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Clinal Application

HRV in Diagnosis and Monitoring

HRV is similarly affected by multiple diseases
- Not optimal for disease diagnosis
Potential in disease monitoring
- Correlation between disease stage and HRV evolution

HRV and diseases

Diabetes

Introduction of Diabetes

Diabetes is a disease in which the body’s ability to produce or respond to the hormone insulin is impaired.

Abnormal metabolism of carbohydrates
Elevated levels of glucose in the blood

Over time, high blood glucose leads to problems such as: heart disease, stroke, kidney disease, eye problems, dental disease, nerve damage, foot problems

Current Monitoring Methods of Diabetes

1. Monitoring blood sugar levels

HbA1c test gives an average of the last 2-3 months
Self-monitoring devices for daily monitoring

2. Heart Health monitoring

Electrocardiogram, Echocardiogram, Exercise Test ØMonitoring blood pressure monthly ØCholesterol monitoring
Nuclear Stress Test, Coronary angiogram

3. Kidney check-ups

Microalbumin test

4. Eye, dental, and foot exams

HRV in Diabetes Monitoring

Higher glucose levels are linked to a lower HRV — Decrease in SDNN, rMSSD and R-R intervals

There is a relationships between decreasing HRV and increasing atherosclerosis among patients with type 2 diabetes

HRV is the earliest symptom of CADN

Failed to find relationship between HRV and lower extremity vascular disease and mortality in diabetes

Reduced HRV can predict progression of coronary artery calcium (CAC) in non-diabetic and Type 1 diabetic patients

Parkinson's Disease (PD)

Introduction of Parkinson's Disease

Parkinson's disease is the second most common neurodegenerative disorder
Characterised by the progressive and selective loss of cells in certain regions of the CNS
Affects 1-3% of the global population older than 65 however it can be present from young adulthood
Hallmark symptoms are bradykinesia, resting tremors and rigidity
Patients in advanced stages require assistance with moving and suffer dyskinesia
Non-motor symptoms can include cognitive changes, sleep disorders and even hallucinations/delusions in advanced stages of the disease

Current Monitoring Methods of Parkinson's Disease

Mainly through clinical examination and referral to scales to assess the severity

Hoehn and Yahr Scale
- Stage 1 – symptoms (tremor, rigidity, bradykinesia) are mild and limited to one side of the body
- Stage 2 – symptoms are seen on both sides of the body without impairment to balance
- Stage 3 – loss of balance, slowness of movements along with previous symptoms
- Stage 4 – noticeably incapacitated and requires assistance with the movement
- Stage 5 – confined to a wheelchair, constant assistance required to help the patient with all daily activities

Movement Disorder Society's Unified Parkinson's Disease Scale
- Part 1 – non-motor aspects of daily living
- Part 2 – motor aspects of daily living
- Part 3 – motor examination of motor symptoms
- Part 4 – motor complications including dyskinesias and fluctuations between off-state and on-state

HRV in Parkinson's Disease Monitoring

Devos et al. reported that day (7am to 6pm) LF power, night (0am to 6am) HF power and day LF/HF ratio were negatively correlated with the off drug UPDRS motor score
- Parameters could be used as supplementary information during an evaluation of the patient’s motor condition
Night pNN50 value was also significantly decreased in a group of patients with L-dopa related motor complications
- pNN50 value could be used to help inform the clinician on if the treatment should be changed
Heimrich et al. reported an increased Hoehn and Yahr stage was significantly associated with lower RMMSD during short term measurements
- RMMSD could be used to help classify the disease severity
Bidikar et al. reported that HRV (RR intervals) during a deep breathing test was reported to be negatively correlated with the Hoehn Yahr stage and the Non-Motor Symptom Scale Score from the UPDRS scale
- HRV could be used for early diagnosis by helping to identify the non-motor symptoms which precede the motor symptoms

Depression

Introduction of Depression

According to the American Psychiatric Association, depression (major depressive disorder) is a common and serious medical illness that negatively affects how you feel, the way you think and how you act.
Some common symptoms are:
- Feeling sad or having a depressed mood
- Loss of interest or pleasure in activities once enjoyed
- Changes in appetite — weight loss or gain unrelated to dieting
- Trouble sleeping or sleeping too much
- Loss of energy or increased fatigue
- Feeling worthless or guilty
- Difficulty thinking, concentrating or making decisions
- Thoughts of death or suicide

