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COVID-19 Involves Oxidative Stress and Inflammation: Antioxidants Are Possibly Therapeutic and Preventative

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SARS-COV-2 (COVID-19 or Coronavirus) is a severe, acute, respiratory syndrome infection that involves the lungs and the immune system.  The major clinical feature is Respiratory Distress Syndrome, and one key complication is Acute Cardiac Injury [1].  COVID-19 is a self-limiting infection and the strength of the immune and respiratory systems is critical in overcoming the infection and surviving the potential morbidity and mortality risks associated with the infection. Several comorbidities have been reported as risk factors for unfavorable prognosis in patients with COVID-19.  The most common comorbidities that influence the outcome of COVID-19 patients are Cardiovascular Disease (CVD), Diabetes Mellitus type 2 (DMT2), Hypertension, Malignancy and Chronic Obstructive Pulmonary Disease (COPD), among others, especially pulmonary disorders.  Smoking and other factors that may compromise the lungs have also emerged as risk factors associated with a worse outcome.  For example, China, which is one of the hardest-hit countries, has the vast majority of its population living in densely populated cities in which there have been significant amounts of construction, and the majority of their heat and electricity comes from burning fossil fuels, especially coal.  This has been the condition for a number of years.  On a visit to a number of their larger cities over a number of weeks in 2014, many of its citizens, especially the younger adult population, were already wearing masks to protect themselves from the heavy particulate pollution.  In other words, by the time of the COVID-19 outbreak, it is reasonable to assume that the population of China was already respiratory-compromised to some degree.

As commented [2], it has been shown that oxidative stress is associated with the same diseases (including CVD and DMT2 [3]) that increase the risk of a severe outcome from COVID-19.  Oxidative stress is a condition of imbalance between the release of Reactive Oxygen Species (ROS) and the endogenous antioxidant capacity of an individual’s system.  It is also well known that smoking can induce cellular oxidative stress while it depletes antioxidants through various mechanisms [4],[5].  Studies have shown that antioxidant deficiency leads to increased sensitivity to even mild oxidative stress, while altered activity and levels of antioxidants have been recognized as markers of inflammation [6].  For example, and specifically for the Respiratory System, dysregulation of Glucose 6-Phosphate Dehydrogenase leads to a greater risk for protein glycosylation [7], a process that plays an essential role in promoting viral pathogenesis, including COVID-19 [8,[9],[10].  This example suggests that antioxidant therapy may help to treat, and perhaps prevent, SARS infections, including COVID-19, as well as Influenza.

It has been demonstrated [11] that human lung epithelial A549 cells with lower G6PD activity (via RNA interference) have a 12-fold higher viral production when infected with human coronavirus 229E, which shares a sequence similarity with COVID-19 and clinically resembles it, compared to control cells [11,[12].  Antioxidants may at least provide heart protection for COVID-19-infected individuals, based on the oxidative stress theory [13].  According to recent clinical reports, the therapeutic time for COVID-19 infection is much longer than 14 days, but long-time viral stimulation is prone to suddenly elicit intensive immunological reactions, cytokine storm, and immune-cell infiltration.  However, some immunocytes, especially Macrophages and Neutrophils, can produce numerous Reactive Oxygen Species (ROS) [13,[14],[15].

A certain level of ROS is important for regulating immunological responses, clearing viruses, and general health.  It is part of the first line of defense by the immune system.  Together with fever, Oxidants (like ROS) are used to “burn” the invading “trash” (i.e., foreign or excessive bacteria, molds, mildews, viruses, etc.) that enters your body every moment.  The immune system collects the Oxidants and dumps them on the invading trash to kill them by oxidizing cellular proteins, membrane lipids, Mitochondria, and even DNA and RNA, etc.  Meanwhile, the body brings in the Antioxidants to “put out the fire” once the “trash” is burned to protect the healthy tissue.  However, excessive ROS (such as with illness, cancer, or Psychosocial stresses – including mental and physical stresses) will cause excessive oxidative stress, overwhelming the body’s reserve of Antioxidants, resulting in sickness and, in the extreme, death.  This is why, in general, it is good to have a healthy Antioxidant reserve, and this is best built up through exercise and diet and, in those at risk, with additional nutraceuticals to supplement.

Oxidative stress may quickly destroy not only virus-infected cells, but also normal cells in the lungs, heart, nerves, and kidneys, resulting in multiple organ failure.  Lungs are susceptible because they are constantly exposed to the outside.  The heart and nerves are susceptible because they contain the greatest number of Mitochondria of all the cell-types in the body.  Ironically, Mitochondria (the power plants of the body) are the greatest natural producers of ROS in the body (think of ROS and oxidants as the “pollution” from the power plants, however, in the case of the body these “pollutants” are used for good, to help the body, under normal conditions).  The kidneys are susceptible because their job is to filter out the toxins from the blood, therefore, they exist in a highly toxic environment.  Thus, a healthy Antioxidant reserve helps to prevent illness and, if ill, helps to treat illness, just like with colds, when people consume additional amounts of Vitamin C, a well-known antioxidant, to help rid themselves of the virus that caused the cold.

Thus, a potential antioxidant therapy could be proposed to alleviate the respiratory, cardiogenic, and other casualties caused by COVID-19.  For example, inexpensive medicinal Antioxidants include Vitamin C (Ascorbic Acid) and Vitamin E.  These work through their reductive Hydrogen atoms react with ROS and then produce nontoxic water [16].  Plant-derived molecules (similar to ancient Chinese medicine), such as Curcumin (aka., Turmeric), may have potential antioxidant efficacy. These well-known Antioxidants and others (e.g., Vitamin A, Glutathione, Resveratrol, Omega-3 Fatty Acids, proper daily intake of water – 48 to 46 oz, etc.) are known to be made more potent through recycling with either Alpha-Lipoic Acid (ALA) or Co-Enzyme Q10 (CoQ10).  While ALA and CoQ10 are arguably the most powerful Antioxidants the body naturally makes, they increase their strength and the strength of the other Antioxidants by redirecting them away from the kidneys for another pass through the body.  ALA tends to be specific for nerves, helping to protect the Mitochondria in the nerves to prevent the nerves from weakening, thereby preventing or relieving the neurological symptoms of illnesses, including viruses, like lightheadedness, malaise, cognitive and memory difficulties, fatigue, etc.  CoQ10 tends to be specific for the heart, helping to protect the Mitochondria in the heart to prevent the heart from weakening, thereby preventing or relieving the cardiological symptoms of illnesses, including viruses, like low blood pressure, lightheadedness, fatigue, etc.

These Antioxidants also help to reduce chronic inflammation [6] which serves to exacerbate the effects of viruses, especially in the lungs as with SARS viruses (including COVID and Influenza).  These Antioxidants are helped with Nitrates (dietary and supplemental) to boost the production of Nitric Oxide in the body.  Nitric Oxide performs multiple functions in the body, including as an Antioxidant and an Anti-inflammatory, and it helps to prevent or relieve Atherosclerosis to improve heart health.  Nitric Oxide also helps to detoxify the body, reducing the prevalence of Oxidants, including ROS.  Nitric Oxide may be supplemented through L-arginine (which is limited by the body’s needs to produce it), L-Citrulline and L-Carnitine (which help the body to produce L-Arginine, and therefore is limited), and dietary Nitrates (the most well-known supplement at this time is Beet Root Extract Powder[1], and there are others).  Dietary Nitrates are not limited and help to produce as much Nitric Oxide as is possible from the amount ingested.  A healthy diet, like the Mediterranean Diet with multiple servings of fresh vegetables and fruits, helps to provide all of the above.  The typical American Diet does not and may be contributing to Americans being more susceptible to illness, including COVID-19.

An optimal immune response depends on an adequate diet and nutrition in order to keep infection at bay [17].  For example, sufficient protein intake is crucial for optimal antibody production.  Low micronutrient status, such as of vitamin A or Zinc, has been associated with increased infection risk.  Frequently, poor nutrient status is associated with inflammation and oxidative stress.  Dietary constituents with especially high anti-inflammatory and antioxidant capacity include vitamin C, vitamin E, and phytochemicals such as carotenoids and polyphenols (i.e., Resveratrol) and sources of other antioxidants (e.g., Glutathione, CoQ10 and ALA), as well as Nitrates and Amino Acids that support proper levels of Nitric Oxide production. Several of these can interact with transcription factors such as NF-kB and Nrf-2, related to anti-inflammatory and Antioxidant effects, respectively. Vitamin D in particular may perturb viral cellular infection via interacting with cell entry receptors such as Angiotensin Converting Enzyme 2 receptors (ACE2).  Dietary fiber, fermented by the gut microbiota into short-chain fatty acids, and other sources of healthy Fatty Acids (e.g., Extra Virgin Olive Oil), have also been shown to produce anti-inflammatory effects, among other benefits for example, to help keep cell membranes pliable and resilient to infection.  These and more are the benefits of a healthy diet with fresh, ripe produce (including extra helpings of dark green leafy vegetables – raw or lightly cooked, they still need to be green; not gray) and well-balanced proteins and fats which reduce inflammation and oxidative stress, thereby strengthening the immune system during any infection, including the COVID-19 crisis.

With all of the above regarding Antioxidants being said, arguably the most powerful and universal Antioxidant is EXERCISE [6,[18]].  Just one example is fever.  As mentioned above, fever is part of the body’s first-line defense against illness and invading pathogens (viruses, bacteria, molds, mildews, allergens, etc.).  While healthy human cells may survive between the temperatures of 98 and 104 °F, pathogens tend to be killed above 101.1 °F.  Mild to moderate exercise for 40 minutes or more a day at least three times per week will simulate a fever (raise body core temperature to above 101.1 °F for at least 20 minutes).  The simulated fever will help the body to eliminate any invading pathogens before they acquire a “foot-hold.” Read that: potentially kill off any COVID-19, Influenza, or other viruses, if exposed, before the pathogens (including the viruses) have a chance to infect you and make you sick.  By mild to moderate exercise, we mean walking, gardening, playing with children, housework, calisthenics, or any activity that raises your heart rate and blood pressure above resting for a continuous 40 minutes and makes you sweat for at least 20 minutes.  Of course, if you are healthy and fit, more strenuous exercise is also helpful to simulate fever.  Exercise will also provide a number of other benefits, including:  happier moods, reduced pain, better sleep quality, improved concentration and creativity, reduced stress levels and anxiety, maintained mental fitness, improved parasympathetic and sympathetic nervous systems function, stress reduction, improved heart and vascular health, improved neuroendocrine health, weight control (loss), reduced risk of DMT2 and metabolic syndrome, reduced cancer risk, stronger bones and muscles, reduced arthritis and other joint disorders, and promoted longevity (promotes living longer) [6].[2]

Exercise is demonstrate to have both short and long term effects by increasing aerobic capacity thereby increasing the function and strength of immune and respiratory systems, particularly those essential for overcoming COVID-19 infections and associated disorders. [18].  Exercise that increases aerobic capacity produces safe improvements in the function of immune and respiratory systems, particularly those specific for COVID-19 infections.  These improvements are mediated through:  (1) improved immunity by increasing the level and function of immune cells and immunoglobulins, regulating CRP levels, and decreasing anxiety and depression; (2) improved respiratory system functions by acting as an Antibiotic, Antioxidant, and Antimycotic[3], restoring normal lung tissue elasticity and strength; and (3) reducing the effects of risk factors such as DMT2,  Hypertension, and CVD, Obesity, and aging, to decrease COVID-19 risk factors, which helps to decrease the incidence and progression of the virus.  To punctuate the issue, a recent review article [19] highlights the impact of “sedentarism” due to the COVID-19 home confinement.  Even a few days of sedentary lifestyle are sufficient to induce muscle loss, neuromuscular junction damage and fiber denervation, insulin resistance, decreased aerobic capacity, fat deposition and low-grade systemic inflammation.  Regular moderate exercise, together with a 15-25% reduction in caloric intake, are recommended for preserving neuromuscular, cardiovascular, metabolic and endocrine health, important in reducing the effects of the virus.


A proper dose of Antioxidants may ameliorate respiratory, cardiac, and other system injuries of critically ill COVID-19-infected patients


Even after a serious infection, like from COVID-19, if the Antioxidant system was over taxed, the virus or infection will leave behind oxidative stress – at the cellular level.  We emphasize “at the cellular level” because often times, the systems seem normal and healthy and all of the tests that most physicians order return normal, yet there are lingering symptoms and even disability, both mental and physical.  The problem is two-fold.  First, while the individual cells themselves are dysfunctional, the net sum total of their functioning still meets the minimum standards for “normal.”  Second, the typical patient’s problem is not at rest (which is when most tests are performed – sitting or lying down) but when active.  It is like a car with a full fuel tank, which idles just fine, but, due to a clogged fuel filter, cannot accelerate when needed.  They look normal at rest, but are quickly fatigued when required to do work, either mental or physical.  Again, Antioxidants, especially ALA, CoQ10, and EXERCISE, will help to relieve the oxidative stress and thereby relieve the fatigue and other lingering symptoms.

Currently, there is a lack of evidence regarding the exact role that Antioxidants play in COVID-19 infection. High-dose supplementation with Antioxidants, when given at an early stage of the infection, may prevent the spread of the virus in the body, thereby providing protective effects and reducing the severity of disease.  This is proven to help in the other well-known SARS viruses including Influenza.  To that end, traditional medicine products, supplements and nutraceuticals that are Antioxidants and anti-inflammatories are amongst the various additive treatments for COVID-19 under investigation [20].


