Cardiology Confusion II

Above: My tutor group's depiction of our final understanding of heart failure.
Below: My notebook version of the whiteboard flow chart. I'm messy.
Overall it is a compilation of all my reading and flow charts from Ettinger's Internal Medicine, Duke's Physiology of Domestic Animals and Cunningham's Veterinary Physiology with the actions of drugs in hot pink. I'm creative like that:)

Cardiology Confusion I

It's been a long week. We're back in tutor group, which is Cornell's problem based learning format. I came to Cornell in large part for the problem based learning aspect of the curriculum, and as I anticipated, it definitely beats sitting in lecture all day. That said, it can be pretty exhausting. I forgot just how much work it can be since last being in tutor group in the fall.

What can make problem based learning so time consuming is that it is often very open-ended. My group made a big effort to make our "learning issues" very specific, but I still ended up researching subjects as enormous as "the progression of heart disease." In fact, I spent Wednesday afternoon, evening and part of the night as well as Thursday evening trying to teach myself everything there is to know about the progression of heart disease. In retrospect, this was a completely ridiculous expectation on my part as their are whole books written on the subject, and some important species variations/predisposing factors, but at the time it somehow seemed entirely reasonable to me. And to my credit, I did a good job of covering a whole heck of a lot of ground those twelve hours in the library.

So for those of you who are interested, here is an abbreviated chronicle of my discoveries.

First off, I approached the problem of the progression of heart disease with the wrong paradigm in mind. I assumed initially that it had to be anatomical changes, such as degenerating mitral valves, that were driving the disease progression. This is true sometimes. But what is more true is the principle that compensatory mechanisms that work in acute situations actually cause the progression of heart disease when they are chronically activated. This finally sunk in after reading that, "Clinical signs observed in heart failure are mainly the result of chronic activation of compensatory mechanisms to restore and maintain blood pressure." And, "A common characteristic of all compensatory responses is that the short term effects are helpful but the long-term effects are deleterious."

With my new perspective, I tackled the compensatory mechanisms that are triggered by heart disease rather than looking for anatomical changes leading to heart failure (however, the two are not totally unrelated). This was after reading a great deal about myxomatous degeneration, genetic factors leading to valvular degeneration, and other factors promoting degeneration of valves such as the loss of the endothelium.

I identified three separate compensatory pathways that result from low blood pressure and volume or pressure overload: activation of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone-system and hypertrophy (eccentric or concentric) and followed each pathway until it led to decompensation (i.e. ultimately feeding back on low blood pressure and creating a vicious cycle).

Then I went and read about drugs that are commonly used to treat heart disease/failure-- their mechanisms and how they alter the compensatory pathways and progression of the disease.

I got really hung up on two points. First, I couldn't understand how mitral valve regurgitation (which is very common in older dogs and was part of the presenting problem in our case) led to low stroke volume. The equation for stroke volume is:
stroke volume= prelooad + contractility -afterload. Well, none of these were changed by the mitral valve regurgitation and so I went in circles trying to understand how the stroke volume was reduced. It turns out to be a special case-- stroke volume is decreased because a portion of the blood is flowing backwards into the left atrium, not due to the other parameters at all! Sometimes it pays to think outside the box a little bit.

I also got stuck on the subject of volume overload. I knew that there had to be volume overload because of the eccentric hypertrophy (which is triggered by volume overload and increased diastolic wall stress in simple terms, though as I discovered after consulting several sources, no one really knows exactly how these factors trigger hypertrophy/what the exact mechanisms are). The key to thinking about the cardiovascular system is that it is a CLOSED system. What the heart pumps out returns to the heart (except in special cases such as hemorrhage). So how does mitral valve regurgitation cause volume overload? I kept thinking that if more blood is showing up in the left ventricle, then it must somehow be lost from another part of the system, but where??? Of course, this doesn't makes much sense. What a kind and brilliant professor finally explained to me is that the volume overload is a result of the low blood pressure (that comes from the low cardiac output that comes from low stroke volume that comes from a significant portion of the blood flowing back into the left atrium instead of the aorta). As a result of the low blood pressure, glomerular filtration rate is reduced, and so less fluid leaves the system, leading to volume overload.

And then there is the whole subject of the renin-angiotensin-aldosterone system that kicks in to help raise blood pressure. But doesn't help long term. I spent quite awhile pondering this as well. From my beloved Boron and Boulpaep (yes, I'm having an affair with my physiology textbook): "Common to these edematous diseases is an abnormal shift of extracellular fluid away from the effective circulating volume... The reason that most of this added extracellular volume remains ineffective and does not restore the circulating volume is not intuitive but reflects the underlying disorder that initiated the edema in the first place. Thus treating these diseases requires generating a negative Na+ balance."

