Endothelium Roundtable Discussion
The Endothelium and It Role as a Marker of Overall Cardiovascular Health
Peter Ganz, M.D., is the Maurice Eliaser Jr. Distinguished Professor of Medicine and the Chief, Division of Cardiology at the San Francisco General Hospital. Dr. Ganz has been active in translational vascular research. His interests have focused on key aspects of human atherosclerosis including endothelial function. His laboratory pioneered methodological approaches that facilitated testing of coronary and peripheral vascular endothelial function in humans that were first published in the New England Journal of Medicine in 1986 (Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW, Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic arteries. N Engl J Med. 1986;315:1046-1051). This led to a further appreciation of the pathobiology of nitric oxide and endothelin-1 in health and their disturbances in diseases. Dr. Ganz’s work research also contributed to a better understanding of vascular and systemic inflammation and atherosclerotic plaque vulnerability. (In 1998, Drs. Furchgott, Ignarro, and Murad received the Nobel Prize for their discovery of the role of nitric oxide in cardiovascular regulation).
Amir Lerman, M.D., Professor of Medicine at the Mayo Clinic, has been active in cardiovascular research throughout his career. His key interests are interventional cardiology, coronary physiology, intracoronary imaging, and heart failure. His many studies have investigated the role of the endothelium and endothelial-derived factors with emphasis on endothelin and nitric oxide as modulators of coronary vascular tone and in-depth investigation of the role of the endothelium in cardiovascular disease. His pioneering work published in the Journal of the American College of Cardiology in 2004 (Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Kuvin JT, Lerman A.) Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol. 2004 Dec 7;44(11):2137-41) validated the use of non-invasive EndoPAT testing as an effective diagnostic tool in the diagnosis of patients with endothelial dysfunction and coronary artery disease.
Joseph Vita, M.D., is a Professor of Medicine at Boston University School of Medicine and a senior staff cardiologist in the Section of Cardiovascular Medicine. Over the years, Dr. Vita has been involved in many important studies with cohorts of patients from the Framingham Heart Study. He is a member of the American Society for Clinical Investigation and the Association of University Cardiologists. He is a Fellow of the American College of Cardiology, and the American Heart Association Councils on Arteriosclerosis, Thrombosis, Basic Cardiovascular Sciences and Clinical Cardiology. Dr. Vita is a member of Cardiovascular Diseases Board of the American Board of Internal Medicine. He has served on numerous study sections for the NIH and American Heart Association (AHA) and is a former Chair of the Cardiovascular Pathophysiology Study Section for the AHA. Dr. Vita is a member of the editorial boards of the American Journal of Physiology, Journal of the American College of Cardiology, and Coronary Artery Disease, and currently serves as Deputy Editor of the journal Circulation.
The Mystery of Broken Heart Syndrome
Doctors don’t know exactly how stressful events cause heart problems for some people—but they have some very good ideas. The body’s stress hormones, when released in large amounts, may cause a spasm in a coronary artery. There could also be some impact on the endothelium, the lining of the blood vessels, which leads to a narrowing of the arteries that supply the heart with blood. Alternatively, the hormone epinephrine (also known as adrenaline) may bind to the heart cells directly, causing large amounts of calcium to enter the cells and render them temporarily dysfunctional.
A study of 19 ABS patients suffering from stress cardiomyopathy, conducted at Johns Hopkins and published in The New England Journal of Medicine, reported that during the 12 hours before checking in to the hospital, every one of the patients had experienced some kind of severe emotional stress: a death in the family, an automobile accident, fear over having to speak in public, an intense and angry argument, or even a surprise party. All but one were women, mostly middle aged and older.
Testing of the patients showed no blockages or clots in the coronary arteries and no heart damage—what would usually be found after a heart attack. They did all have a heart problem: the left ventricle, the heart’s main pumping chamber, was failing to pump enough blood. In some cases, the condition became life-threatening, leading to heart rhythm abnormalities and heart failure. Additionally, all 19 patients did have high levels of stress hormones in their blood: 7 to 34 times the normal levels of adrenaline.