[1] Not the portion of the beet that is typically eaten, the tuber, but the little root below the tuber.

[2] However, as always, an exercise regimen should be started under close physician supervision.  The wrong types of exercise may do more harm than good, including increasing body fat (and thereby weight), fatigue, and pain due to the fact that the body is programmed to over-react to stresses.  Under these conditions, the body sees exercise as stress and works to protect itself against the stress. 

[3] An agent that is used against fungal infections.




[1] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al., Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Lancet 395 (2020) 497–506.

[2] Wang JZ, Zhang RY, Bai J.  An anti-oxidative therapy for ameliorating cardiac injuries of critically ill COVID-19-infected patients.  Int J Cardiol. 2020 Apr 6.  doi: 10.1016/j.ijcard.2020.04.009 (Epub ahead of print).

[3] Moldogazieva NT, Mokhosoev IM, Mel’nikova TI, et al. Oxidativestress and advanced lipoxidation and glycation end products (ALEsand AGEs) in aging and age-related diseases. Oxid Med Cell Longev2019;2019:3085756.

[4] Niemann B, Rohrbach S, Miller MR, et al. Oxidative stress and cardio-vascular risk: obesity, diabetes, smoking, and pollution: part 3 of a 3-part series. J Am Coll Cardiol 2017;70:230e251.

[5] Wenham C, Smith J, Morgan R. Gender and COVID-19 WorkingGroup. COVID-19: the gendered impacts of the outbreak. Lancet2020;395:846e848.

[6] DePace NL, Colombo J.  Autonomic and Mitochondrial Dysfunction in Clinical Diseases:  Diagnostic, Prevention, and Therapy.  Springer Science + Business Media, New York, NY, 2019.

[7] Jain SK. Glutathione and glucose-6-phosphate dehydrogenase defi-ciency can increase protein glycosylation. Free Radic Biol Med 1998;24:197e201.

[8] Watanabe Y, Bowden TA, Wilson IA, et al. Exploitation of glycosyl-ation in enveloped virus pathobiology. Biochim Biophys Acta GenSubj 2019;1863:1480e1497.

[9] Lan J, Ge J, Yu J, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020;581:215e220.

[10] Gumustekin K, Cifttci M, Coban A, et al. Effects of nicotine and vitaminE on glucose 6-phosphate dehydrogenase activity in some rat tissuesin vivo and in vitro. J Enzyme Inhib Med Chem 2005;20:497e502.

[11] Wu YH, Tseng CP, Cheng ML, et al. Glucose-6-phosphate dehydroge-nase deficiency enhances human coronavirus 229E infection. J InfectDis 2008;197:812e816.

[12] Li Y, Liu B, Cui J, et al. Similarities and evolutionary relationships ofCOVID-19 and related viruses. arXiv 2020;2003. 05580 [q-bio.PE].

[13] Loffredo L, Martino F, Zicari AM, Carnevale R, Battaglia S, Martino E, et al., Enhanced NOX-2 derived oxidative stress in offspring of patients with early myocardial infarction, Int. J. Cardiol. 293 (2019) 56–59.

[14] Perrone LA, Belser JA, Wadford DA, Katz JM, Tumpey TM, Inducible nitric oxide contributes to viral pathogenesis following highly pathogenic influenza virus infection in mice, J. Infect. Dis. 207 (2013) 1576–1584.

[15] Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, van Loo G, et al., Identification of oxidative stress and toll-like receptor 4 signaling as a key pathway of acute lung injury, Cell 133 (2008) 235–249.

[16] Erol N, Saglam L, Saglam YS, Erol HS, Altun S, Aktas MS, et al., The protection potential of antioxidant vitamins against acute respiratory distress syndrome: a rat trial, Inflammation 42 (2019) 1585–1594.

[17] Iddir M, Brito A, Dingeo G, Fernandez Del Campo SS, Samouda H, La Frano MR, Bohn T. Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis. Nutrients. 2020 May 27;12(6):E1562. doi: 10.3390/nu12061562. PMID: 32471251.

[18] Mohamed AA, Alawna M. Role of increasing the aerobic capacity on improving the function of immune and respiratory systems in patients with coronavirus (COVID-19): A review.  Diabetes Metab Syndr. 2020 Apr 28; 14(4): 489‐496.  Published online ahead of print,

[19] Narici M, De Vito G, Franchi M, Paoli A, Moro T, Marcolin G, Grassi B, Baldassarre G, Zuccarelli L, Biolo G, di Girolamo FG, Fiotti N, Dela F, Greenhaff P, Maganaris C. Impact of sedentarism due to the COVID-19 home confinement on neuromuscular, cardiovascular and metabolic health: Physiological and pathophysiological implications and recommendations for physical and nutritional countermeasures. Eur J Sport Sci. 2020 May 12:1-22. doi: 10.1080/17461391.2020.1761076. Epub ahead of print. PMID: 32394816.

[20] Fauci AS, Lane HC, Redfield RR. Covid-19: Navigating the uncharted. N Engl J Med 2020;382:1268e1269.

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Mind Body Wellness

COVID-19 (Coronavirus) and Exercise, Diet, and Antioxidants

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COVID-19 Prevention Tips: Exercise And Nutrition

COVID-19, the Coronavirus, like the flu (e.g., the Influenza virus) and similar to colds, may be prevented or mitigated, and are often treated, by the combination of a healthy diet and exercise, and perhaps additional antioxidant; the most common being Vitamin C in some form:  fresh, ripe fruits and vegetables are preferable, and supplements are also good.

In fact, many typically healthy people have contracted COVID-19 and have recovered.  Many more have contracted it and may have even had mild symptoms, but never knew they had it until after having recovered from COVID-19.  This is similar to cases with the Influenza virus or the flu.  So like, the flu, those at risk need to protect themselves and take necessary precautions to stay healthy.  Again, the major contribution to health, even if you are at risk, is a healthy diet full of fresh fruits and vegetables and exercise.


Please, EXERCISE IS NOT A DIRTY WORD!  It does not have to be drudgery.  We are not talking about going to the gym and beating yourself up for hours.  Perhaps a better description is “ACTIVE LIFESTYLE,” which may include exercise (in the sense of the current vernacular), but it should reflect the lifestyle of people before automobiles, elevators, television remotes, and cell phones.  It can be a single (preferably daily) acute bout of physical exertion or muscular activity that expends energy above one’s basal or resting level – frequent movement of some sort.  It is true, siting has become the “new smoking.”  For those who are old enough, we are referring to a time before electronics, when play was not sitting around with computer games getting strong thumbs and weak bodies and communicating with someone was not done electronically developing stronger thumbs.  People walked places or rode their bikes, children were outside walking, skipping, running, jumping, breathing fresh air and soaking in sunshine for their daily dose of Vitamin D.  Adults would do house work, garden, yard-work, walk to the corner store, walk over to the neighbors to check on the children, or have a cup of coffee or tea and catch up on the news of the neighborhood, or simply play with the children at home, take the stairs or shop, etc.  Life was not sedentary.  Life included what we mean by exercise.

The physiologic and psychologic benefits of exercise are numerous.  It is better than any supplement or pill available, and what we mean by exercise is infinitely less expensive.  Again, it is probably better than any combination of supplements or pills or possibly even pharmacological agents available.  In fact, exercise with supplements, etc., including diet which supports exercise, is the best combination for minimizing the risk of illness, including flu conditions, like COVID-19.  Exercise optimizes quality and continuation of life, and minimizes mortality risk, which optimizes longevity and minimizes the impact of disease if and when it happens.  While the diet fuels exercise and provides the nutrients needed for good health, exercise provides many health benefits, like simulated fever and being (arguably) the strongest antioxidant available.  The list of benefits includes:

Wards-off Viruses and other pathogens trying to invade your body by simulating fever.  Exercise raises your core body temperature.  Most pathogens are killed by elevated temperatures (like above 101°F).  Our recommended 40 minute walk at 2 mph typically reaches this core body temperature goal and helps to prevent viruses and other pathogens from gaining a foothold in your body.  In effect the higher temperatures help to “burn-out” the invaders, including viruses.

Happier Moods from the release of endorphins in the brain, and other brain chemicals that elevate mood.  Regular physical activity (3 to 5 times a week for 30 to 60 minutes each time) reduces risk of depression.

Immune Health from two aspects of exercise as mentioned above:  1) Exercise (physical activity) raises the body’s core temperature, simulating a fever (20 minutes or more of exercise, three or more times per week helps to prevent disease before is starts); 2) Exercise is arguably the strongest antioxidant available and provides all of the benefits of antioxidants (like Vitamin C), including defeating (promoting the oxidation of) all types of infections:  viral, bacterial, fungal, etc.

Reduced Pain.  Endorphins are natural pain killers and can help to provide temporary pain relief.

(The brief explanations of the rest of these benefits are available at the end of this document.)

Better Sleep Quality.[1]

Improved Concentration & Creativity.[2]

Reduce Stress Levels & Anxiety.[3]

Maintain Mental Fitness.[4]

Parasympathetic and Sympathetic (P&S) Nervous Systems.[5]

Stress Reduction.[6]

Heart & Vascular Health.[7]

Neuroendocrine Health.[8]

Weight Control (Loss).[9]

Reduced Risk of Type 2 Diabetes and Metabolic Syndrome.[10]

Reduced Cancer Risk.[11]

Strengthen Bones and Muscles.[12]

Promotes Longevity (promotes living longer).[13]

CAUTION:  As always, an exercise regimen should be started under close physician supervision.  The wrong types of exercise may do more harm than good, including increasing body fat (and thereby weight), fatigue, and pain due to the fact that the body is programmed to over-react to stresses.  Under these conditions, the body sees exercise as stress and works to protect itself against the stress.  With certain diseases (e.g., some arrhythmias, diabetes, stroke or aneurysm risk, or heart disease), the wrong type of exercise may also lead to heart attack, stroke, or sudden death.  It is best to start slow and build up and always listen to your body.  Until endurance built, recommended goals may not be reached for a while.  This is not bad; keep at it until the goals are reached.  The health benefits of physical activity far outweigh the risks of getting hurt.

As with a pure Mediterranean diet, strict compliance with the recommended 150 minutes of exercise per week is not required to get beneficial effects.  Smaller amounts of exercise are helpful, just not as much.


Again, exercise is the strongest antioxidant possible.  Less than healthy people, especially those at most risk, because of age or illness have fewer naturally available antioxidants made by their bodies.  Either (1) aging slows the production or (2) the disease is causing the immune system to use them faster than normal and out-pacing the body’s production.  Alpha-Lipoic Acid (ALA, specifically (r)ALA*) and CoQ10 are arguably the two most powerful antioxidants your body makes, and they are made more powerful by the fact that they recycle other antioxidants (like Vitamin C, as well as Vitamins A & E, and Glutathione). The fact that (1) exercise is arguably the most powerful antioxidant of all and (2) healthy youngsters are more active (exercise more) and are making more ALA and CoQ10 naturally than older or sicker folks, goes a long way to explaining the difference in the reaction of healthy youngsters versus healthy older folks.  It also explains why the more active older folks we know that have contracted COVID-19 have all survived.

In addition to helping the immune system, antioxidants also help keep Mitochondria healthy, especially ALA (in the nerves) and CoQ10 in the heart muscle. Again, exercise enhances this as well, as well as releases the endorphins, which helps to minimize depression and anxiety. By elevating mood, illness is minimized or prevented. The cascade goes on. There is a lot of this in the second book we wrote.[14]


Some doctors and scientists are reporting that an immune system gone haywire may be doing more damage than the coronavirus itself in patients with the severest forms of COVID-19.  Exercise, Antioxidants and a proper diet help to stabilize the immune system and keep it stable.  In the case of Severe Acute Respiratory (SAR) type viruses, the out-of-control immune response eventually causes the patients’ lungs to stop delivering oxygen to the body leading to respiratory failure.  It may also cause excessive inflammation that adds to fluid generation in the lungs.  It may also weaken blood vessels adding more fluid in the lungs further exacerbating respiratory failure and, in some cases, may cause death. In this way, the malfunctioning (overactive) immune system may be driving the rapid decline in lung function experienced by some patients.

We have found that the immune system is controlled and coordinated by the Parasympathetic Nervous System.  Further, we have found that an over-active immune system is associated with an over-active Parasympathetic Nervous System, and the opposite is true as well.  We have labeled an over-active Parasympathetic Nervous System as Parasympathetic Excess, or PE.  For example, brain trauma patients with PE are found to have a higher incidence of life threatening pneumonia than those brain trauma patient s without PE.  We have also found that normalizing PE helps to stabilize the immune system and reduces mortality and morbidity risk.

[*] There are two isomers of Alpha-Lipoic Acid, (r) and (s).  Only (r) is used by the body.  The (s) isomer is used for filler and less expensive products.


To slow or stop this process, some are being prescribed standard courses of anti-inflammatories, including steroids, including high dose steroids.  Some believe, high dose steroid is also accepted treatment for COVID-19, therefore if administered prior to detection of COVID-19 may mask COVID-19 in these patients until late in the progression of the disease.  Excessive amounts of steroids may also suppress the immune system which of course would have a negative effect.  Having experienced this, we strongly recommend that patients on high dose steroids be screen for COVID-19, as a precaution.


