Long-COVID Syndrome and the Cardiovascular System: A Review of Neurocardiologic Effects on Multiple Systems.

PURPOSE OF REVIEW: Long-COVID syndrome is a multi-organ disorder that persists beyond 12 weeks post-acute SARS-CoV-2 infection (COVID-19). Here, we provide a definition for this syndrome and discuss neuro-cardiology involvement due to the effects of (1) angiotensin-converting enzyme 2 receptors (the entry points for the virus), (2) inflammation, and (3) oxidative stress (the resultant effects of the virus). RECENT FINDINGS: These effects may produce a spectrum of cardio-neuro effects (e.g., myocardial injury, primary arrhythmia, and cardiac symptoms due to autonomic dysfunction) which may affect all systems of the body. We discuss the symptoms and suggest therapies that target the underlying autonomic dysfunction to relieve the symptoms rather than merely treating symptoms. In addition to treating the autonomic dysfunction, the therapy also treats chronic inflammation and oxidative stress. Together with a full noninvasive cardiac workup, a full assessment of the autonomic nervous system, specifying parasympathetic and sympathetic (P&S) activity, both at rest and in response to challenges, is recommended. Cardiac symptoms must be treated directly. Cardiac treatment is often facilitated by treating the P&S dysfunction. Cardiac symptoms of dyspnea, chest pain, and palpitations, for example, need to be assessed objectively to differentiate cardiac from neural (autonomic) etiology. Long-term myocardial injury commonly involves P&S dysfunction. P&S assessment usually connects symptoms of Long-COVID to the documented autonomic dysfunction(s).

Autonomic Testing Optimizes Therapy for Heart Failure and Related Cardiovascular Disorders.

PURPOSE OF REVIEW: Cardiovascular autonomic control is an intricately balanced dynamic process. Autonomic dysfunction, regardless of origin, promotes and sustains the disease processes, including in patients with heart failure (HF). Autonomic control is mediated through the two autonomic branches: parasympathetic and sympathetic (P&S). HF is arguably the disease that stands to most benefit from P&S manipulation to reduce mortality risk. This review article briefly summarizes some of the more common types of autonomic dysfunction (AD) that are found in heart failure, suggests a mechanism by which AD may contribute to HF, reviews AD involvement in common HF co-morbidities (e.g., ventricular arrhythmias, AFib, hypertension, and Cardiovascular Autonomic Neuropathy), and summarizes possible therapy options for treating AD in HF. RECENT FINDINGS: Autonomic assessment is important in diagnosing and treating CHF, and its possible co-morbidities. Autonomic assessment may also have importance in predicting which patients may be susceptible to sudden cardiac death. This is important since most CHF patients with sudden cardiac death have preserved left ventricular ejection fraction and better discriminators are needed. Many life-threatening cardiovascular disorders will require invasive testing for precise diagnoses and therapy planning when modulating the ANS is important. In cases of non-life-threatening disorders, non-invasive ANS testing techniques, especially those that individually assess both ANS branches simultaneously and independently, are sufficient to diagnose and treat serially.

Autonomic nervous system activity and the risk of nosocomial infection in critically ill patients with brain injury.

PURPOSE: Nosocomial infection contributes to adverse outcome after brain injury. This study investigates whether autonomic nervous system activity is associated with a decreased host immune response in patients following stroke or traumatic brain injury (TBI). METHODS: A prospective study was performed in adult patients with TBI or stroke who were admitted to the Intensive Care Unit of our tertiary university hospital between 2013 and 2016. Heart rate variability (HRV) was recorded daily and assessed for autonomic nervous system activity. Outcomes were nosocomial infections and immunosuppression, which was assessed ex vivo using whole blood stimulations with plasma of patients with infections, matched non-infected patients and healthy controls. RESULTS: Out of 64 brain injured patients, 23 (36%) developed an infection during their hospital stay. The ability of brain injured patients to generate a host response to the bacterial endotoxin lipopolysaccharides (LPS) was diminished compared to healthy controls (p < 0.001). Patients who developed an infection yielded significantly lower TNF-α values (86 vs 192 pg/mL, p = 0.030) and a trend towards higher IL-10 values (122 vs 84 pg/mL, p = 0.071) following ex vivo whole blood stimulations when compared to patients not developing an infection. This decreased host immune response was associated with altered admission HRV values. Brain injured patients who developed an infection showed increased normalized high-frequency power compared to patients not developing an infection (0.54 vs 0.36, p = 0.033), whereas normalized low-frequency power was lower in infected patients (0.46 vs 0.64, p = 0.033). CONCLUSION: Brain injured patients developing a nosocomial infection show parasympathetic predominance in the acute phase following brain injury, reflected by alterations in HRV, which parallels a decreased ability to generate an immune response to stimulation with LPS.

Unexpected SARS-CoV-2 cardiorespiratory arrest in a myopathy patient undergoing immunosuppressive treatment: A case report.

