A Department of Medicine Grand Rounds presented by Hooman Poor, MD, Assistant Professor of Medicine (Pulmonary, Critical Care and Sleep Medicine and Cardiology), Director of Pulmonary, Vascular Disease, Mount Sinai-National Jewish Health Respiratory Institute, Dr. Poor explains pulmonary hypertension disease.
this morning, we have the pleasure of having Dr Human Poor discussing pulmonary hypertension. Dr. Poor received his bachelor's degree from Dartmouth, where he majored in physical chemistry and mathematics. He received his medical degree from Columbia, where he also completed training, internal medicine and pulmonary and critical care. He has been at Mount Sinai since 2013, where he has dual appointments as assistant professor of medicine in the division of cardiology and pulmonary medicine. He is the director of pulmonary vascular diseases for the Mount Sinai National Jewish Health Respiratory Institute, as well as the founder of the multidisciplinary pulmonary Embolism Response Team here at Mount Sinai. Dr. Poor is also the assistant program director for the pulmonary and Critical Care Fellowship training program, and, of course, director for the pulmonary path of physiology Course. For the second year medical students. He is a beloved educator among students and house staff, having received numerous teaching awards and recently published a textbook entitled Basics of Mechanical Ventilation. Please join us in welcoming Dr Poor. Good morning. Thank you all for coming. And thank you for inviting me today. I'm going to talk about pulmonary hypertension. Um, this is actually how we measure pulmonary pressures. We put a cuff around the lungs. Uh, no financial disclosures. So this is a common case, um, that I saw in the emergency department recently. 39 year old woman presented with a few weeks of worsening dismay on exertion. She'd been short of breath after walking only about a half a block. Prior to this, she was extremely active. An echocardiogram is performed. She has normal LV function in size and EF, 75%. And she has severely dilated right ventricle. And the RV systolic function is severely reduced. Her estimated our BSB is 90. So what do you do? Do you do nothing? The LV is fine, and that's all that matters. Do you prescribe calcium channel blocker? You start with this class of medication first to see if it works. You prescribe sildenafil. It's now generic, and it's a better pulmonary nasal dilator than calcium channel blockers. Or do you hide in the bathroom? Uh, pH patients are human dynamically tenuous and code if you glance at them the right way, or do you begin the work up to better characterize her pulmonary hypertension? So I'm being a little bit facetious with respect to a three D, However, I have seen all of them happen. Uh, my hope is that after this talk, we'll get closer to E. So specifically, I'm going to talk about the physiology of the pulmonary circulation, the classification of pulmonary hypertension, the path of physiology of pulmonary arterial hypertension, the vicious cycle of RV failure, the treatment of pulmonary arterial hypertension. And then I'm going to touch on pulmonary hypertension, secondary to heart failure with preserved the F. So the pulmonary circulation is characterized by a low pressure circuit. Uh, you can see here, um, a depiction of the circulation here, Um, the left ventricle pumps into a high pressure circuit. You can see that the mean arterial pressure is about 93. And by the time you get to the capillary bread bed, a lot of that pressure has dissipated down to about 30. And you come back to a low pressure of writing. Feel pressure about two, the pulmonary circulation. On the other hand, the mean p a pressure is about 14 so much lower. And by the time you get to the capillary bed, very little has dissipated and you come back to the left atrial pressure of about five. And so, um, the house staffers probably PTSD when they see this slide. Only because every time I discuss anything, I talk about homes. LA, which is a voltage difference across the resistor, is equal to the current of electrons, times of resistance. And we can apply this to the pulmonary circulation instead of a voltage difference. We have a pressure difference. Instead of a flow of electrons, we have a flow of blood, and that's the cardiac output. And the resistance here is a pony vascular resistance. The pressure difference that we're looking at is the pressure difference between the pulmonary artery and the left atrium. And when we rearrange the equation, we now have an equation for the pulmonary arterial pressure. And you can do the same exact thing for the systemic pressure. Um, Karnik outputs are the same. If there are no crazy shunts, Um, instead you have a systemic vascular resistance and the downstream pressure is ready to pressure. So if the cardiac outputs are the same and the right and left atrial pressures are both very low and about the same, then the reason that the pulmonary pressure is so much lower than the systemic pressures because pulmonary vascular resistance is low and that is essentially the hallmark of the pulmonary circulation. And the resistance is low because of, you know, less muscle and a lesson in the vessels and also this concept of capillary recruitment. Uh, so your capillaries, often particularly those in the higher lung zones, may be compressed when blood flow increases in them because of, say, uh, exercise, they will dilate. And when they dilate, the cross sectional area of the vessels go up, and therefore the resistance goes down. So the definition of pulmonary hypertension is a mean pulmonary arterial pressure of greater than 20 at rest, measured by right heart catheterization. And it's important to note that this pressure has been changed. About a year and a half ago, it used to be a pressure of greater than 25 and that's because this pressure of 25 was sort of randomly plucked out of the air. Um, and it really was because of the study by Kovacs in 2000 and nine, a meta analysis of 47 studies from 13 countries, Uh, and they took about 1200 asymptomatic individuals, no issues who underwent right heart catheterization both at rest and with exercise. And they found that the average mean pulmonary taylor pressure was 14 with the standard deviation of three. So if you do two standard deviations above the mean you now have 20 as you're kind of cut off. So the classification of pulmonary hypertension has classically been primary versus secondary pulmonary pretension. Uh, highly advocate that you do not