May 2021 - Dr. Nicholas L. DePace, M.D., F.A.C.C.

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Notes: This is the second in a series of 5 blog posts about COVID-19 and Autonomic Dysfunction. This a pre-publication release that will be featured in a major medical journal.

Coronavirus Induces Oxidative Stress Leading to Autonomic Dysfunction Often With Delayed Symptom Onset

Heather L. Bloom, MD¹ and Joseph Colombo, PhD, DNM, DHS²

Electrophysiology, Atlanta Veterans Affairs Medical Center and Emory University Medical School, Atlanta, GA
Parasympathetic & Sympathetic Nervous System Consultant, Franklin Cardiovascular Associates, PA & Autonomic Dysfunction and POTS Center, Sewell, NJ, and Senior Medical Director & CTO, Physio PS, Inc., Atlanta, GA, dovetech@erols.com

Correspondence should be addressed to Dr. Colombo, dovetech@erols.com

INTRODUCTION

It is generally well known that many chronic and serious pathologies cause an over-production of oxidants, including Reactive Oxygen Species (ROS), Reactive Nitrogen Species (RNS), and many other oxidative molecules.

What may not be as well-known is the fact that severe acute conditions may also cause an over-production of oxidants. A recent published review [[i]] highlighted this in COVID-19 patients.

Many of the other pathogens that cause severe acute diseases are also implicated, including Influenza (like COVID19, a SARS virus) and many other viruses, bacteria like the Borrelia bacterium that causes Lyme Disease, severe physical or physiological stresses or traumas like that which triggers what is known as Fibromyalgia; as well as severe exposures to cold, heat, chemicals, etc., and severe mental or emotional traumas (e.g., PTSD); to name a few.

An over-production of oxidants is known as Oxidative Stress. While some level of oxidants are necessary for the Immune system as a first-line defense against pathogens, for programmed cell death and other general cellular house-keeping activities, too many oxidants lead to cell and organelle damage, including, damage to Mitochondria.

The cardiovascular and the nervous systems have the highest numbers of Mitochondria per cell and are therefore more susceptible to Oxidative Stress.

As the cardiovascular tissue and the Parasympathetic and Sympathetic (P&S) branches of the autonomic nervous systems (ANS) become disordered, P&S dysfunction accelerates cardiovascular disorder and a downward spiral begins; often long before recognized disease symptoms present.

Further, in addition to collecting oxidants for beneficial use, the Immune system is primarily responsible for balancing the oxidants and antioxidants in the system. With P&S dysfunction this balancing process becomes less effective.

Oxidative Stress-induced P&S Dysfunction may be associated with a huge constellation of symptoms and conditions including Lightheadedness, fatigue, wild fluctuations in blood pressure, blood glucose, hormone levels, and weight; as well as difficult to describe pain syndromes (including complex regional pain syndromes, or CRPS), excessive symptoms of palpitations without clinical correlation to definitive pathology or seizures, temperature dysregulation (to heat and/or cold and sweat responses), and symptoms of depression and anxiety, ADD/ADHD, exercise intolerance, sex dysfunction, sleep or GI disturbance, cognitive dysfunction or “brain fog”, or frequent headache or migraine.

Given the current high volume of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, or Coronavirus Disease 2019, or COVID-19 virus, or COVID), it will be the exemplar severe acute pathology used as a model of other severe acute pathologies.

In patients that recover from COVID, the basic model is:

1) COVID causes Oxidative Stress in most patients who recover;

2) The severity of the resulting Oxidative Stress is debilitating to a sub-population of the patients affected (perhaps 15%, in the case of COVID, [personal clinical observations]);

3) Oxidative Stress damages cell membranes, DNA, and (especially) Mitochondria;

4) as the cells that utilize the most energy (ATP) in the body, nerve and cardiovascular cells are the most susceptible to Oxidative Stress damaged Mitochondrial dysfunction;

5) Mitochondrial dysfunction in the P&S nerve cells themselves and the mitochondrial damaged cardiovascular cells, both cause changes in P&S that manifest three to six months after relief of the initiating pathology (COVID);

6) due to this delay, and the normalcy of the interim, the resulting P&S Dysfunction is not associated with COVID,

7) the resulting P&S Dysfunction causes many symptoms the most complained about is lightheadedness and persistent fatigue that is not treatable by standard therapies.

