2.2 HRV for Sudden Cardiac Death & Methods to Assess Autonomic Nervous System

• So as mentioned in the last talk, will the last major position or consensus paper on heart rate variability put out by a major medical professional society was in 1996. And there were only two clinical indications for Heart Rate Variability mentioned in that position statements. And they were post myocardial infarction, and diabetic neuropathy. So that makes my job easy, because there's only two conditions that really are where, you know, heart rate variability was indicated. And so I'll go into that in a little more detail.
• The thing that many were focusing on during this time was sudden cardiac death, that any clinician who takes their patients will appreciate the significance of sudden cardiac death, which is often attributed to abnormal rhythms such as this is the ventricular fibrillation. I remember my first case, when I was a medical students, there was a portly gentleman came in to the coronary care unit. And we were rounding on this patient. And this patient was very angry about, you know, being in the hospital and having to stay in this unit. And while he was talking, all of a sudden, his eyes rolled back, he fell back onto the bed, and basically was in the bed rest after he got his heart attack. And after that, I have never minimize the importance of ventricular fibrillation. And this is accounts ventricular fibrillation of sudden cardiac death accounts for half the deaths and coronary heart disease in the United States, and often occurs outside of the hospital or the emergency department within one hour of symptom onset.
• So you can see this is the normal sinus rhythm, and then it's really fast for them, which impairs the ability of blood flow to the brain.
• Now, this sudden cardiac death often occurs after a heart attack or myocardial infarction. And you can see that it often occurs right after or immediately in the sort of the few days after a heart attack or myocardial infarction. And you can see that it's the prevalence is much higher than the first month and then slowly goes down over a period of months to years. This graph actually divides into categories of ejection fraction. So after you have a heart attack, and if it's a significant heart attack, you can impair your, the the pumping function of your heart, and it could go down as low as you know, less than 30%. What's normal is around above 55%. So, clearly, if you had a large heart attack, then you have a higher chance of developing sudden cardiac death.
• It is believed that, you know, some have argued that you can divide these categories into three parts, the acute phase, which is about 40 days after the heart attack, or myocardial infarction, sub acute, which is about 40 days to six months and a remote which is more than six months.
• So how does the other mod non make nervous system play into sudden cardiac cardiac death? And why is this important?
• They had studies done in the 1970s, done by Dr. Loud who's a renowned cardiologist from Brigham is that they took dogs, unfortunately, dogs and they measure the EKG and subsequently introduced three pulses where they call the party pulsing. And on occasion, the RT pulsing will lead to nothing that the EKG will return, the heartbeats would return as normal. And in some cases, this would lead to ventricular fibrillation. And what he was able to do was, he would actually be able to stimulate the sympathetic nervous system by finding the sympathetic nerve, or specifically the stellate ganglion, which is part of the sympathetic nervous system stimulate that mean, you can see that this is a normal rhythm, and then it induces ventricular fibrillation. And pressure control just means that the pressure was controlled because sometimes when your heartbeat Your blood pressure is increased, it sort of reduces the sympathetic nervous system. But you can see that when the sympathetic nervous system was activated, there was a higher risk of ventricular fibrillation.
• And on the flip side, the parasympathetic nervous system has a protective effect. And this graph show that began from Dr. Loud in 1977. When you do an RT pulsing, and then after about 50 milliseconds, your your ventricular fibrillation threshold significantly decreases. And then for a while, it sort of returns to normal. However, when you do a stimulation where you activate the sympathetic nervous system, it reduces the ventricular fibrillation threshold even further. And then the duration is longer. So the chances of developing ventricular fibrillation persist longer than without the sympathetic nervous system, and then Rich Slowly returns back to its baseline. And then, if you stimulate the vagus nerve, it reverses essentially, this effect, and that you basically returned the baseline. So, the sympathetic nervous system enhances the possibility of physical tribulation or sudden death, the parasympathetic reverses that.
• These are studies that were done in dogs. Again, at baseline, this was sort of the control, you had closed evaluation of the heart rhythms. When they did an open thoracotomy. Basically surgery to access the heart, you had the ventricular fibrillation threshold decrease, and then the vagal stimulation subsequently returned it if in fact, it sort of even further reduced the chances of getting an abnormal rhythm or V fib, the stimulation directly cause again, reduction of the V fib threshold vagal stimulation address that same with norepinephrine infusion. But interestingly, administrating beta blockers, which antagonize the effects of the sympathetic nervous system. It essentially eliminates any of these interventions, and it sustains this ability to protect against future fibrillation and the vagal stimulation does nothing to change that. So the vagal stimulation reverses what is at higher risk of the sympathetic nervous system. But it basically does it enhance it above what, you know, basically sort of reverses the sympathetic nervous systems effects on ventricular fibrillation.