If you made it to the end of this post, you deserve an award. I'm so tired that I am going to bed shortly. Trying to learn the physiology of the cardiovascular system in one week was way too much work but I think I've got the core concepts finally:)

My Favorite Videos From Vet School Year One

This one, Lucy and Ethyl in the chocolate factory, was part of a meiosis lecture in block I. It pretty much sums up what it feels like to be in vet school, my all time favorite so far.

This one, Living Arrhythmias, was in our cardiology lecture today, pretty hilarious. (Note, it's old time, no sound).

And this one, Pinky and the Brain, shown at the end of our neuroanatomy course as comic relief to counter our stress about the final, was most people's favorite.

Mechanisms of Drugs Affecting the Parasympathetic and Sympathetic Nervous System

Our second week of physiology lecture ended with a laundry list of drugs whose mechanism of action we had to memorize (thankfully not too long). I feel grateful that I've seen some of these used in practice so have some context for their use. I also learned a fair bit about some of these drugs in tech school. Still, it gets tiresome having list after list of things to memorize (I know, welcome to vet school).

For anyone who cares to follow along here is a quick cheat sheet;
Nicotinic receptors are found at ganglia in the parasympathetic nervous system (PNS) and sympathetic nervous system (SNS) as well as at the neuromuscular junction. They are ionotropic channels.
Muscarinic receptors are found at the neuroeffector junction in the PNS and at the neuroeffector junction of sweat glands in the sympathetic nervous system (except in the horse, which has adrenergic receptors). They are metabotropic, or G-protein coupled receptors. There are five types of muscarinic receptors but their significance was not emphasized to us.
Adrenergic receptors are found at the neuroeffector junction in the SNS. They are also metabotropic receptors and come in several flavors, or subtypes.
α1: generally excitatory, contractile on postsynaptic membrane
α2: mostly on presynaptic membrane, part of negative feedback mechanism
β1: mostly found on heart
β2: blood vessels, bronchioles, liver (smooth muscle and metabolic)
β3: adipocytes

Cholinergics:

Atropine: Muscarinic antagonist. Competitive inhibitor at parasympathetic neuroeffector junctions. Can block nicotinic sites only at very high concentrations.
Heart: Tachycardia, but the degree depends on the species' vagal tone, which is high in horses and dogs, producing marked effects in those species.
Blood vessels: Very little effect. Will block vasodilation induced by choline esters.
GI and Urinary Tracts: Reduce tone, motility, secretions
Respiratory: Increase luminal diameter, decrease secretions of bronchioles
Eye: Mydriasis, cyclopegia, increase intraocular pressure
Sweating: Impaired (horse is an exception)
Salivation: Reduced (dry mouth)
CNS: Moderate doses stimulate medullary and higher centers, eventually death by medullary paralysis

Bethanecol: Muscarinic agonist. Parasympathomimetic. More resistant to hydrolysis by cholinesterases than acetylcholine, so it has a longer duration of action that Ach. Never heard of this drug and not sure why someone would use it.

Edrophonium: Anticholinesterase (inhibits enzyme that breaks down acetylcholine, the neurotransmitter at the muscarinic junction). Shortest acting anticholinesterase. Used to diagnose myasthenia gravis (an immune disease where the muscarinic receptors are attacked and subsequently decreased in number).

Neostigmine: Anticholinesterase. Lasts for a few hours. Can be used to treat myasthenia gravis.

Pilocarpine: Muscarinic agonist. Parasympathomimetic. Treatment for glaucoma, lowers intraocular pressure.

Adrenergics:

Albuterol: Selective β2 agonist. Bronchodilate while minimizing stiumlation of the heart. I saw terbutaline used more often to treat asthmatics than albuterol, not sure why from this class. (Maybe later, as a first year there is always later!)

Epinephrine: Directly acting adrenergic agonist. Non-selective for α or β receptors.

Phenylephrine: Directly acting adrenergic agonist. "Pure" α-receptor agonist. Not sure why I've never seen this used in practice, instead always saw use of epinephrine.

Isoproterenol: Directly acting adrenergic agonist. Non-selective for β-recptors.

Phenoxybenzamine: α-adrenergic antagonist. Irreversible non-competitive antagonist that covalently attaches to receptors. I saw this used in the treatment of UO (obstructed cats) with a urinary catheter in place. I always thought it decreased spasms in the urethra. Now I know it blocks the contraction of the urinary sphincters.

Phentolamine: α-adrenergic antagonist. Competitive antagonist. Not sure when this is used.

Propanolol: Non-selective β-adrenergic antagonist. Primarily used to decrease blood pressure, excitability and work of the heart (decrease in heart rate, force of contraction, and cardiac output). Since it blocks β2-receptors in addition to β1-receptors it also blocks bronchodilation and can cause hypoglycemia. Therefor it should not be used in asthmatics or in the case of allergic reaction. It is also contraindicated in diabetes with insulin treatment. Interestingly, this drug is now being used to treat stage fright in people since it prevents the racing heart without affecting the mood.