In a similar vein, evidence suggests that COVID-19 gains entry into cells through the ACE2 receptor.  ACE stands for Angiotensin Converting Enzyme.  ACE-Inhibitors (ACE-Is) and Angiotensin Receptor Blockers (ARBs) are commonly prescribed to patients with high blood pressure (Cardiovascular disease patients and patients with Diabetes).  Of course, the connection has caused concern within these communities.  However, the Cardiology communities (ACC & AHA) have stated that ACE-Is and ARBs are still considered safe and, perhaps, without these medications, those patients would be more at risk for infection (COVID-19 or other).  The concern is that by taking ACE-Is or ARBs, the number of ACE2 receptors in the body will increase, which they will, and that this increase may provide more entry points for the virus.  However, the latter is not likely.  In Angiotensin-mediated Hypertension (HTN), the number of ACE2 receptors is already elevated.  That had already contributed to the HTN.  ACE-Is and ARBs are designed to block the excess receptors to begin with and even block some of the original receptors to ensure lower blood pressure.  If these receptors are already blocked to limit their use for raising blood pressure, then it is not likely that COVID-19 will be able to use them either.  Think of a lock and a key.  Once a key is inserted into the lock, another key cannot be inserted.  The ACE-I or ARB is the first key.  COVID-19 is the second key and is also blocked.

While ACE-Is and ARBs may help those patients to whom they are prescribed have lower risk to COVID-19, they are not being recommended for patients who do not qualify under the guidelines for those medications.  Remember, the patients who are prescribed ACE-Is and ARBs were already at risk due to the HTN.  If you are already prescribed an ACE-I or ARB do not stop it.  If you are not already prescribed an ACE-I or ARB do not start it without physician permission.  As always, never take medication without consulting your physician first.


There is another aspect to the Coronavirus (COVID-19).  The Coronavirus like other viruses and significant infections cause oxidative stress.  Oxidative stress is a stress to the cells of your body.  It is the result of something, in this case COVID-19, attacking the cells’ energy production processes.  The primary component (organelle) responsible for energy production is the Mitochondria.  Mitochondria are like power plants in many ways.  They produce energy.  They also produce waste.  However, in the case of cells, the waste is not considered pollution, it is actually used, and under healthy conditions, all of it used; nothing is wasted.

The waste products are oxidants.  Yes, the very things that destroy cells, and we try to flood our systems with their opposites – antioxidants – are the very things that the Mitochondria make as waste products.  Again, under healthy conditions these oxidants are not “pollutants.”  They are used by a healthy immune system to “burn the trash.”  Pathogens (things invading our bodies and trying to make us sick) enter our bodies every moment.  As long as we are in familiar places, our bodies already have developed a defense mechanism against all of these pathogens, and in addition to fever, another first line of defense is to use the oxidants to burn the trash.  However, once the trash pile is burned, the fire must be extinguished.  The antioxidants are the fire extinguishers, or buckets of water if you will, to put out the fire before it burns healthy tissue.  Therefore, a small amount of oxidant production is healthy, as long as there is an ample supply of antioxidant on hand as well.

Again, as we age or are ill for long periods of time, the natural production of antioxidants declines, and again, fortunately, they may be supplemented.  However, if they are not supplemented sufficiently, the virus may leave behind oxidative stress.  Unfortunately, oxidative stress only reduces the functioning of cells.  This is unfortunate because the organs remain largely functional, and structurally, remain within normal limits.  Therefore, at rest (which is when most doctors assess their patients – sitting or lying down), these patients seem normal.  Yet they complain of fatigue (sometimes debilitating fatigue), lightheadedness or dizziness, poor sleep, brain-fog, memory and cognitive difficulties, sex dysfunction, GI upset (both upper and lower), sensory and temperature hypersensitivity, headache or migraine, depression or anxiety, generalized pain, and more. While it is difficult to measure oxidative stress, we are now able to directly measure its effects, especially on the Parasympathetic and Sympathetic (P&S) nervous systems.

P&S Monitoring helps to document the effects of any serious illness, including oxidative stress due to viruses, including COVID-19, which may leave significant oxidative stress behind.  Since oxidative stress does not do overt damage to the organ system, affecting primarily the mitochondria, cells’ function is sub-par, these patients are affected when they attempt to be active.  It is like having a clogged fuel filter on your car.  Your car will start and idle just fine, but as soon as you hit the gas the engine begins to choke and you are unable to move or move very fast.  Oxidative stress primarily affects the Parasympathetic nervous system, causing it to be more active.  If the Parasympathetics are already overactive (PE) due to immune system excesses, this additional Parasympathetic activation only serves to exacerbate the whole problem and these patients rapidly deteriorate into disability claims, yet they appear healthy.  With no specific disorder, unless the P&S nervous systems are measured independently and simultaneously (as only the technology that we have can – P&S Monitoring), patients will go from doctor to doctor for years and perhaps decades, including recommendations for psychological evaluation, before they find someone with P&S Monitoring, if ever.  In the meantime, they are disabled, out of work, have very poor qualities of life, and are at higher risk for infections such as COVID-19.


A recent patient was admitted to hospital with Inflammatory Myopathy, a large group of potentially treatable myopathies in both children and adults [15].  They represent a heterogeneous group of disorders which include the Dermatomyositis, Polymyositis, Immune-Mediated Necrotizing Myopathy (IMNM), and Inclusion Body Myositis.  There are various strategies for treating Inflammatory Myopathies especially IMNM.  IMNM accounts for approximately one-fifth of all Inflammatory Myopathies and present with severe muscle weakness and high creatinine levels.  They are often seen after viral infections, malignancies (cancer) or connective tissue disorder such as Rheumatoid Arthritis, Lupus and Scleroderma, but can be seen in patients taking statins.

Many of these patients have resistance to conventional immunosuppressive therapy [16].  IMNM is distinguished by the absence of primary inflammation on muscle biopsy and may be associated with myositis-specific autoantibodies.  Prompt treatment is important especially in patients who develop acute or progressive swallowing or breathing abnormalities from difficulty with skeletal muscle function.  Prednisone is first-line treatment, but is oftentimes ineffective and second-line treatment needs to be employed.  Second-line treatment may include disease-modifying agents, such as Methotrexate, Azathioprine or Mycophenolate Mofetil.  Additional second-line treatment includes Intravenous Immunoglobulin (IVIG).  Recent research has suggested a high rate of response to Rituximab in patients with autoimmune myopathies [17].

Immunosuppressive therapy increases the risk of infection including Aspiration Pneumonia [17,18].  Pneumococcal vaccine and yearly Influenza vaccinations are recommended.  Before starting second-line treatment, it has also been recommended to screen for Tuberculosis and Hepatitis B and C.  There are no consensus guidelines for Pneumocystis Pneumonia (PCP).

With the emergence and spread of the 2019 novel Coronavirus (COVID-19) it has become imperative to consider this virus when beginning patients on immunosuppressive therapies.  The virus originated in bats and was transmitted to humans through unknown intermediary animals in Wuhan-Hubei Province, China, in December 2019.  Patients present with fever, cough, sore throat, breathlessness, fatigue, malaise and other symptoms.  This is predominately an upper respiratory infection.  However, a large subset of patients may be asymptomatic [19].  In February 2020, the World Health Organization (WHO) designated the disease COVID-19, which stands for Coronavirus Disease 2019 [20].  The virus that caused COVID-19 is designated as Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2).

This was a case of acute relapsing, remitting IMNM, with progressive severe life-threatening Dysphagia that required enteral feeding and aggressive immunosuppressive treatment.  The patient had no significant symptoms consistent with acute Coronavirus infection and underwent first IVIG treatment, Mycophenolate Mofetil, and subsequently plasma exchange treatment.  After just beginning plasma exchange treatment the patient became acutely Hypoxemic and Hypotensive and sustained a fatal cardiorespiratory arrest.  Postmortem reporting of respiratory secretions at the time of the cardiac arrest disclosed what was positive for COVID-19.  We now propose that even in asymptomatic rheumatological patients with rheumatological disease who are starting advanced immunosuppressive therapy that they be screened for COVID-19 in addition to Tuberculosis and viral Hepatitis.

This is an unfortunate case of a patient with a five-year history of IMNM who, on presentation, initially responded to IVIG, but with the most recent acute flare-up did not have a good response.  Despite high-dose intravenous steroids, IVIG, Mycophenolate (CellCept) and subsequent plasma exchange, the patient did not respond and had an acute deterioration with Hypoxemia, Hypotension, and Cardiorespiratory Arrest, all of which occurred suddenly.  Microbiology disclosed COVID-19.  Pre-mortem, prior to the patient’s Cardiopulmonary arrest, this infection was not suspected.  He had no fever or salient cough.  His shortness of breath appeared to be related to volume overload due to diastolic dysfunction, which responded to diuretics.  He had no significant radiographic infiltrates and no signs of elevated inflammatory markers.  The patient was, however, on high-dose steroids which may have suppressed fever and an inflammatory response.

Among subsets of patients at high risk of developing severe infections are patients with Rheumatic diseases including Lupus, Rheumatoid Arthritis, Scleroderma, Inflammatory Myopathies, and Vasculitis [17, 21]. The European League Against Rheumatism released guidance for patients with rheumatic and musculoskeletal diseases receiving immunosuppressive therapy, including biological agents and disease-modifying anti-rheumatic drugs [22].

COVID-19 can cause viral Pneumonia.  This patient showed no evidence of Radiographic Viral Pneumonia or increased biomarkers.  In addition, COVID-19 can cause myocardial damage and Myocarditis.  This patient’s echocardiogram showed no evidence of myocardial impairment and Troponins and BNP were negative for myocardial injury during the patient’s hospital course.  Also, acute viral infections can be responsible for Acute Coronary Syndrome, and plaque rupture can trigger and precipitate Acute Coronary Syndromes and plaque rupture, but this was not demonstrated in this case [23].  It appears the patient developed an abrupt, overwhelming, acute Respiratory Distress Syndrome, which came on precipitously as a result of the virus in a very immunocompromised host.


Figure: A recent JAMA Cardiology article published the above chart indicating the potential mechanisms for acute effects of viral infections on the Cardiovascular system [23, JAMA Cardiol. Published online March 27, 2020. doi:10.1001/jamacardio.2020.1286]. The pathway outlined in red represents the patient in this case study.



We believe this to be a landmark case and we discuss recommendations for expanded guidelines.  To this end we present a patient with IMNM who required aggressive immunosuppressive therapy because of acute relapse and significant progression of dysphagia.  Unexpectedly, the patient had an acute cardio-hypoxemic episode with cardiopulmonary arrest which was terminal.  He had no significant symptoms or radiographic consistent with COVID-19 acute infection.  He may have developed the infection while in the hospital, but this is uncertain.  We propose that rheumatological patients, even when asymptomatic, be tested for COVID-19 prior to initiating second-line immunosuppressive therapy treatment.





[1] Five or six hours after workout, the decreased body core temperature signals the body to sleep, promoting less time to fall asleep and sounder sleep cycles, resulting in more restorative sleep and less daytime drowsiness.  Also, since Exercise helps to reduce body weight (see below), less weight may mean less risk of Sleep Apnea and snoring.

[2] Exercise increases circulation, thereby increasing tissue oxygenation and removal of wastes from throughout the body (detoxifies).  In the brain, this improves function, including concentration, creativity, and productivity.  In addition to an improved cardiovascular system, the endorphins released stimulate the mind for more creative thoughts.

[3]  “Too busy” is a logical excuse to skip a work out, but physical activity actually helps alleviate stress and promotes productivity.  Exercise increases the body’s ability to handle stress.  It produces higher levels of norepinephrine, a chemical that regulates areas of the brain that send stress signals.  The more the body is trained with the healthy physical stresses of mild to moderate exercise, the better the body responds to emotional and mental (as well as physical) stresses.

[4]  Through aging, brainpower decreases and the brain actually grows smaller.  Mental decline can start as early as 24 years of age.  The elderly who exercise show less brain shrinkage than those who do not.  Therefore, exercise may also reverse brain shrinkage.  Regular physical activity (3 to 5 times a week for 30 to 60 minutes) helps maintain or sharpen thinking, learning, and judgment skills with age, and increases memory by increasing the volume of gray matter in the brain.

[5]  The P&S (autonomic) nervous systems control and coordinate all of the organs and “involuntary” functions of the body.  A proper balance is needed, both at rest and during activity.  Note, sleeping is an activity and so is sitting at a desk and working, but sitting watching television is not.  Exercise by itself can balance the P&S nervous systems better than any supplement or diet alone.  Again, the best is when exercise and diet and the rest of the Mind-Body Wellness Program are taken together!  Establishing and maintaining P&S balance should always be a goal, and mild to moderate exercise (at a minimum) is an excellent adjunct to pharmacology and other lifestyle measures, including diet in this regard.

[6] Exercise reduces stress, reducing cortisol levels (as mentioned above), psycho-social stress, anxiety, depression (as mentioned above), and fatigue.  It reduces oxidative stress, improving endothelial function, increasing nitric oxide production, and the numbers of mitochondria for more energy.

