Tuesday, June 7, 2016

Coronary Artery Disease: A Role For Calcium?

In the heart, there still lie a myriad of mysteries. For everything we know about this integral organ, there are still several things we have yet to figure out. One of the most pressing questions is what factors are “at the heart” of the current coronary artery disease (CAD) epidemic and how can we stop it? It turns out that the answer, while still not fully understood, may have to do with a familiar element. Calcium, the mineral we all know from the milk commercials that is touted for healthy bones and teeth, may play a prominent role in keeping your heart healthy as well.
Anyone who has watched a medical show, from Grey’s Anatomy to Scrubs, will recognize this predictable scene in the hospital:  “Clear!” A flat line appears on a black screen, accompanied by a caustic continuous siren, blaring uproariously. The paddles that conduct electricity failed to restart the heart. “Clear!” The handsome doctor shouts once more after a dramatic pause. This time, the flat line turns into a rhythm and the continuous alarm morphs into a dulcet beeping, indicating the patient will live. Television often portrays the cure all for fixing the heart is simply a little electrical jolt from a defibrillator, easy as that.

The doctor will see you now!


Do not try this at home!

The heart is profoundly affected by electricity. Electrocution is an effective method for execution because sending large currents through the heart can render it useless. At the very least, a small shock can definitely cause your heart to skip a beat (just ask the little brother who stuck a butter knife into a power socket!). Electricity is so essential to the heart, the organ has evolved its own conducting system, which means it can regulate its own beat without input from the brain.



Many ailments can cause a heart to stop, but one disease is wreaking havoc on the human population and killing people in unprecedented numbers. As recently as 2013, coronary artery disease (CAD) has reigned supreme as the most common cause of death worldwide. As many as eight million people a year die from complications caused by CAD. Like cancer, it would be hard to find a person who doesn’t know someone that has been afflicted with CAD. Despite the steep number of people affected by the disease, there is little consensus on what causes this deadly condition or how to stop it.
The theories are numerous and some are understandably more credible than others. Coronary artery disease is thought to have a direct correlation with diet and exercise - most people diagnosed with CAD are obese and sedentary. And indeed, changing your diet, cutting cholesterol, quitting smoking, and beginning a healthy exercise regime does lower the incidence of CAD-related adverse events such as heart attack or sudden coronary death (which is exactly what it sounds like). But that isn’t the whole story, not by a long shot.

It is a difficult decision, but as they say,
"an apple a day keeps the doctor away". www.cdc.gov 
For a clearer view of what is really happening to the heart when it suffers from CAD we need to take a closer look - we need to look at the individual cells in the heart. There are several important players at this level, but the cells that reside in the large middle layer have been shown to play a significant role. This layer is made-up of cardiovascular smooth muscle (CSM) cells and these cells are thought to be the main players in the propagation of CAD.
In a healthy heart, the CSM cells are quiescent, that is to say they are stable, just hanging out and not doing too much. In a heart affected by CAD, however, the CSM cells come to life - they begin to divide and travel. When the CSM cells begin to divide and conquer, things start to go south because the simple act of proliferating and moving causes inflammation below the skin layer of the blood vessel. Like a cut on your finger, the injury causes inflammation and alerts the immune system, which will come to the rescue, close the cut, stave off infection, and save the day! The immune system’s army of white blood cells wants to save the day in the heart vessels as well and, while its intentions are good, the results can ultimately be disastrous. Why? After the work is done by the white blood cells, they leave what can be likened to a “scab” on your blood vessel. This thickening on the wall of the vessel can elicit additional responses from the immune system, thereby compounding the problem and causing the scab-like mound to grow and grow, possibly blocking off the entire blood vessel. When this occurs, it is referred to as a myocardial infarction (heart attack). The blood that supplies your heart is cut off, and the oxygen the heart needs to pump never arrives. When the heart can’t feed itself with oxygen, it certainly can’t send any to the rest of the body!

A clog, even in a small artery, can cause big problem
for your heart and your health. www.cdc.gov

But why do the normally passive CSM cells start to act out and move around? That is the million-dollar question. As mentioned above, the electrical signals in the heart are critical for the coordinated, rhythmic beating of the heart. The constant and familiar lub-dub of the heart is the result of a myriad of events occurring in perfect harmony. Perhaps just as important as the electrical current, however, are the affects it elicits, namely the release of the well-known mineral, calcium.
In addition to being pivotal for healthy bones, calcium is also a crucial player in achieving those perfectly rhythmic heartbeats. Calcium might even explain how the smooth muscle in your heart switches from innocent bystander to mischievous villain. The calcium in the heart acts a second messenger for CSM excitation-contraction (beating) and sends the signals that modulate CSM proliferation, migration, and calcification.

The blue dots represent calcium. When the heart behaves normally, the calcium remains constant and the cells of the heart do not divide. If excess calcium is allowed to build up in the sarcoplasmic reticulum (SR), however, the cells of the heart begin to divide and move. Eventually, the vessel wall becomes so large it is difficult for blood to pass. (modified from McKenney-Drake, Rodenbeck, at el., Atherosclerosis, 20

In order for the heart to beat properly, calcium levels must be precisely balanced with the help of channels or transporters, which regulate the flow of calcium ions in or out of cells. It seems likely that when calcium transporters break down, the mismanagement of calcium will cause problems in the heart. In mild CAD, certain avenues available to calcium transport malfunction, which causes the calcium to aggregate in the sarcoplasmic reticulum (SR, the compartment in the heart cells that stores calcium). When this happens, it essentially “activates” the proliferation of CSM cells. Dr. Dineen-Rodenbeck recently verified this hypothesis by blocking a common transporter that is responsible for bringing calcium back into the SR. When calcium is unable to aggregate in the SR, the cells are not switched “on” and all remained quiet. Once CAD becomes severe, the SR stores are basically depleted and the risk of death caused by complications associated with CAD rise. This is an important discovery because knowing the role of calcium in the heart and understanding what occurs when it is lowered or elevated may lead to treatments. In the end, the regulation of calcium may be the key to managing the CAD epidemic.
These studies should not be taken as proof that you need to regulate your dietary calcium differently – after all, calcium is essential for strong bones and teeth. Rather, these findings will help guide future research and treatment efforts that may be able to manage calcium levels specifically in the heart to alleviate CAD.

Contributed by:  April Barnard

Rodenbeck SD, Barnard AL, and Sturek M. SERCA inhibition attenuates medial thickening in an organ culture model of coronary artery disease. FASEB J (In Press).

Dineen SL, McKenney ML, Bell LN , et al. Metabolic syndrome abolishes glucagon-like peptide 1 receptor agonist stimulation of SERCA in coronary smooth muscle. Diabetes 2015; 64:3321–3327
Sturek M. Ca2+ regulatory mechanisms of exercise protection against coronary artery disease in metabolic syndrome and diabetes. J Appl Physiol. 2011;111:573-586.

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