The Panelists

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.

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.

Introduction

For years, the endothelium had been considered an inert barrier to elements contained in the blood. The single layer of continuous endothelium lining arteries and veins forms a unique thromboresistant layer between blood and potentially thrombogenic subendothelial tissues. However, accumulating evidence now indicates that the endothelium is an active biologic interface between the blood and all other tissues. 

Research also spotlights the endothelium for its ability to modulate hemostasis and inflammation throughout the circulatory system. Moreover, it is now understood that the development of atherosclerosis is due to an excessive inflammatory and fibroproliferative response to the number of insults to the vascular endothelium.

In addition to atherosclerosis, endothelial dysfunction is seen in a variety of pathological conditions, including hypercholesterolemia, hypertension, heart failure, diabetes, and smoking. This suggests that endothelial dysfunction may be a marker of the presence or development of atherosclerosis in at-risk patients. 

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.

Q. Which patients are at risk for developing endothelial dysfunction?

Dr. Ganz: Virtually every Framingham Risk Factor has now been shown to cause endothelial dysfunction. In addition, inflammation, independent of risk factors, can cause endothelial dysfunction. We know that certain conditions such as rheumatoid arthritis can cause it. 

In our lab in the 1980s, we initially described endothelial dysfunction in the coronary arteries. What has been shown since then is that this is a pan-systemic disorder that can occur in other arteries, whether it is in the upper or lower extremities; it’s even in the very small arterials in every part of the body.

Dr. Lerman: Endothelial dysfunction is a systemic disorder. That is good thing and a bad thing. It is a good because you can use other parameters of the endothelium to detect the disease. For example, if you have disease in arteries of the heart, or coronary endothelial dysfunction, then you may be able to detect it by measuring the peripheral circulation to see if there is only disease in the coronaries. Endothelial testing is also good to monitor the reversibility of the disease, to see if the treatment is successful. 

The bad part is that if it is a systemic disease, then you may have other manifestations of endothelial dysfunction that are not only coronary in nature. These can include sleep apnea, erectile dysfunction, renal disease, dementia, and other things.

Q. Why is endothelium testing something physicians should be aware of and something they may want to add to their diagnostic armamentarium?

Dr. Vita: I think there is a large amount of scientific literature sighting the importance of the endothelium and the pathogenesis of arthrosclerosis and the situations that we are interested in: How to manage people with borderline risk? How do we make decisions with drug treatment?

I think that a physician should be aware of this information because of this potential. There are many modalities that have been proposed for the same purpose, including blood tests and different types of imaging. Which ones will emerge as the best way to make those therapeutic decisions is not yet known, but endothelial testing is a relatively simple approach that directly looks at the blood vessels as opposed to things circulating in the blood. And for this reason, I think that it has a lot of potential.

Dr. Ganz: I think endothelial function testing is still an evolving area. When we see an apparently healthy patient, the Framingham Risk Score doesn’t tell the whole story, especially for the intermediate risk patient. Additional risk stratification may be useful and one of those modalities could be endothelial testing.

In the secondary prevention setting, it may be that endothelial testing would be a biomarker of a patient’s response to therapy. 

In medicine, we are beginning to talk about individualized treatment; we will tailor a therapy to a particular patient. Part of that would be the determination of how the patient responded to a particular treatment. One of the useful ways of showing that is by showing improvement in endothelial function.

I do think endothelial testing will be particularly useful in following patients who already have coronary heart disease. There have been several studies showing this. One was a study of high blood pressure. Allsubjects were put on an effective blood pressure lowering treatment and their endothelial function was determined before initiation of the blood pressure therapy. 

The patients that failed to improve their endothelial function continued to be at high risk from hypertension, even though some had improvements in blood pressure. It may be that endothelial function testing will prove to be a useful way to monitor blood pressure medications.

Endothelial testing may be a useful way to tell if patients have a desired response or not to therapy, and I see that as a big application. A second study addressed newly diagnosed patients with coronary disease. All subjects were put on maximal therapy and endothelial function was measured before and while they were on the maximum treatment. The study reported that if someone failed to improve their endothelial function, there was an almost three-fold increase in incidences in coronary heart disease. 

Q. Can endothelial testing be used as an adjunct to the Framingham Risk Score?

Dr. Vita: The Framingham Risk Score takes the simple things that can be measured in the office and can be summed up and an assessment of risk over the next 10 years can be derived from the equation of the Framingham Risk Study. 

The gold standard for a new test is if it can give you more information above and beyond the Framingham Risk Score. Studies show that you get additional information by studying the endothelium.

Q. What is the link between endothelial dysfunction and erectile dysfunction, sleep apnea, and diabetes?

Dr. Lerman: Many of the diseases we are seeing in our patients actually have a vascular mechanism. That means the mechanism of the disease is related to some dysfunction of the vessel at some level. All the diseases mentioned—and even vascular dementia—are a consequence of some dysfunction of the vessel, such as an inflammation or oxidation that can lead to the disease. I think these are different manifestations of the same disease. 

Dr. Vita: The same risk factors that lead to arthrosclerosis are also associated with erectile dysfunction. It is likely a manifestation of vascular disease to the genitals. Arthrosclerosis is a disease that affects blood vessels throughout the body and wherever it occurs it is going to affect the endothelium. It is not surprising that there is a link between endothelial dysfunction and erectile dysfunction.

Dr. Ganz: Sleep apnea is now a newly recognized risk factor for coronary heart disease andone mechanism that links sleep apnea to coronary heart disease may be endothelial dysfunction. Testing endothelial function in that setting might be useful. 

Erectile dysfunction has a very good correlation with endothelial function testing. If a patient presents with erectile dysfunction, we think of that patient as a ticking time bomb; that is, somebody who is at very high risk of coronary heart disease. Looking at common risk factors is helpful, but also doing other stratification testing, such as endothelial function testing, may also be useful.

Q. 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.

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