[7] Physical activity engages the entire body, and a healthier cardiovascular system means the heart is better able to circulate blood to all parts of the body, including in older individuals.  Heart disease and stroke are two of the leading causes of death in the United States.  Following physician recommendations and getting at least 150 minutes a week (2½ hours) of moderate-intensity activity reduces the risk for these diseases.  The more (mild to moderate) exercise, the more that risk is reduced.  Regular physical activity improves almost all cardiac risk factors, including by increasing HDL cholesterol, lowering LDL cholesterol (clears arteries), lowering blood pressure, increasing cardiovascular fitness, and making the blood less prone to thrombosis or clotting, not only around the heart but also in the brain.  Greater blood flow to the brain underlies the brain function improvements mentioned above, including:  restorative sleep, improves mood, reduces depression, helps clear “brain fog,” improves cognitive abilities, and perhaps memory.

[8] Exercise reduces cortisol release for better neuroendocrine balance.  It helps to keep insulin levels healthy and increases insulin sensitivity.  It boosts sex hormones.  It helps to maintain healthy thyroid and hypothyroid hormone levels, including levels of growth hormones, which in adults helps with healing and repair.

[9] Diet and physical activity play a critical role in weight management.  Weight gain occurs when the calories burned, including those burned during physical activity, are less than the calories consumed.  The amount of physical activity required for weight management varies greatly, depending on metabolism (genetics), age (including stage of development), environment, and more.  Physical activity can help with weight loss as well as weight maintenance.  Establishing and maintaining a healthy weight requires both regular physical activity and a healthy eating plan.

[10] Regular physical activity reduces risk of developing type 2 Diabetes and Metabolic Syndrome.  Metabolic Syndrome includes a combination of (1) too much fat around the waist, (2) high blood pressure, (3) low HDL cholesterol, (4) high triglycerides, or (5) high blood sugar.  Lower rates of these conditions are seen with 120 to 150 minutes (2 to 2½ hours) a week of mild to moderate-intensity aerobic activity.  The more exercise, the more the risk is reduced (to a limit – see your doctor).  Regular physical activity also helps control blood glucose levels and can reverse type 2 Diabetes and Metabolic Syndrome.

[11]  Regular physical activity reduces risk of cancers as compared with people who do not exercise regularly.  Physically active people have a lower risk of colon cancer.  Physically active women have a lower risk of breast cancer.  Regular physical activity reduces risk of endometrial and lung cancer.  Improve quality of life.  Cancer survivors who exercise regularly have improved quality of life and physical fitness over those who do not.

[12] Bones and joints, as well as muscles, change with activity level and age.  They also need more protection with age.  Physical activity strengthens them, which protects bones and joints.  Strong and healthy bones, joints, and muscles promote an active lifestyle.  Adding a proper diet ensures the necessary micronutrients to maintain bone, joint, and muscle health.  Physical activity of at least a moderately-intense level slows the loss of bone density that comes with age.  Altogether, exercise helps to reduce the risk of falling in elderly, either due to fewer leg bone fractures or improved muscle strength.  Hip fracture is a serious health condition that often negatively affects quality of life, especially for older adults (e.g., climbing stairs, grocery shopping, or playing with the children or grandchildren).  However, 2 to 5 hours of at least moderate-intensity aerobic activity each week lowers risk of hip fracture.

Regular physical activity reduces risk of developing, and helps to manage, arthritis and other joint disorders.  For arthritis, 2 to 2½ hours a week of moderate-intensity, low-impact activity improves the ability to manage pain and do everyday tasks, and improves quality of life, not just from the pain, but also in terms of range of motion.

Muscle-strengthening activities help increase or maintain muscle mass and strength.  Gradually increasing the amount of weight and number of repetitions provides even more benefits, including endurance, no matter the age.  Regular physical activity helps to return and improve quality of life, reduces morbidity risk (including dizziness and lightheadedness, thereby reducing fall risk), and mortality risk, at any age.

[13] Exercise alone has never been proven to increase longevity.  However, by reducing mortality risk, increasing the antioxidant milieu, boosting immune activity, reducing stress (including pain), and maintaining nervous system and cardiovascular health (establishing and maintaining P&S balance and Mitochondrial health in support of wellness), a patient’s natural longevity is promoted or preserved.  Only a few lifestyle choices have as large an impact on health as physical activity.  People who are physically active for about 7 hours a week have a 40% lower risk of dying early than those who are active for less than 30 minutes a week; and this activity does not have to be vigorous; moderate-intensity is sufficient.  Everyone may gain the health benefits of physical activity.  Age, ethnicity, shape, or size does not matter.  One hundred and fifty minutes of moderate exercise per week (approximately 21 minutes per day) is routinely advocated for patients.

[14] DePace NL, Colombo J.  Autonomic and Mitochondrial Dysfunction in Clinical Diseases:  Diagnostic, Prevention, and Therapy.  Springer Science + Business Media, New York, NY, 2019.

[15] Dalakas MC.  Inflammatory Muscle Diseases.  N Engl J Med. 2015 Jul 23; 373(4): 393-4. doi: 10.1056/NEJMc1506827.

[16] Basharat P, Christopher-Stine L.  Immune-Mediated Necrotizing Myopathy: Update on Diagnosis and Management.  Curr Rheumatol Rep. 2015 Dec;17(12):72. doi: 10.1007/s11926-015-0548-6.

[17] McGrath ER, Doughty CT, Amato AA.  Autoimmune Myopathies: Updates on Evaluation and Treatment.  Neurotherapeutics. 2018 Oct;15(4):976-994. doi: 10.1007/s13311-018-00676-2.

[18] Marie I, Ménard JF, Hachulla E, et al. Infectious complications in polymyositis and dermatomyositis: A series of 279 patients.  Semin Arthritis Rheum. 2011; 41(1): 48–60. doi: 10.1016/j.semarthrit.2010.08.003. Epub 2010 Nov 2.

[19] Singhal T.  A Review of Coronavirus Disease-2019 (COVID-19).  Indian J Pediatr. 2020 Apr; 87(4): 281-286. doi: 10.1007/s12098-020-03263-6. Epub 2020 Mar 13.

[20] McIntosh K.  Coronavirus disease 2019 (COVID-19) – Update.  March 2020;

[21] Hospital for Special Surgery: What to know about Rheumatic Diseases and the COVID-19 coronavirus, published March 11, 2020, access March 13, 2020, rheumatic-disease-and-COVID-19-coronavirus. asp

[22] European League Against Rheumatism (EULAR).  EULAR Guidance for patient’s COVID-19 outbreak. Accessed March 13, 2020

[23] Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O.  Potential Effects of Coronaviruses on the Cardiovascular System:  A Review.  JAMA Cardiol.  Published online March 27, 2020. doi:10.1001/jamacardio.2020.1286

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Autonomic_Changes_With_Age: Diabetic Patients

Biological Aging and Anti-Aging Mechanisms

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The main risk factor for atherosclerosis or hardening of the arteries is usually aging.  The older one gets the more likely they are to have atherosclerosis or hardening of the arteries and complications, such as stroke and heart attack.  In addition, in regard to the nervous system, specifically the Autonomic Nervous System (ANS), there is also a significant risk factor for malfunction with degeneration of nerve fibers; including due to a lack of a proper blood supply to the very delicate fibers.  This is a delicate interaction.  The ANS, specifically the Sympathetic branch of the ANS, controls the vasculature and thereby proper blood profusion of the various tissues.  It is the Parasympathetic branch of the ANS that senses tissue perfusion and drives the Sympathetics to that end.  Normal, natural aging processes cause declines in the Parasympathetic and Sympathetic (P&S) Nervous Systems.  Chronic disease and other chronic condition that cause oxidative stress, accelerate these declines.  Reduced P&S activity to the vasculature reduces blood perfusion, which accelerates the aging of the nerves and tissues, which further reduces blood perfusion, and so goes the circle.  Unfortunately, this is asymptomatic for up to two decades before patients feel it; at which time it is very late in the progression.

See the figure below comparing 300 healthy subjects over time and 500 chronic disease subjects over the same time.  Notice that the upper curves show a gradual decline over time in the healthy subjects.  The lower curves show a more rapid decline in the chronic subjects, then the decline virtually stops once the patients comply with therapy.  Note, however, that the virtual stop occurs just above the horizontal broken line that indicates Cardiovascular Autonomic Neuropathy (CAN) which is end stage autonomic dysfunction and increased mortality risk (a 50% greater chance of heart attack or stroke in the next two years as compared with age-matched patients not demonstrating CAN).  Note, DAN is the abbreviation for Diabetic Autonomic Neuropathy (also known as Advanced Autonomic Dysfunction in non-Diabetics).  DAN is the precursor to CAN.

Eventually, age catches up with the chronic subjects and their decline parallels the healthy subjects with one important difference.  For the healthy subjects the Parasympathetics are a little higher than the Sympathetics.  This is reversed in the chronic subjects.  A little more Parasympathetic activity in the geriatric population is known to be cardio-protective and is associated with lower morbidity and mortality risks.  The more Sympathetic activity in the older chronic patients is associated with greater numbers of co-morbidities (25% more), prescribed pharmaceuticals (37% more), and life-threatening risks (e.g., Major Cardiovascular Adverse Events, or MACE, 18% more).  In addition, with aging we see more small fiber inflammation and subsequent decrease in density of small fibers, which carry sensory pain and autonomic impulses.  For both P&S decline and small fiber decline, early intervention often slows, significantly, the decline of nerve function (see figure below).  In the case of the P&S Nervous Systems, early interventions may return a patient to the normal path and perhaps buy back up to 20 years.

Vascular aging causes degeneration and hardening of the arteries and degeneration of the nerve fibers which ultimately affect every organ creating end-organ changes; particularly, the heart, brain and kidneys are very susceptible.  In general, age dependent injury to the vasculature and the nerve fibers becomes more manifested in the fifth or sixth decade of life.  However, some people develop this more prematurely, such as diabetics or individuals with high genetic lipid disorders, or other genetic disorders.  Some individuals have aging of their fibers and blood vessels more rapidly than other and, therefore, their biological age progresses faster than their chronological age.

There are certain noninvasive tests and blood test and biomarkers that can assess how the aging process is progressing.  Perhaps, the most well known is the length of the telomeres.  Telomeres are repetitions of DNA sequences that protect the end of chromosomes.  With each cell division, the telomere is shortened and at such a point when they get below a critical length cells will be susceptible to death.  As a telomere is shortened, one can get a higher incidence of heart disease, coronary artery disease, and cerebral vascular disease.

Other mechanisms, such as DNA methylation and low-grade inflammation may accelerate the aging process.  The most common inflammation marker that we measure is C-reactive protein.  Interleukin-6 is also another factor, which can be measure and be reflective of increased biological aging.  However, there is no one blood test that can indicate whether an individual’s nervous system or vascular system is aging prematurely or more rapidly.

Recently, the leaky gut disorder has become a very popular topic and has been associated with many changes in the ANS and malfunction and degeneration of the ANS.  Gut or gastrointestinal dysbiosis (microbial imbalance) has been linked to increase mortality risk and to disease.  Increased gut permeability alters the microbiotic composition; that is the composition of one’s intrinsic bacteria in their GI tract.  Toxic metabolites, if they leak through the cell junctions, can enter the blood stream and cause significant damage to blood vessels and nerves in the long term.  Breath tests and various urine tests after ingesting specific compounds can detect Chronic Intestinal Bacterial Overgrowth (CIBO) syndromes which if not corrected can be detrimental to vascular and neural structures.

Many noninvasive tests can assess whether one’s vascular system or neural system is prematurely aging.  We particularly like to assess HRV testing modalities especially coupled with respiration to assess Parasympathetic and Sympathetic power.  Sudomotor testing can assess small fiber integrity, inflammation and deficiency.  Carotid intimal thickness measures the thickness inside the carotid arteries and can also assess plaque burden, volume and density, which can be a surrogate for atherosclerosis and vascular aging.  Endothelial dysfunction, which can be derived from measures of ultrasound flow-mediated dilatation, or other similarly noninvasive techniques, which are easily available to clinicians in a laboratory and can demonstrate a malfunction of the small cells lining the arteries as one ages.  Calcium phosphate crystals deposited in the inner layer of the artery or the arterial intima, which is related to atherosclerosis, can be assessed with various tests.  Commonly used is a CT scan of the heart in which one calculates your Coronary Artery Calcium Score (CACS).  These are tests that can be obtained quite inexpensively and give a scoring system and assess the risk of future cardiac events and your degrees of potential atherosclerotic burden.  This test correlates well with coronary artery plaque burden.

Tests that measure arterial stiffness and velocity in the arteries, such as carotid-to-femoral pulse wave velocity or brachial-to-ankle pulse wave velocity can give an indication of how stiff the arteries are and how they are aging.  A high pulse wave velocity increases risk of cardiovascular disease and mortality from other causes.  Hypertension can promote arterial aging and rigidity as can high cholesterol, sedentary lifestyle and poor diet, such as high meats and saturated fats, high salt intake and high refined sugars.  Cigarette smoking is also a major culprit.  While alcohol in low quantities may be protective for vascular endothelium, high quantities can be deleterious and can accelerate vascular aging.  Sleep habits are also important in regard to aging of the blood vessels and nerves in the body.

