Authors: Nicholas L. DePace; Joseph Colombo

This book establishes and specifies a rigorously scientific and clinically valid basis for nonpharmaceutical approaches to many common diseases and disorders found in clinical settings. It includes lifestyle and supplement recommendations for beginning and maintaining autonomic nervous system and mitochondrial health and wellness. The book is organized around a six-pronged mind-body wellness program and contains a series of clinical applications and frequently asked questions. The physiologic need and clinical benefit and synergism of all six aspects working together are detailed, including the underlying biochemistry, with exhaustive references to statistically significant and clinically relevant studies. The book covers a range of clinical disorders, including anxiety, arrhythmia, atherosclerosis, bipolar disease, dementia, depression, fatigue, fibromyalgia, heart diseases, hypertension, mast cell disorder, migraine, and PTSD. Clinical Autonomic and Mitochondrial Disorders: Diagnosis, Prevention, and Treatment for Mind-Body Wellness is an essential resource for physicians, residents, fellows, medical students, and researchers in cardiology, primary care, neurology, endocrinology, psychiatry, and integrative and functional medicine. It provides therapy options to the indications and diagnoses published in the authors’ book Clinical Autonomic Dysfunction (Springer, 2014).


Drs. DePace and Colombo augmented the Philadelphia Formula for Reversing and Halting Atherosclerosis by adding features that focus on relieving parasympathetic and sympathetic (P&S) dysfunction. Autonomic dysfunction involves any disorder, disease, or malfunction of the ANS, including one or both of its two branches: the P&S nervous systems. Mitochondria dysfunction involves any disorder or disease associated with low energy states (including anxiety secondary to (preclinical) depression). Both mitochondria and the P&S nervous systems effect virtually every cell of the human body, and their proper functioning are considered to be foundational to establishing and maintaining health and wellness. In this chapter the “six-prong” formula is introduced, with its combined (in toto) effect on both mitochondria and the P&S nervous system and thereby its combined effect on the entire body as it subserves health and wellness.

About the Program

Cellular energy production from mitochondria via the citric acid cycle and the electron transport chain is fundamental to health and wellness and life itself. Glucose is the molecule that fuels life, in the presence of oxygen, via cellular respiration, and ATP is the energy molecule that stores and transfers energy to where it is needed. Sufficient levels of cellular respiration are required for health and wellness. A lack of ATP can cause autonomic (P&S) and mitochondrial dysfunction, significantly effecting quality of life (QoL). Typically as ATP production decreases, free radical (including reactive oxygen species) production increases, affecting both mitochondrial and P&S health. The levels of P&S dysfunction include advanced autonomic dysfunction (AAD), also known as diabetic autonomic neuropathy (DAN, if the patient is diagnosed with diabetes), involving morbidity risk, and cardiovascular autonomic neuropathy (CAN) involving mortality risk. Normal system functions may generate oxidants (e.g., free radicals and reactive oxygen species). A small amount of oxidants are actually helpful to the body, especially the immune system where they are used to “burn out” infections (i.e., bacterial, viral, mold, and mildew). There are many adverse environmental and lifestyle sources of oxidants as well, including stress and disease. Too many oxidants lead to disorders, including atherosclerosis, autonomic neuropathy, and mitochondrial dysfunction, and the diseases that often follow those disorders. All in all, it is easy to overwhelm the body with oxidants. This is the basis for the need to have as large an antioxidant pool as possible, both from a healthy diet and from supplements. As people age or become ill, the naturally occurring antioxidant-oxidant ratio declines, and diet becomes not enough, requiring supplements to help establish and maintain healthy antioxidant-oxidant ratios.

Omega-3 Fatty Acids (Prong-1)

Polyunsaturated fatty acids (PUFAs) include Omega-3s, Omega-6s, and Omega-9s. Omega-3s include docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). These are parts of lipoproteins, including low- and high-density lipoproteins (LDLs and HDLs, respectively). LDLs have a bad reputation due to their involvement in atherosclerosis; however, like many things in life, they are needed in moderation. LDLs are critical to life. LDLs are required in nerves for proper nerve conduction and neuromuscular function. LDLs, by themselves, are not bad. They become bad when they are oxidized by free radicals or other oxidants. If there are too many LDLs, then they are available for oxidation (they are not bound to nerve and other membranes and thereby protected from oxidation). When they are oxidized (“burned”) by free radicals, they become “sticky” (known as foam cells) and may adhere to endothelial cells, especially those that line the walls of blood vessels. Foam cells are the start of the process that leads to atherosclerosis. Fortunately this process may be reversed, or better yet prevented, which reduces the risk of heart attack or stroke. All six prongs of the Mind-Body Wellness Program work together to stop LDLs from being oxidized by reducing the numbers of LDLs, increasing the numbers of HDLs (thereby increasing the HDL to LDL ratio), increasing the antioxidant to oxidant ratio, and helping to prevent oxidized LDLs from binding to endothelial cells by increasing nitric oxide levels, through stress reduction, both at the cellular level (oxidative stress) and the system level (psychosocial stress).

