To James Watson & GRG List Members.
Lots of good science here. Thanks. I suggest a very long thread like this be consolidated & summarized much more succinctly in an actionable format enabling a translational researcher to convert it into practical human clinical trials
applications. What specifically should the next researchers do experimentally & why?
For example, references to the effects of CO,NO & H2S could have been set in a format that led to the formation of the successful & profitable company IKARIA.
IKaria was sold recently for about $1.3 billion & a new company was spun off to continue to capitalize on IKARIA technology.
Highly effective communication of scientific information will be essential to achieve human healthspan increases from basic aging research results.
On Feb 9, 2015, at 3:59 PM, John M. Johnny Adams, GRG Exec Director wrote:
Dear GRG Member,
The following is second of three in a Heart Rate Variability (HRV) series.
This one was created by James P. Watson, M.D.
Heart Rate Variability “101”
1. HRV spectrum: Respiratory Sinus Variation (High Frequency), Parasympathetic activity (High Frequency and Low Frequency), vs Sympathetic activity (Very low frequency)
HRV power spectrum analysis can differentiate between HRV changes that are due to breathing (called Respiratory Sinus Variation) and HRV changes that are due to the autonomic system (ANS)
High frequency (HF) variations (power) are due to respiratory variations and are mediated by the parasympathetic system.
HF are frequencies in the range of 0.25 Hz. HF power can be improved with exercise and deep breathing.
Because HF power (respiratory changes) is driven by parasympathetic tone, HF power is dramatically increased in endurance athletes who have a resting bradycardia.
Autonomic system variations in HRV include both sympathetic and parasympathetic activity, but there is a lot of overlap in the spectrum between these two divisions of the autonomic system
Very low frequency variations (power) in HRV are primary sympathetic nervous system activity and include frequencies in the range of 0.04 – 0.15 Hz
Low frequency variations (power) in HRV are due primarily to the parasympathetic system and include frequencies in the range of 0.15 – 0.4 Hz.
However, less sophisticated HRV analysis systems lump VLF and LF into one power spectrum. When this is done, they typically do a ratio of LF to HF (LF/HF), which is normally about 3.6 + 0.7
Here is a graph of these spectrums:
diagram reference: http://ift.tt/1FrbIXS
Conclusion: We need a sensor and software that can tell us the “power spectrum” of HRV, including the HF power (0.25 Hz), LF power (0.15-0.4 Hz) and hopefully the very LF power (0.04-0.15 Hz)
The ratio of LF to HF is normally about 3.7 and ideally, we need a software program that computes this as well
We want to decrease sympathetic tone (VLF or LF), increase parasympathetic tone (HF and LF), slow down heart rate, and increase deep breathing (HF) to improve HRV
These are not going to be easy to do in a rat or a mouse.
We might as well use a sensor that also senses respiration, since this is such an important aspect of HRV
2. HRV Physiology: What “drives” Heart Rate Variability?
There are several anatomic structures in the brain, the brainstem, the aorta (pressure and chemoreceptors), carotid artery (pressure and chemoreceptors in the carotid body),
and the heart (SA node) that “drive” heart rate variability. Stretch receptors in the muscles also “drive” HRV.
Reference for diagram: http://ift.tt/1FrbIY0
3. HRV changes with Posture: Supine vs Sitting vs Standing position
HRV dramatically changes with body position – this is something we will NOT have to deal with in mice or rats (they don’t walk upright)
In the supine position, heart rate and blood pressure are low
In the supine position, sympathetic activity is low and parasympathetic activity is high
Just changing from the supine to sitting position changes these parameters somewhat, which can be measured in the power spectrum of HRV (i.e. LF vs HF)
In the supine position, the HF power spectrum is high. In the sitting position, the HF power spectrum of HRV decreases from 25% to 6.2% (p Increased Sympathetic Affarent output: Reducing autonomic (sympathetic) affarents from the brain, via the cardiac sympathetic nerves
Patients with hypertension and congestive heart failure (CHF) have reduced HRV due to many factors.
After an MI, there is also a decrease in HRV. HRV can predict mortality after an MI and in patients with CHF
The main ones are salt intake, Angiotensin II, decreased endothelial NO, and increased sympathetic afferent output
In these patients, there is strong evidence that reduce parasympathetic activity contributes to the decrease in HRV with CHF
In these patients, there is strong evidence that reducing cardiac sympathetic nerve activity increases HRV
I do not think this would improve that much with polyphenols, but reducing the output from the CNS To the cardiac sympathetic nerves (CSNs) should make a big difference. CSN output is a separate effect from respiratory sinus arrhythmia (RSA).
