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All Posts in Category: Long COVID

Pathophysiology of Long COVID

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By Joseph Colombo and Nicholas L. DePace

 Pathophysiology of Long‑COVID

The mechanism behind the causation of Long-COVID syndrome may be multifactorial.  Immune response, antibody generations, direct effects of the virus, complications of the critical illness, psychosocial factors, and post-intensive care syndrome, post-traumatic stress, and oxidative stress may be operative mechanisms. Cardiac deconditioning may also be a factor.

The mechanism of heart failure involving pro-inflammatory cytokines with interleukin 1 and interleukin 6 tumor necrosis factors may cause prolonged effects. Redox imbalance linking COVID-19 and chronic fatigue syndromes and systemic inflammation and neuroinflammation have also been postulated. Oxidative phosphorylation may be operative in a hyper inflammatory state with altered cardiorespiratory function. It is thought that viral infections cause a shift in mitochondrial energy system contribution from ATP synthesis to innate immune signaling occurring in order to eradicate pathogens, promote inflammation, and eventually restore tissue homeostasis. An increased rate of glycolysis and downregulation of oxidative phosphorylation are seen. Oxidative stress has been implicated in many acquired myocardial disorders and may lead to significant autonomic dysfunction.


This Post is an excerpt from: Current Cardiology Reports HEART FAILURE (HJ EISEN, SECTION EDITOR) Long‑COVID Syndrome and the Cardiovascular System: A Review of Neuroradiologic Effects on Multiple Systems Nicholas L. DePace1,2,3 · Joe Colombo1,3,4 Accepted: 12 September 2022 © The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature 2022

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Long COVID and the Autonomic Nervous System: The Journey from Dysautonomia to Therapeutic Neuro-Modulation through the Retrospective Analysis of 152 Patients

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By Joseph Colombo, Michael I. Weintraub, Ramona Munoz, Ashish Verma, Ghufran Ahmad, Karolina Kaczmarski, Luis Santos, and Nicholas L. DePace

Long COVID and the Autonomic Nervous System

The severity and prevalence of Post-Acute COVID-19 Sequela (PACS) or long-COVID syndrome (long COVID) should not be a surprise. SARS-CoV-2 targets diverse organs and tissues after entry into the human body. Long-COVID syndrome is defined as persistent symptoms beyond 12 weeks after acute COVID-19 infection. Viruses, by inducing an inflammatory state, can damage tissue. At a cellular level, the mitochondria are susceptible to the effects of inflammation and oxidative stress. Given that nerve cells, including brain cells, and heart muscle cells contain significantly more mitochondria than other cells in the body, it is to be expected that they will be the most affected by oxidative stress. The results of mitochondrial dysfunction includes primarily autonomic dysfunction (including both parasympathetic and sympathetic (P&S)) and cardiovascular dysfunction.

 Arguably, the first symptom of P&S dysfunction is orthostatic dysfunction. Orthostatic dysfunction is a significant contributor to poor cardiac and cerebral perfusion (and, of course, all structures around and above the heart). Autonomic dysfunction is also induced as a result of the severity of the infection. Furthermore, COVID-19 injures the lungs, reducing their ability to exchange oxygen, exacerbating the poor perfusion and resulting dysfunctions. The initial respiratory compromise, due to the COVID-19 virus, on the medullary respiratory control centers (including the pre-Bötzinger complex) may be so dramatic that P&S symptoms and signs are often overlooked or misunderstood. Respiratory pacing from the pre-Bötzinger complex involves vagus nerve afferents, among other brainstem structures;  feedback from the COVID-19-damaged lung; aortic and carotid chemo, baro, and vagal receptors; and medullary chemoreceptors. All involving P&S nerves. Brainstem cardiorespiratory centers (e.g., the Nucleus Tractus Solitarius, Dorsal Vagal Motor Nucleus, and Nucleus Ambiguus, all of which are autonomic nuclei) are also implicated in COVID-19 infection. Furthermore, sympathetic involvement in cytokine storms and the angiotensin system, and parasympathetic involvement in immune function, provides further evidence of P&S compromise in COVID-19 infections.