• This is another study that this was also done by Lown, at that time, I wanted to add this on just because I found it interesting was that stress really was an important factor for reducing the threshold for V fib. This was an unfortunate experiment with dogs received a Pavlovian conditioning, basically electric shock daily at each experimental period for three successive days. So that when the experiment started on the fourth or fifth day, they were already stressed. And you know, this is pre stressed. And then when they did the evaluation to see this art, people seem to see whether it's stimulated, or induced ventricular fibrillation. Stress certainly enhanced the possibility of developing V fib. But the administration of a beta blocker, reverse that.
• He also had a very interesting anecdotes of a patient who was very nervous right after her heart attack. And this is number of Ventricular Premature beats. These are these extra beats that come from the ventricle, which can be a precursor to ventricular fibrillation. And when they state stop lidocaine, which is a way to stop arrhythmias, the number of Ventricular Premature beats increased. But then when she meditated, the numbers, these Ventricular Premature beats decreased. And then lidocaine restored basically this the normal heart so that you weren't at higher risk of developing these fatal arrhythmias. So even in the 1970s, the importance of stress, meditation was already understood. And it's surprising to many of us, this hasn't really been emphasized in the 1980s or 90s.
• So they understood in early as early as the 1970s, that the autonomic nervous system is an important component of developing ventricular fibrillation. So how do you evaluate autonomic nervous system, and I felt that it was important to sort of take a little bit of a side note or explanation of how we normally evaluate autonomic nervous system and why Heart Rate Variability has ultimately been the one that many have gone to. And this is a good illustration of the autonomic nervous system. You have basically the two the two systems, the two branches of the autonomic nervous system depicted here, the parasympathetic, and the sympathetic on the bottom here. Both have two sets of neurons in series, a preganglionic neuron and then a on myelinated postganglionic neuron. And you can see that the neurotransmitter that's responsible for the parasympathetic nervous system is acetylcholine both
• At the ganglion at an at the target tissue, whereas for the sympathetic nervous system, it's an acetylcholine at the ganglion, but largely it's nor epinephrine at the target tissue, the exception being the Swetland. And this is sort of an interesting difference about sweat glands, that I don't know why it was evolutionally developed that way. But we know in medicine, that if you're exposed to a dangerous fatal toxin, such as siren, which was something that was released by a group for this cult, in the 1995, they released it in Tokyo subway, and the siren is an acetylcholine esterase inhibitor, it basically prevents the breakdown of acetylcholine. And what we saw was a lot of the parasympathetic changes attributed to this, you know, significant rise of acetylcholine, you have salvation, who have cheering, diarrhea, bronchoconstriction, constriction of the pupil, sweat, and then all that which is attributed to the parasympathetic nervous system. But then you also saw sweating. Because even though sweating is not part of the parasympathetic nervous system, you have the acetylcholine big being responsible for how the sympathetic nervous system operates and the sweat gland.
• So how do you evaluate the autonomic nervous system, the way I've divided is into two parts, you can directly assess the autonomic nervous system, either by measuring exactly the activity in these nerves, or measuring the neurotransmitters, or you could actually visualize it, or you have the indirect assessments, basically, the end results of the sympathetic nervous system. And I could go into a little more detail about the direct nerve activity. So it's sort of direct assessments. First, you have direct nerve activity assessments, something called micro neurography. For the sympathetic nervous system, you introduce a needle electrode into a nerve, and then subsequently target a sympathetic nervous branch in that or bundle within that nerve. And it's oftentimes the nerve that's chosen is the coronial nerve. I've had this done on myself, it's not comfortable, it's also very difficult to find the exact nerve. And also there are different branches within the nerve. So you have to target the muscle sympathetic nerve, sometimes you target the the skin sympathetic nervous system. But you can see here, this is the heart of the EKG, this is blood pressure. And then you can see the sympathetic nervous activity. And you can see some of the heart rhythms. And you can also see a respiratory component in here as well.