use this classification. It's an older classification, and the newer classifications are based on the world symposium. Pulmonary pretension. Uh, the first one was convened in Geneva in 1973 in response to this rise in, uh, the incidents of at that time primary pulmonary hypertension, secondary to the anorexia, gin, Memorex and then in 1998 Evian, France was the next symposium. Um, and this is where the kind of foundation of our new classification was developed. And every five years, This symposium meets Venice in 2003, Dana Point in 2000 and eight Nice in 2013, and then they thought nice was nice. So they went back there again in 2018. Uh, the only reason I show This is mainly for the house staff. When you're choosing a specialty or subspecialty, it's really important to look at where your conferences are held. Um, I'm told the next one is actually in Jersey. I'm not kidding. Um, right. So, uh, to understand the causes of pulmonary hypertension again, the definition is a mean pressure greater than 20 at rest. We go back to this equation. So if the pressure is high, either the cardiac output is high. The pulmonary vascular resistance is high, or the left atrial pressure is high or some combination of the three is high. So with respect to increase cardiac output, this can occur from congenital heart defects with the left to right, shunt and asd rBST uh, cirrhosis. Other high output states like anemia, A V malformations, maybe fistulas. Uh, we recently had actually a few months ago patient. A young woman, uh, present in multi organ failure, RV dysfunction, severe pulmonary hypertension. And ultimately, we diagnosed her with diamond efficiency, and we literally discharge her on timing and her home syndrome. So the craziest case I've seen as well um, increased left atrial pressure. Um, you can have systolic and diastolic left ventricular failure. Valvular disease on the left side, mitral or aortic valve disease. Restrictive cardiomyopathy. And then the increase in pulmonary vascular resistance comes in different flavors. You can have destruction or obliteration of the pulmonary vascular bed from I L D say fibrosis or inflammation. Also, emphysema can destroy the vascular bed, and then, obviously, PE and clot will obstruct the bed. Hypoxia is a very strong stimulus, for for many vascular constriction, it can either be from a disease like COPD or the ambient air, for example, at high altitude will corresponding vascular constriction. And then there's a very specific small pulmonary artery. Arterial vascular apathy. Uh, and that is called pulmonary arterial hypertension. And so the well, World Health Organization classification. This is the most recent one from Nice, uh, breaks the breaks down the pulmonary pretension into five groups. The W H O groups Group one is known as pulmonary arterial hypertension. That is the very specific vascular apathy, which increases pulmonary vascular resistance and secondary to these causes. Here. Group two is secondary to left heart disease. That is an increase in left atrial pressure that has caused this Group three is lung disease and hypoxia, which increases pulmonary vascular resistance. Group four is probably already obstructions, the main one being chronic chronic thrombosis, bolic, pulmonary hypertension. That's clot that increases primary vascular resistance. And Group five is everything they couldn't fit into one through four. And so one of the major reasons why I think primary versus secondary is not a very helpful classification is that if you were to tell me that a patient has pulmonary hypertension, secondary to scleroderma, scleroderma can cause this very specific vascular apathy known as pH. Scleroderma can cause left heart disease and cardiac fibrosis. Scleroderma can cause pulmonary fibrosis and and hypoxia and scleroderma probably increases your risk for developing blood clots. So knowing that you have scleroderma while it's helpful doesn't really give you the whole story. Additionally, it's important to note that primary pulmonary pretension really just refers to these very three rare conditions, Uh, and that the majority of patients, uh, orders of magnitude higher prevalence have pulmonary hypertension, secondary to left heart disease or lung disease. So a few human dynamic definitions it's important to note that pulmonary arterial hypertension and pulmonary hypertension are not the same thing. Pulmonary hypertension merely means that the pressure is elevated in the pulmonary arterial tree. Uh, pulmonary arterial hypertension is a subset of pulmonary pretension, a very specific vascular apathy with these human dynamic parameters. It's also important to note that Group three, which is lung disease in hypoxia, and Group four, which is the large artery obstructions, have the same thermodynamic profile as Group one. You can't tell the difference based solely on their remote dynamics. The other aspect about the definition of pulmonary pretension is that exercise criteria is no longer part of that definition. Previously, if you exercise the patient and their mean pulmonary arterial pressure went higher than 30 that was deemed exercise induced pH And again. This is because of that study by Kovacs, where these asymptomatic patients underwent right heart catheterization at rest and also with exercise. And they found that even with just slight exercise, half of the patients who are older than 50 years old had a mean pay pressure greater than 30. So if you have half the patients are greater than 50 would just mild exercise, uh, having this increase in pressure who are asymptomatic? You can't really call that a disease, and you can imagine why that would happen. When you exercise your cardiac up goes up and therefore your P A pressure goes up. Notably, your vascular resistance should go down because your blood vessels should dilate. There is a condition of exercise induced pH, but it's much more complex than just a fixed number of greater than 30 and that's why it was removed. So to understand pulmonary pretension, it's helpful to understand pulmonary arterial hypertension, uh, as the foundation. And so this is a normal pulmonary artery. You have the internal layer here with the endothelial cells, the smooth muscle cells in the Tunica media, and then the admonition layer. And the lesions that occur are fiber optic and prolific lesions in the small, muscular arteries. Um, the types of lesions that occur and the changes that occur in pH include vessel constriction. So the smooth muscle cells actually vaso