RSA is involved in the high frequency spectrum of HRV, whereas CNS activity is involved with the slow frequency HRV with a period of about 10 seconds
Obviously exercise and sleep will help, but I do not think that yoga, meditation, or Tai Chi is very feasible in mice or rates
We may be able to reduce CNS with an RF interference electrode that could be “trained” to inhibit CSN output.
In rodents with aging that have low eNOS activity and low nitric oxide levels in their blood vessels, chemical sympathectomy with 6-hydroxy dopamine restores HRV (see ref)
We may want to do this.
Conclusion: Controlling HTN is clearly important for keeping HRV high.
There may be a possibility of doing a “chemical sympathectomy” with 6-hydroxy dopamine in our “reference mammals”
5. Reducing Renin-angiotensin signaling
There is some evidence that reducing Renin Angiotensin II signaling (RAS) has a beneficial effect on HRV
This primarily improves low frequency power of the HRV power spectrum
Many studies of sleep have shown that Angiotensin II levels decrease at night in a circadian fashion (no surprise!)
‘At night, there is an increase in baroreceptor reflex sensitivity, which is the highest during dreaming
With CHF, the circadian changes in HR and the baroreceptor reflex (BRS) is blunted.
This explains part of the mortality of CHF that is independent from LVEF
Angiotensin Type I receptors are the main way that this harmful effect of Ang II is mediated
This may be why the ATR1 receptor blockers seem to have a longevity effect
Here is a diagram of what happens with Renin-Angiotensin system blockade and HRV
reference for diagram: http://ift.tt/1FrbIXS
Conclusion: Blockade of the Renin-Angiotensin system increases the area under the curve of the low frequency HRV power spectrum
Using ATR1 blockers appears to be the best way to do this.
6. Exercise and HRV – HF power increases, LF power decreases in endurance athletes. Supine position with exercise.
Endurance, aerobic exercises increases HRV in the high frequency (HF) spectrum (respiratory sinus arrthymia) but actually lowers the low frequency (LF) power spectrum
Endurance athletes therefore have higher HF power spectrum and lower LF power spectrum
This drop in LF power spectrum may represent an imbalance between parasympathetic activity and sympathetic activity, due to the resting bradycardia seen in endurance athletes. This resting bradycardia is due to increase parasympathetic outflow
Weight lifting exercise (supine position)
Because the sympathetic system is dramatically decreased when the body is in the supine position, weight lifters working out in on a bench in the supine position
display a dramatic increase in HRV in the low frequency (LF) power spectrum. This means that there is a decrease in sympathetic activity when in the supine position.
7. Sleep and HRV –
Sleep has a beneficial effect on HRV
At night, Angiotensin II levels go down, increasing HRV
Baroreceptor reflex sensitivity goes up at night
It is the highest during dreaming
Conclusion: Baroreceptor sensitivity can be rapidly “reset” at night.
This is very important for controlling blood pressure
8. Rodents have accelerated telomere shortening that is NOT due to replicative senescence
This means they probably have a lot of oxidative stress.
Although I could not find any articles specifically linking oxidative stress to HRV, I found some articles that showed that ROS-producing chemotherapy (alkylating agents) decreased HRV
Polyphenols and MitoQ may help some, but I think the following would be better:
Bucky Balls, Methylene Blue, and a few of the other potent mitochondrial-specific antioxidants that change the membrane potential across the inner mitochondrial membrane.
These could potentially make a huge difference in HRV
9. Gut bacteria/Celiac disease
Some fascinating stuff is coming out about the effect of wheat intake in patients with celiac disease
Patients with celiac disease have a much lower HRV than controls
Also, patients with celiac disease have less HRV with deep breathing
20% of the patients with celiac disease had parasympathetic dominance, whereas 36% of the patients with celiac disease had sympathetic dominance
44% of the patients did not show parasympathetic or sympathetic dominance
HRV can show decreases in HRV with all three of these groups of celiac disease patients
10. Stress and Glucocorticoids – glucocorticoids, epinephrine (from adrenal gland), and norepinephrine (from sympathetic nerves) all decrease HRV
Stress reduces HRV by several hormones and neurotransmitters, including glucocorticoids, epinephrine, and norepinephrine
Glucocorticoids (cortisol, synthetic steroids, etc.) decreases heart rate variability.
Glucocorticoids also increase systolic BP
The mediator of this is impaired hydrogen sulfide signaling
11. High sodium diet – This decreases HRV
A high sodium diet decreases HRV
The exact mechanism is not clear, but it probably involves blood pressure changes and changes in nitric oxide (NO) synthesis.
