Dr. Mukherjee describes the role of novel echocardiographic applications to detect subtle abnormalities and RV contractility and contractile reserve and classifications of pulmonary hypertension.
Monica Mukherjee, M.D., MPH, FAHA, FACC, FASE
Thank you so much for the kind introduction. So, um I'm my name is Monica mckee and, and as Doctor Tell Raj mentioned, I'm an associate professor in cardiology at Johns Hopkins. And today I will be speaking about multimodality, imaging and pulmonary vascular disease. I have no relevant disclosures. The objectives of my talk today will be to define the world symposium of pulmonary hypertension, updated classification of P H. We will then review the 2015 American Society of Echocardiography Chamber quantification guidelines for the assessment of right heart chamber seism and function in relation to P H. Um I hope to establish the role of novel echocardiographic applications to detect subtle abnormalities and R V contractility and contractile reserve. We will then review some multimodality imaging techniques and applications in pulmonary hypertension. And in the end discuss the importance of cardiac magnetic resonance imaging and tissue characterization and the monitoring of response in pulmonary hypertension. So, since the first world symposium in 1973 P H has always been defined as a mean pulmonary artery pressure of at least 25 millimeters of mercury. However, during the sixth symposium meeting back in 2018, the task force members suggested that this definition actually be changed to a mean pulmonary pressure of more than 20. And the authors base this recommendation on the fact that the original definition of at least 25 was chosen someone arbitrarily and it didn't really represent the upper limit of normal. But the major concern here is that we are including patients now with a mean pulmonary pressure of 21-24. And this is really an at risk population. Um and are we over diagnosing or under diagnosing? So, that's an important consideration. But despite these concerns, all of the studies published in the last five years suggest that individuals who fall into that range are increased risk of poor outcomes and will eventually develop P H one of the most common diagnostic problems. However, remains this distinction between precapillary and postcapillary, pulmonary hypertension due to left side heart disease. So, pulmonary hypertension is simply classified on whether or not it occurs pre or post capillary bed. Pulmonary arterial hypertension is about 4.2% prevalence of pulmonary hypertension subtypes. It's associated with connective tissue diseases. Um HIV uh hereditable idiopathic as well as drug and toxin induce type three is also precapillary. So this is pulmonary hypertension that's due to lung disease or chronic hypoxia such as C O P D I L D, obesity hypoventilation syndrome and OS A Also precapillary is Group four. So chronic thromboembolic pulmonary hypertension or pulmonary hypertension due to pulmonary embolisms or arteritis. And then group five is kind of a catch all of hematologic disorders. Um sarcoidosis falls into group five other metabolic disorders. And as you can see the prevalence of each of these subtypes is actually quite low in comparison to Group two, which is pulmonary hypertension due to left side and heart disease. And that's really from any sort of opathy left uh ventricular systolic or diastolic dysfunction and congenital abnormalities. And this is the overwhelming majority of patients. And it's important to note that group one, pulmonary arterial hypertension can only be diagnosed in the absence of significant obstructive or restrictive lung disease and also has certain hemodynamic requirements. So, the sub categorization and method of detecting pulmonary hypertension relies on invasive right heart categorization. So, precapillary P H is now defined as a main P A pressure of greater than 20 with a wedge that is less than or equal to 15. And the new PV R cut off is actually two in precapillary P H. We have again, group one pulmonary arterial hypertension group three P H, two to lung disease, group four P H, two to chronic thromboembolic disease. And that group five that we talked about Post capillary. On the other hand, is a mean pe pressure that's greater than 20 with a wedge that's greater than 15. And you can uh distinguish isolated postcapillary from combined pre imposed using what's known as the diastolic pulmonary gradient, which is simply the diastolic pulmonary arterial pressure, minus the mean wedge and this is felt to be less influenced by wedge at any level of stroke volume. And in normal subjects is around 1 to 3 P H should really be suspected in any patient with otherwise unexplained shortness of breath on exertion, syncopy or signs of right heart congestion. While P H is exclusively uh diagnosed by confirmatory right heart categorization, multimodality. Imaging is quite useful for screening classifying prognosticating and monitoring the effectiveness of therapy in P H and transthoracic echocardiography is the most common screening modality for P H. And it's really the mainstay of screening monitoring of therapeutic response and prognostication. And so with that, I'd like to review the updated guidelines and standards for chamber quantification from the American Society of Echo Comprehensive Echocardiographic Assessment of the right heart really starts with a morphologic evaluation using both quantitative and qualitative measures. Qualitatively, the R V should appear smaller than the L V, right? Usually no more than two thirds the size. And for any stenographers in the audience, we really want to move the transducer laterally to avoid any drop out of the lateral R V free will two D directed linear measurements of the R V chamber are then taken from the A four chamber view where we can measure the basal linear dimension. This is the transverse R V diameter in the middle third. Um I'm sorry, uh the basal one third of the R V inflow at N diastole from an R V focus view. The mid cavitary linear dimension is that transverse R V dimension from the middle third of R V. And plus so about halfway between the maximum basal diameter and the apex. It's usually at the level of the papy muscles and end dias and then the longitudinal R B dimension is taken from the apex transversing the tricuspid annular plane from the short axis views. um I'm sorry, the personal uh views in short axis and long axis, we can also look at the right particular outflow track approximately and distally. And these are all taken from the parasternal windows. The proximal R V O T can be measured from the parasternal lung or the parasternal short at the level of the aortic valve. And the distal dimension is measured right proximately to the pulmonary aulus. We can also get a measure