Adil Shujaat, MD, discusses pulmonary hypertension in this Grand Rounds presentation to Mount Sinai Morningside and Mount Sinai West.
good morning. Welcome to Grand Rows. It's really lovely to have all of you here, and we're delighted to have Dr Adel Como with us today. He is an associate professor of medicine and department medicine, the Icahn School of Medicine at Mount Sinai, and he is the director of the pulmonary inpatient pulmonary service here at Mount Sinai West. You know, I think organizations a sign of their health is their capacity to certainly retain excellence and find paths for faculty and trainees to remain an institution for a long time and recognizing excellence and people's capacity to do more and more. It's really an indication, I think, over time of an organization's fundamental ability to live in a way that is fostering of creativity and excellence and personal health, and certainly professional development as well. And it's also important for all of us, because we're all continually in the mode of recruiting. We're always recruiting, and that's one of the hallmarks of my career. Took me a while to kind of wake up to the fact that no matter what you're doing in medicine, you're always thinking about how can we invite others to join us or how can we hold on to people that we recognize as being just that high potential people that we want to remain in the family? And in that context, it's a challenge for all of us to maintain. Our networks are professional networks, and they were holding on to people. And one of the hallmarks. I think of Hassan coolies career as he did just that. Hasan, throughout his career, is always maintained a robust network, and it was in this context it was so delightful to know that Hasan had maintained contact with Dr Schuchat and was inviting him back to join us, and that's because he trained with us. He did his residency in our internal medicine program, Dr Schuchat, and then completed his pulmonary critical care and sleep medicine fellowship with us as well. Subsequently, he was in Florida at the University of Florida, Florida, Jacksonville and then at the University of Buffalo. And again we were so delighted to bring him back into the family because of everything that he is. His areas of interests have been hypertension, pulmonary hypertension, vascular diseases of the lungs as well as pleural diseases, and one of the things was fun for me to remind myself about reviewing his CV is the particular focus he's had on limiting risk limiting cost, asking hard questions about who needs what, studying why. So, for example, who needs a spiral CT when they're in the emergency room? They think they might have a pulmonary endless. Who's the right candidate for Thermal Isis? And who isn't? And why is it important for us to be thinking in those ways as we move forward and caring for our patients here at Mount Sinai West? Dr. Shuja, It's already done wonderful work and developing our plural program here and also being a champion for our perp program. For anyone who doesn't know what part is, it's a pulmonary endless response team, and it's a way to bring to bear excellence and expertise in the context of patients when they are acutely diagnosed with pulmonary embolism and make sure they're getting the care that they need a deal. It's really wonderful to have you back. It's wonderful to have you here and welcome Thank you for the generous introduction. Good morning, everybody. So the history of medicine is fascinating and the history of circulation is no exception. I have been on the feast. The Syrian physician in the 13th century was the first who described accurately the pulmonary circulation. Until then, Galen's belief had held for over, uh, millennium, and this slide shows on the left hand side what his beliefs were and on the right hand side, what our current understanding of the cardiovascular system is. He believed that the concoction from food was transported to the liver, where there was imbued with the natural spirit and blood was formed, and it was then transported to the right ventricle, which pumped it to nourish their lives and through pores in the inter ventricular septum. It was passed into the left ventricle, where it mixed with air that was inhaled, and that vital spirit was distributed to the body, and some of it went to the brain where the animal spirit was then distributed through hollow nerves to the whole body. Now, this idea of there being invisible pores was important to perpetuate this understanding. But even in the office was the first to describe that blood had to go through the lungs and the lungs played a more important role. Please excuse my attempt at our point anatomically speaking, the heart is situated between the two lungs, but physiologically speaking, the lungs are between the two sides of the heart and the right side of the heart pumps blood into the pulmonary arteries, into the lungs and from the lungs. Blood is drained, the other pulmonary veins into the left side of the heart, which is then going too complex to the entire body. Now, if I were to indulge you in a little bit of math, there has extrapolated from OEMs law see Transformer Gradient of blood flow across the lungs is equal to the cardiac output off the right ventricle through the lines flow and resistance offered by the pulmonary vasculature. And this gradient is the difference between the main coronary artery pressure and the left heart feeling pressure, whether it's measured as a wedge pressure or actual LB and diastolic pressure. And if you were to rearrange the equation, it becomes easy to understand that men pulled me artery pressure is the product of cardiac output from ambassador existence added to the wedge pressure, and this pressure may go up when any one or more of these three components is affected. Mhm path of physiologically speaking, starting from the left side of the heart and working our way more approximately. We have post capital pulled me hypertension, the left heart. It's muscular because it's a pump that is going to pump blood to the entire body, and it has valves. The pump may be weak, or it may be too stiff to accommodate enough blood to pump in that blood, known respectively, as heart failure with reduced and preserved ejection fractions. And the valves may be affected because they're too narrow or they're too incompetent. So a rise and pushed me archery wedge pressure is found in diseases of the left side of the heart. More approximately, you have the respiratory system, which is made up of the evil of the ESA COPD I'll D. N. H. S. And it's not the COPD effects of calamine. I'll be the left line. It's just consensually and helpful to remember more. Approximately, you have the pulmonary arteries where plots that may be residual and become organized can reduce the available surface area for blood flow and result in the