We strongly promote a Mediterranean diet with high fruits and vegetables, nuts, seeds and legumes, and moderate alcohol consumption with flavonoids and antioxidants, such as with wine products, omega-3 intake with fish.  In fact, omega-3 and fish oils have been shown to potentially decrease telomere length shortening and may have significant anti-aging properties.

There are many natural behavioral and pharmacological strategies which have anti-aging potential on the nerve fibers and blood vessels.  Behavioral strategies include moderate alcohol consumption, exercise 150-200 minutes a week, weight reduction, diet high in antioxidant contents such as the Mediterranean diet and even supplements with antioxidant properties such as Alpha Lipoic Acid, which is extremely beneficial to nerve fibers, specifically autonomic nervous system fibers, or small C fibers.  Cofactors with methylfolate and B vitamins are extremely beneficial also in preserving small fibers and even regenerating growth of them when they are deficient.

We have used Beetroot, L-arginine and L-citrulline as nitric oxide-producing compounds to better enhance endothelial function and preserve endothelial integrity and keep the blood vessels healthy.  These produce nitric oxide by various mechanisms.  As one ages, nitric oxide declines in a linear fashion, which is detrimental to the blood vessels.  High vegetable and fruit intake is also associated with improving endothelial function and decreased arterial stiffness and decreased blood pressure.

Other studies have shown arterial function is less stiff and improves with flavonoids and cocoa, tea, coffee and wine, also in fermented dairy products, nut, seeds and vegetables.  Olive oil and monosaturated fat has been shown to be extremely beneficial as an anti-inflammatory agent and endothelial-improving agent.

Key pathways to be regulated in the aging process that should be targeted are the mechanistic target of Rapamycin (mTOR) and Adenosine Monophosphate Activated Protein Kinase (AMPK).  By inhibiting the mTOR and activating the AMPK, arterial stiffness can improve and blood pressure control can become better.

Regular moderate exercise to strengthen bone helps to keep calcium in the bone and reduce the calcium in arteries which reduces atherosclerosis, thereby reducing arterial stiffness.  Vitamin K2 (not ‘K’ but ‘K2’) is a new consideration in the anti-aging process.  Vitamin K2 works to redirect calcium from the soft tissue (e.g., arteries) to hard tissue (e.g., bones).  However, you must check with your physician to ensure that you are not at risk for blood clots.  Vitamin K2 may increase the risk of blood clots.

Metformin is one of the most prescribed medicines for diabetes.  It has antioxidant effects in addition.  Besides increasing insulin sensitivity, Metformin beneficially activates AMPK and beneficially inhibits mTOR.  Endothelial function, vascular stiffness and carotid artery calcium have been improved with Metformin.  Metformin has cardiovascular mortality benefits independent of its blood sugar lowering results.  In addition, there has been data to suggest it can prevent certain types of cancer such as colon cancer.  Perhaps the best agent to prevent cancers is the Mediterranean diet which has been purported to reduce at least 16 types of cancer.  Resveratrol is a polyphenol naturally present in grapes and berries and especially red wines.  It also activates AMPK and inhibits the mTOR pathways and has been very beneficial in protecting blood vessels and with antioxidant effects protecting nerve fibers.  In animal substances, Nicotinamide Adenine Dinucleotide has been shown to have anti-aging effects on the blood vessels.

Anti-inflammatory agents are being developed to beneficially affect nerve fibers and blood vessels.  More research is needed in that area.  One of the most unappreciated anti-inflammatory agents are Omega-3 fatty acids, such as from or fish or krill oils; especially the compound Eicosapentaenoic Acid (EPA) in fish oils can reduce heart attacks and strokes, up to 25% as found in one study; even on top of statin therapy.

Gut dysbiosis contributes to inflammation and abnormalities of the ANS and the vascular system.  Probiotics have been suggested as being useful in regulating gut dysbiosis as has certain antibiotics.

Risk reduction medicines used in heart disease, such as Aspirin, Statins, and Renin Angiotensin System blockers may have additional anti-aging potential.

Stress reduction and good sleep habits have significant effects on reducing oxidative stress and improving nerve fiber function and reducing degeneration of nerve fibers and improving blood pressure, endothelial function and arterial stiffness.  Relaxation techniques, such as meditation and yoga have been found to be extremely important in this regard.

We specifically use what we consider therapeutic quantities of Alpha Lipoic Acid, L-carnitine, and Co-enzyme Q10 in treating many of our patients with autonomic dysfunction and have found improvement in autonomic neuropathy testing parameters over a period of six months in these patients in our laboratory.  By combining these antioxidants, which we consider a Mitochondrial cocktail, as they produce more ATP energy molecules in addition to being good antioxidants, with Nitric Oxide producing compounds in appropriate concentrations (L-arginine, L-citrulline and Beetroot Extract), we believe we keep both the nerve fibers and arterial/vascular vessels from degenerating and aging.  By lowering LDL cholesterol below 70 and by keeping LDL molecules from being oxidized with the use of antioxidants, by exercising and weight reduction to raise beneficial HDL levels, the vacuum cleaner of the blood vessels, we believe that we can affect reversal of Atherosclerosis in many patient’s especially when anti-inflammatory agents, such as statins (Rosuvastatin) is added in selected instances.

One needs to discuss all of these ideas and concepts with their personal physician who knows their case in detail to recommend what lifestyle, dietary, and pharmacological supplement and other additions or alterations in their regimen need to be done.

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Autoimmune Autonomic Ganglionopathy and Autoimmune Autonomic Neuropathy

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A 50 year-old female was evaluated for progressive symptoms of fainting, dizziness, and significant drop in blood pressure upon standing over the last six weeks.  She had abdominal discomfort, constipation, dry eyes or dry mouth (which may indicate Sjögren’s Disease), and Anhydrosis (inability to sweat or lack of sweating).  She had urinary symptoms of frequency and could not tolerate bright lights.  All of these symptoms were new.  Her blood pressure dropped 45 points from sitting to standing.  She also has low-normal epinephrine levels at rest when tested in the laboratory.  Her pupils were dilated.  She had no abnormal sensory or muscle abnormalities.

In the Autonomic Neuropathy laboratory, she showed evidence of impaired Sympathetic and Parasympathetic parameters.  Her heart rate response to deep breathing was impaired as was her Valsalva response indicating abnormalities of her cardiovagal system.  Beat-to-beat blood pressure responses during Valsalva showed an absent overshoot, indicating Sympathetic abnormalities.

Because of the acute or subacute onset of symptoms in a middle-aged individual, autoimmune Autonomic Neuropathy was suspected.  Various autoimmune antibody tests were conducted, inducing antibodies to reflect Sjögren’s Disease (antibodies to SSA and SSB), Paraneoplastic antibodies (e.g., anti-Hu), and antibodies against Acetylcholine receptors were all negative.  The patient began treatment with conventional medicines to treat Orthostatic Hypotension, including low-dose Midodrine (2.5 mg bid) and Mestinon (30 mg bid).  While the orthostatic blood pressure was better controlled in time, other symptoms of constipation, dilated pupils, bright light sensitivity, and Hypo- or Anhydrosis, continued.  The patient asked if she would benefit from a course of Prednisone or immunomodulating agents such as Intravenous Immunoglobulin (IVIG), as she had been reading up on the Internet, but she may still have an autoimmune type of Peripheral Autonomic Neuropathy that was not picked up by conventional autoantibody testing.

Orthostatic Hypotension is one form of autonomic dysfunction and one of the earliest, and perhaps most debilitating symptoms of autonomic neuropathy.  Orthostatic Hypotension is also one form of Orthostatic Intolerance.  Orthostatic Hypotension presents as a significantly abnormal drop in blood pressure in response to upright posture, including standing or head-up tilt table test.  In fact any blood pressure response to standing that is less than a 10 mmHg increase in systolic blood pressure upon standing is considered abnormal.  Specifically, Orthostatic Hypotension is defined as a decrease in blood pressure upon standing of more than 20/10 mmHg pressure, and other change of less than a 10 mmHg increase in systolic blood pressure upon standing is considered to be Orthostatic Intolerance.  Other autonomic forms of Orthostatic Dysfunction include Postural Orthostatic Tachycardia Syndrome (an excessive increase in heart rate upon standing) and, rarely, Orthostatic Hypertension (an excessive increase in blood pressure upon standing).  While there are several underlying reasons for Orthostatic Dysfunction, other than autonomic dysfunction (e.g., venous valve dysfunction and dysfunction of the smooth muscles in the walls of the lower vasculature), the underlying autonomic dysfunction is known as Sympathetic Withdrawal.

Normally, upon standing, the Parasympathetic first decrease to potentiate and minimize the (alpha-) Sympathetic response.  The Parasympathetic decrease is represented by the blue line decreasing, going down, in the figure, above, right.  This begins the process of vasoconstriction to move blood up to the abdomen to help the heart pump blood to the brain.  Then the Sympathetics increase (represented by the red line increasing, going to the right, in the figure, above right).  This Sympathetic increase sustains the vasoconstriction and continues to shift the majority of the blood volume from the feet, against gravity, to the abdomen so that the heart may more easily pump it to the brain (see figure, above, right).  Think of a car as the model.  The Parasympathetics are the brakes and the Sympathetics are the accelerator.  When stopped at a red light with your foot on the brakes and the light turns green, what is the first thing you do? 

…  You take your foot off the brakes.  Even before you touch the accelerator, you begin to roll, you already begin to accelerate.  Taking your foot off the brakes minimizes the amount gas (read that as Adrenaline) and acceleration (read that as Sympathetic stress) you need to reach your desired speed.  The Parasympathetic and Sympathetic nervous systems normally act in much the same manner:  first the Parasympathetics decrease to facilitate and minimize the Sympathetic response, and then the Sympathetics increase.  Sympathetic Withdrawal is the abnormal decrease in alpha-Sympathetic activity upon standing (see figure, left).



Note, women tend towards Postural Orthostatic Tachycardia Syndrome.  This is due to the fact that, on average, women are born with physically smaller hearts than men.  Therefore, when their hearts become deconditioned, their hearts do not have the leverage to increase pressure to deliver more blood to the brain, so it resorts to the only other way and that is to increase rate to deliver more blood to the brain.  This increased rate is Tachycardia (see figure, lower, right:  the upper panel displays the Sympathetic Withdrawal and the lower panel displays the instantaneous respiratory (gray trace) and heart rate (red trace) during the first five-minutes of standing from a seated posture, note how the heart rate does not return to baseline as would be normal, but increases and continues to increase throughout the stand period and, for the most part, exceeds 120 bpm).


In all patients with Orthostatic Dysfunction, a deconditioned heart is a primary symptom.  A deconditioned heart does not necessarily mean that the skeletal muscles of the body are deconditioned.  Patients with Orthostatic Dysfunction and deconditioned hearts are often in good physical condition and are (or were) able to exercise, even rigorously.  In fact the exercise made them feel better (temporarily) because it used the skeletal muscles to help bring blood to the heart to improve circulation.  Their feet were warmer and, in less pain, and their brains were better perfused and more “awake.”  The exercise was a form of temporary, self-medication.  While exercise is ultimately the best medicine to re-condition the heart, the alpha-Sympathetic nerves need to be “retrained” to respond properly and increase to cause the required vasoconstriction needed to support the heart.  Often this exercise needs to be low and slow, so as to not over-stress the nervous system.  A standard to consider is 40 minutes of exercise per day, walking at no more than 2 mph, every day for six months.

On another note, Autonomic Dysfunction may involve multiple dysfunctions.  Often, Orthostatic Dysfunction (Sympathetic Withdrawal) may be accompanied by a Vagal or Parasympathetic Excess (see figure, right).  Parasympathetic Excess may be associated with Vasovagal Syncope.  The Parasympathetic Excess (represented by the blue line increasing in the figure, right) is the Vagal component, followed by the Sympathetic Withdrawal.  With Parasympathetic and Sympathetic Monitoring (P&S Monitoring, aka, Cardiorespiratory Monitoring) separate, but simultaneous measurements of Parasympathetic and Sympathetic nervous system activity is available in an easy to administer and perform test in the clinic.  With documentation of both Sympathetic Withdrawal and Parasympathetic Excess, both conditions may be treated simultaneously:  one treatment to reverse Sympathetic Withdrawal (e.g., Midodrine, Mestinon, or Alpha-Lipoic Acid) and one treatment to relieve Parasympathetic Excess (e.g., very, low-dose Anticholinergics or low and slow Exercise).

These are specific, common examples of Autonomic Neuropathy.  For Autoimmune Autonomic Ganglionopathy (AAG) and Autoimmune Autonomic Neuropathy we need a deeper understanding of Autonomic Neuropathy and its causes.  An autoimmune mechanism where patients produce antibodies against neuronal tissue receptors is only one cause of Autonomic Neuropathy.  Furthermore, given that the Parasympathetic nervous system controls and coordinates the Immune system, recent evidence indicates that Parasympathetic Excess may induce autoimmunity through an excessively active immune system.

Autonomic Neuropathy is a malfunction of the Autonomic Nervous System (ANS) and is also referred to as Dysautonomia.  Generally, Autonomic Neuropathy refers to the peripheral involvement of the ANS involving the Parasympathetic and Sympathetic and Enteric Nervous Systems, which are all parts of the ANS, and, specifically, the Enteric Nervous System is considered to be a part of Parasympathetic Nervous System.  There are cases of autonomic dysfunction which affect the brain or spinal cord, such as Multiple System Atrophy, but these are separate from Peripheral Autonomic Neuropathies. 

