Since it was established that QT prolongation was a factor that potentiated the risk of SCA, the study should have accounted for any medications which patients may have been taking concurrently which may have lengthened the Q-T interval on EKG. 

So, like I am fond of reminding my patients, with so much of our bodies, particularly the heart, with calcium, you have to be Goldilocks, and say: “Not too little, not too much—just right!” But in the meantime, we’ll be here to help you keep the Big Bad Wolf away from the door