Both Oxidative Stress and P&S imbalance are treatable [[ii]], depending on individual history, 9) rebalancing oxidation and P&S leads to improved outcomes including quality of life (i.e., fatigue is relieved) and improved productivity [[iii]].

The main clinical dilemma is that the connection between COVID and P&S Dysfunction is not obvious. The symptoms of P&S Dysfunction, presenting three to six months after the disease is relieved and apparent normal function is returned, are interpreted as a new condition and misinterpreted as not a continuation of the previous condition.

This causes three problems. First, since only the symptoms are being treated, the therapy plan is often confounded due to conflicting dysfunctions. For example, fatigue is often accompanied by lightheadedness or dizziness, anxiety, depression, sleep difficulties, and loss of productivity.

Treating all of these symptoms individually involves competing agents. Furthermore, and the second problem, since what is being treated are symptoms and not the underlying cause (Oxidative Stress and P&S imbalance), therapies are usually titrated to higher doses; and yet, the patients still do not respond as expected.

Moreover, if and when P&S Dysfunction is suspected, the high doses of these medications often leave the patient sensitized to these medications. This sensitization precludes their use at the very low levels needed for balancing the P&S nervous systems.

All of these treatment issues can leave the Physician thinking that the patient is non-compliant or psychosomatic, which often leads to a psychology referral. This can lead to the breakdown of the physician-patient relationship since the patient is sure that the symptoms are real and not in her or his head.

As suggested by the title of the recently published article [i], a simple P&S assessment may be made in the clinic to identify any P&S imbalance. Relieving the P&S imbalance, which often involves Antioxidants [ii], and thereby restoring P&S and oxidant balance, relieves or prevents the symptoms of P&S imbalance post-COVID; thereby, minimizing any further reductions in quality of life and losses in productivity.

P&S testing is not ANS testing. Most ANS test only test total autonomic function and force assumption and approximation to theorize P&S activity. There is only one P&S test that provides simultaneous, independent measures of P&S activity. What is expected from P&S testing is one or more of four possible P&S Dysfunctions that underlie the Dysautonomia typically associated with Oxidative Stress.

REFERENCES

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[1] Murray GL. COVID-19 cardiac complications: Is an easy, safe treatment strategy right under our noses? J Cardiovasc Dis Diag. 2020; 8:5. doi: 10.37421/jcdd.2020.8.415.

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

3 Acosta C, DePace NL, DePace NL, Kaczmarski K, Pinales JM, and Colombo J. Antioxidants effect changes in systemic parasympathetic and sympathetic nervous system responses and improve outcomes. Cardio Open. 2020; 5(1): 26-36. doi: 10.33140/COA.05.01.04

⁴Colombo J, Arora RR, DePace NL, Vinik AI. Clinical Autonomic Dysfunction: Measurement, Indications, Therapies, and Outcomes. Springer Science + Business Media, New York, NY, 2014.

5 Vinik A, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation. 2007; 115: 387-397.

6 Vinik AI, Maser RE, Nakave AA. Diabetic cardiovascular autonomic nerve dysfunction. US Endocrine Disease. 2007; Dec: 2-9.

7 Malik, M. The Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability, standards of measurement, physiological interpretation, and clinical use. Circulation. 1996; 93:1043-1065.

⁸ Malik, M. and the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability, standards of measurement, physiological interpretation, and clinical use. European Heart Journal. 1996, 17: 354-381.

⁹ Akselrod S, Oz O, Greenberg M, Keselbrener L. Autonomic response to change of posture among normal and mild-hypertensive adults: investigation by time-dependent spectral analysis. J Auton Nerv Syst. 1997 May 12;64(1):33-43.

¹⁰ Piña IL, Di Palo KE, Ventura HO. Psychopharmacology and Cardiovascular Disease. JACC. 2018; 71(20): 2346-2359.

1¹ Arora RR, Bulgarelli RJ, Ghosh-Dastidar S, Colombo J. Autonomic mechanisms and therapeutic implications of postural diabetic cardiovascular abnormalities. J Diabetes Science and Technology. 2008; 2(4): 568-71.

12 DePace NL, Vinik AI, Acosta C and Colombo J. Oral vasoactive medications: A Review of Midodrine, Droxidopa, and Pseudoephedrine as Applied to Orthostatic Dysfunction. NEJM. 2020. Submitted.