• There's also direct assessments of the vagal nerve. They've only done this recently in the 2020s. And the only reason they've done this in humans recently, is because it's a very hard nerve to access. Basically, it's right next to the jugular vein and the carotid artery. And they really needed the ultrasound to visualize to make sure that the needle wasn't penetrating one of these, you know, dangerous arteries or veins. And you could see the the activity of the vagus nerve. And then when you do a root mean squared, you could see the activity of the vagus nerve here.
• Then you could assess the neurotransmitters directly, either by collecting True Blood tests or urine test and assess for the catecholamines that are in the system. They're often norepinephrine, dopamine, these other compounds.And then you could do radio labeled or adrenaline spillover tests, I'm not going to too much detail that, but you administer a radial labeled, nor N nor adrenalin, some of it gets absorbed into the nerve. And then some of it gets excreted, you could do a calculation to assess the activity of the sympathetic nervous system. Or you could do what's called an MIB G scan, you inject this radio, nuclear or radio labor labeled compound chemical called MIB G, it gets absorbed in the sympathetic nerves. And this is an image of a person who is normal or healthy. And you can see that the MHC accumulates in the heart a lot of accumulates in the liver. But a person with an automatic autonomic nervous condition has no absorption of this into the heart. So it indicates that basically, there's hardly any active, sympathetic nervous system in the heart for this individual.
• The last direct assessment is to actually do a skin biopsy and why skin it's big because there are three areas where the sympathetic nervous system clearly has an influence. One is the direct appeal like muscle when you are nervous, or it's like getting goosebumps, and the causes the hair to rise. The other place is the blood vessels, the sympathetic nervous system innervates, the blood vessel. And the last one is the sweat glands, as I discussed before, so when you take a biopsy of the skin, you could actually take a look at the nerves that sympathetic nerves which is labeled here in green. And this is a comparison between a healthy person and on on the left side compared to a person with diabetic neuropathy. And you can see that the sympathetic nerve is intact in the sweat glands for the healthy person not so much in the diabetic neuropathy patient. Same with the erector P line. And then for the blood vessels, you can clearly see that difference. But these are clearly invasive approaches. So you want to take a look at indirect assessments because that's more practical.
• The way we do that is to take a look at these and orchids basically, where the parasympathetic and the sympathetic nervous system as we see that the pupil has both parasympathetic and sympathetic nervous system for heart does as well. Swetland is uniquely the sympathetic nervous system. But and then also, the parasympathetic nervous system is important for the you know, the gastro intestinal tract in the in the urinary system, but I didn't include it here. Now, the question is, where's blood vessels for parasympathetic nervous system? Does the vagus nerve innervate or affect the blood vessels? And the answer is actually no, there is hardly enter any parasympathetic nerve innervation of the blood vessels, particularly arteries. There are some exceptions, there are some innovation of the facial vessels of the coronary arteries, and then also genitalium vessels, so that a lot of the erectile function is dependent on our sympathetic nervous system. And this is important to know because this is how we can differentiate what's happening in terms of the parasympathetic sympathetic nervous system because most of the vascular contraction or dilation is mediated by the sympathetic nervous system.
• So what are the indirect assessments? You have, in most hospitals, an autonomic lab, or an autonomic testing lab. This is a picture that was sort of put took from YouTube. And it has a number of devices. And he had something called a tilt table test. And what they do in these labs is you are connected to a lot of these measuring devices. But then you introduce a lot of these provocations, provocation, intervention interventions, fall, Salba was a type of maneuver, deep breathing, isometric handgrip hold precedent, mental arithmetic, active standing Tilt Table step prayer reflex sensitivity, I'm not going to go into details about that. But what when they do that intervention, they are continuously assessing heart rate, blood pressure, in this case, they measure entitled co2, which is carbon dioxide, and then cerebral blood flow. And this is the normal response when you do a tilt table, basically a person's flat. And then as you are measuring his heart rates and blood pressure, you slowly elevate the person to an upright position. And you can see that the heart rate increases, the blood pressure name remains stable. However, in this person who has neurogenic syncope or loss of consciousness or fainting, what happens is that as you're slowly tilting up, you could see that the blood pressure drops down, a heart rate tries to compensate, but at some point, it fails. And then the heart rate drops down, and that person basically loses consciousness. So this is something that you could evaluate with these autonomic tests.
• And then you have indirect tests, again, of sweats.  You have the thermo regulatory sweat tests, where they apply a dye, which is called when is air and it's a powdered dye that you apply to the front of the ventral side or the front side of a person being applied all across the body. So it's, it's an inconvenient test because you have to strip down and then it changes color. It ramps to the sweat somehow, and it creates this purplish color. And so this is a normal response. However, in a person with multiple system atrophy with autonomic neuropathic problems, you can see About the lower parts of this person's body, and some parts of the upper body were not functioning well, the sweats just simply weren't functioning so indicates this is a marker of autonomic nervous dysfunction.