Because the ANS controls or coordinates all organs and systems of the body, all organs and systems are affected, some perhaps more so than others; at least at first.  Therefore, patients with broader or more advanced autonomic neuropathies may have urinary symptoms (such as urinary retention or urinary incontinence), gastrointestinal symptoms (such as abdominal pain, nausea, gastroparesis, diarrhea, constipation or swallowing difficulties), and may have disturbances of heart rate where the heart rate can be very fast, very slow, or have swings in between.  Patients may also have significant drops in blood pressure, a condition known as orthostatic hypotension, especially when stranding from a lying or sitting position.  Many patients have exercise intolerance and cannot increase their heart rate effectively when they exert themselves.  They can have abnormal pupil responses or sweat disturbances:  either sweating too much or too little.  Patients may have dry eyes or dry mouth (so called Sicca Syndrome, aka. Sjögren’s Disease).  The patients may also fail to recognize, or have defective, warning symptoms of hypoglycemia.  Most importantly, people with Peripheral Autonomic Neuropathies should have no evidence of Parkinson’s disease or abnormalities of the cerebellum with gait disturbances as is seen in more serious diseases known as Multi-System Atrophy (MSA).

When a person presents with symptoms of Peripheral Autonomic Neuropathy, we often seek the cause.  Many have had antecedent, recent viral or bacterial infections.  Some may have had concussions or head trauma or a motor vehicle accident.  Occasionally, we see people with severe, acutely emotional stress.  Patients with Ehlers-Danlos Syndrome (EDS) or Hypermobility usually develop a more gradual type of autonomic dysfunction and not an acute or subacute type.  Diabetes is probably the most common cause of autonomic dysfunction and also causes gradual nerve damage throughout the body.  We can also see certain medicines, such as use of cancer chemotherapy or radiation therapy causing injury to nerves which can produce autonomic neuropathies.

A rare disease, Amyloidosis (AL) which affects organs in the nervous system due to build up to abnormal proteins can occur, specifically those related to light chains or a familial type related to a different type of abnormal protein called Transthyretin (hATTR).  The latter is a build-up of a genetic mutation that results in a misfolded Transthyretin protein.  This causes Amyloid deposits in various organs, including the heart, nerves and GI tract.  When it occurs in the nerves, patients can develop Autonomic Neuropathy and Orthostatic Hypotension.  Neurodegenerative disease, including Parkinson’s disease or Lewy Body Dementia and even Multiple Sclerosis, eventually lead to autonomic dysfunction.  Interestingly, although Parkinson’s disease and Lewy Body Dementia affect the central nervous system, the autonomic dysfunction that results is due to a Peripheral Autonomic Neuropathy.  There are certain hereditary causes of Autonomic Neuropathy.

Some autoimmune diseases, however, can cause autonomic neuropathies.  This is when a person’s body produces antibodies that attack nervous system components.  One such case is Autoimmune Autonomic Ganglionopathy.   Occasionally, similar mechanisms are seen in people who have cancer where they produce antibodies against their nerve tissue that can affect the Peripheral, the Sensory-Motor, and Central nervous systems in these people.  This is known as a Paraneoplastic Syndrome.  We can send out for testing of antibodies if this is suspected.  Other autoimmune diseases, in which the immune system damages nerve fibers, include Sjögren’s syndrome, Systemic Lupus Erythematosus, Rheumatoid Arthritis, Mixed Collagen Vascular Diseases, Celiac Disease, and occasionally Guillain-Barre Syndrome.  Chronic Alcoholism can also cause chronic Peripheral Autonomic Neuropathy.  Although rare, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) can have some elements of autonomic dysfunction.

Usually autoimmune diseases can come on quickly, such Guillain-Barre Syndrome, in which autoantibodies attack the nervous system.  At times, they can occur subacutely and rarely chronically evolve.

Eloquent rabbit and other animal experiments have shown that Autoimmune Autonomic Neuropathy may be caused by autoantibodies that the body produces against nerve tissue.  A human study[1] followed 112 patients with type 1 Diabetes and upon examination found the presence of circulating antibody to ANS structures.  They concluded that circulating antibody to autonomic structures was associated with development of autonomic dysfunction in young diabetic patients.  They found this to be independent of blood sugar control.  Their perspective study demonstrated that the detection of circulating autoantibodies in the nervous system and subsequently over time the development of autonomic dysfunction most likely having a cause and effect relationship.  In this study, they also tested for somatic neuropathy with deep tendon reflexes, ankle reflexes, and vibratory perception to follow the evolution of sensory types of neuropathy found in diabetics.  Blood sugar control when it was poor appeared to accelerate into sensory neuropathy abnormalities that were followed with these physical examination parameters, but blood sugar did not predict the Peripheral Autonomic Neuropathy manifestations of the autoimmune components.  Autoantibodies to ANS tissues preceded the development of Autonomic Neuropathy in many of these patients.  Type 1 Diabetic patients who developed Cardiac Autonomic Neuropathy had a prevalence of 68% antibody positivity when tested, which was significantly higher compared to antibody-negative patients.  The most impaired test was Parasympathetic Nervous System response to deep breathing, which is mainly mediated by the Parasympathetic Nervous System.  It is believed that autoimmune mechanisms that target Sympathetic and Parasympathetic structures play a significant causative role in the development and progression of autonomic dysfunction in type 1 diabetics, long-term, and the finding of autoantibodies in the blood, even in type 1 diabetics who do not have Autonomic Neuropathy predicts, with high positive predictive value, those who will develop Autonomic Neuropathy.

Autonomic Neuropathy is a continuum, starting with Peripheral Autonomic Neuropathy and ultimately progressing to and ending with Cardiovascular Autonomic Neuropathy (CAN).  From P&S Monitoring, Peripheral Autonomic Neuropathy is characterized by abnormal challenge responses (that is to deep breathing, Valsalva, or stand or tilt) with normal resting responses.  The next phase of Autonomic Neuropathy is Diabetic Autonomic Neuropathy (DAN, if the patient is diagnosed with Diabetes) or Advanced Autonomic Dysfunction (AAD).  DAN or AAD are characterized by abnormally low, resting Parasympathetic or abnormally low, resting Sympathetic activity, but the resting Parasympathetic activity is greater than 0.1 bpm2 (see figure, right).  One branch activity low is sufficient for AAD, both indicates a more advanced AAD.  AAD or DAN is associated with more overt symptoms of Autonomic Neuropathy, and significantly greater morbidity risk leading to numbers of co-morbidity.  Unfortunately, the co-morbidities tend to be treated independently, leading to significantly increased numbers of medications, rather than seeking the underlying cause and treating that to relieve multiple symptoms and co-morbidities.  While DAN or AAD is not life threatening, it does threaten quality of life.

End stage Autonomic Neuropathy, CAN, is defined by resting Parasympathetic activity less than 0.1 bpm2 (see figure, right), regardless of the level of resting Sympathetic activity or challenge responses.  Returning to the car analogy, this would be like worn brakes.  Regardless of the state of the accelerator, without any brakes, you may not stop and the possible crash may be life threatening.  It is similar with CAN.  Without significant levels of resting Parasympathetic activity to balance resting Sympathetic activity, mortality risk escalates, and the risk is stratified by the level of imbalance between the P&S branches, known as Sympathovagal Balance (SB:  for CAN patients, the range of normal SB is 0.4 < SB < 1.0).  Normalizing SB, treats CAN, and normalizes mortality risk.

Other studies have shown relationships between autoantibodies and development of autonomic dysfunction.   These have shown an independent relationship with blood sugar control as well.  The mechanism in autoimmunity in type 1 diabetics is similar to what is seen in Paraneoplastic dysautonomias in which patients with cancers develop antibodies against their Acetylcholine receptors and develop severe autonomic dysfunction.  The higher the levels of antibodies, the worse the autonomic dysfunction is in these patients.  This indicates a therapeutic role for Acetylcholine inhibitors in the improvement in autonomic dysfunction.  It is interesting that type 1 diabetics also have an autoimmune mechanism where there is an active B-cell response against pancreatic and nervous system tissue.  It may well be that autoantibodies attack both the pancreas and the ANS.

The mechanisms differentiating sensory neuropathy and Autonomic Neuropathy in type 1 Diabetes are different.  The sensory neuropathy is associated with blood sugar control.  The Autoimmune Autonomic Neuropathy is not.  Also, 30% of patients who develop signs of peripheral somatic neuropathy, such as sensory or motor abnormalities, do not have associated autonomic dysfunction.  There appears to be two different mechanisms operating:  (1) sensory neuropathy in diabetes appears to be effected by poor blood sugar control and may be related to metabolic or oxidative end products with poorly controlled diabetes; whereas, (2) the diabetic type 1 Autonomic Neuropathy appears to be autoimmune as an individual produces antibodies against neuronal tissue and is not related to the blood sugar level.  The authors stated that they do not know whether the autoantibodies enhanced the presentation of antigens or a lead to Channelopathies.  Therefore, based on results of animal experimental studies and the perspective followup of over 16 years of type 1 diabetes, it is now established that autoantibodies may cause a Peripheral Autonomic Neuropathy.

Autoimmune Autonomic Neuropathy appears to affect the Acetylcholine Ganglionic receptors.  It is an antibody-mediated response that usually presents with autonomic failure involving the Sympathetic, Parasympathetic and Enteric nervous system.  Various portions of the Acetylcholine receptor can be affected by antibodies attacking different locations within the receptor.  Usually, this evolves over acute or subacute course.  50% of individuals will have antibodies to the Acetylcholine receptor and the other half will not.  However, the half that do not have antibodies detected and do not have any Paraneoplastic antibodies detected probably still have unknown antibodies for which we have not been able to search.  Higher titers of antibodies usually correlate with the severity of the Dysautonomia.  Patients with high antibody titers in a study by Vernino in the Annals of Neurology, 2003, had a combination of Sicca Syndrome with marked dry eyes and dry mouth, abnormal pupillary light response, upper gastrointestinal symptoms and neurogenic bladder.  Higher antibody titers appear to be associated with more frequent Cholinergic Dysautonomia.  Chronic cases occasionally occur and are difficult to separate from advanced autonomic failure, which is a separate disorder, quite rare, which can remain chronic or evolve into a more severe central disorder or a degenerative disorder, such as Parkinson’s or MSA.  Orthostatic Hypotension, widespread Hypo- or Anhidrosis, dry mouth, dry eyes, sexual dysfunction, urinary retention, impaired pupillary responses, reduced heart rate variability and gastrointestinal symptoms ranging from gastroparesis to postprandial abdominal pain, to diarrhea and more commonly constipation can occur.  Rarely, intestinal pseudo-obstruction, a severe form of hypomotility of the GI tract can occur.  Oftentimes, a virus, a recent immunization, or surgical procedure is reported prior to onset of symptoms which are similar to what we see with Guillain-Barre Syndrome, which does not usually involves the autonomics, or only mildly, but involves the sensory and motor components of the nervous system.

Interestingly, in the treatment of advanced Autoimmune Autonomic Neuropathy, if one has high levels of anti-Acetylcholine antibodies, they will come down.  Also, high levels of antibodies against Acetylcholine receptors are associated more with acute and subacute onset and more severe Dysautonomia with prominent Cholinergic features (i.e., Sicca complex, prominent gastrointestinal dysmotility and pupillary abnormalities).  Low titers are often seen in more indolent and chronic phenotypes.  As mentioned, half of patients may not even have titers that are positive for antibodies and a yet unidentified antibody may be the culprit.

Occasionally, in the chronic forms that evolve patients present with Orthostatic Hypotension as the more prominent feature and oftentimes they cannot stand for periods of time and may even faint.

Low plasma Catecholamine levels, such as reduced Norepinephrine release, are seen in patients with autoimmune widespread dysautonomia.  Sudomotor testing, which reflects postganglionic dysfunction indicating dysautonomia, is easily performed in laboratories and clinics.  Studies of Sympathetic cardiac innervation with MIBG scans showing abnormal cardiac uptake in Norepinephrine spillover tests may confirm a postganglionic dysfunction.  It is important to differentiate between acute and subacute onset Pandysautonomias with prominent Cholinergic abnormalities, as these respond well to immunotherapy, such as IVIG, Prednisone or other immune suppressive agents.

If only one feature of dysautonomia is present, usually antibody titers to Acetylcholine receptors are not present.   An individual could have an isolated entity known as Chronic Idiopathic Anhidrosis.  These patients have heat intolerance.  They have a better prognosis as this is a restrictive type Dysautonomia.  However, only about 16% of people test positive for Acetylcholine receptors with this disorder, and they usually have a low titer.

The Burning Feet Syndrome, usually due to Small Fiber Neuropathy seen often in diabetics, usually affects small unmyelinated nerve fibers, but some may not have any etiology, and it is postulated that this could be an autoimmune mechanism with distal fiber neuropathies.  However, these patients have low positivity of Acetylcholine receptors.

Chronic Pseudointestinal Obstruction, where patients get frequent obstruction of the bowel, a severe dysmotility disorder may be caused by many mechanisms.  No specific antigen or antibodies have been identified.  However, if one has positive antibodies against the Acetylcholine receptor, this may represent a form of Autoimmune Autonomic Neuropathy affecting the GI tract more selectively.  In other words, this could be another variant of Autoimmune Autonomic Neuropathy caused by Autoimmune Autonomic Ganglionopathy (AAG).

