What is the endothelium?

The vascular endothelium is the one cell thick inner lining of all blood vessels, from the heart chambers to the smallest capillaries (lymphatic endothelium lines the lymphatic vessels). It is a specialised form of skin cells (squamous cells), and acts as a selective barrier between the blood and the rest of the body, and influences blood clotting and clot breakdown. The endothelium also produces nitric oxide which is a major contributor to the relaxation of the muscles in the blood vessel wall. This allows the blood vessel to dilate and increase the blood flow to the tissues downstream, as required. A healthy endothelium is needed for healthy blood vessel function and structure. 

What is endothelial dysfunction?

The systemic (whole body) disease state known as endothelial dysfunction is when the endothelial cells are inflamed and damaged, and not able to perform their barrier, anticoagulation and vasodilation/vasoconstriction (vasomotor) function. This damage initially leads to reduced ability to relax and dilate the vessel, and progresses to swollen, stiff blood vessel walls (arteriosclerosis, high blood pressure), then the accumulation of inflammatory fats and debris in the wall (atheroma), and then the rupture of the endothelium over the fatty plaques (thrombosis and emboli leading to heart attack and stroke) or the gradual obstruction of the blood vessel lumen and decreased blood flow downstream (angina, peripheral claudication).

Endothelial dysfunction can be defined as reduced bio-availability of Nitric Oxide (decreased production and/or increased destruction by free radicals) which plays many roles in maintaining vascular health, especially in vasomotion. Hence, endothelial dysfunction is defined as an impairment of endothelium-dependent vasodilation. In their 2005 Circulation publication, Lerman et al. (1) defined endothelial dysfunction as “the ultimate risk of the risk factors”, acting as a summation of the integrated effects of many cardiovascular risk factors.

(1) Lerman A and Zeiher A. Endothelial Function, Cardiac events, Circulation 2005, 111,363-368.

Endothelial dysfunction, as assessed by the EndoPAT via the percent of flow-mediated dilation, is the earliest clinically detectable stage of cardiovascular disease, and is a predictor of later cardiovascular events (these are the commonest causes of death in the West - stroke, heart attacks, kidney failure etc). 

What are the causes of endothelial dysfunction?

Causes of endothelial dysfunction include oxidative stress (from free radicals), inflammation (from tissue damage and infections), insulin resistance (from high carbohydrate intake and inadequate physical activity) and autoimmunity. Risk factors include high oxidised LDL-cholesterol, small LDL particles, high blood sugar and insulin, high blood pressure, smoking, ageing, physical inactivity, obesity, chronic infections (i.e. gut, oral, sinus), persistent toxin, allergen and heavy metal exposures (from air, water and food pollution).


What are the consequences of endothelial dysfunction?

The main consequence of endothelial dysfunction is the initiation of an inflammatory process which leads to the formation of atherosclerosis and its late sequel, cardiovascular morbidity (disease) and mortality (death). Endothelial dysfunction is involved in numerous systemic disease processes such as: erectile dysfunction, metabolic syndrome, cerebrovascular diseases (stroke/TIA), pre-eclampsia toxemia, renal failure, sleep apnea, peripheral claudication and gangrene.

How does the EndoPAT measure endothelial function?

EndoPAT™ quantifies the endothelium-mediated changes in vascular tone, elicited by a 5-minute occlusion of the brachial artery (using a standard blood pressure cuff). When the cuff is released, the surge of blood flow causes an endothelium-dependent Flow Mediated Dilatation (FMD) of the blood vessels downstream. The dilatation, manifested as Reactive Hyperemia, is captured by EndoPAT as an increase in the PAT Signal amplitude. A post-occlusion to pre-occlusion ratio is calculated by the EndoPAT software, providing the reactive hyperemia index, or percent flow-mediated dilation.

 

Who should have an EndoPAT test?

Cardiovascular diseases (heart attack, stroke, kidney failure, etc) are the commonest cause of death of men and women in the West. They are poorly predicted by the traditional risk markers. In a study of over 100,000 people hospitalised with coronary artery disease (heart attack, angina), 77% had normal LDL cholesterol, 45% had normal HDL cholesterol, and 61% had normal triglycerides. Fifty percent of people who die suddenly from a heart attack have normal LDL cholesterol. Fifty percent of men and sixty-four percent of women had no symptoms before their first heart attack. Often, the first symptom of blood vessel disease, is sudden death.

The EndoPAT doesn’t look at risks of cardiovascular disease, it detects the actual cardiovascular disease, and it detects it years before any other imaging technique.

Roger VL, Go AS, Lloyd-Jones DM, et al; for The American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stoke Statistics 2011 update: a report from the American Heart Association. Circulation. 2011;123:e18–e209.

Sachdeva A, Cannon CP, Deedwania PC, et al; for the Get With The Guidelines Steering Committee and Hospitals. Lipid levels in patients hospitalised with coronary artery disease: an analysis of 136,905 hospitalisations in Get with the Guidelines. Am Heart J. 2009;157(1):111–117.e2.