Metoprolol: Cardioselective β1 antagonist. More potent for cardiac effects. Avoids the side effects of blocking bronchodilation and potentially causing hypoglycemia associated with propanolol. Never heard of this or seen it used either but sounds useful in certain cases.

Pain Receptors And Chili Peppers, Garlic, Wasabi And Menthol Mints

We had an interesting lecture this week titled "Molecular basis of nociception." Hot chili peppers (specifically the chemical capsaicin) induce pain by binding to transient receptor potential vanilloid-1 (TRPV1), an ion channel of non-selective cation permeability that transduces specific noxious stimuli (in this case capsaicin) into electrical impulses. What's interesting is that the TRPV1 channel is also activated by temperatures higher than 43 degrees Celsius and acidic extracellular pH. My notes explain, "Because capsaicin activates TRPV1 as effectively or more effectively than noxious heat, it evokes a similar hot and burning sensation like hot temperature does."

My notes continue, "TRPA1 is an ion channel frequently co-expressed with TRPV1 in heat sensitive sensory neurons. TRPA1 is activated by pungent chemicals, including allicin from garlics and mustard oil from Japanese Wasabi roots." TRPA1 is also activated by THC (the active ingredient in Marijuana) and some pungent anesthetics like isoflurane, desflurane and propofol. Interestingly, "because TRPA1 positive neurons usually contain TRPV1, allicin and mustard oil evokes hot burning pain similar to how chili peppers do."

Finally, another channel in the TRP family, TRPM8, is "considered to be the molecular cold sensor for thermal sensation." It is activated by temperatures lower than 30 degrees Celsius. It is also activated by menthol, which explains the cool sensation associated with menthol mints.

Fugu (Puffer fish/Blowfish) Sushi, Black Widow Spider Venom And Other Interesting Toxins

Yesterday we had a lecture titled "Neuromuscular Pharmacology" which touched on some interesting toxins:

Fugu sushi is known for its potentially lethal toxicity if it is not prepared correctly. The toxin involved is called tetrodotoxin and is found mainly in the gonads of the fish, although it is also elsewhere in the body. Tetrodotoxin works by blocking voltage-gated sodium channels from the extracellular side. Supposedly fugu sushi gives you a little buzz when you eat it (I don't quite get this-- how does one get a buzz from a toxin that blocks action potentials?)

Saxitoxin is another toxin that works by the same mechanism-- blocking voltage-gated sodium channels. It is found in the single cell algae responsible for the red tide. During red tide, shellfish concentrate this toxin, which can lead to "shellfish paralysis" if the shellfish are consumed.

Latrotoxin is found in black widow spider venom and mediates fusion and release of vesicles containing acetylcholine at the motor neuron terminal even in the absence of calcium-- an impressive phenomenon whose mechanism remains a mystery. After this massive release of acetylcholine there is subsequent decreased synthesis and release of acetylcholine.

No, I don't expect to be treating domestic species for these toxins (with the possible exception of black widow spider bites), they are just illustrations of how toxins work at the neuromuscular junction, which I find pretty cool.

Equine Nigropallidal Encephalomalacia

I'm done with neuroanatomy (yay), at least for now, but this is one interesting disease that we learned about that I didn't write about at the time. Here's what my notes say:

Damage to the basal ganglia in humans causes debilitating motor and cognitive deficits [not surprising as they are involved in the cognitive aspects of motor coordination and planning] as demonstrated by Parkinson's disease (degeneration of the substantia nigra) and Huntington's disease (degeneration of caudate nucleus and putamen). In domestic animals, disease processes are rarely as restricted and specific as in these human diseases. One exception to this is Equine Nigropallidal Encephomalacia, which can be seen in horses that have eaten Yellow Star Thistle or Russian Knapweed (both found in the Western US). These horses develop motor dysfunction associated predominantly with their facial muscles and die of starvation because they cannot prehend food. Lesions can be identified in the substantia nigra and globus pallidus.

I know from living in California tha there is lots of Yellow Star Thistle around (at least in the Bay area) so I imagine this is of concern to horse owners, although I had never heard of the disease prior to this class. Interesting stuff.

On a related note, the Corticospinal (Pyramidal) pathway is the major pathway for voluntary control of motor movements in primates, particularly for fine motor movements of the digits. It is not nearly as developed in domestic animals, with the possible exception of raccoons who use their fingers extensively to almost "see" by feeling. However, in horses the related corticobulbar tract [note corticobulbar means going from cortex to brainstem rather than cortex to spinal cord as in the corticospinal] is the major pathway that innervates the muscles that control the lips. I remember my professor saying something like, "as horse people know, horses can do all kinds of amazing things with their lips." In a way, horse lips are akin to human fingers! Just in case you are wondering, the major pathway for voluntary movement in domestic animals is the Cortico-rubrospinal tract. But I won't get into that.