constrict. You get actual remodeling of all three layers so the internal Leo will thicken, become vibe Roddick. You'll get smooth muscle hypertrophy and hyperplasia and then advantage Shal um uh thickening as well, as well as inflammation with lymphoid follicles. There is this very strange lesion known as a plexi form, lesion. Areas of injury occur with endothelial cells. Now break into, uh, the artery and include the artery. And then you can also develop inside to thrombosis. And all of these, as you can imagine, decrease cross sectional area and increase pulmonary vascular resistance. And the pathogenesis involves kind of the trinity of pathways. Um, the end of the island pathway in these patients is up regulated, and North Island results in vessel constriction and proliferation of smooth muscle cells and remodeling. The nitric oxide pathway is down. Regulated nitric oxide leads to increased cyclic GMP cyclic GMP is Veysel dilatory and anti proliferated, and the process cycling pathways down regulated process. Cycling results in increased cyclic GMP and its vessel dilatory and anti proliferated. So diving deeper into Group One, we can break this group into other, uh, subsets. There's the idiopathic form. Uh, there's inheritable form. Uh, 70% of those with a heritable form have a germline mutation in the bone. More photogenic protein receptor, too. However, it's important to note that only 20% of those who have the mutation will develop pH. So the penetrates is relatively low. There's drug and toxin induced, uh, chemotherapeutic agents like this, It nip and Rx engines like fen phen and the Memorex and elicits um, most recently being crystal meth being a huge rise in the incidence of Ph. And then there's the associated ph connective tissue diseases, specifically scleroderma and Lupus and congenital heart disease. As I mentioned before, you have left to right shunt, uh, where you have increased flow and pressure through the right side of the heart and the pulmonary vasculature that high pressure and flow will cause injury to the vessels, Uh, and resulting pH portal hypertension. The idea is that blood bypasses the liver, and certain toxins now injure. Uh, the pulmonary circulation HIV and worldwide schistosomiasis is, uh, because the epidemiology of pH. It's a relatively rare disease. The prevalence is about 15 to 50 per one million adults. Um, but the prevalence varies amongst, uh, specific patient populations. So in scleroderma, 10 to 15% will develop Group one pH portal. Hypertension ranges from 2 to 16% and then congenital heart disease. If you don't have your A S C repaired, it's about 10%. If you don't have your VSC repaired. It's about 50% within ph half are idiopathic, and about half are associated with a small percentage heritable and within the associated half for college and vascular disease, about 20%. Congenital heart disease, 10% portal hypertension, drugs and toxins. HIV. It's a deadly disease. Median survival of untreated idiopathic pH is about 2.8 years, and survival at five years is 34%. And this survival varies depending upon the demographics. So those who have congenital heart disease have the highest survival. Uh, five year survival is in the 80% range. Those with college and vascular disease much worse and idiopathic is right in between. And if you take, uh, certain disorders who are at high risk, for example, scleroderma patients with limited scleroderma without pH have survivals around 80% in five years. A patient with limited squared with pH has a dramatically lower survival, about 10% at five years, so you can imagine a very specific patient populations. It is a major cause of morbidity and mortality, so the underlying lesion and pulmonary arterial hypertension is a vascular apathy of the pulmonary arterial tree. Um, however, uh, the cause of symptoms and mortality is because of right ventricular failure. And the question is, uh, you know, we see tons of patients with systemic hypertension. Um, why is it that patients with systemic hypertension don't have median survivals of 2.8 years? Um, and the answer is that the pump behind the circulations are different. You know, the right and left ventricles. Um, classically, the right ventricle has been viewed as merely a weak version of the left ventricle. Uh, but it turns out that's not the complete story. Uh, they are Embry logically different there, right and left ventricles. Myocardial varies from different origins, and they're structurally different. This is a short axis view. We've basically cut the heart, um, crosswise like that. The LV is concentric shape, like a circle. The RV is crescent shape. The RV free wall here is much thinner about 2 to 3 millimeters compared to the L B free wall, which is 8 to 11 millimeters. And the L V has the circumferential fibers that go around in the circle, and they provide the majority of the systolic force. Uh, the RV lacks these and relies predominantly on the longitudinal fibers. Instead, they are functionally different. The RV is much more compliant. It's like a floppy balloon. And the R V myocardial energy is expenditure is much less about 1/5 of the l b. And so, um, to understand, again, the role of these ventricles and their function it's helpful to go back to first year medical school, Um, and the pressure volume relationships of the ventricles. Uh, so at this point here, the mitral valve opens. Uh, the LV fills, um, and then the mitral valve closes and the L V begins to contract, and there's a clear period of what's known as isil. Limit contraction. That means the Elvis contracting pressure is going up, but no volume is being ejected. The aortic valve then opens, blood flows out, aortic valve closes, and then the LV starts to relax. However, uh, no blood is being ejected or filling. This is known as I subliminal relaxation. So if you look at the RV, turns out there is no clear period of ice of economic contraction or relaxation. When it starts to contract, blood gets ejected. When it starts to relax, blood gets ejected, much more efficient. The question is, is this intrinsic to the RV and LV, or does it have anything to do with the pump that the circulation that these ventricles are pumping into. So what if we took an RV and hooked it up to a system with an increased RV after load, for example? Harmonic stenosis. Well, then the pressure volume relationships look very similar to that of an L B. Uh, with clear periods of isotonic contraction and relaxation. What if we took an L V and hooked it up to a low pressure circuit? For example, after