The earlier you diagnose cardiovascular disease and initiate a cardio-protective program, the cheaper and more effective is the disease reversal. EndoPAT can detect cardiovascular disease many years before other imaging modalities and decades before signs and symptoms develop. Earlier detection allows easier reversal and prevents progression to life-threatening disease. 

Candidates include men between the ages of 40 and 70 and women between the ages of 50 to 70 with one or more of the following risk factors for heart disease:

  • Cigarette smoking
  • Diabetes
  • Elevated total cholesterol level, triglycerides, lipoprotein a, homocysteine, C-reactive protein, fibrinogen, small LDL or HDL particles or oxidised LDL particles
  • Family history of heart disease (sudden death, heart attack, or need for angioplasty or bypass surgery) in a first-degree male relative (parents or siblings) 55 years old or less, or a first-degree female relative 65 years old or less.
  • High blood pressure
  • Obesity
  • Sedentary life style
  • High stress
  • Poor sleep, shift work
  • Poor heart rate variability or heart coherence.

Individuals with multiple risk factors, or one particularly severe risk factor, need to talk to their doctor about earlier intervention. For example, for a 35-year-old male whose father died at the age of 41 of a heart attack, an EndoPAT test would be warranted.  


Is there any special patient preparation needed before an EndoPAT test? 

It’s recommended that the patient fast 3 hours before the test. In addition, the following drugs should not be used for 24 hours before testing:

• Nitroglycerine

• Alpha-blockers, beta-blockers, and calcium channel blockers

• ACE inhibitors

• Statins

Ideally, repeat tests are performed at the same time of the day, and always in a temperature-controlled room.


How is the EndoPAT test performed?

First, the sensors are placed on your right and left index fingers and a blood pressure cuff is wrapped around your non-dominant arm. A six minute baseline blood flow reading is made. Then the cuff is inflated, stopping blood flow to that arm and hand. The finger sensor on the affected arm will then show no blood flow, while the sensor on the opposite index finger will continue to display your normal blood flow level.

After five minutes, the blood pressure cuff is released, allowing blood to flow back into the affected lower arm. The readings are continued for another five minutes. If the finger sensor on the affected arm shows a rush of blood, your vessels are functioning normally. However, if the blood flow return is sluggish, your vessels are unhealthy.

This finger test is so beneficial because the arteries in your heart (your coronary arteries) react to stress the same way blood vessels in your arm react to constriction of the blood pressure cuff. If your arm vessels are sluggish, then your coronary arteries are likely to be sluggish as well. And this endothelial dysfunction can lead to the buildup of atherosclerosis and increase your risk of a heart attack.

What is the RHI and how it is calculated?

RHI stands for Reactive Hyperemia Index. This is the final report of the EndoPAT test. It is a ratio of the post-to-pre occlusion PAT amplitude of the tested arm, divided by the post –to-pre occlusion ratio of the control arm.

The higher the RHI, the better the health of the endothelium and the lower the risk for heart and blood vessel disease.


There are three basic categories for RHI:

Red Zone: Score of 1.67 and lower. 

You do not have proper endothelial function and this could be an important signal of an imminent cardio-vascular problem. This RHI may indicate the presence of disease and that an immediate evaluation and intervention may be needed, whether it is aggressive medical therapy or a medical procedure, it’s imperative that endothelial health be restored.


Yellow Zone: Score between 1.68 and 2.1

Your endothelium is healthy and while you don’t have any additional risk, you are still not in the well-protected Green Zone.

It’s important that you now take charge of your own health and do everything you can to improve your RHI. Good health depends of certain lifestyle choice you make that include what you eat, how active you are, how well you sleep, whether or not you smoke, and how you deal with tension and anxiety. 


Green Zone. Score between 2.1 and 3. 

Your endothelium is functioning optimally, and you have maximum protection. Keep up whatever it is that you are doing, because your lifestyle has positively affected your cardio-vascular health.


What should be done with the score of 1.67 and below? What is the treatment strategy?

An RHI score of 1.67 and below correlates to endothelial dysfunction. Endothelial dysfunction is treatable and reversible. Endothelial dysfunction can be treated and reversed by many existing therapies such as lifestyle modification (diet, physical activity, sleep optimisation, stress management), natural remedies (such as L-Arginine, niacin), drugs (e.g. statins to lower high cholesterol, ACE inhibitors or ARBs used to treat high blood pressure, PDE5 inhibitor used to treat erectile dysfunction) and treatment of co-morbidities (e.g. glycemic control for diabetics, treating chronic infections). 


Can the EndoPAT help predict endothelial dysfunction and cardiovascular events?

Results of a 2009 study conducted by researchers at the Mayo Clinic and Tufts reported that the EndoPAT test is “highly predictive” of a major cardiac event, such as a heart attack or stroke, for people who are otherwise considered at low or moderate risk based on their Framingham Risk Score (FRS).  The FRS is the commonly used risk predictor and was developed from the Framingham Heart Study, an ongoing longitudinal study of heart disease.