Current Monitoring Methods of Depression

Currently, doctors mainly use scale tests and subjective judgment in the clinical diagnosis of depression. Therefore, its monitoring is mainly based on check subjective controls to the clinic, followed by a questionnaire that helps quantisise the effects of the mental illness on the patient.
Treatment:
- Antidepressants
  - Selective serotonin reuptake inhibitors (SSRIs)
  - Serotonin-noradrenaline reuptake inhibitors (SNRIs)
  - Noradrenaline and specific serotonergic antidepressants (NASSAs)
  - Tricyclic antidepressants (TCAs)
  - Serotonin antagonists and reuptake inhibitors (SARIs)
  - Monoamine oxidase inhibitors (MAOIs)
- Combination therapy
- Mental health teams

HRV in Depression Monitoring

Previous researches have shown that depression is associated with autonomic nervous system (ANS) dysfunction. Depression patients show reduced parasympathetic modulation.
The depressive sample displays lower HF power values compared to healthy controls. This result can be interpreted as a reduced ability of the para-sympathetic nervous system to regulate the heart rate via vagal activity.
- After taking antidepressants for two weeks, values of HF power and Non-linear parameters increased over time and were even more pronounced in women than man and may be interpreted as an increase in vagal activity.
- 2018 Paper: some antidepressant classes (such as tricyclics) generally worsen HRV, whereas others (most notably selective serotonin reuptake inhibitors) have a more positive influence.
RMSSD, SDNN, HF, LF, ratio of low and high frequency (LF/HF), PNN50, SDSD, non-linear methods (Poincaré plot).
Time readings:
- 13 min reading (2011).
- data acquisition: 9:00–12:00 a.m. and 14:00–18:00 p.m.
- EEG and ECG signals were measured in the same room between 8:00 a.m. and 2:00 p.m.

COVID-19

Introduction of COVID-19

A coronavirus identified in Dec. 2019, SARS-CoV-2, has caused a pandemic of respiratory illness, called COVID-19.

Inflammation
- A normal reaction in response to injury or pathogenic infection.
- Uncontrolled inflammation is sometimes caused when infected by the coronavirus, leading to a cytokine storm, an extreme release of cytokines in response to infection due to a loss of regulation on the release of proinflammatory cytokines.

COVID-19 and Inflammation
- Pro-inflammatory markers associated with a cytokine storm have been detected in diabetic COVID-19 patients.
- Moreover, a cytokine storm is proposed to be the cause of acute respiratory distress syndrome (ARDS) and multiple organ failure, both of which present in severe COVID-19 cases.

Current Monitoring Methods of COVID-19

Diagnosis Method

Polymerase chain reaction (PCR) tests
- Mechanism: Reverse transcriptase or DNA polymerase are added to a sample to replicate any viral RNA that may be present.
- Shortages:
  - Time consuming
  - False negatives can occur up to 30%
  - False positives due to dead, deactivated virus

Lateral flow tests (LFTs)
- Mechanism: A sample is placed on a small absorbent pad, which is drawn through a capillary line to antibodies, which specifically bind to SARS-Cov-2 proteins
- Shortages:
  - Low average accuracy of 72% in symptomatic people and 58% in asymptomatic people

Antibody tests
- Mechanism: Blood sample used to test the antibody level, but they are usually produced with a delay of several days after infection or even after recovery
- Shortages:
  - Ineffective in protective diagnosis, delay in antibody production

HRV in COVID-19 Monitoring

HRV as a non-invasive, inexpensive, and sensitive measure of inﬂammatory processes and immunomodulation
- The vagus nerve maintains tonic inhibitory control of pro-inﬂammatory cytokines via acetylcholine release into the reticuloendothelial system (e.g., spleen, gastrointestinal tract, heart, liver), mediating the inﬂammatory reﬂex through the cholinergic anti-inﬂammatory pathway

An HRV measure — RMSSD is sensitive to the inﬂammatory processes in viral infection