a mustard repair where now the LV is pumping into the low pressure pulmonary circulation and the RV is pumping into the high pressure and systemic circulation, The L V now looks very similar to that of the RV. So the function and the characteristics of these ventricles depends highly upon the circulation that they're pumping into. So to understand, RV failure, it's important to understand how a pump in general works. So imagine you have, you know, a tube filled with blood and blood is flowing. Uh, and now you're at a pump. So when you add a pump, you increase the flow through this pump, and when you do so, um, the pressure before the pump goes down and the pressure after the pump goes up. That's basically what a pump does. So imagine that this is your right ventricle and therefore it's pumping into the pulmonary arteries and it's, you know, draining from the systemic fames. And so if we induce RV failure, what will happen? Well, first of all, the flow will go down, and when the flow goes down, there's less flow to the left side of the heart. The left side of the heart then pumps out less blood. You have decreased cardiac output, and these are the symptoms of decreased perfusion, so dysosmia chest pain and in more severe cases, lightheadedness sync API and frank shock. Additionally, this pressure difference will now become less, and the systemic vein pressure will go up. You get increased venous congestion, you get lower extremity edema and the sides and these are again the signs of RV failure. So the important question that's come up a lot is does RV failure occur because of an intrinsic problem with the RV, or is it secondary to something else? Do this, you know, signs of, uh, increased venous congestion, lower extremity edema. Are they secondary to problems with the R V. And so this was studied many years ago in 19 fifties, where they took animals and actually charged the right side of the heart trying to induce RV failure. Um and so what they wrote is a red hot soldering iron was laid repeatedly all over the surface of the right ventricle. Um, and they write that after the right ventricular wall had been attacked repeatedly with the Kateri only minimal changes of Venus pressure followed the most extensive damage to the right side of the heart that we knew how to inflict. Um, so besides, the fact that these authors probably would benefit from some anger management classes um, you know, this demonstrates that, you know, perhaps, uh, charring this RV and making a dysfunctional doesn't necessarily lead to our failure. And again, this was repeated again by because, um, where again they charge the right ventricle and they found that there was still pressure being generated in the pulmonary arterial tree and thus actively functioning right ventricle is therefore not absolutely necessary for the maintenance of a normal pressure gradient in the pulmonary arterial tree. And again, this concept was taken even further What if we, you know, did a full thickness ventricular to me cut the heart completely at the ventricle and then re so it, uh, such that the right ventricle is now electrically isolated. So the right ventricle is electrically isolated from the rest of the heart, and they placed a whole bunch of probes and electrodes, electrodes in the right atrium, left ventricle and right ventricle, pressure probes in the left ventricle and the right ventricle and a flow probe in the pulmonary artery. And, uh, you know, what they did was when they stimulated the right atrium, it would de polarize the right atrium, and it would lead to deep polarization of the left ventricle. But because the right ventricle was electrically isolated, it would not be polarize the right ventricle. In order to de polarize the right ventricle, they had to simultaneously do it independently by the right ventricle. And so you can see here that they would de polarize the right atrium here, which would lead to a deep polarization of the left ventricle, and they simultaneously de polarize the right ventricle. And that led to pressure generation in the LV pressure generation in the RV and flow coming out of the pulmonary artery. They continued stimulating the right atrium, which led to deep polarization of the LV. But then they shut off the right ventricular stimulation. And now that the right ventricle is electrically silent and interesting, and what they found was there was still pressure generation in the L V and more interestingly, still pressure generation in the RV and flow coming out of the pulmonary artery. So much so that greater than 65% of the pressure, um, development and volume outflow was being generated. Despite the RV being completely electrically style, this was not enough. So years later, the Hoffman and his group took hearts and they literally locked off the right ventricle. They just cut it off, and instead they replaced it with bovine pericardium. So non contract I'll tissue. Um, and what they found was having non contract I'll tissue for your RV free wall. You would still generate RV pressure, and you would still generate flow out of the pulmonary artery. And most importantly, there are patients who lack RVs, and they are doing fine. Uh, and these are patients who have congenital heart disease who have undergone um, procedure called the Fontane procedure. Uh, we're essentially, uh the systemic veins are hooked up to essentially the pulmonary circulation, and it's a pressure within the systemic veins that drives blood through the pulmonary circulation into the left side of the heart. Um, and these are patients that are living well into adulthood, and they don't have RVs. Which begs the question. If one doesn't need a right ventricle, then how do patients end up in your I see you with right ventricular failure. And the answer to that is that you need a functioning right ventricle in the setting of increased right ventricular afterward. And so the definition of after load is impedance during ventricular ejection. Essentially, that means there's something in front of their RV can't pump. Um, and it's also the wall stress during ventricular ejection ways that most commonly, um, RV after load has increased include increases in pulmonary vascular resistance, uh, decrease in pulmonary vascular compliance or too stiff uh, and then the downstream pressure. The left atrial pressure is high. The l B is, uh, particularly tolerant to increases in after load. So if you clamp the aorta and increase after load, Uh, and increase the aortic pressure. You see that stroke