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Endothelial Function, the ability of the artery wall to generate Nitric Oxide, is a key determinant of short, intermediate, and long-term CV health. Risk factors cause plaque formation, progression, and rupture through the final common pathway of endothelial dysfunction. Poor endothelial function reflects vulnerable biology and increased vascular risk. Conversely, by improving endothelial tone, we can attenuate or neutralize the adverse effects of your risk factor burden.
The Endothelium refers to the single layer of cells that line our arteries and veins, a mass of tissue the size of the liver. Think of the endothelium as a biochemical factory, the leading edge of the atherosclerotic (and anti-atherosclerotic) process. Mediators (or more precisely the balance of mediators) generated by the endothelium determines blood vessel dilation vs. constriction, platelet stickiness vs. non-stickiness, oxidative stress vs. vascular wall antioxidant function, an uncontrolled vs. a modulated vascular wall inflammatory response, etc. Stated otherwise, control of the endothelium leads to control of the atherosclerotic process.
Flow Mediated Vasodilation is used to measure endothelial function, and together with Carotid IMT to gauge the success or failure of our risk factor reduction efforts. In response to increased blood flow (how exercise and EECP help you) the endothelial cells lining our arteries convert arginine into nitric oxide. Nitric oxide (NO) in turn rapidly dilates the artery.
For testing purposes, we use non-invasive pulse amplitude tonometry (PAT) to measure blood flow at the level of the finger tip. A BP cuff is inflated above systolic pressure for five minutes, limiting blood flow to the arm. The cuff is then released, blood rushes into the arm, and this increased flow leads to increased nitric oxide generation and the blood vessel dilation, to a degree determined by the level of endothelial health that you bear. Accuracy and predictive value of the EndoPAT device correlate well with other invasive and non-invasive means of endothelial testing and EndoPAT is FDA approved for this purpose. Testing is convenient, reproducible, and without risk to you.
An EndoPAT score below 1.7 is abnormal, and correlates with endothelial dysfunction as determined by invasive testing; 1.7 to 2.0 is borderline, and a score > 2 reflects intact endothelial tone. However, we really should look at endothelial function in a continuous as opposed to a “cut-off” fashion, just as we look at BP, blood glucose, and cholesterol. When I trained a BP of 140/90, a fasting glucose of 110, and a cholesterol < 300 were considered “within normal limits”. We now understand that “lower is better”, so with respect to your EndoPAT score, “higher is better”. We will measure your endothelial status under pristine conditions, early in the day, with an empty stomach, and hopefully in a low stress environment. If we were to repeat your study after a sugar load or high fat meal, when you are stressed, or following exposure to cigarette smoke or automobile exhaust, we would see a decrease in your score. Measures that optimize resting endothelial tone also blunt the adverse effects of these environmental/dietary endothelial stressors, so the better your resting score, the greater will be your endothelial reserve.
We’ve carried out your EndoPAT evaluation and determined your score. Now, what can we do to increase your score and thus optimize your level of vascular protection? Plenty, if we understand and support the factors that contribute to endothelial health.
Oxygen ——————————> Superoxide
NITRIC OXIDE SYNTHASE
Arginine ——————————> Nitric Oxide
( – ) Asymmetric Dimethylarginine
When things are going well, the enzyme Nitric Oxide Synthase (NOS) converts dietary arginine into Nitric Oxide (NO). It is NO that dilates our vessel, renders platelets non-sticky, and resists plaque formation; it is NO that takes the “vulnerability” out of vascular biology. From the perspective of preventing CV disease, NO is a good thing, and we want a lot of it.
In biology, however, too much of a good thing, at the wrong time, can be a problem. Let’s say you got up one morning, left your cave, and got bit by a saber tooth tiger; your wounds bled and your BP begins to fall. Or maybe you ran out of water during a trip across the desert in search of food, or you developed sepsis when a wound failed to heal. In these conditions, we don’t want NO dilating our blood vessels or inhibiting clot formation. We want the opposite, and here Mother Nature gives us Superoxide, the antagonist to NO. Superoxide is a free radical. It instantly degrades NO, leading to instant blood vessel constriction, immune system up regulation, and an increased clotting tendency, great ideas when you are bleeding out following the tiger bite. However, it is Superoxide that damages endothelial function. It is Superoxide, canceling out Nitric Oxide that is the ultimate cause of cardiovascular disease. Mother Nature did not give us Superoxide to kill us. Rather, the risk factors that contribute to CV disease are interpreted by our physiology as the threats to survival commonly encountered by primitive man – hypotension, bleeding, and sepsis. Mother Nature misconstrues risk factors as threats, so she up regulates Superoxide and shuts down NO production, generating the chronic vascular wall inflammatory condition that today we call atherosclerosis.