condition called CTF. Chronic pulmonary hypertension or the pulmonary arteries themselves can become diseased, and the vessels become narrowed or obliterated, and that entity is called pulmonary arterial hypertension. Mhm and all of these affect the pulmonary vascular resistance. And last of all, if there is a condition that results in an increase in cardiac output, like anemia or morbid obesity or left to right cardiac or extra cardiac shunt that will also result in an increase in the formulary. Pressure pulled New app. Attention mhm. So to put it. And two classifications for me hypertension as defined by right heart catheterization at rest as a mean peer pressure of 25 or greater. And if the wedge pressure happens to be 15 or less, it is pre capillary, and if it is greater than 15, it's Post cavalry, and the World Health Organization classifies these two even dynamic categories into groups. Group one is pulled me arterial hypotension. Group four is CTF. Group three is putting hypertension secondary to lung disease and sleep disordered breathing group to a secondary to left heart disease, and Group Five comprises forming hypertension with unclear and multifactorial mechanisms. So how prevalent are these different kinds of formally hypertension? I have to say that the most common cause of pulmonary hypertension is left heart disease, the second most common causes left heart disease, and the third most common cause is left. Heart disease makes up 80% of the causes of called me hypertension. PH, for which there is a trillion dollar pharmaceutical industry, actually constitutes only 2.3% of cases of hypertension. CTF is even rare with 0.6%. So what is pulmonary arterial hypertension? It's an arterial Kathy, and it develops in those with risk factors or associated conditions or genetic predisposition. Associated risk factors and conditions. Maybe connective tissue disease HIV for the hypertension, drugs and toxins and the most commonly known genetic mutation is the BNP are two mutation. This results in a vascular injury, and there's industrial dysfunction, resulting in an imbalance of phase of active mediators where there is an abundance of basic constrictors. And it's not just as a constriction, but also proliferation. So you can see that parts of physiologically the smooth muscle undergoes hypertrophy and the infamous starts proliferating. And as the disease progresses, there are vessels that become narrower and some are obliterated, and at places you must see plexus formed lesions. These are thought to be possibly from from for me and as Massie's and the mediators that play the most important role are nitric oxide, prostaglandins and tended to lean. Psychiatric oxide is one of the most powerful ways of dictators. So is crossed. The cycling and under 13 is one of the most powerful basic constrictors and proliferators. So how common is pulling the arterial hypertension? It is a rare disease, and its prevalence is 15 million adults, and the idiot plastic kind, formerly known as primary pulmonary hypertension, has seen approximately six per million adults. Idiopathic charitable and drug induced pH constitute 50% of Ph and connective tissue disease, mainly systemic sclerosis, is the most common Associated pH and the prevalence of pH in the associated conditions. It's 5 to 12% in systemic sclerosis, 1 to 5% in four portal hypertension and 0.46% in HIV. There are certain drugs and toxins. Some have a closer association, others possible association and the diet suppressants our most well described and the original NIH registry back in the eighties, at a mini epidemic of cases that made up that registry. So how does a patient with Ph present most of them are young, they're 45 to 55 years of age, and it affects predominantly women. The ratio 3 to 1. And there are non specific symptoms that can be seen from any cardiopulmonary disease. Disney in exertion and Galadima, dry cough and exercise induced nausea, sometimes vomiting when there's a bad congestion. Yeah, because blood cannot be forced forward into the lungs so it backs up in the liver. And there are some unusual symptoms hoarseness, wheezes and Gina that are from mechanical complications when the coronary artery becomes humongous and it stretches the recurrent laryngeal nerve and they say a picture's worth 1000 words. Let's look at this CT scan and coronary angiography pictures explaining how you can have angina from compression of the left main coronary artery by a humongous pulled the artery that is more than four centimeters and a CT scan so you can see the left man coming out of the root of the older, and this is the artery pressing against it. This is how narrow it is on coronary angiography, and this is after it has been standard, and there may be symptoms of underlying disease, crest calcium, nurses, radars and self insure This motility scared actively and educations. What are the signs? Have put me hypertension, right? Heart failure? Sure, everybody is familiar with it. Right? Heart, You loud p two and s three gallop That's right. Sided apparent systolic murmur from trackers Petrie Gourgeon in extreme cases, an early diastolic murmur from regurgitation, pulmonary valve, jugular, venous, distention, distention, maglia sides and oedema. And then there are signs of an underlying cause. Crest or cirrhosis and clubbing is common to cirrhosis. And I'm anger except one patients yellow and the other blue wh group to pull me hypertension, secondary left heart disease May Brazil from systolic or diastolic dysfunction or from valvular heart disease. And it is extremely common. Most of the patients eventually develop pulmonary hypertension, and it may be seen in 100% of patients with mitral valve disease when left untreated. So I'm going to return to this equation and refer to it again and again. When left untreated. The elevated left heart filling pressures results in an increased wage pressure that will cause a passive covering Venus hypertension. But eventually the end ethereal dysfunction together with unknown genetic risk factors or environmental risk factors. or non cardiac risk factors for more abilities like COPD os A i L d chronic pes in front of kidney disease adds insult to injury, and the vessels started undergoing a vascular remodeling and the thermodynamic profile changes from an isolated post capital. Very passive Venus hypertension to combine post and pre cap reacted pulmonary arterial hypertension like profile, where the pulmonary vascular resistance is also increased more than what is normal. Consider three with units as the cut off. Group three is pulmonary hypertension, secondary to Lyme disease and hypoxia, and most commonly, these are COPD, Io, the USA and Obesity hyperventilation syndrome. How common is this? Very calm. PH is common in severe COPD, and I yelled, but it is mild. Severe pH is uncalled on. The other hand, in ohms pH may be severe, but it's partly from the high card. A gap was required to meet the demands of adequate tissue. Here is, uh, diagram explaining the That's the physiology behind pulmonary hypertension. COPD. So hyper inflation results in order people an increase in the plural and extra cardiac pressures which transmitted to the pulmonary arteries and veins. And there is a direct increase in those pressures. Moreover, hypoxic primary basic constriction, vascular remodeling policy, Thenia, destruction of vascular bed and compression of the Alberta vessels will result directly in increased pulmonary vascular resistance. Yeah, wh Group four seater chronic from Metabolic pulled me hypertension and other pulmonary artery obstructions, which are weird and just sarcoma and arthritis, to name a few. And how common is this? 3.2 per million adults, and it seemed in as many as 4% of cases after an acute PE. And that's as much as you will see after two years, and it plateaus subsequently and their associated conditions. 