<small>Go back to transcript catalogue: [[Video Transcripts]]</small> -------------- [Introduction to Cardiovascular Physiology: What People with Dysautonomia Should Know by Heart](https://www.youtube.com/watch?v=kzxuiF9naqM&list=PLN9-2-rvxt7OEhQVjBOndedhcKEpCJGzF&index=88) <small>Lecture (Dysautonomia International Virtual Conference, 2022) | 1:02:55 h</small> ---------------------- #### Introduction ![[Pasted image 20231002012122.png| 400]] ![[Pasted image 20231002012139.png| 400]] BP is measured by inflating a cup on the arm to a supra-systolic pressure (meaning it's higher than your systolic pressure) and you wait until you hear a sound, which is going to be the opening of your arteries. BP isn't something that stays stable over time. It changes with every single heartbeat. ![[Pasted image 20231002012756.png| 500]] ^ doesn't capture hypotension, which has no definition and is based on symptoms. ![[Pasted image 20231002013015.png]] A healthy person might have a pulse pressure of 40 (e.g. 120/80). Someone with hypertension has a higher pulse pressure (e.g. 140/90, pulse pressure 50). For POTS, people often have a lower pulse pressure (e.g. 90/60, pulse pressure 30). ![[Pasted image 20231002013255.png| 500]] It's really hard to change blood viscosity (only changes in severe heart disease) and the texture of the blood vessel is more of an issue in vascular disease. However the stretchiness can change the pressure as well in the resistance. ![[Pasted image 20231002013743.png| 500]] We get an increase in HR, the blood volume is decreased, because you got more blood pooling in the gut-vasculature and the legs. There's also wider blood vessels, because they can't vasoconstrict as well, so you get less resistance to the flow. But because these things kind of balance out, because of the low blood volume and the wider blood vessels, the BP in POTS can be low, it can be a little bit high, but it's usually pretty normal. The doctor will say "your blood pressure is good" even though they don't see the all the underlying changes that are happening to make that pressure at a normal level. ![[Pasted image 20231002014333.png| 500]] ![[Pasted image 20231002014434.png| 450]] ![[Pasted image 20231002014551.png| 350]] ![[Pasted image 20231002014916.png| 250]] Cardio exercise doesn't work for everyone, just like any treatment - some people respond, some people don't and there can be a lot of side-effects. #### Autonomic Nervous System ![[Pasted image 20231002014957.png]] ^ Autonomic Nervous System controls everything that you don't think about. From your breathing, to your heart rate, to your digestion and even sexual function, etc. ![[Pasted image 20231002015123.png| 500]] Heart is regulated by both Sympathetic (fight and flight) and the Parasympathetic (rest and digest) nervous system. ![[Pasted image 20231002015135.png| 500]] The blood vessels specifically are only controlled by the sympathetic nervous system. Nuclei in the brainstem (the preganglionic sympathetic nerves) project to the spinal cord (intermediolateral cell column). And the postganglionic sympathetic nerves project to the blood vessels, synapsing on the alpha 1 adrenergic receptors (α1). ![[Pasted image 20231002021450.png]] The nuclei in the medulla (which is part of the brainstem), the dorsal motor vagus (DMV) and the nucleus ambiguous (NA), project through the vagus nerve (CNX) onto the heart through cholinergic receptors and slow heart rate. Then there's a feedback system of sensory nerves through the vagus and the glossopharyngeal nerve (CNIX) that synapse on the nodose ganglia back to the nucleus of the solitary tract. ![[Pasted image 20231002021547.png]] Sympathetic projections from the brain: The rostral ventrolateral medulla (RVLM) projects onto sympathetic preganglionic neurons and then (through sympathetic chain ganglia in the spinal chord) projects to the heart and synapses on beta 1 adrenergic receptors (β1) to affect heart rate (and these are norepinephrine secreting neurons). ![[Pasted image 20231002021606.png]] Then there are also projections (that are also norepinephrine releasing neurons) directly to blood vessels, that synapse onto alpha 1 adrenergic receptors (α1) to induce vasoconstriction. ![[Pasted image 20231002021619.png]] There are also beta 1 adrenergic receptors (β1) in the kidney that trigger renin release. (We'll talk more about that later) #### Vascular Implications ![[Pasted image 20231002021636.png| 450]] Even in healthy people there's a redistribution in blood volume that occurs when you change from supine to standing. You get a drop in blood flow to the brain (which isn't really drastic in healthy people but in people