RATIONALE: It is recommended that patients with Rheumatic diseases that are at high risk of developing active infections be screened for Tuberculosis, Hepatitis B, and Hepatitis C before receiving second-line immunosuppressive therapies. With the emergence 2019 novel coronavirus (SARS-CoV-2), expanded guidelines have not been proposed for screening in these patients before starting advanced therapy. PATIENT CONCERNS: We present an unique circumstance whereas a patient with a 5 year history of inflammatory muscle disease, diagnosed by clinical history and muscle biopsy with elevated creatine kinase levels, suffered a hypoxemic cardiopulmonary arrest due to asymptomatic SARS-CoV-2 after receiving advanced immunosuppressive therapy. DIAGNOSES: The patient presented with an acute exacerbation of inflammatory muscle disease with dysphagia, muscle weakness, and elevated creatine kinase. INTERVENTIONS: After no improvement with intravenous immunoglobulin the patient received mycophenolate and plasma exchange therapy. OUTCOMES: Subsequently the patient suffered a fatal hypoxemic cardiopulmonary arrest. Polymerase chain reaction test was positive for SARS-CoV-2 RNA. LESSONS: We conclude that rheumatic patients, asymptomatic for SARS-CoV-2 infection, be screened and tested before initiating second-line immunosuppressive treatment.

Differential effects of adrenergic antagonists (Carvedilol vs Metoprolol) on parasympathetic and sympathetic activity: a comparison of measures.

BACKGROUND: Cardiovascular autonomic neuropathy (CAN) is recognized as a significant health risk. Specific and sensitive measures of CAN are needed for early identification and treatment to avoid complications, preferably in the preclinical state. OBJECTIVES: In this first of two articles, the patient cohort is described and two measures of autonomic function are reviewed: the traditional heart rate variability (HRV)-alone method and the newer parasympathetic and sympathetic (P&S) Method. These systems are then evaluated against known effects of the alpha/beta-adrenergic blocker, Carvedilol, and the selective beta-adrenergic blocker, Metoprolol, on P&S activity. METHODS: Serial autonomic nervous system test data from 147 type 2 diabetes mellitus patients from eight ambulatory clinics were analyzed. Patients were grouped according to whether a beta-blocker was (1) introduced, (2) discontinued or (3) continued without adjustment. Group 3 served as the control. HRV-alone parameters are computed according to standards. The P&S Method, which is a time-frequency analyses of concurrent respiratory activity and HRV, is elucidated, as developed at MIT and Harvard Medical School (1981). RESULTS: The HRV-alone demonstrated that introducing either medication increased low frequency (msec(2)) and standard deviation of the beat-to-beat (N-N) interval (msec), as expected. The other HRV parameter responses were not consistent with expectations. Similar inconsistencies occurred when either medication was discontinued. The P&S Method demonstrated that introducing or discontinuing either agent decreased or increased sympathetic activity, respectively, according to expectations. With ongoing treatment, resting parasympathetic activity decreased with Metoprolol but increased with Carvedilol. CONCLUSION: Autonomic assessment fidelity was significantly higher with the P&S Method as validated by comparison with previously known physiology of the cardiovascular system.

Differential effects of adrenergic antagonists (Carvedilol vs Metoprolol) on parasympathetic and sympathetic activity: a comparison of clinical results.

BACKGROUND: Cardiovascular autonomic neuropathy (CAN) is recognized as a significant health risk, correlating with risk of heart disease, silent myocardial ischemia or sudden cardiac death. Beta-blockers are often prescribed to minimize risk. OBJECTIVES: In this second of two articles, the effects on parasympathetic and sympathetic activity of the alpha/beta-adrenergic blocker, Carvedilol, are compared with those of the selective beta-adrenergic blocker, Metoprolol. METHODS: Retrospective, serial autonomic nervous system test data from 147 type 2 diabetes mellitus patients from eight ambulatory clinics were analyzed. Patients were grouped according to whether a beta-blocker was (1) introduced, (2) discontinued or (3) continued without adjustment. Group 3 served as the control. RESULTS: Introducing Carvedilol or Metoprolol decreased heart rate and blood pressure, and discontinuing them had the opposite effect. Parasympathetic activity increased with introducing Carvedilol. Sympathetic activity increased more after discontinuing Carvedilol, suggesting better sympathetic suppression. With ongoing treatment, resting parasympathetic activity decreased with Metoprolol but increased with Carvedilol. CONCLUSION: Carvedilol has a more profound effect on sympathovagal balance than Metoprolol. While both suppress sympathetic activity, only Carvedilol increases parasympathetic activity. Increased parasympathetic activity may underlie the lower mortality risk with Carvedilol.

Comparison of HRV analysis methods during orthostatic challenge: HRV with respiration or without?

Heart Rate Variability (HRV) analysis has become an important tool in assessing human Autonomic Nervous System (ANS) activity in recent years. Orthostatic challenge is one of the most common tests to detect ANS dysfunction. In this study we looked at the changes in ANS activity of normal subjects to orthostatic challenge and compared the results of 3 different HRV analysis methods: Time-Domain Methods, HRV spectral analysis without respiratory analysis (RA) and with RA. Although all three methods have indicated an increase in sympathetic activity and a decrease in parasympathetic activity from baseline to stand, the only significant increase in sympathetic activity was observed in HRV with RA method. Additional information from RA enables isolating the sympathetic and parasympathetic branches in HRV signals and therefore reflects ANS changes more accurately. On the other hand, sympathetic and parasympathetic power may not be separated properly if respiration-dependent fluctuations in HRV are ignored. It is expected that the differences between methods would be very clear with low respiratory rates. However, we focused on studies with normal respiratory rates and have also found significant differences among the methods.