32% of patients with C to overthrow of Ophelia and 3% of them have a history of having had their spleen removed. Group five is ordinary hypertension with unclear or multifactorial mechanisms both, and they may include pathological disorders, systemic disorders or other conditions. And sickle cell, which is a common hemolytic anemia, is included here. So our model proliferated disorders to ask. The most commonly encountered Group five for my hypertension is sarcoidosis. Former tumor From what? My grand job with the and chronic dialysis kidney disease with palaces or without Dallas, and they're also multi factory and just to show how sarcoidosis can cause pulling hypertension can result in actual destruction of the primary vascular bed cause. Hypoxic basic construction, they told me. Arteries can be compressed by and large notes or media town necrosis. There is a coronary vascular phenotype. Patients with chocolate doses are at high risk for me embolism. Liver involvement may result in portal hypertension and that causing for only hypertension. My accordion involvement because left our dysfunction and then patients with sarcoidosis are also at high risk of obstructive sleep apnea. So trying to figure out which of these causes is playing a role in treating it is the way to go in soccer doses associated with hypertension, now putting it all together. So you have a person in whom symptoms and science and history suggested putting hypertension. The next step is an echocardiogram, and they will show if they have put hypertension or not. And if they have put me hypertension than considering heart and lung diseases of the common causes, you look into confirming that possibility by doing e k, g, k, f, d and L C O chest X ray and, if necessary, a high resolution CT scan. So echocardiogram will be helpful in telling you if there is heart failure with a reduced ejection fraction or valvular disease, it's more difficult to grasp the concept of preserved ejection fraction. And yet having the heart failure. Moreover, Echo is not foolproof. And there are variables that affect measurement of the This is dollar peer pressure. Everybody has a certain degree of track has been regurgitation, and that's what is examined to measure the gradient across the track us about. And that gradient across the track of spit valve is equal to four, multiplied by the square of PTR jet velocity and rearranging. This equation shows that this, together with the right engine pressure, gives us the RV systolic pressure and provided there's no RV outflow tract obstruction. It approximates the systolic pressure, and a cut off of 40 defines pH by echo. So how do you measure the RFP? Depends on what method you use, whether you're looking at how much the IBC collapses or not with respiration, or you actually measure the J B P, or if there is a central gonna sign in place. And if the TR jet velocity is not accurately measured, and that's going to be squared and then multiplied by four. You can see how one person may go from having Ph Do not having pH and right heart cath or vice versa. Yeah, despite that it has a modest sensitivity of 83% based on a meta analysis of studies looking at the diagnostic accuracy of trans thoracic echocardiography. What about C. T. Scott, which have become so common on a CT scan? Looking at the diameter of the pulmonary artery and comparing it to the diameter of the order can tell you if a person has a high probability of pulmonary hypertension and a ratio greater than one indicates for many hypertension, with the sensitivity of 74% and specificity of 83%. And this is, uh, my analysis that I did with one of the residents, Natasha Guard, who's going on to Dr Fellowship here and presenting of the 80 s in May. So the two appeared to be complementary. And if they're complementary, what is the diagnostic accuracy of the two combined? If we look at just the TR jet velocity, not looking at the systolic pressure and making it more inaccurate and the ratio of the pulmonary artery to order being greater than one. Then the sensitivity approaches 98% and makes for an excellent screening test to exclude formally hypertension, where your probability is intermediate, too low to begin with. So this summarizes the diagnostic accuracy ensures the two tests are complementary, and the combination of two can virtually exclude for me hypertension with those and whom the probability is learned to enter me. So how does wh Group one pH compared to group to heart failure from left side their clinical features? Radiologic features E K G and Transkaryotic Echo, so there may be history of having used an oxygen's. They may have an associated condition, whereas patients with left heart disease are older. Suffer from metabolic syndrome may have coronary disease a faith and contain a consultant and nocturnal episodes. And on exercise, there may be an unusually high blood pressure. Just X ray will show that the central part of the pulmonary arteries are enlarged and peripherally there pruned because they're narrowing literary, whereas in left heart disease will secretly be lines demons through the fusion and large left atrium, explained the main branch i e. K G consists of predominantly right sided findings in pH, whereas it's freedom in that side of findings in left heart disease. So you have a chest X right here, showing homemade artery next to the Broncos intermediates and larger than its diameter and peripherally. There are no vascular markings. And on a lateral, the RV is touching the sternum all the way up. The E K G will show right axis deviation, right picture to the adventure fee and signs of right heart strain and people in Ali. Echocardiography is the most common test to use to distinguish the two, based on the probability that you've already developed using history and exam. So this is pre cavalry and post