Nitric Oxide (Prong-2)

Nitric oxide is a small molecule gas that is primarily produced by epithelial cells throughout the body (e.g., the inner lining of blood vessels, the blood-brain barrier, and barriers in the gut and around reproductive structures). Nitric oxide is known as the universal messenger, made in ubiquitous quantities to signal both defense mechanisms blocking harmful substances from entering the body and the mechanisms that permit helpful substances to enter the body. As such it is involved in many processes, for example, detoxification and the urea cycle, tissue regeneration, blood flow, prevention of atherosclerosis, and regulation of inflammation and oxidation. A large reservoir of nitric oxide is very important to health and wellness, but not too large. As with everything else in life, there still needs to be a proper balance. However, with the typical Western lifestyle, most do not have nearly as large a reservoir as is needed for wellness. Therefore, supplements are strongly recommended.

There are two processes by which supplemental nitric oxide may enter the body. The primary pathway is through the gut by consuming foods that are rich in the precursors to nitric oxide (e.g., L-arginine, L-citrulline, and L-carnitine). However, this pathway is limited. The secondary pathway is not rate limited and is assisted by friendly bacteria in the mouth. The secondary pathway is supplemented by products such as beetroot powder. Granted eating red beets is very healthful and does help, but it is not possible for the average person to eat enough red beets to match the nitric oxide-producing potential of one serving of beetroot powder.

The benefits of beetroot powder are discussed in examples involving heart failure, erectile dysfunction, and the nervous system. Also, there is a “dark side” to nitric oxide. Again, too much is not good either. The dark side of nitric oxide and how it may be avoided will also be discussed.

Oxidative Stress Reduction (Prong-3)

Stress reduction is a major theme of the recommendations in this book. Oxidative stress is “stress” at the cellular level. Arguably, the most critical damage caused by oxidative stress is to mitochondria function. There is a direct causal relationship between oxidative stress, mitochondrial dysfunction, and many clinical syndromes, especially those that may be relieved but are difficult to cure, including parasympathetic and sympathetic dysfunctions. Reducing mitochondrial dysfunction is the beginning to the cure of many of these syndromes and a critical step on the path to wellness. A little oxidative stress is healthy. Too much oxidative stress accelerates diseases and ultimately the aging process, destroying mitochondria, and thereby cells, and thereby membranes, and thereby tissues, and ultimately organs and organ systems. While mitochondria, when they themselves are dysfunctional, contribute to oxidative stress, the reactive species they produce normally are helpful to the body, including the immune system, contributing to the passive defense, literally “burning out” foreign agents. Reducing oxidative stress also helps to maintain proper nitric oxide function which feeds back and helps to further reduce stress, preventing the dark side of nitric oxide. The main object of this chapter is to demonstrate means of reducing oxidative stress and how reducing oxidative stress helps to relieve diseases and establish and maintain wellness.

A proper antioxidant reservoir and maintaining a proper antioxidant-oxidant balance are the keys to minimizing oxidative stress effects. A proper reservoir is built on supplements including alpha-lipoic acid and CoQ10; B vitamins, including folic acid (vitamin B9); tryptophan; and nitric oxide.

Mediterranean Diet (Prong-4)

The Mediterranean diet is one of the lifestyle modifications recommended in the Mind-Body Wellness Program. It is not simply a diet. It is a lifestyle. It is a stress reducer, both at the cellular level (oxidative stress reduction) and the system level (psychosocial stress reduction). It includes a philosophy to cook and choose foods to eat where the foods themselves and how they are prepared is, itself, medicine. Preparing the food fresh and preserving its nutrient content enable food to be antioxidants, anti-inflammatories, and anti-atherosclerotics, as well as provide vitamins, minerals, nutrients, and the energy needed for health and wellness. The Mediterranean diet is founded on olive, grape, and whole wheat. Aside from these three ingredients, the Mediterranean diet adds polyphenols and resveratrol to the mix to further the benefits of the program.

The Mediterranean diet provides the fuel and raw materials needed to support exercise and the other prongs of the Mind-Body Wellness Program to minimize disease frequency and severity and preserve quality of life. The diet, enjoyed with family and friends, relaxed and including a little wine, is the goal. Reversing the trend, prevalent in the west, of “fresh from the factory” and returning to “factory fresh.” With the Mediterranean diet, the supplements of this program truly are supplements to a healthy diet and not replacements for a healthy diet. Enjoy!

Exercise (Prong-5)

“Exercise” covers a range of activities. However, the essential component is an “active lifestyle.” “Exercise” is not a bad word! It does not have to be drudgery. Exercise should reflect the lifestyles 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. Exercise can also be a daylong habit of activity, included but not limited to household chores, taking the stairs, shopping, gardening, walking, and playing with children. The physiologic and psychologic benefits of exercise are numerous.