How does Mother Nature throw the switch? What tells NOS to generate Superoxide as opposed to NO? The key determinant is the ratio of ADMA to arginine. ADMA is short for asymmetric dimethylarginine, arginine with two methyl (CH3) groups attached. When the ratio of ADMA to arginine is high, NOS stops making NO and starts generating Superoxide. Next question – what factors determine ADMA levels, the ADMA:Arginine ratio, and thus NO vs. Superoxide production?
( – ) Risk Factors
ADMA is generated at a constant rate and is excreted by the kidneys (kidney disease leads to vascular disease via the mechanism of impaired ADMA excretion). ADMA is degraded by the enzyme DDAH (Dimethylarginine Dimethylaminohydrolase). So, if we do not want vascular disease, we want DDAH functioning normally, to prevent a buildup of ADMA. All CV risk factors lead to oxidative stress, which in turn inhibits DDAH, leading to a high ADMA:Arginine ratio. NOS generates Superoxide (SO) as opposed to NO, endothelial dysfunction follows, leading to CV disease. The long-term risk factors (and the oxidative stress they generate) born by modern man are interpreted by our physiology as threats to the short term survival of primitive man, and this leads to the long-term maladaptive process that we call atherosclerosis, initiated and driven by endothelial dysfunction.
What can we do to lower the ADMA:Arginine ratio and prevent vascular disease? We can resolve our risk factors. If we lower cholesterol, BP, homocysteine, glucose, etc., lose weight, stop smoking and deal with sleep apnea, oxidative stress will lessen, DDAH will be dis-inhibited, ADMA will fall, and NOS will start cranking out NO as opposed to SO. However, if we cannot (or cannot rapidly) resolve your risk factors, what we can do is to supplement with arginine to “rebalance” your high ADMA:Arginine ratio. During health, there is plenty of arginine available. NO production is normal and providing additional arginine does nothing. Your BP will not fall and you will not begin to bleed; rather nothing will happen. However, if due to risk factors and oxidative stress your high ADMA:Arginine ratio has shut off NO production, dietary arginine will rebalance the ratio. You still have a high ADMA level, but if we counter with extra arginine, the ADMA:Arginine ratio will fall, and it is the ratio, not the absolute levels of ADMA and arginine that determine the activity of NOS. Thus Arginine is a universal antidote for endothelial dysfunction. Arginine has been shown to improved endothelial function when it is compromised by risk factors. Via the mechanism of improved endothelial function, arginine therapy has been demonstrated to improve symptomatic status and/or outcome in all forms of chronic CV disease. Pain improves and treadmill time increases in patients suffering from angina or claudication. Heart failure patients enjoy a better quality of life and effort capacity. Erectile function improves. Arginine has universal preventive value when risk factors are present. In head to head competition, arginine is equal to and in some patients superior to statin therapy with respect to improving endothelial function (the ultimate mechanism through which statins, ACEI inhibitors, and ARBs improve endothelial function and help us is to decrease SO production within the artery wall; they are good at this and we will use them for this purpose). Arginine supplementation makes sense if you suffer from endothelial dysfunction.
Other nutritional factors help determine the state of endothelial health. NO lasts 1/10th to 1 second. We store NO by reacting it with sulfhydryl (SH) bearing molecules, such as cysteine and glutathione. SH bearing molecules are destroyed by free radicals and they are tied up by toxic metals, especially Mercury (the mechanism of benefit of chelation therapy is to remove these metals that compromise endothelial chemistry). Thus we wish to bolster our antioxidant defenses, with special emphasis on SH bearing antioxidants (such as N-Acetyl Cysteine) and SO neutralizers such as Vitamin C. Bioflavonoids stabilize Vitamin C, explaining how tea consumption, red wine, and cocoa consumption all improve endothelial function.
Folates, particularly methyl-folate and tetrahydrobiopterin (BH4) are required for proper function of NOS. Methyl-folate also squelches peroxynitrite (an anti-endothelial free radical that is formed when SO destroys NO), and thus folate/methyl-folate supplementation makes sense if endothelial tone is compromised.
Magnesium is required to generate the energy needed to power NOS. In patients with angina, magnesium supplementation has been shown to improve endothelial function, symptomatic status, and treadmill time. A fluid endothelial cell membrane is needed for arginine to enter and NO to exit the endothelial cell, and via this mechanism fish oil supplementation improves endothelial function and outcomes in all CV disease states. Taurine has a stabilizing effect on endothelial tone is smokers and is also likely of benefit in other risk factor states.