Remember, seronegativity or absence of antibody responses, measured in patients with acute and subacute and occasionally chronic peripheral autonomic neuropathies does not exclude an autoimmune mechanism.  It just may imply that the responsible autoantibody has not yet been identified.  Some of these patients will respond to steroids and immunosuppressive agents such as IVIG and it is worthwhile considering this.  Sandroni and Low in a paper, Other Autonomic Neuropathies Associated with Ganglionic Antibody Production, concluded that “similar phenotypes may have very different pathogenetic mechanisms” and “idiopathic” should not equate “autoimmune.”

While AAG patients do not typically have sensory abnormalities, some may describe minor sensory symptoms such as tingling, but with objective testing, sensory loss is not present, however, they have preserved reflex knee jerks, tickle sensation and so forth.

Immunomodulator therapy, such as Prednisone, IVIG, and other immunosuppressive agents may be very useful when used early in patients with Autoimmune Autonomic Neuropathy.  The higher the titers, for example, greater than 1 mmol/spot per liter, usually implies that one can improve with therapies.  Also, the more severe Orthostatic Hypotension patients with high levels of Acetylcholine receptor antibodies appear to improve with immunomodulator therapy.  Both seropositive and seronegative AAG patients may respond to therapies, including plasma exchange and some combinations of immunosuppressive therapy especially if they do not respond to IVIG initially.

The clinical features of AAG reflect impairment of Sympathetic function with Orthostatic Hypotension, Syncope, Anhidrosis, Parasympathetic dysfunction (including, dry mouth, dry eyes, and impaired pupillary constriction), and Enteric dysfunction (including, gastrointestinal dysmotility, constipation, gastroparesis and rarely pseudo-obstruction)[2].

In regard to the Enteric Nervous System, there were two main plexus, the Myenteric (Auerbach’s) and Submucosal (Meissner’s neurons).  The Enteric Nervous System controls most gut functions, such as secretion, absorption, vascular tone and motility.  An enteric ganglionitis is an inflammatory neuropathy with inflammation and immunological insult to the intrinsic innervation supplying the GI tract.  It may be associated with Paraneoplastic Syndrome and even infections such as Chagas Disease.  There are diffuse lymphoid infiltrates in the small intestine, and this can cause pseudo-obstruction or infiltration of myenteric ganglia and can also cause Achalasia, which is a contraction and motility disorder of the Esophagus.  Autoantibodies, including antineuronal antibodies, are associated with this disorder, and it is oftentimes associated also with Paraneoplastic or cancer syndromes.  Clinical features of Enteric Ganglionitis include, dysmotility and delayed transit depending on what is affected in the gastrointestinal tract, whether it be the Esophagus, lower esophageal sphincter, stomach with gastroparesis ,or colon with an intestinal pseudo-obstruction and colonic inertia and even megacolon.

Paraneoplastic syndromes can cause a Peripheral Autonomic Neuropathy even before cancer becomes manifested.  Oftentimes, they present as a subacute sensory neuropathy.  These patients may usually have a small cell cancer and anti-Hu antibodies.

As mentioned earlier, other types of neuropathy, such as the sensorimotor neuropathy, Guillain-Barre Disease, and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Brachial Plexopathy and Vasculitis Neuropathy may cause autonomic dysfunction in addition to sensory symptoms and sensory ataxia.  Oftentimes, some of the sensory impairments are painful.  Fiber loss is predominate in small myelinated and unmyelinated fibers.   These can have similar antibodies detected as is seen in Paraneoplastic syndromes.

Connective tissue diseases can be associated with subacute neuropathies.  This has been seen frequently with primary Sjogren’s syndrome where seven forms of neuropathy can be identified.  A variable degree of autonomic dysfunction occurs with these collagen vascular and connective tissue diseases.  They may have Hypo-or Anhidrosis, abdominal pain, constipation, and diarrhea.  These mechanisms may be different than autoimmune type autoantibodies seen in the conventional AAG patients.  In these instances, T cells attack tissue or ischemia due to vasculitis may be operative.  Interestingly, in many of these collagen vascular connective tissue vascular dysautonomias, SSA and SSB antibodies, which are often seen in Sjogren’s syndrome normally are not present.

In addition to Guillain-Barre, subclinical autonomic dysfunction has been reported in up to 25% of CIDP patients involving both Parasympathetic and Sympathetic components.   Vasomotor and Sudomotor fibers are involved when the Sympathetic systems is affected.  Autoimmune antibodies may not be present in these syndromes.  Alexander Szali , [Autoimmune Diseases, 2013] discussed autonomic involvement in subacute and chronic immune mediating neuropathies.  He concluded that autonomic function may be impaired in subacute and chronic immune mediated neuropathies in which Sympathetic, Parasympathetic and Enteric arms of the ANS are affected.  When a physician sees Orthostatic Hypotension, gastrointestinal dysmotility, pseudo-obstruction, urinary retention, etc., one should be alerted to the fact that this could be an autoimmune mechanism.  Also, one should be alert for the possibility of underlying occult cancer when an Autonomic Paraneoplastic disorder is suspected.

In an editorial by Muppidi, February 2018, in Clinical Autonomic Research, the author writes that Ganglionic Acetylcholine Receptor Antibodies are known to have a pathological role in AAG as an individual can produce antibodies against the Ganglionic Nicotinic Acetylcholine Receptor and disrupt cholinergic transmission at the Sympathetic and Parasympathetic ganglia.  This is the mechanism behind the Pandysautonomia.  One should have a low threshold for ordering ganglionic AChR antibodies in patients with acute and subacute onset focal or generalized autonomic dysfunction syndromes.  Muppidi makes a distinction between those that are seropositive and have positive antibody levels, and those who have negative antibody levels.  Those with negative antibody levels, or seronegative patients, appear to respond to high dose steroids whereas those who have positive autoantibody responses appear to more respond to plasma chains, IVIG or Rituximab.  The author postulates that there may be different underlying mechanisms in patients who have seropositive and seronegative AAG, and they propose a cell-mediated or inflammatory immune process rather than antibody-related mediated mechanism in those patients who are seronegative who may respond to high dose steroids.

Different assays test for Nicotinic Acetylcholine receptors.  Conventionally, Radioimmunoprecipitation (RIP) assays have been used for sensitive detection of autoantibodies to Ganglionic Acetylcholine Receptors in serum of patients with AAG.  In Japan, they have developed a Luciferase Immunoprecipitation System (LPS) which does not involve radionuclide administration.  As mentioned earlier, one can do a cardiac MIBG scan which will show decreased cardiac uptake, which also can be seen in Lewy Body Disease and Parkinson’s Disease as well as Dementia with Lewy Bodies in these Peripheral Autonomic Neuropathies.  The heart-to-mediastinum ratio is calculated and if low in these patients the ratio reflects a peripheral mechanism of autonomic dysfunction.

AAG should not be confused with Myasthenia Gravis (MG) in which there is an Autoimmune Channelopathy that is caused by autoantibodies to the neuromuscular junction apparatus.  In 80%, of these patients, these autoantibodies are noted against the muscle-type of Nicotinic Acetylcholine Receptor, not the ganglionic-type as seen in AAG.

High levels of antibodies in AAG patients are seen in patients with more significant autonomic dysfunction.  However, Ganglionic Anticholinergic Antibodies have been found in patients with Postural Orthostatic Tachycardia Syndromes only.  Chronic Idiopathic Pseudo-Obstruction patients typically have chronic idiopathic Anhidrosis and Distal Small Fiber Neuropathy albeit in low titers as we have previously discussed.  Interestingly, several researches have also reported that patients with other neuroimmunological disorders, such as Myasthenia Gravis, Lambert-Eaton Myasthenic Syndrome, Guillain-Barre Syndrome, and Chronic Inflammatory Demyelinating Polyneuropathy may have antibodies to ganglionic Acetylcholine receptors and autonomic symptoms.

In 2009, researchers reporting in the Journal of Immunotherapy Cancer, describe a seronegative AAG from dual immune checkpoint inhibition in patients with Metastatic Melanoma.  This is a very sophisticated new class of cancer treating agent using Immune Checkpoint Inhibitor therapy.  It described a patient who developed symptoms of nausea, constipation, weight loss, fatigue and hypotension with systolic blood pressures as low as 70 and holding the Immune Checkpoint Inhibition caused resolution of the symptoms.  In these patients, antibodies against Anticholinergic Receptors, anti-GAD 65 antibodies, Paraneoplastic Syndrome Antibodies (Mayo Clinic panel), ANA, Lyme, Syphilis and HIV testing were all negative.  The patient also responded to treatment with pulse doses of IV Solumedrol and received IVIG.

In summary, AAG is one form of an autoimmune autonomic dysfunction syndrome due to autoantibodies.  When it is seropositive with high antibody titers, autonomic dysfunction is usually quite severe, and we can follow antibody titers which lower with treatment.  They respond more to immunosuppressive agents such as IVIG.  It appears that seronegative patients with features consistent with AAG respond better to steroids, and this may reflect a cell-mediated and not a humoral mechanism.  Patients with autonomic neuropathy often have Orthostatic Intolerance, severe GI symptoms with nausea, vomiting, early satiety, constipation, bloating and may even present with Achalasia and Paralytic Ileus.  Sudomotor dysfunction in these patients is abnormal as there can be postganglionic disorders.  Pupillary dysfunction with bilateral Mydriasis, which reflects Parasympathetic denervation, is often prominently seen in AAG.  We refer to this as an Adie Pupil.  However, some cases of pupil dysfunction can be mixed problems with Sympathetic and Parasympathetic dysfunction.  There is also a slow form of AAG which resembles another disorder, Pure Autonomic Failure, which is more of a neurodegenerative disease due to an Alpha Synucleinopathy disorder.

In regard to our clinical vignette, which we presented at the beginning of this treatise, this patient appears to have a seronegative type of Autoimmune Autonomic Neuropathy.  Consideration for immunotherapy and immunomodulating therapy should be given although some literature suggests that high-dose steroids may be a better first option.

While not the most common cause of Peripheral Autonomic Neuropathy, Autoimmune Autonomic Neuropathy does exist and one needs to think of it, test for it and follow the clinical course clearly to be able to make the diagnosis and initiate early treatment.


[1] Maria Zanone MM, Raviolo A, Coppo E, Trento M, Trevisan M, Cavallo F, Favaro E, Passera P, Porta M, Camussi G.  Association of Autoimmunity to Autonomic Nervous Structures With Nerve Function in Patients With Type 1 Diabetes: A 16-Year Prospective Study .  Diabetes Care Apr 2014, 37 (4) 1108-1115; DOI: 10.2337/dc13-2274.

[2] Winston and Vernino, 2010, Current Opinions in Neurology



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What is Postural Orthostatic Tachycardia Syndrome (POTS)

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Patients with Postural Orthostatic Tachycardia Syndrome (POTS) are often quite symptomatic and have Orthostatic Intolerance (an abnormal blood pressure in response to upright posture, including standing) and Orthostatic Tachycardia (a high heart rate response to standing).  Many times, there is an antecedent viral infection and this suggests that there may be an element of autoimmunity triggered by a viral infection.  Note, tachycardia is mediated by beta-Adrenergic nerves innervating the heart and orthostatic dysfunction is due to an alpha-Adrenergic insufficiency in the lower vasculature.  POTS patients may also demonstrate a Parasympathetic Excess, further exacerbating their condition.  Due to the fact that all three of these disorders involve three different portions of the autonomic nervous system, all three dysautonomias may present simultaneously.

Orthostatic dysfunction is one form of autonomic dysfunction.  It is of the earliest results of autonomic dysfunction and perhaps the most debilitating symptom of autonomic neuropathy.  Orthostatic Hypotension is one form of Orthostatic Intolerance.  Orthostatic Hypotension presents as a significantly abnormal drop in blood pressure in response to upright posture, including standing or head-up tilt table test.  In fact any blood pressure response to standing that is less than a 10 mmHg increase in systolic blood pressure upon standing is considered abnormal.  Specifically, Orthostatic Hypotension is defined as a decrease in blood pressure upon standing of more than 20/10 mmHg pressure, and other changes of less than a 10 mmHg increase in systolic blood pressure upon standing is considered to be Orthostatic Intolerance.  Other autonomic forms of Orthostatic Dysfunction include Postural Orthostatic Tachycardia Syndrome and, rarely, Orthostatic Hypertension (an excessive increase in blood pressure upon standing).  While there are several underlying reasons for Orthostatic Dysfunction, other than autonomic dysfunction (e.g., venous valve dysfunction and dysfunction of the smooth muscles in the walls of the lower vasculature), the underlying autonomic dysfunction is known as Sympathetic Withdrawal.

Normally, upon standing, the Parasympathetics first decrease to potentiate and minimize the (alpha-) Sympathetic response.  The Parasympathetic decrease is represented by the blue line decreasing, going down, in the figure to the right.  This begins the process of vasoconstriction to move blood up to the abdomen to help the heart pump blood to the brain.  Then the Sympathetics increase (represented by the red line increasing, going to the right, in the figure to the right).  This Sympathetic increase sustains the vasoconstriction and continues to shift the majority of the blood volume from the feet, against gravity, to the abdomen so that the heart may more easily pump it to the brain.



