Dr. Raymond Benza is the inaugural George M. and Linda H. Kaufman Academic Chair of Cardiology for Eastern Virginia Medical School at Old Dominion University. Dr. Benza is an internationally recognized leader in advanced heart failure, pulmonary hypertension, cardiac transplantation, and mechanical circulatory support. He brings a distinguished career of academic excellence, translational research, and innovative clinical leadership to Sentara Health. Here he shares key insights from his ongoing work and discusses the evolving landscape of treatment for Group 2 pulmonary hypertension.
So today we're gonna be uh talking about group 2 pulmonary uh pulmonary hypertension trying to understand uh the mechanics of this very complex and very fatal disease. Here we go, these are my disclosures. So we only have 20 minutes to discuss this topic. Uh, usually takes me a full hour to do that. So what we're gonna do is we're going to condense it and give you the really the main facts focusing on the prevalence and impact of this form of pulmonary hypertension, go over its classification. review some of the pathophysiology and path of biology. What I really want you to remember out of this is that group 2 pulmonary hypertension is a four compartment disease involving the left ventricle, the left atrium, the pulmonary veins, and the pulmonary arteries, and then we'll go with some management principles based on these four compartments and finally we'll add a little bit about uh monitoring of this disease with some new technology. So let's go over the prevalence and impact of group 2 pulmonary hypertension. As many of you know, there are 5 distinct classifications for pulmonary hypertension and pulmonary vascular disease. Each one of these 5, components are distinguished by the triggers that induce the pulmonary hypertension in the pulmonary vasculature. In the case of group 2 pulmonary hypertension or pulmonary hypertension due to left heart disease, the trigger is a high left atrial pressure. And this could be related to left ventricular uh systolic dysfunction. Left ventricular diastolic dysfunction which we're getting to appreciate much, much more since we've done a better job characterizing patients with hepa but even more importantly we're beginning to understand the grasp of valvular heart disease and causing this type of pulmonary hypertension in the past mitral stenosis was thought to be the most common valvular disease, uh, causing pulmonary hypertension. Now that we know it's clearly mitral insufficiency. And this impacts some of the really fantastic work that we're doing in the structural heart disease is whether these patients have pulmonary hypertension as a component of the valvular heart disease. It can also be seen in congenital, uh, uh, heart disease and and congenital, uh, abnormalities of the pulmonary veins, but suffice it to say the most common forms that you'll see are related to heart failure reduced ejection fraction and heart failure preserved ejection fraction. So group 2 pulmonary hypertension is the single most prevalent form of pulmonary hypertension that we will see in the clinical environment and because of this, it should be the first thing that comes into your mind when you see a patient with pulmonary hypertension in the clinic, not these other four subgroups that I told you about earlier. In fact, when I educate my residents and trainees, I let them know that 7 out of 10 people that you see in your clinic with pulmonary hypertension will have group 2 disease, and you have to prove it to me. They don't have group 2 before you call them anything else particularly group one disease. Now how prevalent is this? Well, if you look at the, uh, uh, code disease mixture in patients with heart failure reduced ejection fraction and heart failure preserved ejection fraction, you can see pulmonary hypertension complicates these diseases in anywhere from 40 to 80%. 8 out of 10 people with heart failure that you see will have a comorbidity of pulmonary hypertension that will impact uh their uh their prognosis. So do a little math here. If there are 5 million people in the US with heart failure, roughly 2.5 with half and 2.5 with half path, and 62% of all ref and 52% of all half have pulmonary hypertension. That's a lot of people walking around with group 2 disease in the United States. That's a pandemic. And now that we know that pulmonary hypertension complicating this disease results in a reduced survival, there's a lot of people at risk for high mortality with heart failure walking around that we haven't done much for. Now the mortality rates in group 2 pulmonary hypertension are reflective of two physiological principles the filling pressure of the left atrium, which is characterized by the wedge pressure, and the pulmonary vascular resistance, which is the downstre damage to the pulmonary architecture that's a result of this chronic high left atrial pressure. When people are in the beginning of their disease, those with isolated post-capillary pulmonary hypertension, their mortality is directly related to the elevation and left atrial pressure. However, when this disease starts changing the architecture of the pulmonary arteries, the wedge is no longer the effect of component terminating mortality, it's actually the pulmonary vascular resistance and as you see in this slide, it's