Some Theoretical contributions
- Owens, Critchley and associates studies of HRV as a remote digital biomarker (Owens et al., 2018)
- Thayer’s neurovisceral integration approach (Thayer and Lane, 2020)
- HRV is related to inﬂammatory processes in humans (Williams et al., 2019; Jarczok et al., 2021)
- Identification of a HRV related cholinergic anti-inﬂammatory pathway (Thayer and Fischer, 2009)

Potential Direction
- Refine the algorithm of converting inter-beat interval (IBI) to RMSSD and include other physiological parameters such as temperature, respiration, SPO2, and heart rate as diagnosis
- Quantify the level of infection and monitor progression

Systemic Lupus Erythematosus (SLE)

Introduction to SLE

SLE is a chronic disease which can cause inflammation and pain in any part of your body however it most commonly affects the skin, joints and internal organs such as the kidney and the heart. Common symptoms of SLE include:

Extreme fatigue
Pain or swelling in the hands, feet or around the eyes
Headaches
Sensitivity to sunlight

However, SLE is difficult to diagnose because its symptoms are vague and overlap with other connective tissue diseases such as rheumatoid arthritis, chronic fatigue syndrome and fibromyalgy. Research was undertaken to see if SLE is associated with changes in HRV to evaluate whether HRV can be used as a diagnostic tool.

HRV in SLE Monitoring

Matuskin et al. conducted a review of studies comparing HRV between SLE patients and control groups, most studies reported changes in SDNN, rMSSD, pNN50, LF, HF and LFHF.

HRV in Diseases with Shared Symptoms

Chronic Fatigue Syndrome

General Health

The Basics of Health and Longevity

Reasons that make HRV a good biomarker for general health
- Parasympathetic nervous system "Rest and digest"
  - Also linked to body's adaptability (Thayer) "provides support for the idea that HRV may index the degree to which a mPFC-guided “core integration” system is integrated with the brainstem nuclei that directly regulate the heart."
- Sympathetic nervous system, regulates short term. "Fight-or-flight"
- "(The) most comprehensive biomarker of health, longevity & performance" (EliteHRV website)
HRV is linked to a range of different lifestyle factors + diseases:
- Stress – HRV candidate biomarker for mental health resilience, general indicator for indivicual's capacity to adapt their psychophysiological responses when facing stressors. (Perna Et Al. 2020)
- Nutrition - Higher prenatal blood levels of omega-3 fatty acid increase infant HRV. (Speer 2020)
- Sleep
- Exercise
- Smoking – low HRV linked to both addiction and smoking during pregnancy has a clear effect on lowering HRV in children (Speer 2020)
- Psychological diseases – lower vagally mediated HRV associated with psychiatric disorders, higher resting SDNN better at regulating cravings. Anxiety linked with overactive HRV. (Perna Et Al. 2020)
- Cardiovascular Diseases – lower HRV linked with both susceptibility to disease as well as poor prognosis in patients with the disease. After acute myocardial infarction, a stronger indicator of mortality than measures of pump failure, age, Holter variables. (P < 0.0001 for RR interval) (Kleiger 1987)
- Metabolic Diseases – Direct relation between linear HRV parameters (RR interval + SDNN) and waist size (p < 0.001). The inverse relation between nonlinear HRV parameters (SD1) and fasting plasma glucose (p = 0.02) for Metabolic Syndrome (Stuckey et Al. 2015)

Current Monitoring Systems

EliteHRV
- Biomarker for overall health, used to guide lifestyle interventions to improve health + fitness
- Sell an app + Heart rate monitor that you attach to your finger while taking a reading

Kubios
- Physiological stress and the effects of different therapies/lifestyle interventions on HRV
- How the user compares with average values worldwide
- Looking for risk factors for metabolic and cardiovascular diseases
- HRV analysis software, HRV analysis app that is compatible with many leading commercial HR monitors (Polar, Suunto, Garmin)

Fitness bands (Whoop, Firstbeat)
- As a metric for fitness improvement (Whoop looks at RMSSD over time)
- Constantly monitor heart rate + HRV through wrist-bands

Molecool:Clinical Application

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