Swinford Titin defect

This is for my family that have tested positive for a defect in the titin protein (or the TTN gene). Let’s start with some basics. The heart is divided into the atria (in the top half) and the ventricles (in the bottom half). The heart tissue has three main components; the structure (muscle fibers), plumbing (the blood vessels), and the wiring (nerve fibers). Plumbing problems are what lead to heart attacks; while we have some of that in our family, this gene has nothing to do with that. Instead, we have structural and wiring problems.

For every gene in our body, we have two copies of its blueprint. We get one from each parent. If one of those blueprints is messed up (defective), then the protein we build from it can also be defective. Sometimes it doesn’t matter. If we get one good copy from one parent and one bad copy from the other, the body can sometimes either self-correct by destroying the defective result (it gets built but never used) or the defect is trivial and doesn’t matter. Other defects cause massive problems.

Titin is the largest known protein. It makes up the stretchy part of muscles, and acts as the spring to let the muscle snap back to its neutral position. There are a lot of ways it can be defective, and the type of defect determines what the effect is. Sometimes you have to get a bad copy from both parents before it matters (some of the muscular dystrophies, for example). Other times, having one good gene and one bad is enough to throw the system off.

We have a defect in Titin that was previously known but the significance of it wasn’t fully understood until our family came to their attention (Invitae reclassified the defect because of us). With our defect, having a single bad gene (instead of both) is enough to be dangerous. However, having the defect doesn’t guarantee you’ll have problems; it just means it’s (much) more likely. There are two primary issues that can arise. The first, and more common, is early-onset atrial fibrillation. The second is dilated cardiomyopathy. We don’t know yet why some have problems and others don’t.

Atrial fibrillation (AFib) is a condition where the wiring of the heart goes haywire. There’s usually a single natural pacemaker in the top of the heart that triggers each heartbeat. It pulses ≈ 80 beats a minute, and each pulse then runs down some wires (nerve cells) into the bottom of the heart. The bottom of the heart provides the main force of each heartbeat. However, sometimes there are other cells in the top of the heart that try to take over. These abnormal impulses slide their signal into the wiring and trigger extra, uncontrolled heartbeats. The result is that the top of the heart is firing erratically and sometimes very fast. This gives you an irregular heartbeat that can be slow or fast. It sometimes makes people tired, short of breath, weak, or dizzy. Because the beat is so erratic, the muscles in the top of the heart don’t have time to reset between beats, so some parts squeeze while others are trying to rest. The overall result is the top part of the heart looks like it’s quivering. In medicine, a quivering muscle is said to be fibrillating, hence the name (the atria are fibrillating). When the atria are fibrillating, they’re not squeezing smoothly. This jostles the blood in that area and can cause blood clots to form, since the blood is turbulent. When a blood clot eventually gets pushed out, the first pathway it comes to are the blood vessels going to the brain, so you get a stroke from AFib. It doesn’t really affect the plumbing in any way. Consequently, heart attacks do not occur from AFib, strokes do.

AFib is treated by trying to prevent it with antiarrhythmic drugs. These are special, powerful medicines that regulate how the impulse runs through the wires, effectively keeping those extra signals from slipping into the system. Most of the time it works, but people will have breakthrough episodes occasionally. Therefore, people with AFib have to take powerful blood thinners so they don’t get a blood clot and stroke.

The other issue that we are prone to develop is dilated cardiomyopathy (DCM). That’s where the heart gets larger and thinner. Think of the heart as being made of Play-Doh. If you stretch it out and make it bigger, but don’t add any more clay, then the walls have to get thinner. That’s what happens to the heart with DCM. There’s other types of an enlarged heart where the heart gets too thick, but that’s not the case for us. The walls get thinner, and since the muscle is thinned out, it gets weaker. The overall result is heart failure. Also, because the tissue is stretched out, it causes the wiring in the lower part to stretch and sometimes malfunction. In this case, that can cause sudden cardiac arrest.

Some of our family have already had issues related to Titin defects. Quite a few of us have had AFib and at least one is currently living with dilated cardiomyopathy. We have almost certainly lost some of our family to this as well. This doesn’t mean we have to live scared, but we do need to be careful. For those of us that have had issues already, there are a couple of options. All of us need to continue to stay in touch with our regular cardiologist. Additionally, those of us who developed AFib before the age of 60 can also enroll in a study at Vanderbilt on the subject. There are a couple of benefits to doing that. They will NOT be taking over your care, so you’ll still need your regular cardiologist. But they will do additional genetics tests to see if you have other defects that have added to your particular situation. If you are part of the study, you will also have additional tests. Probably the most important test is an MRI of your heart. A cardiac MRI lets them look at the muscle tissue in the heart. One concern with titin defects is that you can have fibrosis (scar tissue) form inside the heart muscle, which both weakens it and predisposes you to bad (potentially lethal) heart rhythms.

For those who have never had any issues but have a positive test, the recommendations are not clear. We have only had access to the highly specific genetic tests for around a decade, and this is a rare enough problem that there isn’t enough data yet to know what to say. Part of the study at Vanderbilt is to try and determine what the best course will be. Anyone who did a test with us and tested positive is included in a registry at Vanderbilt, and as new tests and treatments become available they’ll contact you to discuss. The most important thing for people without symptoms (documented AFib or DCM) is to try and avoid other damage to the heart. There are some things that are known to accelerate or increase your risk. This would include smoking, excessive alcohol consumption, and obesity. Excessive is defined as more than two drinks in 24 hours for a male and more than one for a female. Even this may not be wise, but we don’t know enough to say what a safe limit would be. Any female with a positive test result that gets pregnant should consult with a maternal/fetal medicine doctor at an academic center to be followed, as pregnancy is a major risk to trigger cardiomyopathy. It does not mean pregnancy is off-limits, just that closer monitoring is needed. An Apple watch that does constant EKG/AFib monitoring is very useful, and home handheld EKG machines can be bought at Amazon for around $80. These pair to your smartphone and tell you if you’re having AFib. I’m a big fan; whenever I feel a little out of sorts I’ll do a quick check of my heart rhythm with one. The most recognized one is the Kardia Mobile single-lead for $79. There are other brands as well, some of which can be used without a smartphone; these aren’t as recognized or validated in cardiology, but I have one of them myself and have found it reliable. The price is about the same, so the Kardia is probably the best bet.

Probably the biggest problem that all of us will face is the fact that this is a new issue. This in-depth knowledge of heart problems has only been studied for a few years, and most regular cardiologists are not going to be familiar with it. Given how few patients it will affect, most cardiologists are not going to prioritize studying it when they could spend their time keeping up with heart disease or other issues that affect a much larger percentage of their patients. The American College of Cardiology (ACC) does recommend genetic testing for patients that have AFib before the age of 45 (in Europe, they use the age of 60). However, the current guidelines don’t go beyond that with recommendations (What do we do with the results? What about family members? We don’t know!) The ACC guidelines are what cardiologists use to make sure they’re treating people correctly, and we are currently in uncharted territory. Hopefully the studies at Vanderbilt and other institutions will provide further clarification for cardiology across the board.

For those who have symptoms (documented AFib or DCM) and wish to pursue further testing at Vanderbilt, contact Hollie Williams at hollie.williams@vumc.org. She’s the coordinator for the Early AFib clinic. She has seen everyone’s names as the test results have come across, but you will need to tell her that you’re part of the Ponder/Swinford family. April and I would strongly encourage it, as we have found that very few outside cardiologists know much about this field, at least in UAB/Birmingham. And feel free to reach out to me with questions. I may not have an answer, but I’ll do what I can.