Heart for Life Funds Research Project at University of Michigan C.S. Mott Children’s Hospital
Transplant Coronary Artery Disease (TCAD) is the leading cause of failure of the transplanted heart in patients who have received a heart transplant. It likely occurs for many reasons and it affects all coronary branches both large and small. Over time, the arteries become increasingly smaller and eventually may be completely blocked with obstructs blood flow to the heart muscle itself, eventually leading to heart failure. Unlike atherosclerotic coronary artery disease which typically blocks large vessels and can be bypassed, since TCAD affects is a diffuse phenomenon, affecting both large and small arteries, stenting and bypass surgery is largely ineffective in changing the overall course, the only cure is to re transplant. If it occurs, patients will generally will start seeing signs of TCAD 5-10 years after transplant. The current method used to detect coronary TCAD is through invasive catheters and echocardiograms.
We are partnering with University of Michigan C.S. Mott Children’s Hospital to try to better understand the causes of TCAD so that we can develop ways to prevent it. First, some background. In order to perform a heart transplant, the surgeon must sever the vagus nerve, which connects the heart to the brain. Nerves do no regenerate, so once it is severed it cannot be reattached. The vagus nerve is part of the parasympathetic nervous system. The parasympathetic nervous system helps to regulate the heart’s response to stress or recovery from stress, so one function of the vagus nerve is to help you to calm down when the sympathetic nervous system releases cortisol as part of your body’s flight or fight response to a threat or even just normal exercise. As part of this calming function, it also helps to regulate your heart rate. Without this nerve, the heart depends on other signals from the body to regulate it, including hormones – chemical signals sent from other parts of the body.
Going back to TCAD, although the complete mechanisms underlying this disease are not fully understood, it is possible that the constant stimulation of the muscles lining of the coronary arteries from hormones released from the body eventually cause abnormal changes in how the coronary functions and it’s anatomy. These particular hormones are called catecholamines, and we understand well how they work. Because of that, we know there is a type of drug that blocks the receptors in the lining of the blood vessel. The medicines are called alpha-receptor blockers. Using this drug may stop the arteries from being continually signaled by the catecholamines and may also stop the long term chronic changes caused by the catecholamines.
As mentioned above, all transplant patients must go through heart catheters to check for rejection, monitor heart function, and look for early signs of TCAD. Although adults generally go through a catheter procedure awake, children are usually sedated. The drug that is most often used at our center to sedate them is called Dexmedetomidine, which happens to be an alpha receptor blocker. The experiment we are funding would look at blood pressure and other readings before administration of Dexmedetomidine and after to determine if there is a significant change in vascular function of the coronary artery. If there is, that may be a clue that these alpha receptor blockers do change the way the coronary artery functions and may help us in the fight against TCAD. Another alpha blocker is Clonidine, which is currently used in children to treat high blood pressure among other things. Since many transplant patients are already on high blood pressure medicine, one solution may be as simple as changing their prescription to Clonidine, which would not only control blood pressure, but also may improve coronary health and prevent TCAD. This may be a rather simple solution to a complex phenomenon, but it is only a theory right now. Funding this type of research is the only way we will know for sure and provide evidence that can lead to change in the way we care for children who have received a heart transplant.
Transplant Coronary Artery Disease
Transplant coronary artery disease (TCAD) remains the most significant cause of morbidity and mortality after orthotopic heart transplantation. Transplant coronary artery disease is largely an immunologic phenomenon, driven by an inflammatory milieu consisting of multiple cell types that contribute to fibromuscular and smooth muscle cell proliferation with subsequent coronary obstruction. Multiple clinical factors contribute to the development of TCAD. Coronary angiography is the gold standard for the diagnosis of TCAD. Current treatments for TCAD include pharmacotherapy, percutaneous coronary intervention, and repeat transplantation, although other novel therapies are emerging. Although percutaneous coronary intervention has generally demonstrated high procedural success rates, it has been plagued by a high incidence of in-stent restenosis. Drug-eluting stents reduce in-stent restenosis compared with bare metal stents. Repeat transplantation is the only definitive treatment. Prospective randomized trials comparing different pharmacotherapies as well as revascularization strategies are needed to identify the optimal therapy for patients who develop TCAD.
heartforlife.org 