12. Gasotransmitters – Nitric oxide (NO), Hydrogen Sulfide (H2S), and Carbon Monoxide (CO)
Much has been learned about HRV from patients with congestive heart failure (CHF) and patients with coronary artery disease (CAD)
In CHF, there is a dramatic decrease in heart rate variability (HRV) and an increase in low frequency systolic blood pressure variability (SBPV)
CHF also increases in breath interval variability (i.e. snoring, sighing, etc.), and an increase in apneic episodes (like in obstructive sleep apnea)
These effects in CHF are thought to be mediated by the carotid body (CD), which senses oxygen levels. Hypoxia causes an increase in CB signaling
The molecular mediators of these changes in CHF include sympathetic dysregulation, renin-angiotensin dysregulation, increased atrial naturetic peptide (ANP)
increased brain naturetic peptide (BNP), and increase in Hypothalamic-pituitary-adrenal axis hormones (cortisol, epinephrin, aldosterone). However
the most recent molecular mediator discovery in CHF is thegasotransmitters – they play a major role in the pathogenesis of CHF.
These gasotransmiters and their dysregulation plays a major role in the decrease of HRV that occurs with these diseases.
Nitric Oxide is “good”, but NO dysregulation is “bad”- acute exogenous NO administration is ‘good”, but chronic exogenous NO administration results in “nitrate tolerance”.
Inhibition of endogenous NO production decreases HRV in some circumstances. In others, inhibition of endogenous NO production increases HRV
Nitric oxide has “good” and “bad” effects that are very hard to understand.
Nitric oxide is thought to play an important role in the tonic control of carotid body (CB) chemosensitivity
Both eNOS and nNOS are present in the CB.
NO inhibits CB activity by suppressing the CB chemoreceptors during normoxic periods
Basal NO production, eNOS and nNOS expressio in the CB are depressed with CHF. Thus there is no inhibition of the CB in CHF, due to a decrease in NO
Part of the Paradox of NO is due to the differences between endogenous production of NO and exogenous production of NO
In addition, part of the paradox is due to the differences between “acute” exogenous NO administration vs “chronic” exogenous NO administration.
Acute NO administration reduces sympathetic activity and increases vagal outflow
Chronic NO administration results in a loss of these effects and the development of “nitrite tolerance”
The easiest way to understand this is that “nitric oxide acts at distinct levels in the autonomic system to control cardiac rate, with opposing effects at different sites
In general, endothelial nitric oxide has mostly “good effects”
For instance, neuronal nitric oxide inhibition decreases HRV 3-fold by inhibiting vagal stimulation, whereas increased neuronal NO increases HRV
For instance, endothelial Nitric oxide synthase 3 increases NO after an MI and this increases survival from an MI – this increases HRV
Nitric oxide increases in response to a high sodium diet – this reduces HRV
For instance, with CAD, nitric oxide levels from eNOS fall.
Conclusion: Administration of exogenous NO (acutely for a short period of time) may increase HRV, whereas chronic administration would not
Aministration of an exogenous NO donor (such as L-arginine) would also increase HRV, but probably not continuously on a permanent basis
Hydrogen Sulfide is “good”, but dysregulation of H2S is “bad” – H2S is involved with carotid body chemoreceptor sensitivity and with breathing control
Inhibition of hydrogen sulfide restores normal breathing, but increased hydrogen sulfide increases survival after an MI
Hydrogen sulfide also increases antioxidant gene expression via an Nrf2-mediated pathway
H2S product by the enzyme CSE is not decreased in CHF – CSE inhibition with CHF reduces carotid body afferent responsiveness
There are a lot of puzzling paradoxes about H2S that I do not understand
Hydrogen sulfide signaling upregulates antioxidant gene expression by the transcription factor, Nrf2 – this is a “good thing”
Hydrogen sulfide also increases survival after an MI via a nitric oxide synthase 3 dependent mechanism – this is a “good thing”
However, H2S production by the carotid body chemoreceptors can also have “bad consequences”
H2S is known to be an important signaling molecule in the carotid body (CB)
H2S is synthesized by cystathionine gamma-lyase (CSE) in the CB
Carbon monoxide (CO) inhibits CSE, thereby increasing HRV.
Exogenous CSE inhibitors such as PAG also increase HRV
Evidently in response to hypoxia, hydrogen sulfide signaling reduces HRV and causes abnormal breathing (apnea and increased breath intervals)
Increased hydrogen sulfide signaling from the carotid body hypoxia sensor is part of the pathology of CHF.
These effects in CHF are thought to be mediated by the carotid body (CD), which senses oxygen levels.
In CHF, there is an increase in carotid body (CB) chemoreceptor outflow due to hypoxia. The “signaler” is the gasotransmitter, hydrogen sulfide
Thus CHF results in increased CB hydrogen sulfide synthesis, which reduces HRV. increases breath interval variability (BIR), and increases apneic episodes
Inhibitors of hydrogen sulfide synthesis (by cystathionine gamma-lyase) like the drug di-propargylglycine (PAG) inhibit H2S synthesis by the CB
In rodes, this reduced the apnea index by 90%, reduced breath interval variability by 40-60%,
This is a large reason why HRV decreases with aging.