In this Mayo Clinic study, published in the Journal of the American College of Cardiology, Amir Lerman, M.D., a cardiologist at Mayo Clinic and senior author of the study, and other researchers, used an EndoPAT to measure the endothelial health of 270 patients between the ages of 42 and 66 and followed their progress between 1999 and 2007.  These patients already knew that they had low-to-medium risk of experiencing a major adverse cardiac event, or MACE, based on their FRS. Some of their risk factors included high blood pressure, high cholesterol, obesity, and a family history of heart disease.

The study results: The rate of MACE in patients who tested positive for endothelial dysfunction was 39% vs. normal endothelial function 25% (p=0.024). The study showed that patients at low FRS risk but with endothelial dysfunction measured by the EndoPAT were at a higher actual risk of future CV events than patients with high FRS but normal endothelial function.

Furthermore, endothelial dysfunction was found to be an independent risk factor for future MACE on multivariate analysis (p=0.002).

* Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Nelson RE, Pumper GM, Lerman LO, Lerman A. Assessment of Endothelial Function by Peripheral Arterial Tonometry Predicts Cardiovascular Events Beyond the Framingham Risk Score. JACC 2009; Suppl.


Is the EndoPAT test used in cardiac-related research studies?

The EndoPAT has been used in dozens of clinical studies conducted at such renowned medical institutions as The Mayo Clinic, Johns Hopkins Medicine, Harvard Medical School, Cleveland Clinic, the Framingham Heart Study, and Mount Sinai Hospital (NY).


How well do conventional cardiovascular risk factors (Framingham Risk Score) correlate with the EndoPAT?

Since 2003, the Framingham Heart Study has included endothelial function measurements with EndoPAT. All three study cohorts (the original study population, the offspring, and the third generation cohort) have been tested with EndoPAT, totalling over 5,000 subjects.

Hamburg et al published a cross-sectional analysis of 1,957 third generation subjects in 2008*. The study demonstrated a significant inverse relation between RHI and multiple CV risk factors, including: male sex, body mass index, total/HDL cholesterol, diabetes, smoking, and lipid-lowering treatment.

*Hamburg NM, Keyes MJ, Larson MG, Vasa RS, Schnabel R, Pride MM, Mitchell GF, Sheaf J, Vita JA, Benjamin EJ Cross-Sectional Relations of Digital Vascular Function to Cardiovascular Risk Factors in the Framingham Heart Study. Circulation 2008; 117: 2467-2474.


Is there a threshold for a good EndoPAT result?

Yes, the threshold for a good EndoPAT result is an RHI of 1.67 and above. The threshold of 1.67 was determined following the study of Bonetti et al* which was performed at the Mayo Clinic. In this study the EndoPAT was found to be correlated with coronary endothelial function using the gold standard method of assessment which is injection of acetylcholine during coronary artery catheterisation.

I am 56 years old and my RHI is 2.95. I'm not an athlete, but I put attention on my diet, physical activity, stress management, sleep and hormone balance. I don't drink alcohol, smoke or take recreational drugs. My heavy metal levels are low, and I know and avoid my allergens. These lifestyle techniques promote a healthy endothelium and minimise my risk of cardiovascular disease - the commonest cause of death in the West.

*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. JACC 2004; 44: 2137-2141


What are treatment options for endothelium dysfunction?

The degree of endothelial dysfunction will influence the treatments chosen. The success of treatment can be assessed by retesting with the EndoPAT.

General treatment options for endothelium dysfunction may include proper diet (flavonoid-rich fruit and vegetables, potassium, reduced trans fatty acids from hydrogenated products), physical activity, weight loss in the overweight and reducing or eliminating smoking and excessive alcohol consumption.  Several pharmacological choices are available (statins, ACEI, ARBs).  Natural remedies include L-Arginine and Niacin.  

Endothelial dysfunction is treatable and reversible.


How can EndoPAT, which measures changes in vascular function in a fingertip, ensure that the endothelium of the entire vascular system has been checked?

The endothelium is the same throughout the body, and when damage is noted in the fingertip, it indicates that the endothelium is damaged throughout the body - that it’s a systemic dysfunction. Endothelial dysfunction is involved in numerous systemic disease processes, including: erectile dysfunction, metabolic syndrome, renal failure, sleep apnea, and stroke.

In a study performed by Bonetti et al* at the Mayo Clinic, a group of 94 subjects underwent angiographic assessment of coronary endothelial function and subsequent EndoPAT tests. Coronary endothelial function was quantified by injection of acetylcholine into a coronary artery during angiography.

The EndoPAT, which is a non-invasive test, was found to be highly correlative to the angiography results. It was this study that helped EndoPAT receive final FDA clearance for the detection of coronary endothelial dysfunction.  An RHI of 1.35 provides a sensitivity of 80% and a specificity of 85% for diagnosing coronary endothelial function.

* 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. JACC 2004; 44: 2137-2141.