The lack of exercise may place a patient on an accelerated track to autonomic neuropathy, accelerating the aging effect, keeping moving, and helping to keep joints, muscles, and nerves healthy. The Rostral Ventrolateral Medulla (RVLM) is a brain stem nucleus that receives a wide variety of inputs, including cardiovascular and exercise-related inputs from both central and peripheral sources, regulating sympathetic control over baroreceptor reflex and thereby blood pressure and under abnormal conditions, hypertension. Directly and indirectly, through the nervous system, exercise affects sleep, cognition, and memory; immune function; cardiovascular and endothelial function; GI function; endocrine and exocrine function; in fact, all systems of the body are positively impacted by appropriate levels of exercise. Exercise may be the most powerful antioxidant available. Further, it helps to elevate mood and relieve depression and, at the same time, relieve stress and potentially anxiety. Always consult your physician before starting an exercise regimen.

Psychosocial Stress Reduction (Prong-6)

Stress is an insidious factor in the lives of many, if not all, people. A little stress is actually healthy and helps people stay strong and healthy and even well. However, the stress levels in today’s society are too high for almost all people. There is little that can be done to escape it: young people are made to grow up too fast; girls are not pretty enough; boys are not strong enough or sensitive enough; the old standards are gone, including sexual identity; and no one is good enough, smart enough, rich enough, young enough, etc. This is now the norm. This before the violence of life (bullying, rape, murder), and diseases and injury, is added; even food and exercise have become stressors in many situations. As discussed earlier in this book, of this excess stress is damaging at the cellular level as oxidative stress. However, oxidative stress is exacerbated and further induced by any and all of these systemic, or psychosocial, stresses.

Systemically, these stresses are perceived by the brain and transmitted to the body and down to the cellular level through two main pathways: the hypothalamus-pituitary-adrenal axis (hormonally) and the parasympathetic and sympathetic nervous systems (neurally). Physiologic and psychologic stress and emotions (both happy and sad emotions) modulate hormonal and neural activity. Negative stresses may cause inflammation at the cellular level, suppress immune activity at the system level, and cause major adverse cardiovascular events (MACE, including stroke and sudden death). Causal factors and stress reduction factors are presented and discussed, including stress reduction as a powerful antioxidant. A tested, tried, non-pharmaceutical method to help reduce stress and mitigate its effects is presented.

Mind-Body Wellness Program Benefits

To ensure that the supplements recommended with the Mind-Body Wellness Program do not add to stress through contraindications, the contraindications are described. For example, alpha-lipoic acid may lower resting blood pressure, contraindicating it for patients with low resting pressure. The recommended supplements and lifestyles form this kernel of a Wellness Program. The weight of scientifically rigorous and statistically significant evidence behind this program is brought to bear in this chapter as it subserves functional medicine as well as clinical medicine. For example, additions to this kernel that help to tailor the program to specific conditions are presented. For example, by adding cannabidiol, the program is customized for pain management (including fibromyalgia) or anxiety. Neurofeedback is also introduced as another means of treating P&S imbalance, as an adjunct to the program.

A series of quality of life questionnaires, specific for autonomic dysfunction conditions (e.g., diabetes, Ehlers-Danlos syndrome, and autonomic neuropathy), are presented to help in the clinic with diagnoses and therapy planning. To further support therapy planning, examples of the program’s application to various therapies and diseases are discussed, including: (1) evidence that supplements and nutraceuticals, augmented by the program, help to improve pharmacology in those patients that respond to the nutraceuticals (i.e., omega-3s help to close the Statin Gap and help to treat atherosclerosis); (2) evidence that various antioxidant treatments, augmented by the program, may treat atrial fibrillation or neurogenic orthostatic hypotension; (3) evidence that the program treats anxiety, depression-anxiety syndromes, PTSD, ADD/ADHD, some forms of migraine headache, chronic fatigue, and persistent fatigue by helping to restore and establish proper brain perfusion and energy production; (4) evidence that reducing stress (both oxidative and psychosocial) as part of the program helps to treat autonomic dysfunction and small fiber neuropathy, as well as cardiovascular diseases and cancer (including breast cancer); (5) forms of hypertension, specifically, hypertension secondary to parasympathetic excess and hypertension secondary to orthostatic dysfunction, are presented with therapy options; (6) mitochondrial dysfunction associated with neurodegenerative disorders is presented with therapy options; and (7) longevity which is addressed through a discussion of telomere length and its maintenance with the program, including fish oils and antioxidants.


‘RFa’ is known to be a measure of Parasympathetic activity and ‘LFa’ is known to be a measure of Sympathetic activity, based on reference: Colombo J, Arora RR, DePace NL, Vinik AI, Clinical Autonomic Dysfunction: Measurement, Indications, Therapies, and Outcomes. Springer Science + Business Media, New York, NY; 2014.