cavalry forming hypertension. So you see the right side of chambers are larger than the left, and here it's the other way around. Then the left ventricle on cross section is D shaped. The septum is pushed into it as opposed to the left side, retaining its circular, wind shaped appearance and left heart disease. IBC. Maybe dilated and fixed or dilated and not move much with respiration. On the other hand, it's easily collapsible and left heart disease and you have the ratio of the mitral flow Velocity E and the early mitral annular tissue, Doppler velocity E prime as an echocardiogram, traffic equivalent of your left heart feeling pressure and the magic number happens to be 15. So an E to e prime ratio greater than 15 on an echo is saying the same thing as somebody's pull me up. Too much pressure is greater than 15 or the NBN castle pressure is greater than 15. So how does wh Group one called me arterial hypertension compared to put me hypertension from lung diseases and hypoxia, High resolution CT will show that there are characteristic airway abnormalities and of ranking no abnormalities. PFD s will show that lung function is more than modestly affected. F 50 one's less than 60% in COPD, and FBC is less than 70% in I P F. On the other hand, a person with updo idea of may also have pulmonary hypertension of the one kind, which maybe attributed to the lung disease itself. But if their lung function is mildly affected, then the lung function is not responsible for that artery apathy. So an F 51 of greater than 60% of the patients COPD and pulled me hypertension means it's not from the COPD likewise, and i pf when it's FBC is more than 70%. That's not the case. The pH, not from the lung disease cardiopulmonary exercise test, will refine this, and there will be featured result and exhausted circulatory reserve in case of pH, as opposed to patients who have true pulled me hypertension from and I pop see it where they will be featured. Soften exhausted, then to enjoy the results. How does wh Group one compared to Group four, which is chronic zone by body pulling hypertension on the CT scan dilatation of bronchial arteries, which provide collateral blood flow, bypassing the narrowed obstructive coronary arteries whether they be from Ph or CTF is very common. 73% of such cases as opposed to much less commonly seen th and a combination of mosaic attenuation and variation in size, segment of programming heartbeats again, Common and Sita. But let's come in. Th sambas itself is usually central Luminal webs and bands and central and peripheral pulmonary arteries and see tough, whereas rarely there may be an opposition that on my scene and pull me arteries when they become so huge and blood flowed through them is so sluggish that a layer of thrombosis develops. Here are seriously this kind from a case showing the strongest that has become organized and part of the world with the right form, the artery and here on subsequent section and the left one is plugged up with a large cloth, and here, lower down, you can make out present of the organized clock, making the vessel itself much narrower than it originally was. And coincidentally, if you pay attention to the heart, you can make out. The right atrium is the size of the patient's head, and the RV is pushing the set them into the L V, which is squished, So putting it all together. If you have made a diagnosis of left heart disease or lung disease, then the next step is is told me. I have a tendency. There is the army dysfunction. If there isn't any, then treat the underlying disease. If there is severe pulled me hypertension and RV dysfunction, even if the person has heart disease or lung disease, then you should refer them to a pH. Experts set on The other hand, if a person has neither left heart disease or lung disease, then you should do a VQ scan and look for the possibility of seeing. And if there are ventilation profusion defects showing that there is CTF, then the next step would be to do a CT or MRI angiography. On the other hand, if there are no plots on VQ scan and you've screamed out the possibility of CTF, then pH is likely and you should do specific diagnostic tests, which would be connective tissue disease. Serology is hepatitis B and C psychologies HIV and in some cases, the NPR, too. Mutation testing. And okay, As you see TEF, you should consider it from a video work up. Cardiac catheterization History was made here in New York City in Bellevue, like Columbia's first division back in the forties, when the Frenchman Andrea Constand and the American Dickinson Richards pioneered cardiac catheterization and refined the technique and were awarded the Nobel Prize in medicine. When do you perform a right heart catheterization, N. P H and C T f. To confirm the diagnosis to guide treatment and th which will include best reactivity testing and informing hypertension secondary left heart or lung disease. You should consider it if the heart or lung transplant is being considered, and you should also consider it if pH just sit there or are. The dysfunction is seen on echocardiography and the right heart catheterization allows you to measure not only the pressures and the chambers and wage pressure, and they will be invested. All the pressure may be required sometimes, but also the cardiac output more accurate and pulmonary vascular resistance, which defines formally Arcuri. Apathy can only be calculated if you have these parameters mean peer pressure minus two. Put me off your blood pressure. That radiant, divided by the cardiac output and oxy hemoglobin saturation will tell you if there is a step up when the saturation goes up when you're entering the right atrium because there is an SD and blood coming from the website or when you're entering PRB and there's a BSD and bloods entering from the left to the right, and there is a step up in the saturation. What is? There's a reactivity testing This testing is done to determine who will benefit from calcium channel blockers so that the insurance companies are spared having to prescribe and cover the extremely expensive pH specific medicines that I will talk about. It's in any Catholic heritable and drug or toxin and use pH that this testing should be done and only 10% of patients with such pH. Responders and the honeymoon period is over in 1 to 2 years, so they're not going to last that long. A positive response is defined by a decrease in mean peer pressure by 10 or more to 40 of us with an increase or unchanged cardiac up. And the most commonly used agent is inhaled nitric oxide 10 to 20 parts per million for a five minute period. That's it. I be proportional. Lowland is an alternative. And sometimes, when the diagnosis of heart failure with preserved ejection fraction is in doubt, so provocative testing may be required. Where the wedge pressure maybe on the fence, maybe it's 16. Maybe it's 14 