Circadian Medicine Part 1 Flashcards
Circadian rhythm signaling in disease
- proper circadian rhythms confer growth, health + survival advs
- Circadian disruption
○ –> Phase dissociation = dissociation b/w the master clock + peripheral clocks + also not aligning w/ the light-dark cycle
○ –> Rhythm attenuation/ dysfunction = - Short-term + long-term adverse effects on fitness + health –> several diseases
- Does not lead to acute death in animals/ humans
Symptoms or disease onsets + circadian preference
- Circadian onset of disease symptoms:
○ Night-time exacerbation of asthma + other inflammatory diseases = asthma symptoms are manifested in the early hrs of the morning (does occur at these hrs as well)
○ Late afternoon/ evening sundowning (refers to a cluster of symptoms) of Alzheimer disease
§ restlessness, agitation, irritability, confusion - Early morning peak of myocardial infarction (death of the myocardial cells (cells in the myocardium = heart)) + stroke
- Circadian precision of episodes of headache attacks
*Symptoms linked to + cause disrupted sleep-wake rhythms
Asthma and endurance athletes
- Endurance sports might increase risk for asthma development:
○ swimming + cross-country skiing - Elite endurance athletes:
○ Have increased airway hyper-reactivity + asthma symptoms
§ caused by high min ventilation in an env w/ airway irritants e.g., chlorine by-products or cold air = cold dry air can stimulate asthma - Analysis of FINA World Championships + 2004 + 2008 Olympic Games
○ Endurance athletes had higher rates of documented asthma than nonendurance athletes
○ Endurance swimmers had the highest prevalence for any analysed athlete subgroup (15% for the 2004 and 21% for the 2008 Olympic Games)
(Amrol, 2015 Editorial)
Asthma symptoms, deaths and their timing
- Survey: 7729 patients w/ asthma (Litinski et al., 2009)
○ 74% awoke at least 1x/week w/ symptoms
○ 64% reported nocturnal symptoms at least 3x/week
○ 40% experienced symptoms nightly - Diurnal (during the day) differences in symptoms + deaths
○ Cough + dyspnoea (SOB = shortness of breath) worsen in early hours of ~04:00am
○ sudden death at ~04:00
§ ☼ diurnal variations in airflow limitation, airway hyperresponsiveness
(Durrington et al.,2014)
Time-of-day variation of airway conductance
Airway calibre:
* Increases w/ deep breaths + at exercise onset
- Displays diurnal variation – nadir at 4am (low conductance, high resistance), acrophase at ~mid-noon
Airflow limitation
- Can measure airflow limitation = the movt of air from atmosphere into air passage, into the lungs = by either way of airway resistance (how resistant is the movt of air into the air passage) + opposite way airway conductance (is the inverse of airway resistance) = when you have high resistance = have low conductance
Spirometry
- FEF 25-75% (forced expiratory flow rate)
○ a test of small airways obstruction examines the flow-rate during the middle 50% of the exhaled curve
○ Early indicator of obstructive dysfunction
○ Divide the vol by the time = your flow rate - FEV1%
○ forced expiratory volume in 1s
○ a test of airways obstruction
Time-of-day variation of spirometric parameters
- Each exhibits nadir at around 4-5am + acrophase at around mid-noon
Asthmatics are especially prone to bronchoconstriction at night than in normal subjects because:
- of the circadian increase in airway resistance
- of an increased airway hyperreactivity
- FEV1% nadir occurs at 4-5am
- FEF25-75% nadir occurs at 4-5am
Airway inflammation = peaks at around 4:00am
Subjects w/ nocturnal or nonnocturnal asthma (Kraft et al., 1999):
- In nocturnal asthma:
○ At 0400 than at 1600: alveolar eosinophils significantly higher
○ High eosinophil levels associated w/ low nocturnal FEV1
○ [Bronchoscopy + transbronchial biopsy at 1600 (peak lung function) + 0400 (airflow limitation worst)] - Patients w/ mild atopic asthma (mean FEV1 of 93%±4% of predicted value) (Kelly et al., 2004 ):
○ At 0400 than at 1600: greater numbers of macrophages, neutrophils + CD4 T lymphocytes in bronchoalveolar lavage fluid
○ At 0400: high % CD4 T lymphocytes associated w/ low FEV1 - How do you tell there is inflammation = by means of measuring some blood markers = your white blood cells such as eosinophils, macrophages etc but particularly eosinophils (WBC = are pro-inflammatory)