not a linear relationship like the wedges. This is an actual cliff. When people reach a PVR of 2.5 to 3 woods unit, these people are about to fall off their survival curve, so it's really important to identify people who have reached this stage. Now what's the prognostic significance of having pulmonary hypertension? I showed you how frequently it occurs, but if you look at these odds ratios, there's a very high risk of mortality when pulmonary hypertension complicates the course of someone with heart failure not only from a mortality perspective but also a very, very significant morbidity, uh, concept. These people are being hospitalized constantly because of this comorbidity. So in fact, not only there's a high mortality and morbidity, but people with pulmonary hypertension combined with left heart disease not only has this negative impact on the outcome that I mentioned, but it results in more severe symptoms and worse exercise tolerance for these patients. Well let's talk a little bit about how we classify group 2 pulmonary hypertension because it comes in several flavors. The most recent uh WHO meeting on pulmonary hypertension really simplified how we classify group two pulmonary hypertension and it's really dependent upon the evidence of pulmonary vascular resistance in the circuit. So pulmonary hypertension, as you know, in and of itself is a hemodynamic definition. It's anyone that has a mean pulmonary artery pressure greater than 20 millimeters of mercury in the context of group two disease, you must also have an elevated left atrial pressure. Remember I said that's the trigger. Now an isolated post-capillary pulmonary hypertension, the degree and elevation and mean pulmonary artery pressure is directly related to the filling pressures of the left atrium or the left atrial pressure. And that's referred to as isolated post-calate pulmonary hypertension. Combined post cap preca pulmonary hypertension means that chronic pressure from that high elevation left atrial pressure is exerted back on the pulmonary arteries and it's changed their architecture and it increased resistance. So combined precaulary post capulary pulmonary hypertension is not only an elevated wedge and being pulmonary pressure, but you must have an elevated resistance with this disease. Well, why is that important? When you look at the survival between these different subgroups you can see that the survival in people with isolated post cap pulmonary hypertension is still worse than those people who don't have pulmonary hypertension, but much, much better comp uh compared to people who have group one pulmonary arterial hypertension. But when you evolve to CPCPH, the mortality is as severe as primary pulmonary hypertension or PAH. That is significant. These people would combined pre-capillary post-capillary disease have a greater than 50% chance of dying at 5 years when this complicates their setting of heart failure. Well, let's talk a little bit about pathophysiology and pathology because this is a four compartment disease as I mentioned, the left ventricle, the left atrium, the pulmonary veins, and the arterios and it's essential that you remember this because this is what complicates the management is people don't remember these four compartments and try to rush just to try to understand what's happening in the pulmonary arterial. Well, the mechanisms that cause group tumor pulmonary hypertension again relate from a high left atrial pressure, whether this is from systolic dysfunction or diastolic dysfunction or even loss of left atrial compliance and. We can see in some restrictive cardiomyopathies and even more commonly now after doing uh uh pulmonary uh vein ablations and afib ablations which could really reduce left atrial compliance but the trigger for this disease is an increased left atrial pressure. And what this pressure does is then works back on the pulmonary arteries to the endothelial cells uh of that network and causes an elaboration of a variety of cytokines and growth factor that changed the structure of the pulmonary arterial and remodels it and makes it uh adversely inefficient to accepting higher loads of cardiac output. This is an actual slide of patients who have pulmonary arterial hypertension and pulmonary hypertension related to left heart disease, and they're indistinguishable from one another. The vascular remodeling in the pulmonary artery is identical between these two subsets of disease. What's different, however, is what's happening in the veins. And this is what everyone forgets about group 2 disease that it is not just an arterial disease that high left atrial pressure is also causing the pulmonary veins to remodel. And you become distinctly thickened and they develop an intima and even the media that was never there before so the Venus system becomes a high resistance circuit in addition to the arterial system and I want you to remember that because this is the component of the disease that is often forgotten and trips everyone up when they just try to treat the arterial segment of this disease. So this is the evolution that we see in these uh two variants of pulmonary hypertension. Everyone starts with isolated postca pulmonary hypertension. You become this progressive remodeling section to we have this reactive pulmonary hyper. which the vessels still respond to