Think of a car as the model.  The Parasympathetics are the brakes and the Sympathetics are the accelerator.  When stopped at a red light with your foot on the brakes and the light turns green, what is the first thing you do?  …  You take your foot off the brakes.  Even before you touch the accelerator, you begin to roll, you already begin to accelerate.  Taking your foot off the brakes minimizes the amount gas (read that as Adrenaline) and acceleration (read that as Sympathetic stress) you need to reach your desired speed.  The Parasympathetic and Sympathetic nervous systems normally act in much the same manner:  first the Parasympathetics decrease to facilitate and minimize the Sympathetic response, and then the Sympathetics increase.  Sympathetic Withdrawal is the abnormal decrease in alpha-Sympathetic activity upon standing (see figure, left).




Note, women tend towards Postural Orthostatic Tachycardia Syndrome (POTS).  This is due to the fact that, on average, women are born with physically smaller hearts than men.  Therefore, when their hearts become deconditioned, their hearts do not have the leverage to increase pressure to deliver more blood to the brain, so it resorts to the only other way and that is to increase rate to deliver more blood to the brain.  This increased rate is Tachycardia, see figure, right:  the upper panel displays the Sympathetic Withdrawal and the lower panel displays the instantaneous respiratory (gray trace) and heart rate (red trace) during the first five-minutes of standing from a seated posture.  Note how the heart rate does not return to baseline as would be normal, but increases and continues to increase throughout the stand period and, for the most part, exceeds 120 bpm.



In all patients with Orthostatic Dysfunction, a deconditioned heart is a primary disorder.  A deconditioned heart does not necessarily mean that the skeletal muscles of the body are deconditioned.  Patients with Orthostatic Dysfunction and deconditioned hearts are often in good physical condition and are (or were) able to exercise, even rigorously.  In fact the exercise made them feel better (temporarily) because it used the skeletal muscles to help bring blood to the heart to improve circulation.  Their feet were warmer and in less pain and their brains were better perfused and more “awake,” less “brain-fog” and memory or cognitive difficulties.  The exercise was a form of temporary, self-medication.  While exercise is ultimately the best medicine to re-condition the heart, the alpha-Sympathetic nerves also need to be “retrained” to respond properly and increase to cause the required vasoconstriction needed to support the heart.  Often this exercise needs to be low and slow, so as to not over-stress the nervous system.  A standard to consider is 40 minutes of exercise per day, walking at no more than 2 mph, every day for six months.

On another note, Autonomic Dysfunction may involve multiple dysfunctions.  Often, Orthostatic Dysfunction (Sympathetic Withdrawal) may be accompanied by a Vagal or Parasympathetic Excess (see figure, right).  Parasympathetic Excess may be associated with Vasovagal Syncope.  The Parasympathetic Excess (represented by the blue line increasing in the figure, right) is the Vagal component, followed by the Sympathetic Withdrawal.  With Parasympathetic and Sympathetic Monitoring (P&S Monitoring, aka, Cardiorespiratory Monitoring) separate, but simultaneous measurements of Parasympathetic and Sympathetic nervous system activity is available in an easy to administer and perform test in the clinic.  With documentation of both Sympathetic Withdrawal and Parasympathetic Excess, both conditions may be treated simultaneously:  one treatment to reverse Sympathetic Withdrawal (e.g., Midodrine, Mestinon, or Alpha-Lipoic Acid) and one treatment to relieve Parasympathetic Excess (e.g., very, low-dose Anticholinergics or low and slow Exercise).

In an article by Li and coworkers in the Journal of American Heart Association in 2014, the authors showed that patients with POTS have elevated levels of Alpha 1 AR autoantibodies.  These exert a partial peripheral antagonist effect which causes a compensatory Sympathetic activation of the Alpha 1 AR for vasoconstrictors and the Beta AR-mediated tachycardia.  They concluded that coexisting Beta 1 AR and Beta 2 AR agonist autoantibodies facilitated a tachycardia.  They felt that this may explain the increased standing plasma norepinephrine and excessive tachycardia observed in many POTS patients, the so called hyperAdrenergic POTS syndrome. They examined the serum of 14 POTS patients and concluded that the POTS serum acted as a partial Alpha-1 antagonist and caused a compensatory Sympathetic activation.  They concluded that their data supported an autoimmune mechanism for POTS patients.  Perhaps future management, they predicted, would ideally block autoantibody activity and leave the receptors unblocked.

In a diagram in the article, they show how in the upright position of POTS patients there is pooling of blood in the veins and a slight drop in blood pressure, which causes a baroreceptor activation.  Alpha 1 AR-Ab impaired vasoconstriction results, and this is an impaired Alpha 1 AR-mediated vasoconstriction.  This increases the drop of blood pressure, which causes an exaggerated baroreceptor activation then an exaggerated sympathoneural response with resultant tachycardia.  These investigators also found that Beta 1 AR activating autoantibodies were also present in all of their POTS patients tested, and this facilitated the Beta 1 AR agonist activation in in vitro testing with cyclic AMP.  There was also a variable presence of Beta 2 AR autoantibodies.  These autoantibodies contribute to exaggerated tachycardia in POTS patients also.  They postulated that these antibody receptors may also cause abnormal neurohumoral responses in people with cardiomyopathies.

In the Annals of Clinical Translational Neurology, an article published by Watari and co-workers, evaluated the association between POTS and circulating anti-ganglionic Acetylcholine receptors (gACHR) antibodies.  They used a special test for gACHR antibodies, known as the Luciferase Immunoprecipitation System.  These investigators found that antecedent infections were common in POTS patients.  They also had autoimmune markers and comorbid autoimmune diseases frequently in seropositive POTS patients.  Anti-gACHR antibodies were present in a significant number of POTS patients. They had two groups of patients.  Ten were seropositive for autoantibodies with POTS and ten POTS patients who were seronegative.  They found that antibodies were more frequently detected in patients with POTS than patients with neurally mediated syncope (NMS).  This was an observational study, but it showed that anti-gACHR were detected more frequently in patients with POTS compared to vagal syncope patients.  This supported an autoimmune mechanism for at least 29% of POTS patients who had anti-gACHR Alpha 3 and Beta 4 antibodies in the serum from POTS patients.  In 2016, Fedorowski demonstrated a strong relationship between Adrenergic antibodies in patients with POTS.  They showed the shift in Alpha 1 AR and Beta 1 AR responsiveness is important in the pathophysiology of POTS.  A large percentage of the POTS patients had autoantibodies that activated Alpha 1 AR, Beta 1 AR and Beta 2 AR, respectively.

They concluded that their studies affirmed the concept that common cardiovascular dysautonomias includes a spectrum of autoantibodies which contributed to the clinical manifestation.  They compared this with inappropriate sinus tachycardia (IST) with circulating antibodies against cardiac B receptors, as previously reported by Chiale (Heart Rhythm, 2006).  They emphasized that the catecholamine surge in POTS patients is seen as a compensatory mechanism to override the Alpha 1 AR malfunction with autoimmune blockade seen in POTS patients, but not seen in vagal syncope patients.

An article by Gunning and his coworkers in the Journal of the American Heart Association, volume 8, #18, discussed POTS associated with elevated G-protein coupled receptor autoantibodies.  The authors noted that in most cases the POTS patients had at least one elevated G-Protein coupled Adrenergic autoantibody, and in some instances, both Adrenergic and Muscarinic autoantibodies which supports the hypothesis that POTS may be an autoimmune mechanism disorder.  They evaluated antibodies levels against four subtypes of G-Protein coupled Adrenergic receptors and five subtypes of G-Protein coupled Muscarinic Acetylcholine receptors by an ELISA technique.  Eighty-nine percent of patients had antibodies against the Adrenergic Alpha 1 receptor, and 53 percent against the Muscarinic Acetylcholine M4 receptor.  Four patients had elevations of G-Protein coupled antibodies against all nine receptor subtypes measured in their study.  Five POTS patients had no elevation of any autoantibody and controls had no elevation.  They postulated that their findings suggested that possibly immunomodulating medications may be a therapeutic target in the future for POTS patients who are refractory to other forms of treatment.

POTS affects 3 million people in the United States, particularly young women of childbearing age.  Many mechanisms related to the etiology of POTS demonstrate that viral infections, Celiac disease, Thyroiditis, and joint Hypermobility may trigger it.  The authors used ELISA kits purchased from CellTrend GmbH (Luckenwalde-Germany) to detect antibodies against nine different G-Protein coupled receptor antibodies, including four anti-human AdrR epitopes and five anti-human mAChR epitopes.  The authors cited Li reporting antibodies to Beta Adrenergic B2 and Muscarinic M3 receptors by ELISA and 75% of patients with significant Orthostatic Hypotension and that subsequently antibodies of both Adrenergic Alpha 1 and Beta 1 receptors were reported in POTS patients along with angiotensin 2-type autoantibodies also found in POTS patients.  The most prevalent autoantibody in their investigations was anti-Adrenergic A1 receptor and that one had to have an elevation of autoantibodies against A1 to also have other Adrenergic and Muscarinic receptor autoantibodies.  The A1 Adrenergic receptor function is a vasoconstriction and antibodies specific to this G-Protein coupled protein receptor would therefore cause an ineffective response to simulating resultant hypotension and then a compensatory tachycardia would result through a baroreflex mechanism.

In the Journal of American Heart Association recently, an article titled Adrenergic Aorta Antibody-Induced Postural Tachycardia Syndrome in Rabbits, Li and coworkers build on their previous work of Adrenergic autoantibody in POTS.  In this study, they develop and Adrenergic receptor peptide-immunized rabbit model.  The Adrenergic antibodies were similar to antibodies isolated from patients with POTS syndrome.  The POTS-like phenotype in rabbits was induced by these Adrenergic autoantibodies, and the rabbits actually demonstrated postural orthostatic tachycardia.  This study showed that there is an animal model of POTS based on autoimmune causes.  The immunization of rabbits with Adrenergic receptor peptides induced a POTS-like presence of symptoms and orthostatic tachycardia.  In an article by Miller and Doherty entitled Hop To It: The First Animal Model of Autoimmune Postural Orthostatic Tachycardia Syndrome, they review the importance of the work done by Dr. Li with the rabbit model.  They also were impressed by not only the Adrenergic autoantibodies inducing a POTS-like phenotype in rabbits which exacerbated orthostatic tachycardia and produced Adrenergic receptor dysfunction, but this was suppressed by selectively clearing the antibodies in vivo.  This gives promise to future research in humans if an autoimmune mechanism could be further substantiated.

Autoantibodies to Adrenergic receptors contribute to the pathophysiology of POTS is a hypothesis.  The Adrenergic receptors are key regulators of blood pressure and heart rate.  Patients with POTS have impaired Alpha 1 Adrenergic receptor 1-induced vasoconstriction and compensatory enhanced Beta 1 Adrenergic receptor-induced tachycardia.

The study by Li on rabbits not only develops an animal model but a potential target of therapy for POTS.  It established a target immune therapy, the potential therapy for POTS.  Twenty-five percent of POTS patients become disabled and cannot work or attend school.  In the United States, for immune therapy targeting autoantibodies, we rely on plasma exchange, Intravenous Immunoglobulins (IVIG), and possibly B cell depleting strategies.  There are risks with plasma exchange, however, including hypotension, coagulopathy, central access problems, etc.  IVIG has adverse effects, including inflammatory reactions, Hemolytic Anemia and Aseptic Meningitis.  B cell depleting therapy such as with Rituximab, which targets CD20+ B cells to remove B cell populations that are precursors to antibodies producing plasma cells, has been considered.  However, this agent has a strong safety profile although infections and severe reactions to first infusions can occur.  There are other new techniques being developed for immunoabsorption that could be promising in the future.  The question remains, will the rabbit model of POTS be representative of the various presentations of the patient’s population with POTS and further research needs to be done.  In an article by Gunning, coworkers and Grubb, they note that POTS is usually misdiagnosed as chronic anxiety or panic disorder because their autonomic failure is not usually severe.  However, they nicely demonstrated 89% Adrenergic Alpha 1 receptor antibodies in 53% Muscarinic Acetylcholine antibodies in the patient patients with POTS.

All of this data points to an autoimmune mechanism in POTS as possibly the common final pathway.  An animal model now produced may be very useful in research.

Also, Yu and coworkers in the Journal of American Heart Association published an article, Angiotensin II Type 1 Receptor Autoantibodies in Postural Orthostatic Tachycardia.  They acknowledge that autoantibodies to Alpha 1-Adrenergic and Beta 1/2-Adrenergic receptors had previously been found in serum from patients with POTS.  They investigated the role of AT1R autoantibodies in POTS patients.  They found that most patients with POTS did have AT1R antibody activity.  This supported the concept that AT1R autoantibodies and anti-Adrenergic autoantibodies act separately or together and exert a significant impact on the cardiovascular pathophysiology characteristic of POTS.

In total, all of this data shows that with POTS patients there is an association with autoantibodies to various Adrenergic receptors and Angiotensin receptors.  The animal model makes a cause and effect theory plausible to fulfil Hills Criteria of Causation.

Unfortunately, testing for antibodies to these receptors is still in the experimental stage and no definitive treatment has been published in controlled studies.  However, this is very promising research information for future endeavors.

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