volume only goes down minuscule amount, whereas you do the same with the right ventricle. The right ventricle is very intolerant of increases in RV after load. Uh, an increase in R V after load will lead to precipitous drops in stroke volume and cardiac output. Additionally, the right and left ventricles are essentially roommates in a small New York City apartment. Pericardium, Uh, when the right ventricular, um uh, the right ventricle dilates. It does so at the expense of the LV because it's constrained by the pericardium, and this is known as inter ventricular dependence. When the septum bows in, the L V is now unable to pump out blood partly because it can't fill and partly because it's altered its geometry and systolic function. And so have many patients with pulmonary pretension that are out in the community. They're doing fine there at work. They're exercising. Um, yet they have some small insult, whether it be a bleed and infection. Um, a small pulmonary embolism. Uh, and then very rapidly, uh, there in your I see you on, you know, radioactive medicines, uh, intubated. And the question is why is there such rapid decompensation in these patients? And it has to do with this vicious cycle of right ventricular failure. As I mentioned, um, the primary problem in Ph is an increase in R V after load, which, as I demonstrated, reduces RV output. The RV is what fills the left side of the heart, and therefore the LV pre load goes down. If the pre load of the left ventricle goes down, it pumps out less blood. Additionally, an increase in R V after load will increase the wall stress of the RV when the stress on the wall of the RV increases, uh, the RV becomes more ischemic, and ischemic RV cannot pump out as much blood. The RV again is like a floppy balloon. When the RV afterward goes up, it dilates. And if you remember LA Plaza Isla Uh, when the radius uh, goes up the wall, stress goes up. Additionally, to try custom valve collapse like this, when the RV dilates, it gets pulled apart. You get more, try custard regurgitation, and this leads to less effective RV output. Also in the RV dilates. As I mentioned, the RV septum bows into the L V and that causes a decrease in LV preloaded cannot fill as much. Additionally, that septal shift alters the geometry of the LV and reduces systolic function and contracting pretty leading to decrease LV output. Part of the L V output is your coronary circulation the R C. A blood flow goes down, making the RV more ischemic. This goes around and round and round and round and round you get cardiogenic shock and that's bad. And so, uh, you know, this is important to realize, partly to prevent this from happening and also when this starts to happen, to know how to stop it, to prevent its progression and basically pull these patients back from the cliff. There are things that we do in the hospital for other patients, um, that are very harmful to patients with primary pretension, uh, specifically giving them lots of fluid. Uh, this leads to more RV dilatation more RV wall stress more. Try custard regurgitation. More septal shift that will lead to actually paradoxical worsening in human dynamics. Also, intubation is extremely high risk for these patients. These patients require often sedatives and, uh, that will result in vaso dilation of other blood vessels. Blood goes to their kneecaps. Not too. There are CIA and these are patients that will have a cardiac arrest during induction. So the foundation of the diagnosis and kind of characterization of Ph is the right heart catheterization. Essentially, uh, through a vein in the neck or through the family federal vein. We advance the catheter, um, through the right side of chambers, the right atrium, right ventricle into the pulmonary artery. Uh, and we measure the pressures to right. Atrial pressure, right. Ventricular pressure, peer pressure. And ultimately, the wedge pressure, which is a surrogate for the left atrial pressure. I'll discuss it a little bit. We're able to measure Craig output with this. And then based on our equation, we calculate the pulmonary vascular resistance. These are all the things we measure. This is calculated. So this is a question I often ask which hemo dynamic parameter does not correlate with survival in patients with pulmonary arterial hypertension. Is it pony vascular resistance, right. Atrial pressure mean pulmonary arterial pressure or cardiac index, which is your credit output relative to your body surface area. So it turns out the answer is C and you probably are scratching your head because I just told you that the definition of Ph is a mean pay pressure greater than 20. So you would think if I have more of this, that would probably be worse. Um, and understanding this concept is key with respect to, um, understanding. PH and it's therapy. So here are two patients. Patient A patient B Patient A. Has a pulmonary pressure of 90/25 systolic diastolic with a mean of 45 patient B has a P a pressure of 45/20 systolic diastolic with a mean of 30. And you think all right, clearly patient is sicker than patient be. The pressures are higher in a than be, but it turns out, when you look at the rest of the hemo dynamic data. The cardiac index for patients is 3.2 versus 1.4. For patients, be a normal index is about 2.5 to 4. So this is dangerously low. While this is normal and the right atrial pressure is normal here, about four and dangerously high at 24 patient be so patient. A is probably patient out in the community a little bit short of breath. Patient be Is someone in your ICU who's very sick passing out? You're probably in shock. Uh, and to understand why this occurs, it's helpful to look at the natural history of pulmonary hypertension, using this equation as our guide and to make this a little bit, you know, simpler, I'm going to remove the left atrial pressure aspect. So pulmonary arterial hypertension is a progressive vascular apathy where you have an increase in pulmonary vascular resistance over time. Um, initially, you have your right heart able to maintain its cardiac output. So if the cardiac output stays the same and the party vascular resistance goes up, that means your public pressure will go up. And this is the patient who's asymptomatic and doesn't really realize they have pulmonary hypertension. As time goes on, the pulmonary vascular resistance continues to increase, and now the right ventricle is unable to perform its job and cardiac output starts to drop. When cardiac output starts to drop and pulmonary vascular resistance rises, you