with dysautonomia this can be quite severe), BP drops temporarily, there's more blood that pools in the legs (as well as in the lower gut), there's less return of blood to the heart and cardiac output drops, because there's less blood pumped by the heart. ![[Pasted image 20231002023844.png]] (As mentioned before, the sympathetic nervous system controls blood vessels through the sympathetic neurons that synapse on the alpha 1 adrenergic receptors.) There are also beta adrenergic receptors on the blood vessels (beta 2 receptors, which are kind of different than the ones in the heart). Epinephrine is the primary neurotransmitter, that binds to the beta receptors, and norepinephrine binds more to the alpha receptors. Alpha-adrenergic receptor activation is decreased in people with POTS in general. People with POTS have a lot of beta-adrenergic receptors activated by epinephrine in blood. This mechanism is actually exaggerated in people with POTS because we tend to have higher circulating catecholamines than healthy people. ![[Pasted image 20231002025008.png]] Many studies have now shown that there are auto-antibodies to these adrenergic receptors, specifically to the alpha-1 in the largest study by Dr. Grubb. But there is another study that found that all POTS patients have autoantibodies to beta-1 adrenergic receptors (which explains the tachycardia piece to this). ![[Pasted image 20231002030029.png]] I've also done some research in Ehlers-Danlos Syndrome (which, basically everyone with EDS has some type of autonomic dysfunction). And we found in these patients, they actually have an increased elasticity in the arteries. There have been some small studies in patients in POTS that haven't found differences. But I'm not convinced that this isn't a mechanism in POTS as well. So if the arteries are more elastic, they're gonna pool more blood, not vasoconstrict well and this is probably part of the physiology of POTS. ![[Pasted image 20231002030309.png| 500]] Just a word about Small Fiber Neuropathy - a lot of people think that this is just the sweating response (if you've ever had a QSART test). But it's important to note, these neurons I talked about, that control the blood vessel vasoconstriction (the tightening of your blood vessel), are also small fibers that are very sensitive to nerve damage. ![[Pasted image 20231002030548.png]] So like I said, the QSART measures the sweat-response because these sudomotor nerves are very close to the skin, they're easy to measure non invasively through the sweat-testing, also you can biopsy them. It's really hard to get a sense of the nerves that control the blood vessels, because they're much deeper, but they're also sensitive to Small Fiber Neuropathy. ![[Pasted image 20231002031214.png]] The most common method to measure cerebral blood flow (blood flow to the brain) is called transcranial Doppler, where you put an ultrasound probe on the temple, where you have a little window to get to the bone (ultrasound is really not good at getting through the bone, so you have to find a little window) and they're measuring blood flow in the middle cerebral artery (which is one of the main arteries in this circle that supplies the brain with blood). There's also some other methods, like FMRI, which is becoming more popular (it's a little more expensive and difficult to do). People are also using near infrared spectroscopy (NIRS), especially on the forehead - that uses light patterns to look at blood flow more in the front of the brain though, so that's better for cognitive studies. ![[Pasted image 20231002031352.png]] One of the main findings people have seen in POTS is that blood flow to the brain drops significantly. In healthy people when you tilt them, blood flow to the middle cerebral artery drops by about 10% and it drops twice that in people with POTS. ![[Pasted image 20231002031848.png]] Also there's something called cerebral autoregulation. So usually if you're gonna get a drop in blood flow to the brain, it's because you have a severe drop in BP (such as like during shock or hemorrhaging). Your body is meant to really protect blood flow going to the brain and to the central organs. But even though BP stays the same or even increases in some people with POTS when they're tilted upright, blood flow to the brain still drops. This mechanism of regulating blood flow to your brain is really "messed up" in POTS. ![[Pasted image 20231002032228.png| 500]] There's a reason that you might have brainfog - the aforementioned is probably one of the mechanisms. Because blood is important, since it delivers oxygen and nutrients to the brain. So if you're not getting enough blood flow to