¹³ Vinik AI, Bloom HL, Colombo J. Differential effects of adrenergic antagonists (carvedilol vs. metoprolol) on parasympathetic and sympathetic activity: A comparison of measures. Heart International. Heart Int. 2014; 9(1): 7-14; DOI: 10.5301/HEART.2014.12495.

¹⁴ Bloom HL, Vinik AI, Colombo J. Differential effects of adrenergic antagonists (carvedilol vs. metoprolol) on parasympathetic and sympathetic activity: A comparison of clinical results. Heart Int. 2014 ; 9 (1): 15-21; DOI: 10.5301/HEART.2014.12496.

¹⁵ Murray GL and Colombo J. (R)Alpha Lipoic Acid is a Safe, Effective Pharmacologic Therapy of Chronic Orthostatic Hypotension Associated with Low Sympathetic Tone. Int J Angiol. In Print, 2018.

KEY WORDS

Coronavirus, Parasympathetic, Sympathetic, Oxidative Stress, Antioxidants

ABBREVIATIONS

ALA Alpha-Lipoic Acid

ANS Autonomic Nervous System

CoQ10 Co-enzyme Q10

COVID-19 Coronavirus (SARS-CoV-2)

P&S Parasympathetic and Sympathetic

PE Parasympathetic Excess

POTS Postural Orthostatic Tachycardia Syndrome

SE Sympathetic Excess

SW Sympathetic Withdrawal

[i] Murray GL. COVID-19 cardiac complications: Is an easy, safe treatment strategy right under our noses? J Cardiovasc Dis Diag. 2020; 8:5. doi: 10.37421/jcdd.2020.8.415.

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

[iii] Acosta C, DePace NL, DePace NL, Kaczmarski K, Pinales JM, and Colombo J. Antioxidants effect changes in systemic parasympathetic and sympathetic nervous system responses and improve outcomes. Cardio Open. 2020; 5(1): 26-36. doi: 10.33140/COA.05.01.04

Click here to download this post

Notes: This is the first in a series of 5 blog posts about COVID-19 and Autonomic Dysfunction. This a pre-publication release that will be featured in a major medical journal.

Coronavirus Induces Oxidative Stress Leading to Autonomic Dysfunction Often With Delayed Symptom Onset

Heather L. Bloom, MD¹ and Joseph Colombo, PhD, DNM, DHS²

Electrophysiology, Atlanta Veterans Affairs Medical Center and Emory University Medical School, Atlanta, GA
Parasympathetic & Sympathetic Nervous System Consultant, Franklin Cardiovascular Associates, PA & Autonomic Dysfunction and POTS Center, Sewell, NJ, and Senior Medical Director & CTO, Physio PS, Inc., Atlanta, GA, dovetech@erols.com

Correspondence should be addressed to Dr. Colombo, dovetech@erols.com

ABSTRACT

Coronavirus, like other viruses and many chronic and serious pathologies, induce Oxidative Stress. Oxidative Stress largely affects the Mitochondria of cells. Cardiac and Nerve Cells are known to contain the largest numbers of Mitochondria of the cells in the body.

The effect of Oxidative Stress on the Parasympathetic and Sympathetic (P&S) branches of the Autonomic Nervous System is to induce dysfunction. P&S Dysfunction further affects the heart and other organs and systems of the body.

Since the P&S branches are designed to work together to maintain normal organ function, even when dysfunctional, organ dysfunction is often delayed until P&S dysfunction is very significant. Symptoms are not induced or realized until organ dysfunction presents.

This delay in symptoms often appears to be healthy, and therefore is often not associated with the causal factor, such as Coronavirus. Symptoms resulting from P&S dysfunction are often long-term and significantly impact patient quality of life and productivity.

Symptoms include severe fatigue, anxiety, depression, lightheadedness, sleep difficulties, brain fog, cognitive and memory difficulties, GI disturbances, shortness of breath, palpitations, and more.

Unfortunately, these symptoms are often not believed because these patients’ resting state is normal, including office exams, blood work, urine analysis, and other tests administered at rest, including many autonomic tests.

However, the underlying P&S is not evident during the resting state it is only evident during the dynamic states when tests are typically not performed. This editorial highlights the possibility of delayed Coronavirus-induced Oxidative Stress-induced P&S dysfunction, describes the possible types of P&S dysfunction, and offers possible therapy options to restore proper P&S function (balance).