now have a plateau of the pulmonary pressures. And this is the patient. Now who is a little short of breath, you know, walking a block or so as this continues to progress, the vascular resistance continues to rise. Now the right ventricle is in frank failure and can't do anything. Um, and now you have a paradoxical drop in your pulmonary pressures. So when you have a decrease in your pulmonary pressures, you don't know if you've gone this way and have an improvement in your situation. Or if you've gotten this way into frank RV failure and are in a worse situation, and it's important to note that this decrease in cardiac output are the cause of your symptoms of low profusion, dizziness, passing out and then right here is a right atrial pressure. You see a massive rise at the end. These are the signs of symptoms of congestion. Again, with this diagram that I drew before, this is your decrease of cardiac output, signs of decreased perfusion and your increase in right atrial pressure. The signs of increased the cause of your increase in edema and cities. So the unfortunate term pulmonary hypertension implies that the problem is the pressure. Um, when in reality as I mentioned, it's It's not the pressure. That's the issue. Um, so I've suggested Maybe we should change this turn from pulmonary pretension to the elevated right? Ventricular impedance syndrome or nervous? No, just in case. I've already copyrighted it. Sort of. Just kidding. Um, but, uh, the essential, um aspect is that treatment for pulmonary hypertension is different than that of systemic hypertension. Uh, systemic hypertension. The high blood pressure is the actual problem. It is the high pressure that is damaging the blood vessels that is causing organ dysfunction. Whereas in pulmonary pretension, it's not the pressure. That's the problem. It's the fact that the right ventricle is can't pump. There's something in front of it. And so treatment is really to get the system working better and more efficient. And so, with respect to treatment, the first question is that a visa reactivity and during the right heart catheterization, uh, we often administer a short acting bronchodilator can be proportional, Dennis Seen most commonly, we use inhale metric oxide and a visa responders. Someone who drops. They're mean pulmonary arterial pressure by greater than 10 to less than 40 basically close to normalizing without a concurrent drop in cardiac output. So, again, this equation that will haunt you. Um, if the end to make this simpler will remove the left atrial pressure if the pulmonary pressure drops and your cardiac output does not change or at least does not go down. That means that your pulmonary vascular resistance has gone down. So this is a test to see. Does your pulmonary vascular resistance immediately go down? Because if it does, you're more likely to have a sustained, beneficial response to a calcium channel blocker. And, uh, this was demonstrated by Stew Rich in 1992 where he took patients who were at the time called primary pulmonary pretension. And he gave them, uh, he did catheterizations and gave them calcium channel blockers as the short acting bronchodilator. If they were, if they were not Visa responders, he did not give them calcium channel blockers and he sent them home. Uh, and this is their survival. You could see very poor about 40% at 60 months. And these are two historical cohorts in comparison. If, on the other hand, they were visa responsive, he gave them calcium channel blockers. Uh, and you could see significant improvements in survival. Um, you know, close to nine higher than 90%. So the important fact here is that if you look at the underlying pathology, this really just means that the major cause of the permanent retention is activism constriction. Because if you give a short acting vassal dilator, the only thing that's going to get better is activism. Constriction. You're not going to undo remodeling. You're not going to remove plexi form lesions and traumatic lesions. They are looking for the final type of activism constriction and therefore a drug that merely vessel dilates should be sufficient. However, this test should really only be done in those who are quote unquote primary. So these three groups idiopathic, heritable and drug and toxin induced. And this is a very small subgroup of patients, as I mentioned. And then it's also been shown that of that subgroup, only 13% are actually Veysel responders. And of those only half remained Veysel responders at about a year, Uh, which means that a very small percentage of patients who have pulmonary pretension should actually be on calcium channel blockers. So what do we do? Uh, well, prior to 1995 the answer was nothing. Um, you know, it was diuretics, anti coagulation, things that didn't really work that well. And then in 1995 intravenous proportional was approved. Um, a proportional is a same as process cycling. It has a very short half life, 3 to 5 minutes. And for that reason, patients who have this in the outpatient world require a continuous pump and a central catheter. Um, and, uh, it's an extremely effective medication. Uh, and this is the seminal study, um, in the New England Journal. 80 patients with severe pulmonary arterial hypertension, or at this case, primary. And, uh, at 12 weeks, there was a significant survival difference. Um, all the patients on a proportional survived eight patients in the conventional therapy, um, died. But as you can imagine, uh, the administration of this medicine can be quite cumbersome. Uh, it's a central line. It's a continuous pump if it stops there. A lot of issues. Um, And so for those who had milder disease, this was pretty significant. Severe therapy. Uh, and then, in the early two thousands, the first oral medicine was approved, both sent in. And then since then, we now have 12 FDA approved therapies for pulmonary arterial hypertension. Uh, they come in oral forms inhaled ivy subcutaneous, and they target this trinity of pathways that I mentioned early on, we have the endothelial receptor antagonists that block and Ethel undies or oral medicines both sent in amber sentence and mass attention and the nitric oxide pathway that results in cyclic GMP. We have, uh, fossil diaries five inhibitors that prevent the breakdown of cyclic GMP sildenafil in Tudela film. We also have the soluble Guangdong Cyclist stimulator Rio Sig. What? That helps convert GTP to cyclic GMP. In the process cycling pathway, we have the actual process annoyed. You propose an ultra processed