Conclusion: Since CSE is not down regulated in CHF, hydrogen sulfide probably plays a supportive role, rather than a causal role in CHF
I am not sure if we want to inhibit it or activate hydrogen sulfide signaling – in CHF, we probably want to inhibit it. Under normal conditions, I am not sure
If we want to improve breathing, however, we will need to inhibit H2S production.
If we want to increase Nrf2 gene expression, however, we will want to activate H2S production or give exogenous H2S
To improve HRV, we may need to use a H2S synthesis inhibitor like PAG to down regulating H2S signaling from the carotid body
Carbon Monoxide is “good”, but dysregulation or too much CO is “bad” – CO production in the CB is due to HO-2 gene expression and is reduced in CHF
Carbon monoxide (CO) is the 3rd and last gasotransmitter to be discovered.
CO is very important to health. The first case of a human to have a gene mutation in HO-1 (the enzyme that synthesizes CO) died at age 6
HO-1 gene knock-out models in mice and rats also die at a young age.
It came as a surprise to many that the body synthesizes CO – to be exact, it makes 16.4 micro moles per hour of CO – all from heme breakdown
The total amount of CO produced per day is 12cc (see ref below)
In the pulmonary artery, CO relaxes the pulmonary vasculature under normoxic conditions
In the carotid artery, CO regulates (decreases) the sensitivity of the carotid body to hypoxia
However, CO plays a much greater systemic role in the body – CO is synthesized during heme breakdown by heme oxygenase 1 (HO-1), heme oxygenase 2 (HO-2), and heme oxygenase 3 (HO-3)
HO-1 is the inducible form of the enzyme and is primarily found in the spleen, but is also expressed in other tissues in lower amounts
The spleen is the only organ where HO-1 overpowers HO0-2 – HO-1 is NOT expressed in the carotid body (CB)
HO-2 is the constitutively activated form that is mostly expressed in the brain and testes – it IS expressed in the carotid body (CB)
HO-3 is another constitutive form of the enzyme that has only been found in rat tissues
With CHF, the expression of the constitutively activated HO-2 in the CB is decreased. This means there is less CO produced by the CB with CHF
Conclusion: Exogenous administration of low dose CO (acutely only) may have a beneficial effect on HRV, since this inhibits CSE and thereby H2S production
Exogenous administration of low dose CO (acutely) also induces the enzyme that makes endogenous CO, HO-1.
For this reason, exogenous CO administration should have both a direct and indirectly beneficial effect on HRV, but no one has measured this yet
13. Chronic Hypoxia, Rapid ascent to altitude, High Altitude Acclimatization, and High Altitude Training in Athletes
Chronic hypoxia does not affect heart rate that much, but it has a dramatic negative effect on HRV. This is why obstructive sleep apnea and COPD are so bad for health
Rapid ascent to altitude decreased HRV in both the LF and HF power spectrums. In these individuals who ascended rapidly to altitude, 48% of them developed acute
mountain sickness (AMS). This happened in individuals who developed AMS and in those who did not develop AMS (no difference).
Acclimatization has been reported to have conflicting results on HRV
One study found that acclimatization at low altitudes (2,000-3,000 meters) and high altitude (5,000 meters) did modify HRV in any statistically significant fashion
Another study done in tourists at 2,700 meters and at 3,700 meters showed a decrease in HRV at both altitudes. This decrease in HRV occurred in both the
HF and LF power spectrums. At 3,700 meters, the sympathetic system was dominant over the parasympathetic system.
Another study done in high altitude mountaineers found that at sea level, postural changes are mainly controlled by increases in sympathetic tone with sitting and standing,
whereas at high altitude, postural changes are mainly controlled by a decrease in parasympathetic activity and not an increase in sympathetic activity (5,000 meters)
However, high Altitude does not necessarily impair HRV, even though they are continually exposed to low oxygen tension
In trained Andean participants, completing a marathon at 4,220 meters elevation transiently increases sympathetic predominance of HRV
after the marathon for less than 1 day. Then their HRV returns to a healthy, baseline where parasympathetic tone dominates over sympathetic outflow
Conclusion: I do not see any way how manipulating atmospheric pressure by reducing it would help HRV
14. Air pollution
Air pollution has been shown to decrease HRV (that’s bad!)
The best study on this was done at Harvard’s School of Public Health
They found that pollution in general reduced HRV and Blood Pressure Variability (BPV), but that ozone (O3)
and moving averages of particulate pollution in the air (PM2.5) were most associated with a decrease in HRV and BPV
The decrease in standard deviation of normal-to-normal HRV (SDNN) and low frequency power spectrum (LF) were greatest in diabetics.