Time-of-day exposure to allergen affects the size of the inflammatory response in asthmatics
- Time of allergen exposure
- Lung clock in the Clara cell (epithelial cells)
- /4. Crosstalk b/w lung clock + clocks of immune cells in airway + lung interstitium (space b/w all the cells)
- Local cytokines, chemokines, inflammatory cell recruitment depends on circadian timing = means how the immune cells react to this allergen depends on the timing
- Effective treatment of asthma depends on the timing of drug treatment, e.g., inhaled + systemic meds (β agonists (Beta adrenergic agonist = act to cause bronchodilation = relax the smooth muscle cells that line the air passage) + steroids = are anti-inflammatory agents)
- B agonists prescribed in less severe asthma, both b agonists + steroids prescribed for severe cases
Current treatment guidelines in asthma do not reflect chronotherapy
- Chronotherapy: need synchronize timing of asthma drug delivery to rhythms in disease activity –> to increase efficacy + reduce adverse effects (Krakowlak & Durrington, 2018)
- B agonists = 6:00pm = help protect for the night as we know that’s when exacerbation/flare up of asthma takes place
- Steroids can suppress the effectiveness of b agonists
- 3:00pm for steroids
- If steroids given at b/w midnight to 4:00am = can cause adrenal suppression = in other words it will reduce the effectiveness of your bronchodilators, the b agonists
- But b/w 8:00am + 4:00pm = there is no adrenal suppression by steroids = during that time is good
Factors that can increase the risk for adverse cardiovascular events
Individuals are susceptible depending on their genetics, depending on their lifestyle factors + env + circadian rhythm = can lead to adverse events
Hypertension + cardiovascular risks
Hypertension
* the most powerful risk factor for stroke, coronary artery disease, heart failure, chronic kidney disease, and aortic + peripheral arterial diseases
* Marked diurnal variation in the onset time of cardiovascular events
○ w/ the peak in early morning = symptoms + events occur in the early morning hrs
* BP also exhibits a diurnal variation, w/ a decrease during sleep + a surge in the morning
Day-night pattern in BP
- Changes in upright posture + physical activity do not fully explain the day-night patterns in BP
- A lot of variation, especially during the waking period = mainly because BP is easily affected by many factors such as PA, postural stress etc
- What indicates/tells you about your peripheral vascular tone = DBP = during diastolic, ejection has finished, blood simply flows through the entire vascular system + when there is no pressure pushing from the heart = whatever resistance there is in your blood vessels i.e. resistance offered by atherosclerosis, plaques or lipids that fill the BV = offers resistance = so it is during diastolic we measure vascular tone
- If absorb too much Na+ also absorb too much water = rise in BP + if vascular tone is high = your vascular resistance is high, your DBP is high
- Autonomic NS = when SNS drive is high = lead to high BP e.g. ppl w/ obstructive sleep apnoea experience increased SNS activity as stop breathing many times throughout the night = why they are mostly hypertensive = many don’t die of sleep apnoea but of CV diseases
Dippers vs Non-dippers in blood pressure
- Normal phenomenon: BP dip (>10%) during sleep w/ a normal morning surge (not > 23 mmHg)
- “Dippers” defined as:
○ Nocturnal dip in BP by 10-20% of daytime level in normal + hypertensives - “Nondippers” defined as:
○ those who display <10% dip in BP during sleep –> associated w/ sleep apnoea, advanced kidney disease, nocturia, malignant hypertension - Highest BP value is at around midmorning
Implications for exaggerated morning BP surge
- In dippers + non-dippers:
○ If exaggerated morning surge >23 mmHg
§ –> cardiovascular events (stroke, myocardial infarction)
○ ** Higher incidence of sudden cardiac death in the first 3h after awakening
AN ABNORMAL BP PATTERN INCLUDES:
- high BP during the night
- high BP early in the morning
- Nondipping BP (defined as displaying a less than 10% drop in BP)
NORMAL:
- BP that drops in the later arvo + evening
Dippers = green line
Non-dippers = red line
= both can have a BP surge