your brain, it's kind of hard to think (so the brainfog is infact all in your head 😉). ![[Pasted image 20231002032754.png]] The kidneys are also really important to cardiovascular physiology in maintaining fluid balance (in healthy people too, but especially in people with dysautonomia). The kidneys produce renin, which is really important for fluid homeostasis, the adrenal medulla creates catecholamines (epinephrine aka. adrenaline, norepinephrine aka. noradrenaline) and the adrenal cortex produces aldosterone (really important for retaining solids and fluids), cortisol (which is a stress hormone) and some sex hormones as well. ![[Pasted image 20231002034634.png]] So the adrenal medulla releases catecholamines (these are sympathetic nerves sent from the hypothalamus, which is right above the brainstem, to the spinal chord, which then triggers the release of catecholamines from the adrenal medulla). Epinephrine and Norepinephrine increase heart rate (one of the mechanisms of POTS), they also inhibit secretion of stomach acid (which is part of the mechanism for gastroparesis, so this kind of this fight and flight response because you don't digest as well if you're sympathetically activated). This constriction of blood vessel "thing" doesn't happen very well in dysautonomia (as explained before, because of neuropathy and changes in the receptors with autoantibodies). Also this hyperglycemia or pre-diabetic state - some research studies are coming out to say that's more prevalent in people with dysautonomia as well. ![[Pasted image 20231002035234.png| 500]] The adrenal cortex releases aldosterone (as well as cortisol and other hormones), which tells the kidneys and also the large intestine to absorb more water and sodium to increase blood volume. There's this pituitary hormone called antidiuretic hormone, also called vasopressin, and it really tells the kidneys "let's not pee out all our blood, we need more blood". That signals aldosterone release from the adrenal glands. The pituitary is up in the brain, kind of below the hypothalamus, so it's kind of like a brain-to-kidney adrenal gland response. ![[Pasted image 20231002040143.png]] ![[Pasted image 20231002040158.png]] The kidney releases renin, which converts angiotensinogen to angiotensin-I and then angiotensin-II, which is important for this feedback loop that happens in the kidney. Angiotensin-II binds to blood vessels, which raises BP, so that's one mechanism that's probably abnormal in POTS (there have been a couple studies on that by Julian Stewart). It also triggers aldosterone release from the adrenal gland (which is important for retaining salt and fluids). Part of this feedback is, when BP falls, it increases renin release, which then goes back into the system to catalyze the reaction of angiotensinogen to angiotensin-I. ![[Pasted image 20231002040908.png]] So in normal people there's this aforementioned feedback loop, where you have low blood volume, then you increase renin and aldosterone and then that signal increases the blood volume. However in people in POTS this just doesn't work. There's only one study on this (actually back in 2005) and I don't know why there haven't been any since. Really should be common knowledge, but a lot of doctors ask me why people with POTS are dehydrated. I'm like "Well, they don't have enough renin and they don't have enough aldosterone, even though their plasma volume is low. So the kidneys really aren't able to signal getting more fluid, they're always saying 'Help', but they can't do it, because they're not getting enough of these hormones. And then because renin and aldosterone are low, there's this feedback to keep plasma volume low, because the body just isn't using this hormone system correctly - so the whole feedback loop is broken". ![[Pasted image 20231002040944.png]] ![[Pasted image 20231002041135.png]] #### Treatments to Increase Blood Volume ![[Pasted image 20231002041304.png| 500]] ![[Pasted image 20231002041414.png| 500]] It mimics aldosterone, so it helps retain salt and increase blood pressure. ![[Pasted image 20231002041647.png| 500]] A similar drug to florinef, which mimics vasopressin (ADH). Different to florinef, it can be used as needed. ![[Pasted image 20231002041723.png]] It helps raise blood volume. There's a study that came out from the group in Vanderbilt that said it decreases norepinephrine release as well (there's less plasma norepinephrine and HR was decreased after 4 days of high salt diet). ![[Pasted image 20231002042110.png| 500]] ![[Pasted image 20231002042459.png| 500]] There's a difference between rehydration and volume expansion. So a lot of times when you drink fluids, it's