• Another swept test is electrodermal activity, this is something that you could use using a watch. This is the pataga E for watch, which measures electrical skin conductivity with time, and you can measure it and if there's any stressful events, it you could see a quick rise in the conductivity.
• The final sweat evaluation tests is something called cue starts. Again, I'm not going to go into too much details, but it's a complicated system that could only be done in the laboratory in the hospital, you introduce electrical stimulation to the skin into the system where it has acetylcholine, the acetylcholine stimulates the sweat duct here, whether there's a back or antidromic, and that orthotropic response so that the adjacent sweat glands respond accordingly. And then you will see that they will apply this to multiple parts, usually in the forearm, proximal leg, distal leg and the foot. And you can see the response. And if you have problems in the lower leg, you will for instance, not see this rise when you're introducing the acetylcholine. So these are the indirect sweat activity. 
• The final one is the pupil allometry. And you could study the size of the pupil. A constricted pupil is is mediated by a parasympathetic nervous system, a dilated pupil is responsible for the sympathetic nervous system. And so you could take advantage of this. The problem is that the pupil sis pupils respond to several stimuli, one being light, the other one is near fixation. So if you're focusing on something nearby, it constricts. And then mental effort, which is sort of mediated by both of these autonomic nervous system. And so when you introduce light, either red or blue light, you can see that the pupil size really starts to decrease. And that rises up after you stop shining the light onto the eye. When you're focusing closing on to something, the heart, the pupil size decreases. And then for mental effort, on the other hand, it is only five maybe 5%, the amounts of in terms of magnitude the response compared to like or near fixation. So when you're doing some kind of memory load, in this case, you're trying to remember the number of digits and you can see for three to five, you know, the response isn't that significant. But then when you're trying to remember seven numbers, but pupils dilate a little bit. And what's interesting for me here is that, you know, it correlates a little bit with a number of how hard the math the mentor effort is. So the more you have to remember, the loop, the greater the pupil size, although it's, it's really the magnitude is not that much. And this is actually an average of 25 files. What's also interesting to me is there's an anticipatory factor here. So you're anticipating before you see the numbers, and you are already responding. So if you are able to control a lot of these factors, like lights or near fixation, and you're able to do multiple trials with a significant memory load or mental efforts, then maybe pupil size is something that you'd evaluate. But it's highly inconvenient, and very difficult to do.
• And the final one is heart rate variability. So to summarize, I think many have wondered, like, why are we focusing on heart rate variability, why not some of these other options, and already by, you know, hearing some of the things that I've discussed to you, you can already tell that a lot of these are very impractical, only can be done, or many are invasive. And the other thing that is worthy of note is this is the summary of the direct and indirect assessments is that many of them are most of them are focusing purely on the sympathetic nervous system.
• For instance, the neurotransmitter based measurements, which measure catecholamine levels, we're not able to do this for the vagal system is because the vagal system relies on acetylcholine, and there's a large amount of Cetyl choline esterase in our bodies, which breaks down this unit bowling so you lose the ability to measure that into the blood system. And then there's also very few parasympathetic nerves that you can see in the skin and and sweat is largely mediated through the sympathetic nervous system. So a lot of this is predominantly separate nervous focused.
• The ones that are vaguely mediated are, you know, this is micro neurography, which is right by the neck very difficult to do, again, highly risky. You can do the autonomic testing that's done in the last fight, introducing various provocations. But it's inconvenient because not only you need to do a lot of these measurements, not only heart rate, blood pressure is very important. If you can incorporate blood flow, for instance, blood flow to the brain that would also significantly help it out. Those are things that are very difficult to do at home. So the options that are available for researchers like us that don't have access to many of these labs is basically to electrodermal activity where you could get the impact that you for any other skin conductance devices, unfortunately, they're very expensive. 
• Or you could do heart rate variability. And heart rate variability is the only one that really evaluates the parasympathetic part of the branch. Well compared me electrodermal actually using these skin conductance devices don't measure parasympathetics at all. So that's kind of like the summary. This emphasizes why Heart Rate Variability has been the focus in much of autonomic nervous system research and will probably be the focus for wearable research as well in the near foreseeable future.

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