Nitric oxide also had a powerful immune modulating effect. Our Immune Mechanisms in CV Disease presentation (3 DVDs) discusses the deleterious effects of chronic inflammation and immune dysregulation. High levels of vascular wall NO will keep vascular inflammation in check. Treatments that improve endothelial function also attenuate inflammation. If you review our IMT presentation, you will see that these treatments also lessen IMT. Inflammation, endothelial dysfunction, IMT, and plaque formation are all different expressions of a common biological flaw – high levels of SO and low levels of NO. We can fix this!
While NOS dysregulation is our most important endothelial biochemical problem, up regulation of ACE (Angiotensin Converting Enzyme) is a close second. In the circulation, the product of ACE, Angiotensin II, is a vasoconstrictor, a cause of hypertension and fluid retention. Blockade of ACE has been a main stay of hypertensive management for 25 years. However, the majority of ACE is present within our cells, and within the endothelium, the generation of Angiotensin II
Angiotensin I ———————> Angiotensin II
ANGIOTENSIN CONVERTING ENZYME
leads to superoxide formation, and with this endothelial dysfunction and immune dysregulation. Blockade of endothelial ACE with a fat-soluble ACE inhibitor (quinapril and ramipril but not lisinopril or enalapril), or an agent that blocks the angiotensin receptor (ARBs – angiotensin receptor blockers) will blunt superoxide formation, improve endothelial tone, and quiet down an abnormal immune response. If your BP is at all elevated, or if you have heart failure, I will emphasize this class of drugs in your treatment (Quinapril has been shown to improve outcome in certain coronary conditions even when BP is normal). The use of these drugs is associated with a high benefit to risk ratio.
Cholesterol enrichment of the endothelial cell membrane compromises endothelial function. High cholesterol ® endothelial dysfunction ® increased endothelial uptake and oxidation of cholesterol ® immune dysregulation ® CV disease. If the cholesterol is oxidized, this progression is accelerated. Low cholesterol is associated with a reduced risk of atherosclerosis. If you have atherosclerosis, lowering cholesterol (and blunting its oxidation) will be beneficial. Statin drugs will lower cholesterol, but that is only part of how they work. Statins block the cholesterol biosynthetic pathway at a step that would otherwise activate several pro-inflammatory pathways (conditions that lead to increased cholesterol production also up regulate our biochemical “fight or flight” responses). One of these pathways, Rho Kinase, up regulates the production of superoxide within the artery wall. Statins block Rho Kinase, and when Rho Kinase is up regulated (and SO levels are thus high), statin therapy will improve disordered endothelial function (why statins improve outcome in active CV disease even when cholesterol is normal). Conversely, when Rho Kinase is not up regulated, statin therapy has no effect on endothelial function. Thus the relative benefits of statin therapy rise in relation to the degree of inflammation and oxidative stress present. Statin therapy is more valuable to you when plaque is unstable as opposed to when plaque is stable. Statin therapy has some downsides (mediated via reductions in Co-Enzyme Q10, Vitamin D, and steroid hormone generation; downsides that we can measure and rectify). If you just experienced your third heat attack following your second bypass surgery, then statin therapy is right for you. Conversely, the use of statins in younger patients with uncomplicated high cholesterol probably has more long-term down side than benefit. Red Yeast Rice Extract (RYRE) contains several naturally occurring statin compounds, and while less powerful than statins with respect to cholesterol reduction, RYRE will provide qualitatively similar anti-inflammatory and pro-endothelial benefits. One important note, when the ADMA:Arginine ratio is elevated, statin therapy will not improve endothelial function, while arginine monotherapy, or arginine + statin therapy will. Remember, there is no rule that says we have to be drug only or nutritional only doctors. The goal of this practice is to integrate the best of pharmacologic/invasive cardiology with the principles of nutritional/detoxification medicine to obtain the best outcomes for our patients!
Our approach to your endothelial status will be tailored to your risk factor and
clinical status, but our generic approach is given below:
1. Arginine supplementation – relatively low in cost and essentially risk free*. Options include: A. Standard arginine 4,000 mg (1 & 1/3rd teaspoon) three times a day. The poor taste can be masked with “Yuck-Away” or by mixing the arginine powder into warm water.
B. ArginCor 2 scoops twice a day. One scoop provides 1,500 mg arginine, 200 mcg folic acid, 100 mg magnesium, and 1000 mg of beet root powder, and has a pleasant taste.