vasodilators and then finally they resolve into this more permanent form where there's permanent vascular remodeling in the arterials and venues and called CPCPH with the highest mortality exists. So what are the 4 management principles based on on these 4 compartments? Well, here's how we treat it. This is how we treat group 2 pulmonary hypertension now we try to optimize treatment for the underlying condition. We refer to an expert center and that groups, uh, the drugs that are designed for group 1 disease are not recommended in left heart disease. It's not really a lot to help us manage these people, but I think that there are different ways that we can manage these based on these four compartments that will go into each other. So remember the principles of managing disease are based on these compartments and there's one central principle and two adjunct principles. The main principle is that you have to aggressively manage left atrial pressure. If you do not change this, you will not change the course of this disease. The second principles involve managing the underlying substrate, fixing what's going on in the left ventricle, modifying as much as you can, and then once you do those first two things, then you start thinking about inducing vascular remodeling. But if you do the last first and you ignore these two, first principles, a lot of bad things happen. You will get reduced pulmonvascular resistance by just focusing the arterial you'll increase preload to these clogged veins and noncompliant left atrium. You'll further increase left atrial, uh, heart, uh, left atrial pressure and left heart failure, and you'll get pulmonary edema. And once you get pulmonary edema, this is gonna worsen the pulmonary hypertension. It's gonna cause RV ischemia it's gonna lower your cardiac output and resent in patient compromise so you can't ignore these first two principles and dive right into fixing those arteries. It just doesn't work. You have to remember that group 2 disease is a four compartment disease and you have to fix these other compartments before you focus on those arterials. So what are the management principles? How do you lower left atrial pressure? Well, obviously the most, uh, uh, easy way to do this is with, uh, direct, uh, uh, drugs that will drop, uh, volume which are diuretics, but many people forget that you can't just put a patient with CPCPH on a diuretic. They really had to be protocol driven. There has to be frequent readjustments based on symptoms and other markers to make sure you've decompressed this department. And you make sure that you optimize your mineral corticoid receptor antagonist to counter the sympathetic response that you get with regular loop diuretics because that is deleterious to the pulmonary arteries also. For patients who have left atrial noncompliance, particularly those who in which you feel there's a lot of fibrosis in the left atrium, RNs and SGLT2 inhibitors have been found to be very useful in proving left atrial noncompliance. And then finally, if none of these measures work, you can mechanically uh offload the left atrium using LVADs and left atrial pumps, but these require chronic consisting unloading. Possible only with multiple speed optimizations of these devices to make sure they're decompressed. Well, we used to have to do this blindly we would have patients come to clinic we'd have them send us weights from home we'd have to give details of their uh of their symptoms, but all of these are really late manifestations of volume accumulation the left atrium. Now we have a lot of toys that we can use in our clinic to detect this elevation left atrial pressure even in its asymptomatic phase, and these include using impedance testing devices. Like what we see in our CRT devices or with the metronic link or with the reeds vest or the sentinel device that checks thoracic impedance or lung volume in the lung. And also now we have left atrial monitors including the Victoria sensor which measures left atrial pressure directly so there's no reason to do this blind anymore and there's no reason that this requires a physical touch point with the patient you can get this information all from home to make sure that you're constantly decompressing the left atrium. The second main uh philosophy is you've got to buff the underlying substrate. You gotta figure out what the mechanism, uh, uh, of this high lift atrial pressure is and try to throw whatever you can to reorganize that substrate. In the instance of heart failure, you have to make sure that your patients are on the 4 pillars for for therapy for he ref and the 3 pillars of therapy for he path, including ACE, Abs, and Arnes for both forms, beta blockers and those who have uh heart failure reduced ejection fraction. And then aldosterone antagonist, SGL-2 inhibitors, and GOP receptor agonists, particularly those who have HE and then CRT and those who have, uh, uh, heart failure reduced ejection fraction, you have to make sure you're controlling exacerbating conditions that can also increase the stiffness of the left ventricle like uh obesity and obstructive sleep apnea, diabetes and hypertension. And you have to fix anatomical lesions like we heard in our structural heart disease talk today if they have severe mitral insufficiency and their candidates to get the valve fixed, fix it because that's how