and they're in their sixties, the metabolic syndrome and you're wondering if they have left heart disease or true pH. And you mean depending on what the pretest probability is, resort to actually exercising them, giving them a volume challenge or nitric oxide and seeing what happens to the wage pressure. If that remains Hi are Horsens, then it's heart failure. On the other hand, if you have a patient is also hypertensive and you give them nitroglycerin or metric aside, and there wedge pressure comes down and it brings down the pressure and PBR heart failure with preserved ejection fraction. So the right heart catheterization is important to try to accurately determine what exactly is the underlying human dynamic profile. So when do you perform a left heart catheterization coronary angiography? Not just the right heart catheterization when you're interested in measuring the GDP or if there are symptoms of angina and the risk factors for coronary disease. And if you're planning on Wolverine from endarterectomy for CTF or a lung transplantation. So pH is formally hypertension when, uh, wedge pressure of 15 or less and no other cause of pulling hypertension. No cardiac disease, no respiratory disease, no blood clots, essentially a diagnosis of exclusion. And what is its natural course? Progressive till it kills the patient, PVR will continue to rise Mm, and the reactor pressure will increase. There will come a time when the patient starts becoming D compensated and the cardiac output starts falling when the cardiac output starts folding, then the pulmonary artery pressure will also start falling. So do not be misled by thinking that if serial echocardiography is showing, told me acupressure is improving. You have to treat the patient, not the number. Once a diagnosis of primary arterial hypertension is made, we risk stratify patients into low, intermediate or high risk of death. 30 Compensation based on progression of symptoms, including sick API signs of right heart failure. The World Health Organization Functional class six minute walk distance cardiopulmonary exercise test being peptide transfer as an echo where with the other cardiac MRI and right heart classifier ization to decide on how to treat them. This is the simplest way of describing the W H O functional class 1234 Symptoms with extraordinary activity. Military activity less than ordinary activity and symptoms addressing What are the symptoms? Definitely have fatigue. Chest pain on the so what is the treatment approaching pH. Their general measures supportive therapy specific therapy and when all else fails. Lung transplantation. Yeah, the most important one in women is too while becoming pregnant, because the increased blood volume associated with pregnancy, it will not be handled by the right side of the heart immunization. Any infection in sexist with it's increased metabolic demands cannot be met by heart, which is limited, and it's reserved by putting health attention. And these are young patients who may have their life short when given such a diagnosis. So a lot of psychosocial support is required, and some of them may require oxygen, intravenous pumps and medication. And so a lot of support is needed in that regard. We should tell them to just stop exercising because they pass out from little party up. But but there should be supervised exercise training, and when they travel by air in flight, oxygen should be provided to those with modest hypoxia. And if elective surgeries required an epidural is preferred to general anesthesia. Supportive therapy comprises oxygen in those who are modestly hypoxic, diabetics in those with right heart failure and hyper Slovenia anti coagulation. In those with idiopathic charitable and drag, the toxin induced pH and those who are on intravenous flowing so that the catheter through which the medicine is running lot thought correction of anemia or iron status of both, and treatment of any abnormal, tired function can sleep out yet. Mm pH specific therapy. Robin Bars spent her career at Columbia, where she was professor emeritus, and she possibly a few years ago and was a pioneer in the field of drug therapy. And there's a lead author on the 1995 any GM publication of the first randomized controlled trial of what was the only medicine available back then. Flow then and for the next several years, we've come a long way from 1995 to now, and there is an abundance of medicines. Following the first trial, the first oral medicine became available in 2000 and 1% in and then a decade following floor, Land said in a field was found to work informing hypertension. Who knew that A D and Ph had something in common? The medicine, of course, had to be marketed under a different name. Instead of Viagra, it was labeled as Riboletta. These are three different pathways that are implicated in the development of portal hypertension. You have the end of the lien *** God's process cycling, and this is where the different classes of medicines, what the E. R. A and with 13 receptor antagonist and the sGC simulator and PDE five inhibitors and crossed recycling or cross recycling agonists. And these are the medicines percent in and resenting massive Tintin so beneficial. And to the L. A. Phil, we're seeing what and among the process, Sakhalin's and their analog people posting on is the most well known. Either process is inhaled. Christina is available in a variety of forms. Whether you want to inject it into the veins, the skin or inhale it or give it orally. It's just not available as an enema that would work back then. CPR was done that way, but I'm not talking about that. Celexa Park is the newest medicine, so let's talk about these different medicines briefly in one slide. That's all I'm going to give them. Calcium channel blockers in high doses. I mean constipated doses. Nifedipine deltas. Um, can you imagine 7 20 mg of 2000? You start low and you go up slow, and please don't use it if somebody's already in Hartford. Trump's Anderson receptor antagonists are highly terrible genic, and patients are advised to exercise two forms of contraception. Both sentence can cause abnormal LFTs, a monthly LFTs are required and resenting because the Dema yes, that's like when you're watching out on television and tell your policy statement cause indigestion. One. I think, in the first place massive Kenton. Because anemia nitric oxide pathway your P d 51 rarely can cause oneness can come in and use. The nitrates can cause a profound hypertension, so you've got to stop those for one. Another reason. They were also taking process, citing analog flow. Land has an extremely short half life, only 3 to 5 minutes, and it's stable at room temperature for only eight hours. Now there is thank God, a room temperature stable formulation available. Their side effects are well known. Flushing, joking, headache, diarrhea, local pain