Why older women are the group most vulnerable to stress cardiomyopathy? Some heart experts suspect that it may be that estrogen serves to protect the heart cells from the effects of stress hormones like epinephrine. As women age and their estrogen levels decline, their hearts may become more vulnerable to the effects of stress hormones, particularly in large amounts seen in this syndrome.
Taking Control of Your Health – Lisa’s Story (cholesterol issue)
The 100,000 miles of blood vessels you have in your body are alive and vital like any other organ in the body. All of them are lined with a carpet of endothelial cells only one cell layer thick and so thin that they cannot be seen by the naked eye. Although the endothelium seems almost of no importance, it’s actually a critical part of the human anatomy. Maintaining its health and vitality is of utmost importance.
The endothelium exerts control over blood flow. Since it’s the innermost lining of the blood vessels, it has direct contact with blood and serves as the interface between blood and the vessel walls. When it’s healthy, it produces nitric oxide, which is its own powerful heart medicine that is able to relax blood vessels and allow more blood to be delivered to the heart.
Unfortunately, the endothelium can be damaged by poor diet, lack of exercise, and by other modifiable risk factors such as high blood pressure, high blood sugar, high cholesterol, and smoking. The vessel walls become thicker as a consequence and they tend to constrict rather than dilate, and it is more difficult for blood to flow though them. In order to produce the same amount of blood flow, the heart has to pump harder and this leads to health issues.
A healthy endothelium is like nonstick pan surface: it enhances blood flow. An unhealthy endothelium is a different story: white blood cells and platelets stick to it like glue, plaque starts to develop, and blood pressure rises. You then have endothelial dysfunction; the lining of the blood vessels is damaged and needs to be repaired.
Traditional heart disease risk assessment using the Framingham Risk Score is certainly a start in uncovering people at risk for heart disease, but it misses too many people. However, measuring endothelial health is becoming an important new non-invasive in-office test that can gauge the current health of your blood vessels and help predict heart disease years in advance of a heart attack.
Medical experts are now recommending that by restoring and maintaining a healthy endothelium through diet, exercise, and medication, you will slow the progression of heart disease and may even reverse its course.
Roundtable - Endothelium
Itamar Medical recently hosted a roundtable discussion featuring top cardiovascular experts who addressed issues concerning the growing role for endothelial assessment of patients and provided clarity about in-office testing of the endothelium to better risk stratify patients.
- What is the endothelium and what does it do?
Dr. Vita: The inner lining of all blood vessels is the endothelium, a thin layer of cells that regulates the function and health of those blood vessels. The vessels send blood to vital organs such as the heart and brain. The endothelium regulates the transport of nutrients into the tissues. The endothelium also helps keep the blood flowing and prevents it from clotting.
When there is a problem or infection, the endothelium directs your immune system—the white blood cells—to that location to fight off the infection. It is very important for regulating your health.
The problem is that if you have risk factors for heart disease such as smoking, high cholesterol, high blood pressure, and diabetes, the endothelium becomes abnormal and can no longer perform those normal functions. People who have abnormalities are at higher risk for stroke or heart attacks.
- Is the endothelium one of the first indicators that something is wrong is with the body?
Dr. Ganz: If you raise cholesterol, the endothelium is damaged. It is a very early sign of damage to the artery. Damage to the endothelium is the initiating phase of atherosclerosis or hardening of the arteries.
- What is the role for traditional cardiac risk factors and the role of endothelial testing?
Dr. Vita: The way I think about this is that your blood vessels are exposed to different risk factors. Since there are inherent differences between people that may be related to genes, or related to lifestyle, or things in their diet, or drugs that they take, all of this contributes to the endothelium’s ability to fight off the adverse effects of risk factors.
Some people can smoke and have nothing wrong with their endothelium. Some people can be marathon runners and die of a heart attack at a younger age. We don’t really understand why some people are more resistant to risk factors than others.