Any resulting damage to these nerves further implicates P&S dysfunction in long-COVID syndrome. Long-COVID symptoms may be explained by a pro-inflammatory state with oxidative stress and P&S dysfunction. This study presents the data obtained from autonomic dysfunction patients who were P&S tested and treated prior to COVID-19 infection due to other causes of autonomic dysfunction. Then, they were P&S tested and treated after surviving COVID-19 infection. Long-COVID symptoms may be explained by a pro-inflammatory state with oxidative stress and P&S dysfunction. This is hypothesis generating. Long COVID is characterized by parasympathetic excess and alpha-sympathetic withdrawal. Anti-cholinergic therapy may relieve post-COVID-19 symptoms associated with parasympathetic excess. This is hypothesis generating and further trials are needed.

This Post is an excerpt from NeoroSci:

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Long COVID and Cardiac Involvement: Understanding the Impact and Implications

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By Dr. Nicholas DePace and Dr. Joseph Columbo

Long COVID – Cardiac Involvement

Common cardiac problems may occur with labile heart rate and blood pressure responses to activity.

Myocarditis and pericarditis may occur chronically. In the acute stages, myocardial infarction, cardiac failure, life-threatening arrhythmias, and sudden cardiac death have been described.

The incidents of arrhythmias in Long COVID syndrome are unknown, but many individuals have palpitations, and studies using ambulatory monitoring need to be further conducted.

Sequelae from acute COVID may occur, such as coronary artery aneurysm, aortic aneurysm, atherosclerosis, and venous and arterial thrombotic disease including life-threatening pulmonary embolism.

These structural abnormalities may manifest itself in Long-COVID syndrome long after recovery of acute illness and predispose to arrhythmias, breathlessness, and acute coronary events, such as heart attacks and chest pain syndromes.

Myocardial injury is the most common abnormality detected with acute COVID infection. It is usually detected even when patients with no cardiac symptoms demonstrate elevated cardiac troponin levels, which may be evident in a high percentage of patients with COVID-19 [69].

Further research is ongoing as to whether this myocardial injury pattern, even when subclinical, may lead to increased arrhythmias and heart failure in the long-term.

Echocardiographic studies have shown abnormalities with COVID-19, including right ventricular dysfunction 26.3%, left ventricular dysfunction 18.4%, diastolic dysfunction 13.2%, and pericardial perfusion 7.2%.

To what extent this is reversible in patients who go on to Long-COVID syn drome is not known. In addition, sleep abnormalities and difficulties that reduce quality of life have been noted in Long-COVID syndrome patients.

These may also adversely affect cardiac function, provoke arrhythmias, elevate blood pressure, and exacerbate or cause hypertensive states. Chest pain and palpitations are status post-acute phase of COVID-19.

Palpitations were reported in 9% and chest pain in 5% of patients 6 months after follow-up. To track heart inflammation, one of the most effective and sensitive tests is cardiac magnetic resonance imaging (MRI).

Inflammation rates may be as high as 60% more than 2 months after a diagnosis of COVID, although this is a very difficult test to obtain in many centers that do not have it readily available.

Long-COVID syndrome patients may present with chest pain in 17% of patients, palpitations in 20% of patients, and dyspnea on exertion 30% of patients.

The question of myocarditis is always raised especially in children, but adults are also known to have myocarditis.

One small study showed that in healthy college athletes with mild COVID-19 symptoms, 15% had evidence of MRI findings consistent with myocarditis on a screening study.

More importantly, many of the chest pains and palpitations, which appear to be cardiology in etiology, are actually due to autonomic dysfunction, including the postural orthostatic tachycardia syndrome (POTS).

Therefore, the importance of not only doing cardiac imaging, ambulatory monitoring, stress testing, 6-min walk test, echocardiography, and other noninvasive cardiac workup, but also autonomic Current Cardiology Reports 1 3 testing, such as cardiorespiratory monitoring, HRV interval testing, beat-to-beat blood pressure with tilt testing, and sudomotor testing may be useful in diagnosing autonomic nervous dysfunction. Arrhythmias are noted with Long COVID, but attention to the use of anti-arrhythmic drugs, amiodarone, for example, must be used carefully in patients who have fibrotic pulmonary changes after COVID-19.

This Post is an excerpt from Current Cardiology Reports:

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Long COVID Symptoms

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By Dr. Nicholas DePace and Dr. Joseph Columbo

Long‑COVID Symptoms

Long-COVID symptoms may be explained by a pro-inflammatory state with oxidative stress and P&S dysfunction.

Cardiopulmonary testing for unexplained dyspnea post-COVID-19 was reported. Patients with symptoms consistent with chronic fatigue had an abnormal pattern of oxygen uptake on cardiopulmonary testing consistent with what is seen with chronic fatigue syndrome.