and those who have intravenous continuous infusion upon malfunction, maybe federal by causing rebound, forming hypertension. And, of course, there are always risks of Catholic related bloodstream infection and thrombosis. Anybody who has a Catherine list, randomized controlled trials and former arterial hypertension have evolved in the two decades since the study of flowed at, and the endpoint has improved from the surrogate six minute walk distance to now composite of clinical outcomes, and there are more and more patients who are already background therapy, and the number of pH expert centers has gone up from 12 to more than 16. The United States alone and there have been a number of medicines that have become available nowadays. So these are the original, short lived trials that helped all of these medicines get FDA approved because they showed an improvement in six minute walk distance. And an improvement in 61 distance may not help patients live longer, it turns out, so more recent trials have been larger, longer and necessary because these drugs also had to find a nation market. So what better way of selling a drug than saying we actually save lives? So what are the different outcomes that are used in the most recent morbidity and mortality trials? There may be worsening pH based on worsening six men walk distance, worsening symptoms, hospitalization or the need to start intravenous except you across the cycle monologues, lung transplantation or its bridge balloon. It will set pasta me and, of course, all cause death. So whether it's Surfin Griffin or ambition, any of these three child's they all have more or less the same composite endpoint and you'll see the hazard ratio is showing a 50 to almost 50% reduction in the event rate. Here is Sarah for ensuring mass attendance at the high dose compared to placebo over the course of 36 months. Three years. And here is Griffin showing oral Celexa tag compared to placebo, with a hazard ratio showing 40% reduction. And then you have ambition, a combination of every sentence and to Delafield showing a 50% reduction, too. But when drugs failed, what should we do? Lime transplantation. This is James Harden nature of surgery at the University of Mississippi Medical Center, who in the sixties made history by performing the first successful lung transplant. The patient lived 18 years. The event was overshadowed by the death of civil rights activists on the same day would come in with the gunshot wound in the over next door. But next year, history was made when he transplanted it. Chimpanzees hardened for human, so non transplantation took another 20 years to be refined and become a safe enough procedure. And you really transplant an organ where everything you in hell is going to enter and then you'll be on immune suppressants. It's been tough, right? Fewer and fewer patients now undergo lung transplantation for pH because of the availability of so many drugs. And it's the lungs that need to be transplanted, not the heart, because the disease is in the blood vessels in the alarms. Once the lines are transplanted, the plumbing vascular resistance returns normal. The RV starts undergoing reversal of the arbitral fee. It's no longer dilated and goes back to working well. So this is the treatment algorithm in pH. So pH is confirmed by Expert Center. There is an acute busy reactivity testing done in those who require it. And if there is a reactive calcium channel, blockers have started those who are not, depending on the risk profile. As I discussed taking all those variables into account. If it's low intermediate, you can start with one or two or medicines, and if they have a high risk of death of the compensation, then you start with the combination that includes intravenous medicines. If the response remains inadequate, inadequate means that you're still unable to achieve or maintain a low risk profile. Then you should go on to double or triple sequential combination. And if that fails, then you should consider lung transplantation. We should consider that at an earlier stage to start listing the patient. Now a few slides about the remaining period. So we hypertension, secondary left heart disease or Lyme disease. The saying is. Always treat the heart or treat the locks so you have to optimize treatment of the underlying disease. Optimize volume stairs with diuretics in case of lung diseases or wages. Optimized gas, exchange with oxygen or, if necessary, noninvasive ventilation and screen for other causes of portal hypertension. And treat that and consider right heart catheterization. If you're planning on transplanting the heart of the lungs or if there is severe pH or are the destruction of both and if there is, then you should refer those to a P H expert. You should avoid P a specific therapy and those with less severe th Why? Because in left heart disease you will be literally opening the floodgates. So here are diagram showing the right and the left heart and series with the left atrium transmitting pressure into the lungs of the arteries. And this is the compliance curve for the left atrium. As the L G becomes stiffer and the L A becomes large and stiffer. Pressure is transmitted the cavalry's and that's transmitted into the prison RV. So if you want to give nitric oxide and bring down the after load. And on the other hand, if you were to give an electric oxide for me, aren't you hypertension specific therapy? Then it open the plumbing arteries. More blood will flow forward, but the bottleneck is here in the left heart and double flat the locks. Yeah, this is an implantable pressure monitor. Cardio memes that you can see is barely over a centimeter in length and is placed in one or the other pulmonary artery. And it allows the poor artery pressure to be monitored by the cardiologist and guiding the patients. Therapy to the pressure has resulted in a 50% reduction in hospitalizations for left heart failure. This was published in Lancet, and the champion investigators have subsequently published follow up longer studies showing consistent benefit now in line diseases, ventilation, profusion, mismatch, which may be worsened. So here is a to Alberta's model pull me arteries, refusing them and put remains training them. If the longest disease, then the artery, supplying that part of the lung, undergo a hypoxic basic construction as a compensation mechanism to divert the better way to the normal parts of the lung. And if you give a visit, dilator, undo the hypoxic, revisit constriction, making blood flow through parts of the line that are disease and not picking up oxygen, so it makes the hypoxia worse. On the other hand, if you were to introduce and inhale, pull me arterial hypertension specific medicine, then it will actually go into the better part of the lung. Open up these arteries more not affect the other parts of the lungs or their