C. Neo-Forte one tab twice a day. Neo-Forte contains beet root powder, a source of nitrate. The idea here is that nitrate will be back converted into NO and improve endothelial function. This methodology probably does work, but we have no clinical studies demonstrating actual benefits on endothelial function or symptomatic status/outcomes, while we have 100s of positive arginine studies. I do not discourage the use of beet root powder, but right now I do not advocate it as the best approach.
D. ArginCor 1 scoop mixed with 1 & 1/3rd teaspoon of Arginine twice a day. Taste is acceptable and this hybrid therapy will be out most cost-effective approach.
2. Co-factor support will be a function of your nutritional assessment**, but as
1. N-Acetyl Cysteine 500 mg daily and Vitamin C 500 mg twice a day.
2. Magnesium Glycinate 600 mg (pill form) or ½ tsp. (powder form) twice a day.
3. Folic acid 1,000 mg/day or preferably methyl-folate 800 mcg/day.
4. Fish Oil 2,000 mg/day.
5. Taurine 500 mg twice a day.
3. Pharmacologic intervention. While we prefer to minimize drug intervention, if your endothelium is on fire, I need to douse the flames, and do so rapidly and here we will exploit the benefits of ACEI/ARB and statin therapy.
4. Hormonal support. Estradiol in women, testosterone in men, and DHEA in both genders supports endothelial function. Conversely, the reduction in endothelial function seen with ageing is in large part due to a loss of hormonal support. Hormone replacement therapy improves endothelial function (this is the key mechanism through which testosterone replacement therapy improves endothelial tone, blunts inflammation, and improves symptomatic status in men with CV disease). There are a number of pros and cons to hormone replacement therapy, but if you chose to receive HRT, we would utilize bioidentical molecules, delivered in a physiologic fashion, with close monitoring of hormone levels and hormone metabolites.
5. Detoxification of pro-oxidant metals and organic pollutants. When I trained atherosclerosis was a disease of old men and much older women. These days we see heart attacks in 50 year olds with normal cholesterol levels. Environmental toxins deplete our nutritional reserves, generate oxidative stress, and damage our endothelium as well as our DNA. Remove these toxic molecules from your body. I have been trained in chelation therapy and help teach this technique to other physicians and am an investigator in NIH Trial to Assess Chelation Therapy. We are more than happy to help you remove toxic metals and organic pollutants form your body.
A DVD on endothelial function is in the works. I understand that all of this is rather technical, but I want you to understand the factors that cause and resolve cardiovascular disease. “Do as I say” medicine rather than “please understand your disease” medicine is also available to you, but this will be a medicine confined to drugs and surgery. We will use drugs to improve endothelial function and invasive therapies when appropriate (and I refer patients for bypass surgery and stent placement all the time) but for my patients (and myself) I want something beyond this. I want an integrative approach to cardiovascular and overall health.
James C. Roberts MD FACC FAARFM
* The herpes virus grows more rapidly in a high arginine environment and is inhibited by lysine. If cold sores or other herpes virus related conditions develop in relation to arginine supplementation, add lysine 500 mg twice a day to your program.
** We can assess your nutritional status and level of oxidative stress with the Genova Labs NutrEval study, which is covered under Medicare (typical co-pay is $170 for private insurance).
High levels of glutathione and cysteine within the endothelium help to maintain a “ready reserve” of NO.
N-Acetyl cysteine, lipoic acid, and glycine help support the endothelial glutathione pool.
Free radicals such as superoxide degrade NO into peroxynitrite, a particularly damaging free radical.
Vitamin C squelches SO and methyl-folate neutralizes peroxynitrite.
Angiotensin Convertin Enzyme (ACE) not only generates Angiotensin II, but also degrades Bradykinin.
Bradykinin up regulates the production of NO and Prostacyclin (PGI2 in the diagram),
the metabolite of fish oil that protects against CV disease.
Blockade of ACE within the endothelial cell preserves the vascular benefits of bradykinin.
Phosphorylation of serine at the 1177th amino acid position within the NOS molecule, rapidly upregulates its ability to generate NO. Testosterone, estradiol, and DHEA increase the formation of NOS, but also activate the enzyme systems that phosphorylate serine 1177. This explains why intracoronary testosterone dilated coronary arteries and how IV or topical testosterone rapidly improves treadmill time in coronary patients.
Inflammation leads to up
regulation in iNOS (inflammatory NOS) which generates too much NO, at the wrong
place and at the wrong time. This activates the enzyme arginase, which degrades
arginine, increasing the ADMA:Arginine ratio and compromising endothelial
Thus we wish to support our immune defenses while at the same town protecting against inappropriate chronic inflammation.