Circulatory impairment, abnormal ventilatory pattern, and chronic fatigue syndrome may be common in patients with post-acute sequelae of post-concussive syndrome, and this accounts for the mechanism of dyspnea in many patients who do not have pulmonary disease from Long-COVID or myocardial dysfunction.

The symptoms of Long-COVID syndrome may all be associated with autonomic dysfunction as measured with cardiorespiratory testing and Current Cardiology Reports 1 3 relieved with appropriate parasympathetic or sympathetic therapies based on the cardiorespiratory test.

This Post is an excerpt from Current Cardiology Reports:

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Defining Long COVID

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By Dr. Nicholas DePace and Dr. Joseph Columbo

Long‑COVID Definition

What exactly is Long-COVID syndrome?

Long-COVID or post-COVID-19 is an umbrella term that refers to symptoms persisting past the initial phase. There are many definitions that have been offered.

Official Definition of Long-COVID

Long-COVID has recently been defined as “the condition that occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis”

 Likewise, there now exists an International Classification of Diseases, Tenth Revision (ICD-10) code corresponding to Long-COVID condition—U09.9.  Basically, there are individuals who do not completely recover over a period of weeks, usually 2–3 weeks. Since COVID-19 is a novel disease, there is still no consensus of the definition of Long-COVID symptoms.

Prevalence and Symptom Categories

Systematic Review Findings

A systematic review documented 20% of the reports of long-term COVID symptoms involved abnormal lung function, 24% involved neurological complaints and olfactory dysfunction, and 55% on specific widespread symptoms, mainly chronic fatigue and pain.

WHO’s Clinical Case Definition

The World Health Organization (WHO) developed a clinical case definition of Long-COVID by Delphi methodology that included 12 domains. However, the understanding of this definition has been going through changes as new evidence emerges, and we are gaining a better understanding of the consequences of COVID-19 and its mutations.

Symptom Duration and Impact

Usually, three or more months past the acute COVID-19 infection, symptoms that last for at least 2 months and cannot be explained by alternate diagnoses may ft this definition. These symptoms include fatigue, shortness of breath, cognitive dysfunction, and symptoms that affect the functional capacity of patients with daily living and productivity. Symptoms may fluctuate, fare up, or relapse over time, adversely affecting multiple organ systems.

P&S Nervous Systems Dysfunction in Long Covid

Role of P&S Nervous Systems

We propose that the delay between surviving the acute COVID infection and the onset of the Long-COVID symptoms is a function of the P&S nervous systems.

The P&S nervous systems function together to coordinate and control organs and organ systems to maintain normal organ function, even when the two nervous systems are dysfunctional.

Dysfunction and Symptoms

Prolonged P&S dysfunction, once severe enough, then leads to poor organ control and then symptoms. This process may take up to 3 months, faster if there were prior comorbidities, including age.

This is the basis for our claims that Long-COVID is a combination of both parasympathetic dysfunction(s) and sympathetic dysfunction(s). In our experience, the prolonged severe immune responses to COVID-19 seems to cause prolonged excessive parasympathetic responses, leading to secondary, prolonged, excessive beta-adrenergic (sympathetic) responses which prolongs and exaggerates heart rate, blood pressure, histaminergic, inflammatory, pain, and anxiety responses.

Gastrointestinal and Other Symptoms

The parasympathetic excess may also lead to both upper and lower GI symptoms.

The oxidative stress of the acute COVID-19 infection also causes oxidative stress which often leads to alpha-adrenergic (sympathetic) dysfunction which leads to orthostatic dysfunction and poor coronary and cerebral perfusion and the perfusion of the anatomy in between causing many of the rest of the symptoms of Long-COVID. Long-COVID may directly affect the lungs, heart, nervous system, kidneys, and pancreas.

Challenges in Research and Treatment

Lack of Standardized Definition

Unfortunately, the lack of a standardized definition for Long-COVID syndrome presents obstacles for researchers Fig. 1 The cytokine storm involved in COVID-19 infections is a source of oxidative stress.

Viruses and traumas (mental or physical) in general may lead to oxidative stress, which may lead to parasympathetic or sympathetic dysfunction(s), known as dysautonomia (adapted from Rasa et al.) ◂ Current Cardiology Reports 1 3 in studying the condition with controlled studies and arriving at a precise diagnosis and treatment algorithms. In addition, many patients with Long-COVID syndrome require rehospitalization especially those with comorbidities, such as cardiovascular disease, diabetes mellitus, obesity, cancer, and kidney disease.  


This Post is an excerpt from Current Cardiology Reports:

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