on island cross, and then we also have the receptor agonist Celexa peg in this pathway. It's important to note that these therapies are only approved for pH Group one, not the other ones, with the exception of Rio Ciguatera for inoperable CTF. So these therapies really are just for this small subgroup. Yeah. Um and so the way these therapies used to be used, particularly for milder disease, is you would give an oral therapy to a patient. You would evaluate them at a year or two years and and see what happens, and then consider adding a second one later on. But it turns out that most of these patients essentially all of them, would progress, and they would require a second therapy. And the question was asked, Well, what if we gave them both at the same time at the beginning? And this was the Ambition trial that was published in 2015, where patients were randomized to tidal flow, which is a fossil diocese five inhibitor versus Amber Centene, which is an e. R a. Versus both of them at the same time. Uh, and what they found was given combination therapy compared to just one resulted in decrease adverse events, things like hospitalization, worsening functional class survival as a composite endpoint. And this is the concept of what's called up front dual oral combination therapy. Um, which now begs the question. Well, if two is better than one, what if we do three instead of two? And this is the Triton trial, which, um is, I think, completed. Um, but it's a delightful, which is a fossil diocese five inhibitor Massey tent in an e. R. A. Plus Celexa peg, which is an oral ip receptor agonists versus these two medicines and placebo and the primary endpoint is looking at pulmonary vascular resistance, so stay tuned. So what's happened to survival Respect with respect to these therapies? This is the original NIH registry. You can see one year survival about 68% 3 year survival of 48%. Pretty dismal. Um, since then, survival rates have improved significantly. Um, you know, upwards 90% 1 year survival in these registries, uh, 75% 3 year survivals. And as you can see what these dates, this is prior to many of the therapies that we have, and especially prior to the concept of combination therapy and triple therapy. So when giving pulmonary soda, there's there's some considerations. The first is not only do they decrease pulmonary vascular resistance, they also decrease systemic vascular resistance, so you must use them cautiously in those who have are hypertensive. Also, it's important that these medicines should not be withdrawn abruptly. If they stopped immediately, you can develop what's called rebound palmeri vessel constriction and pulmonary hypertension. Uh, these medicines need to be gradually weaned the oral medicines and particularly the ivy and sub subcutaneous medicines. Um, this is a question. I asked my fellows all the time. What happens when a pH patient in the ICU receiving continuous I ve proportional loses all I V access. The answer is this You have manure and a fan. Um, the point is, um it's extremely important when starting these therapies that there be a backup plan. So if a patient is receiving these therapies in the ICU, they must have two I V s one for the I V professional one. If that ivy stops working because you don't have time to search for another I v. Additionally, um, patients who are out in the community who have these pumps. Um, they all have my phone number because the second that pump stops working, which doesn't happen frequently. But if it does, uh, they need to be, um, you know, at an emergency room getting that therapy immediately to prevent that from happy. There's also a worsening wiki matching, and you have to be cautious and those who are hypoglycemic, especially those who have intrinsic lung disease. So this is these are your lungs ventilating these alveoli and the blood going by them. If you have, um, an area of the lung that is poorly ventilated, let's say you have fibrosis or mucus? Plug. Uh, this area will become poorly ventilated and hypoxic, and your lungs are smart. Well, vessels constrict this area right here, allowing blood to go to the good area. This is what's known as VQ matching. You're matching the ventilation to profusion. If you now administer systemically administered pulmonary vessel dilator, you now dilate everything and you remove that compensatory mechanism and you now have blood flowing by the poorly ventilated, hypoxic region. And that's known as V Q mismatch. One way to circumvent this problem is to actually administer the medicine through the inhaled route. Uh, and now you are preferentially pulmonary vessel, delaying areas of the lung that are well ventilated. Um, so only these vessels will become dilated. This is why, for example, we use nitric oxide in patients with severe a R. D s. We are trying to improve gas exchanges as such. And then finally, there's an increasing pulmonary capital pressure. Um, and the concern for pulmonary oedema with those who have left sided disease and elevated left atrial pressure. So if we have high pressure on the left side of the heart, um, that means there's high pressure in the pulmonary veins and high pressure in the pulmonary capillaries and assume that there's increased vessel constriction here as well. Uh, if we now give up, um, arepas a dilator, we remove this constriction, more blood flows through here. This results in increased pressure in the pulmonary capillary pulmonary oedema and further increases in left atrial pressure. Which is the last thing you wanna do for these patients. Um, and this has been studied ivy, proportional and systolic Heart failure was stopped early because it increased mortality both sent in an e r a. Resulted in increased chf exacerbations in systolic heart failure. And this is particularly important for the subgroup of patients with left heart disease who have heart failure with preserved ejection fraction. Um, so hefty f, also known as huff puff sometimes, uh, is a great mimic er of pulmonary arterial hypertension. Um, Hef is essentially having heart failure symptoms, um, a preserved EF and evidence of essentially die stock LV dysfunction. And, uh, at least half the patients with heart failure f f f. And this proportion is actually rising. And the risk factors include things like being older female having hypertension, diabetes, coronary artery disease, atrial fibrillation, chronic kidney disease, obesity and COPD. And you know, differentiating have pet from Ph. Really depends on the human dynamics, because with half past