One of the things that we did observe is that in people who are susceptible to heart disease, their endothelium is a barometer for their risk. If their endothelium is abnormal, they appear to be at higher risk. I think of the endothelium as a sign of the overall health of the blood vessels. It’s a reflection of how it is responding to the various risk factors.
Dr. Ganz: Cholesterol can damage vascular health and so can smoking, but all of these risk factors converge on the endothelium. I think endothelial function is a very sensitive barometer of the health of the arteries.
- If your patient ate cheeseburgers and smoked, what would happen to their endothelium?
Dr Vita: When it is healthy, the endothelium will open up and direct blood to where it is needed. When you eat too much fat and you smoke, your endothelium no longer operates as it should and the blood flow is limited. We believe that one of the ways that bad habits or poor diet leads to heart disease is through their effect on the endothelium. People who have abnormalities early on eventually develop hardening of the arteries and are at higher risk of heart attack or stroke.
- Is endothelial dysfunction reversible?
Dr. Ganz: The easiest way is to take away the various risk factors. Take away the smoking, reduce cholesterol, exercise more, and control high blood pressure. Endothelial dysfunction is reversible and reversible quite rapidly.
Dr. Vita: It’s absolutely reversible. There are lifestyle changes, medications, and dietary changes that are known to improve the health of the endothelium. Cholesterol lowering drugs, drugs that lower your blood pressure, particularly the ACE inhibitors, are all beneficial. Lifestyle changes, such as losing weight and stopping smoking have been shown that they help your endothelium get better. What is interesting is that same list of things to improve your endothelium has also been shown in randomized studies to reduce your risk of heart disease. That suggests there is a very close link to how your endothelium behaves and your risk for cardiovascular events.
- What patients are at risk of developing endothelial dysfunction?
Dr. Lerman: The scope of the problem is increasing. If you asked me this question 20 years ago, I would say someone who is 40 to 50 years old, a smoker, and someone with high cholesterol. Now you can see endothelial problems developing in teenagers.
- Why is it important that patients know about the health of their endothelium?
Dr. Ganz: If a patient comes to me and asks, “Am I a high risk for coronary heart disease since I smoke and have high cholesterol,” I begin by assessing the common risk factors. They are important, but they don’t tell the whole story. By performing some test, such as endothelial testing, it may be an independent way to find out if the patient is at high risk or not.
Knowing the level of endothelial dysfunction might lead to more intensive treatment of the risk factors by the doctor. We need to do much more research in this area but I do think that endothelial dysfunction may be a warning sign that more treatment is necessary.
- Should endothelial function testing be an adjunct or a replacement for the Framingham Risk Score?
Dr. Lerman: Using data from the Framingham Heart Study, the Framingham Risk Score helps estimate10-year risk of heart attack and death based on your age, gender, total cholesterol, HDL cholesterol, systolic blood pressure, whether you currently take blood pressure medication, and whether or not you are a smoker.
The Framingham Risk Score has to be the first screen that a doctor uses, but endothelial testing should be an adjunct.
Dr. Ganz: I think endothelial function testing is still an evolving area, but when we see an apparently healthy patient, the Framingham Risk Score doesn’t tell the whole story, especially for the patient at intermediate risk.
- Why should a doctor perform an endothelial test?
Dr. Lerman: First, the doctor wants to feel that he or she is providing better care for the patient, because they are not just looking at markers, but also the disease itself. Second, endothelial testing can guide therapy. Third, based on how well they do on their endothelial test, it can be used to stratify the patient to a low, medium, or high risk. Fourth, endothelial testing can be used to determine if therapy is successful, whether that is through lifestyle changes or medication, or the combination of the two.
Dr. Ganz: I think we all recognize that if one can show a patient the damage to their arteries, an endothelial function test may be the wake up call they may need to become compliant and follow through with treatment.
Dr. Vita: Endothelial testing has the potential to guide decisions and give us information above and beyond what we can gain by doing blood tests and looking at traditional risk factors. Testing the endothelium could be used in that way.