adjacent blood vessels, and you could improve not only the pulmonary vascular resistance, but also the gas exchange and inhaled. Nitric oxide is available in hospitals as these large portable but impractical to use every day as an outpatient cylinders this in a pulse device barely £2.5 and in phase three trials at the moment to see if this, together with the use of oxygen, can beyond improving pulmonary hypertension, improve other parameters, functional capacity and more to come later as those trials evolve so and put me hypertension secondary to COPD, the approaches to contract hyperinflation from rivers, a constriction from ambassador remodeling and policy. Athenians. Hyperinflation is best contracted by pharmacological and volume reduction. You could have bronchus copy or surgical, likable and reduction. Also, oxygen is the strongest as a dilator. For these patients, the bottom is required when they are policy TV and PS specific therapy. Rarely when fully hypertension and sit there before we go on to become trigger happy about prescribing medicine. Noninvasive ventilation, even when they put me hypertension is as severe as a mean peer. Pressure 49 used with an iPad to CPAP of 21 or five after three months, can result in beautiful reduction in the mean peer pressure to 31 with an improvement in six minute walk distance from 303 to 384 so in warrants. So if you have COPD patients or HS patients with hyper cap me and put me help attention, even if it's a there, this is the way to treat it when everything else has failed or you treated it to the best of your abilities, and the person still has severe pulled me hypertension and you call it pulmonary hypertension out of proportion to left heart disease or COPD or I'll D than do these medicines have a role, so we use them on compassionate grounds. It's non FDA approved indication there's one pilot study in heart failure with preserved ejection fraction of 44 patients from Italy, where it showed significant improvement in public human dynamics and quality of life with the NFL. Mhm n c o P d. We didn't my analysis of sand in my seven randomized trial that showed a significant improvement and mean peer pressure in six minute walk distance. But the sample size, even for mental analysis, was too small to show an effect on Cardiac Index and PBR. There were no adverse effects because these patients have severe pH. So it's not just COPD causing pH. They actually have a four million bacteriology, and I'll be there is American Al Icis that one of the residents will be presented at the 80 s of 200 patients, 50% of whom had I PF showed significant improvement and mean peer pressure cardigan mix and PVR, but not six minute walk distance again. There were no adverse effects and gas exchange in these patients with severe pH. The last of all pulled me hypertension. The virtually curable Nina Braunwald is credited as having performed the first successful pulmonary thrombosis and our trek to me at UC San Diego. Yes, and for those of you who are cardiologists or becoming cardiologist, Eugene Braunwald is her husband. Um She moved to Boston to Harvard, and her colleagues carried out throwing our pregnancies, and to this day is the world's most renowned center. Having performed the largest number of reasonable and our curriculums car, they put me bypass. Do not me and these are called out you're cured. But not everybody is lucky. There are patients who are inoperable because the disease is too distant, and there are those in whom, even after moving the approximate cloths, there is residual disease. So beyond lifelong anti calculation, the treatment algorithm requires assessment of operability by multidisciplinary CTF team. If it's technically operable and the risk benefit ratio is acceptable, go ahead with it. If not, then you have to use pH specific therapy, and the only one approved by the F. D. A is really big wad, which the pharmaceutical industry needed a niche in the market to sell their drugs. If they're persistent symptoms of what we have attention despite and attracted me. Then again, pH specific therapy if the patient is technically not operable. P a specific therapy balloon pulled me. Angioplasty is rarely performed in the U. S. It's a well known procedure in Japan and last of all lung transplantation. If everything else fails, so international treatment consists of balloon atrial, SEPTA asked me, punctured the atrium, creating a shunned So the right side of the heart dumps its blood into the left side so that the Carnegie output is preserved, even if it at the expense of hypoxia. Nobody died of that poxy tell it was dropping. That's it. ECMO right ventricular assist device. And for those in whom it's not urgently needed, they can proceed onto lung transplantation or hardline transplantation. Screening for pulmonary hypertension is an important part of medicine, especially in those disorders and which there is a high probability of this being found eventually, because they may be patients may be limited by other symptoms in their country capacity. Systemic sclerosis is one of the most important. If you're considering northern transplantation, they happen following an acute PE after three months and those who have the NPR two mutation, first degree relatives of patients with heritable forming arterial hypertension. And with this last light, I conclude my talk. Thank you for letting me go over time. We started a little later than usual. I'm happy way to some of the questions you want out squeezing conducted rod. Sorry. Okay, well, thanks for a great part, I It's kind of delighted in seeing some of your early slides when he talked about findings like he clouding of the retro channel Clear space and what have you. And I'm curious if you could comment upon the sensitivity of those findings and separate from that in terms of screening for patients, when you think it's appropriate to start, Thank you for those questions. So the sensitivity of those, uh, radiologic findings and exam findings were modest to begin with. And unfortunately, in today's day and age, where two thirds of the population in the Western Hemisphere has become obese or overweight, it's gone down even more. I don't know the exact numbers because I didn't care for them. So I'm sorry, I don't have the exact numbers and, uh, you asked about screening when you start screening protocol for diseases like systemic sclerosis should be at the time the person is diagnosed with the disease. And pulling hypertension itself is an indication for transplanting along real hard and those with lung disease that is severe COPD, or IPTF, heart disease that is severe. And so, if they are found to have, for me hypertension, when they are periodically being followed up as part of their objective surveillance. In addition to this objective improvement to block their often symptoms and his talents for