really triggered by your thirst and you're just replacing your fluid volume, as opposed to creating more fluid volume, in which you actually have to fight against your thirst, which can be really hard to do (so that's also where IV saline can be really useful). ![[Pasted image 20231002043722.png]] However there's real risk to IV saline therapy. If you've asked your provider for this and they said 'no', probably because there's a high risk of infection, if you need to get a central line (such as a PICC or a port), especially a long term central line. The problem with this is, you're putting these catheters into the vena cava, by which you're sending clots and infections directly to your heart, which can create a serious life-threatening situation. So IV saline probably not worth it in this case. What can you suggest to reasonably get IV saline treatment? Only use peripheral IV access, keep your frequency low so you don't run out of veins (the people who were able to maintain therapy for up to 6 months in these studies, did IV saline once a week or less), use it in combination with other treatments (I like to think of IV saline as like the temporary patch, so that, while you're trying other treatments such as exercise or different pharmacological therapies, you can kind of play with those while getting the benefits of IV saline to get you extra energy and treat you sometimes temporarily), have a plan for when you lose access (that is not PICC or port) for when you lose veins for example. ![[Pasted image 20231002044413.png]] If you really want the absorption power of a rehydration salt, low sugar isn't gonna do it. There's actually a study using oral rehydration salts in pediatric POTS and they found that it decreased tachycardia more than IV saline did (they didn't measure any symptoms in this study and it was a small study of about 14 patients. So it can work, I would say most patients don't find it as helpful as IV saline, but it's worth a try). ![[Pasted image 20231002045216.png]] It's kind of a risky drug (it's what Lance Armstrong got in trouble for using, for blood doping). It stimulates the production of red blood cells from the bone marrow. But it is quite effective - it's only used in refractory POTS patients because it does have a lot of risks to it, it's also really expensive - so, an option if you've failed a lot of treatments and you see a cardiologist who's willing to try it. #### Drugs to Lower Heart Rate ##### Beta Blockers ![[Pasted image 20231002045608.png]] Decrease heart rate and contractility (meaning the force of contraction of the heart). These are activated by epinephrine, bind to the beta-1 adrenergic receptors in the heart and go through this G protein-coupled receptor mechanism. ![[Pasted image 20231002045652.png| 500]] ###### Propanolol ![[Pasted image 20231002050231.png]] Propanolol is a non-selective beta adrenergic receptor antagonist. It decreases HR and contractility (like I showed you through those beta-1 receptors), but it also binds to the beta-2 receptors on blood vessels and it blocks the binding of epinephrine to those receptors so you don't vasodilate as much. So it also adds that stabilization to this elasticity of the blood vessels as well (which hasn't really been studied in dysautonomia, but we study it in other diseases and we know the drugs work this way). ###### Cardioselective Beta Blockers ![[Pasted image 20231002050550.png]] Then there's all these cardioselective beta blockers, which are basically all the other ones, except Propanolol. They mainly work with this beta-1 receptor. They do activate those beta-2 receptors in the blood vessels at very high doses though. And the research for these ones are really not as good, there's really no evidence that they help for POTS. However lots of people take them, lots of people have benefits, the research just does not back that. ##### Ivabradine ![[Pasted image 20231002050756.png]] A newer drug acts at the funny channels in the hearts, which is really selective to decreasing HR. So some people who have more side-effects with betablockers, find Ivabradine helpful because it's really specific to just affecting the HR in the SA node. And there have been several studies in POTS that show that it doesn't affect BP like betablockers do. ##### Alpha Blockers ![[Pasted image 20231002051045.png]] Alpha Blockers have lots of side-effects, but they mediate the norepinephrine release from nerve terminals and decrease that by blocking the receptors, so norepinephrine can't bind. These are helpful for sleep and people with severe hyperadrenergic POTS, where they have supine hypertension. #### Vasoconstrictors ##### Midodrine ![[Pasted image 20231002051222.png| 500]] It's not active in the brain, only in the peripheral blood vessels. ![[Pasted image 20231002051259.png]] It's kind of similar to norepinephrine, that's why it binds to this receptor and activates it so well. ##### Octreotide ![[Pasted image 20231002051458.png| 500]] ##### Stimulants ![[Pasted image 20231002051743.png| 500]] There's not a lot of evidence for this, but it might help brain fog. The only problem is that if you have POTS, it can cause tachycardia. Some sites have used them in combination with betablockers to prevent that. Modafinil is a newer drug that is not a stimulant exactly, helps with awakeness and doesn't cause tachycardia as often. #### Meds to Increase Vagal Tone ##### Droxidopa ![[Pasted image 20231002052022.png]] Droxidopa is converted to norepinephrine in the periphery. It's really a drug that's useful for orthostatic hypotension and it would increase vasoconstriction in the blood vessels, but could also cause tachycardia if it binds to the heart. ##### Pyridostigmine ![[Pasted image 20231002052421.png]] Mestinon increases cholinergic activity by preventing the breakdown of acetylcholine. This does lots of stuff, the primary mechanism is to slower HR, but it also can constrict airways (so it has to be used in caution in people with asthma). It also stimulates digestion (so it can be useful for gastroparesis especially if you have constipation). ##### Vagal Nerve Stimulation ![[Pasted image 20231002052545.png]] Vagal Nerve Stimulation is more experimental, but there are some studies in other comorbidities of dysautonomia where it's been approved. This is still in the research phasis. No doctor is gonna prescribe this for you for POTS specifically. ##### Implantable Vagal Nerve Stimulator ![[Pasted image 20231002052648.png]] This would increase parasympathetic tone (rest of digest response). ##### Immunoglobulin - Intravenous or Subcutaneous ![[Pasted image 20231002052750.png| 500]] #### Q&A Round - "What causes coat-hanger pain?" Probably decreased blood flow through the carotid and up to the brain. [Addition from host: It's actually common in many different autonomic disorders. I would say also a potential other mechanism - if you have EDS it could be some joint issue, some spine compression on things that shouldn't be compressed, if you have a small fiber neuropathy, you can actually have small fiber neuropathy in your upper back, in your upper body, so in some diseases they do a skin biopsy in your upper back to look for a small fiber neuropathy but they haven't started doing that in POTS yet.] - "Why would you not want to overdilute hydration product?" Specifically for oral rehydration salts, they have a very specific osmolality, so the concentration of sodium and glucose is very is really specific. So if you overdilute them, they won't be absorbed correctly. [Addition from host: They're meant for rapid absorption, so if you change that ratio you're messing that up.] - "Why do we have to watch our diet in POTS, as in sugar?" So there isn't really a recommendation to watching sugar specifically. There have been some studies showing hypoglycemia in POTS. It's probably a sympathetic related mechanism, so the autonomic nervous system controls your insulin and glucose release and that can be abnormal. Some people with POTS kind of get a sugar-rush after they eat sugar and they get more pooling in the GI tract but there isn't a strong recommendation to avoid sugar. [Addition from host: There was a dysautonomia international funded study at Vanderbilt showing that POTS patients when they have glucose intake, which is sugar, get really excessive tachycardia in response to sugar, way more than a healthy person. Even small doses of sugar. It's very new, so it's not in all the published guidelines, but Dr. Shabao is saying this is really good evidence for why POTS patients should try a low-carb diet. Not in any kind of obsessive way, it's not dangerous to have sugar, but it just might make you feel more "tachycardic" and she also that POTS patients have insulin resistance.] - "The Levine protocol emphasizes recumbent workout. Why does upright exercise trigger dysautonomia symptoms?" Basically that redistribution of blood volume that happens when you sit and stand can make your dysautonomia symptoms flare, so when you start an exercise program, you should probably start supine or sometimes in the pool, because that adds compression and then you can advance as you get through either the Levine protocol or the CHOP protocol, any kind of graded gradual exercise protocol, you do get into the seated and then upright exercises as you increase your time.