you're gonna fix their pulmonary hypertension, the same thing for stenotic lesions and then if all else fails, you can always remodel the left ventricle chronically unloading it using left ventricular cyst devices. Well, there's a lot of information now that's coming out how the medicines that we use to treat uh heart failure also favorably affect the pulmonvasculature and the RV myocardium and an example for this are arteries, particularly in the face of heart failure produced ejection fraction which can markedly reduce PA pressure and reduce adverse remodeling in the pulmonary arteries in addition to what they do to the left ventricle and right ventricle. Mineral cortico receptor agonists that we use also act directly on the pulmonary vasculature to remodel those pulmonary arteries. Same thing for SGLT2 inhibitors and GLP-1 antagonists. So these medicines that we're using to treat heart failure, it's incredibly important to buff these drugs because they're also benefiting the pulmonary arteries at the same time. Well, how do you manage the pulmonary arteries themselves once you've, uh, controlled these two mechanisms you got the left atrial pressure low, you've managed the, uh, the substrate. Is there anything that we could do to reduce this vascular remodeling and reduce it? Well, if you look at the recent guidelines just recently published a year ago, there's really not much there in the recommendations in terms of drugs that we can reverse the pulmonary artery modeling it. In fact, they give a very cautious tale here not to cross treat group two disease with drugs intended to treat pulmonary arterial hypertension like endothelium antagonists, PD 5 inhibitors, guanolate cyclase agonists, and particularly procyclins. In fact, there's some grade 3 recommendations about using these drugs in these particular substrates. So when you look at uh studies in group 2 pulmonary hypertension, uh, particularly those in HPE, which is the most common form that's tested, you can see that when we apply group 1 drugs in this situation that the results of the trials have been uniformly dismal or negative. In addition, even some of the contemporary trials, uh, that we've seen utilizing drugs that we often use in group one disease have again been very disappointing drugs like Levassementin, uh, Rioequwat, uh, uh, Mir Bran, which is, uh, uh, a, a beta 3 agonist, uh, tadalafil have all shown very disappointing outcomes in patients with group 2 disease when used indiscriminately. But I can tell you when you look at these uh studies, there are a lot of things that these studies did wrong. They ignored the four compartment model. They went directly to arterial remodeling. There was no chronic control of congestion or left atrial pressure. There was no maximization of of a guideline directed medical theory to manage the substrate. There was no attention to the ploy venous department, and they relied on conventional efficacy measurements to measure success. In addition, this problem was confounded as these required multiple touch points with the patients in order to access each of these departments. Well, I think there is a way that we can treat this disease. We just haven't found the right management principle, but I wanna give you an example of how you might be able to manage this disease with a lot more information using impedance testing or left atrial monitors to watch your left atrial pressure and PA monitors to watch your pulmonary vascular changes as you're trying to induce this remodeling. And here's an example of using the four compartment syndrome. And utilizing these type of uh novel sensors to really make an impact in group 2 disease. So this is the patient with or group 2 pulmonary he related to heart failure heart failure preserve for action. How many are you pressure Uh, which was very, very. And their uh uh and their total distance is 10. So this is a cardio if many remember how to use this, you could see that blue bar is the PA pressure, the green bar is the pulmonary artery. And the red bar diastolic pressure. And the purple output and the orange is a total assistance that you get from so as we apply this for principal department we started goal direct therapy we made sureize these drugs and a little reduction in in using this uh this gene. Multiple red patient to detect fluid and when we hit a point where the patient was evolemic had and started an inhibitor drug designed one diseaseha of a controlled subs and a chronically low atrial pressure. When these first twos were applied, used a drug for arterial rearing, we have a significant decline pressure. We made sure we kept the pressure low while so we could continue uh favorable remodeling. And we were so we were able to drop. At the end of this uh therapy and then very uh well for many hypertension principle. Had a marked reduction in total pulmonary. And improvement in cardio as seen by the. Have a study that uh designed and registered this trial looking at approach four prong compartments try to treat uh the hypertension 2 disease. There is hope on the for treating this very fatal. Using advanced technology and hopefully newer drugs in the future will give us an even bigger impact than remodeling some of these drugs that we have already and with that I thank you for your attention.
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