labor because and cirrhosis yeah, liver is preventing blood from the gut to go into the right side of the heart when the liver is transplanted. All of a sudden you're opening the floodgates, and there is a large bowl is a portal blood going into the rights of the heart so the patient will pull me. Hypertension will die on the operating table, and that was learned years ago. So now all of those patients with cirrhosis who particularly who are being considered for liver transplantation, should be screened for forming appetites, and they found to be severe and will not be able to handle the increase in venous return upon receiving the new liver ship have that treated, and there we peer pressure brought down less than 50 for them to safely undergo transplantation. Prostitute p. There are a number of prediction models that we use in determining who and patients who have suffered a QP should be followed that. But David will disagree with me, and he will say that everybody was suffered from should be screened for Sita as early as three months old. Yes, so we don't have good data. But unfortunately, it's such a rare disease poster QP 4% that we don't have a large enough number of patients to know if we will, in the long run, even make any difference if we were to screen and find the disease. Can I make a comment from ST Luke's? Yes. Thank you, Doctor. Yes, this was a suspended talk indeed. And on a high note, I historic note. I have my House staff training on the Columbia Division at Bellevue in the late forties and early fifties. And, uh, that was the time, as you pointed out, when right heart catheterization was being used to evaluate patients in heart failure from COPD, and it was dramatic. Patients would come in multiple Dominus. 20 and £30 overweight, Markedly hypoxic. They would be oxygenated the pulmonary artery. Pressure would come down. They would diaries, and they would be restored to reasonably functional state. It was dramatic. And it really was, at that time, a therapeutic breakthrough. And it was great to see it going on. Actually, at the bedside on the ward at Bellevue. It's amazing. Thank you for sharing your experience. And, yes, it was the days of when it was a combined cardiopulmonary fellowship. Hi. Thank you so much for the talk. I just have a question, um, regarding, uh, advising patients to avoid pregnancy. Uh, with pH Is our contraceptive, uh, bills still, um, still allowed, or is there a specific contraception that is contra indicated? Given the higher risk of, uh, you know, thrown by embolisms. So thank you for asking. That's a good question. Yes, contraceptives are required and recommended, and a barrier method in addition is preferred. The class of medicines and insulin receptor antagonists are also theragenics. So it's more important from that point of view as well. And of course, should one conceive then they should be followed closely, but oral contraceptive pills are recommended. And as far as anti coagulation is concerned, we don't have good data on if everybody with Group one community inhabitants shin should be routinely given anti coagulation. But we've moved on from the era of warfarin to now having new or anticoagulants directly working or anticoagulants that are easy to comply with. Hopefully, we will have data on if they should be used or not. But the mayor high risk of BTE is not the contraindications to its, uh did they use a lot of contraceptives? Thank you for a wonderful organized talk with the evolution from getting are beginning knowledge of our circulation. I wanted to ask another question because I'm confused as to what to do. UH, that is in pulling from a mental embolism. The initial recommendations were treated with three months, and now that's mixed up to six months. But in finding CT people prime example, journalism is in two years should be, in fact, do it longer than six months. So that's question them home because I know it's a risk benefit. Uh, consideration and studies may be ongoing. I don't know yet The other question is, How do other comorbidities alter your algorithms? Severe renal disease patients and balances? Does that change your approach to the analysis and the treatment? Thank you for the wonderful questions. So for an acute P E, the guidelines recommend three months of therapy when there is a working factor, and for idiopathic at least three months to indefinitely. One elegantly performed randomized control trial from Italy showed that patients benefited from warfarin as long as they were on it for 18 months. Following that for a year and a half that both groups were followed. The risk became similar in both the placebo group and those who had received 18 months of orphan therapy. So indefinite antique regulation following the initial three months required course if those who have a high risk of major bleeding or when the risk benefit ratio along favors indefinite attic violation, then aspirin 100 mg a day. Yes, there's no such thing as 100 mg today in the US to minimize controlled trials published in any gym come from Europe is, uh, better than nothing. And your other question was about comorbidities, especially in those with multifactorial forming hypertension. If we find any cause of forming hypertension and be treated, and hypertension persists. We then go on to pursue the possibility of them having a coronary artery apathy that needs to be addressed as one would address pH and because there is a significant component of volume and cardiac output in determining the pulmonary artery pressure. So, yes, you're right. A person with hand stage renal disease who's on dialysis and since Medicare will only cover dialysis three times a week, even though some patients require more than that and there is no scientific reason for them to be only guys three times a week. Unfortunately, that's how reimbursement was set. But here or there, they may be given extra sessions of dialysis by those centers on charity basis, or where they know that it will prevent hospitalizations in such cases. One elegant study looked at using ultrasonography of the IBC during dialysis to determine when they had reached You've Olympic status, and you could see respiratory variation in the IBC again, meaning that they will no longer hyperbole Mick, rather than approximating their trial wait based on the standard and age old method. So that would be wonderful if we can find a way to optimize their problem. Stairs. Unfortunately, uh, and a professional, by creating an increased cardiac output also adds insult to injury. So sometimes, if the flow through the fistula is larger than it should be, that may also require a revision to improve the person who told me about the tension. So it has to be individualized to what you come down to finding out is the particular because the mechanism of probably hypertension. Well, thank you very much. Thank you. Mhm. Okay.