the problem is the left atrial pressure with pulmonary arterial hypertension. It's the vascular apathy, the increase in pulmonary vascular resistance. And so the way that we estimate the left atrial pressure is with the Polaroid capillary wedge pressure. We snake this catheter into the pulmonary arterial tree, and we lodge it into a branch of the pulmonary artery and include this vessel. And now, when we include this, there is no flow from here to the left atrium, and therefore we have a column of blood with no flow, which means the pressure here has to equal the pressure there. And that's how we estimate left atrial pressure. And so if the wedge pressure is greater than 15, that's considered post capillary pulmonary hypertension. The pressure. The problem is after the capillary that's consistent with increased left atrial pressure. If it's less than 15, we consider that pre capillary and in the setting of a normal ish cardiac output, that's consistent with an increase in pulmonary vascular resistance. So this is actually a patient I saw a couple weeks ago who was admitted here. She was a 77 year old woman who has a past medical history of hypertension, diabetes, obesity, osa COPD, a fib CD. And she had been undergone a right heart catheterization at another institution because of this, me on exertion. And she had a mean peer pressure. 45. So she has permanent pretension. Her watch pressure is 14. So this is pre capillary. Cardiac output is normal, and her vascular resistance is high greater than three. She was diagnosed, therefore with pulmonary arterial hypertension, and was started on dual upfront oral therapy with Adolfo and Amber scented She then a few weeks later, presented to our hospital with worsening dismay on exertion, hypoglycemia and pulmonary oedema. And so the question is, does this patient actually have pH When you're looking at these risk factors, you kind of raise your eyebrow. And I would argue that she doesn't that she actually has heart failure to preserve the f um causing her pH. But then you ask me, Well, why is the resistance elevated? I thought this was a problem with left atrial pressure, and the answer is that an increase in pulmonary and left sided pressures and left atrial pressure will result in an increase in the pressure in the vein and the pressure in the pulmonary capillary and the pressure here and that increase in pressure will cause endothelial dysfunction, which then causes vessel constriction and remodeling and ultimately, an increase in pulmonary vascular resistance. This is still a problem with the left side of the heart as the underlying ideology as to why this occurred. Additionally, we're like, Okay, fine. But why is the wedge pressure less than 15? Um, this is 14. You just told me that, you know, post capillary has to be greater than 15. This is, you know, 14. And the answer is that a catheterization is a snapshot in time. Um, these are my kids. Um, they are in an airplane. They are being cute. They are behaved. They are being quiet. This is a snapshot in time. And so, um, you know, when you do this, you have to realize that you're doing a catherization. They haven't May have been diaries. They may be calm. They may be sedated, you know, some other things may be going on. Um and that the current, more common state is the following, um, where they may be raving lunatics. Um, in which case the wedge pressure is more than 15, uh, more commonly. And so how would we be able to assess this? One way is to look for clues on the echocardiogram because if you have increased pressure in the left ventricle from, say, heart failure preserved the F this pressure over time will cause concentric L V H. The left side of the heart will will hypertrophy to decrease its wall stress. Additionally, if their increased pressure in the left atrium the left atrium will dilate. And so if you see these signs, then you should kind of think, Well, perhaps this is actually a f f pH. Uh, and giving them Pommery visa dollars will worsen the situation. And in this patient that we saw recently, you know, her echocardiogram did show concentric L V H and a severely dilated left atrium. Um, and in the setting of these risk factors, kind of screaming f f ph. Uh, so it's not surprising that she, um you know, felt worse with this. So, in summary, um, remember this equation uh, and determines, Uh, kind of pulmonary human dynamics. That pulmonary arterial hypertension is not the same as pulmonary hypertension. Pulmonary hypertension is a mean pay pressure greater than 20. Pulmonary arterial hypertension is a subset of Ph. A very specific vascular apathy. Uh, you should consider that very specific vascular apathy in high risk populations. Specifically those with, say, scleroderma, congenital heart disease, um, portal hypertension. Be cognizant of the vicious cycle of RV failure A to prevent it from ever occurring. And once it occurs to know how to stop it. Um, Palmeri visa violators are effective. Treatments For who? Group one pH. That's what they are approved for. Um, and always suspect as a cause of pH when you have the appropriate risk factors and echocardiogram thick findings, early referral to a permanent retention program is essential. Um, if you have any questions, email me. Um, thank you. That's that. The most mhm shit it is. Well, it allowed would tolerate better. Yeah, we're so perfect. A lot of Yeah. Great. The So Is there any from the Bruce? Sure. Yeah, Yeah, that So working over. Did you? Yeah. I prepared for that question, actually. Um, right. Um I I don't know, is the first answer. Um, but, uh, you know, again, it's it's unclear. You know, there are clearly many people that live at altitude and not all of them, um, you know, have this vascular apathy and NPH. And, uh, the thought is that this is kind of a two hit hypothesis where, um, various injuries increase your probability of the resulting in this in this problem, whether it be genetic or whether it be environmental diseases like scarred Irma portal, hypertension or drugs. Uh, so some people are predisposed to it for whatever reason, but there clearly is a higher incidence in those populations and particularly those who go to altitude. Um, so when we, you know, assess for patients who have Ph um, you know, I always ask their history and, you know, specifically have they lived at altitude for a while? Because that is a one of the hits that they can have with respect to the development with respect to those two populations. I don't know. Yeah, thanks. Thank you very much. Okay,