of the pulmonary artery using that parasternal short at the level of the aortic velvet angling up. And there's there are several important considerations in these measurements. So for the views, the images are highly dependent on whether or not you can fully see that lateral um wall. And you really want to make sure that you're not foreshortening. And here are some of the reference values that we should keep in mind when we're looking at the right heart from the A four chamber view, we can also look at right atrial dimensions and area. So this is in ventricular cysty. You just want to trace the endocardium from the lateral to the sexual aspects of the tricuspid aulus. And the upper reference limit uh for area is 18 centimeters squared but similar to L A volumes. R A volumes are really not sensitive markers to acute changes in filling pressure. So you can see a dilated R A in patients with no normal R V filling pressures. You can see uh increased flow in the setting of athletes, heart or left to right SHS all of these may increase R A size without increasing pulmonary pressures. So R A volumes are a better reflection of chronic changes in R V filling pressures rather than acute from the parasternal short X is view at the level of the mit valve. We can also assess what's known as the Centricity index, which is simply looking at the intraventricular septal morphology. So the magnitude of intraventricular septal flattening can be quantified using this measure and all that it is, it's defined as the ratio of the length of two perpendicular L B dimensions, the anterior posterior dimension and the septal lateral dimension from the parasternal short in normal hemodynamic states. This ratio should be around one in both cysty and diastole which reflect a roughly circular contour of the L B throughout the cardiac cycle and E index that's greater than one and N diastole is suggestive of R V volume overload. Whereas a value of greater than one in N cysteine and, and, and diastole can indicate the presence of R V pressure overload using echo, we can also noninvasively perform a swan. So uh we all know the Bernoulli equation which takes four times the peak tricuspid regurgitant velocity squared. And when we add right at pressure to that, that is then equivalent to your pulmonary arterial systolic pressure. So here we see a tricuspid regurgitant signal. Um it's hard to see but the it's 3.8 m per second. So 3.8 m per second squared times four is 58 plus whatever the right atrial pressure is, we can also measure and dia diastolic pressure. So this is the pulmonary arterial n diastolic pressure is equal to four times the end diastolic pr velocity squared. And then again, we add the right atrial pressure and this is felt to be a direct correlate of P A dias so pressure and an indirect correlate of L V E D P. So in this example, the end regurgitant velocity is 2.54, We square that and multiply by four. So the pulmonary arterial and diace pressure is around 26 plus whatever the right pressure is using Echo, we can also calculate the mean pulmonary arterial pressure using uh we have about four formulas depending on what is included in your echo exam. And then last, we can calculate noninvasively pulmonary vascular resistance using the Abbas formula. So this is the T R velocity divided by the velocity across the R V O T multiplied by 10 with an additive uh 0.16 and PV R are greater than two is considered to be abnormal by echo. And here's how we measured that. But the ability to calculate hemodynamics is noninvasively um dependent on the presence of an analyzable Doppler signal. And so here it is again, in kind of a, a bigger shot. So when we look at right at pressures, this is most commonly estimated by uh the diameter of the inferior vena cava from the seyo view and the presence of inspiratory collapse. And this is really not an accurate reflection of what your right atrial pressure is if in ventilated patients with high peep. And also in pregnancy I V C diameter is um the measurement is taken from the subcostal view at an expiration. We use a cut off of 2.1 and then we look at collapse with normal respiration and we use uh three millimeters when the diameter is small and it collapses 15 of the diameter is enlarged and doesn't collapse and then eight for anything that falls in between. And I also frequently comment if the I V C is small and collapse being suggestive of hypo aia. However, it's important to remember again that non-invasive measurement of all of these factors um is based on the modified Beli equation. And we looked at a study of patients who um had A T RT that was analyzable and then went on to have a right heart cast and really, it varies um on how well this correlates. So, in this prospective study of 65 patients with various forms of P H who underwent comprehensive echo within one hour of a clinically indicated right heart cap, we compare non-invasive hemodynamics with invasively measured values. And here you can really see that um in an echo that was performed one hour from right heart cath what that scatter was. Um So the magnitude of pressure underestimation is actually greater than overestimation. And we also see that in tricast regurgitant lesions. So here we see an example of a patient with wide open T R. So here's the R V in flow view, this is the tricuspid valve and you can see here that there's a big coaptation gap meaning that the leaflets are not coming together. And when we place a color uh Doppler signal across that jet, you can kind of see that there's two and fro flow. So this is known as laminar flow. When we have laminar flow and a wide open tricuspid valve, you can see here that the Doppler signal is not reflective of how severe the pulmonary hypertension is. So there's rapid equilibrate of the pressures between the right atrium and the right ventricle because functionally this is a single chamber. And when we look at tricuspid regurgitant lesions, and you're seeing, you know, uh t R that's disproportionate to the R V S P as well as mal coaptation. You really want to move on to the next stage of imaging, which is T E E because there's a number of really exciting trials coming out on Tricuspid um on per both percutaneous and surgical options for the tricuspid valve. Now, the next step in looking at an echocardiogram and P H is the functional assessment. So we can measure what's known as fractional area change, which is the measure of systolic function that correlates very well with R V E F by C M R. And all you're doing here is is measuring the R V uh chamber taking care of avoiding any trabeculations. In end dias and N cysty, we can also use taps, which is a tissue Doppler method that measures the distance of the systolic excursion of the R V annular segment. So this is acquired by placing an M O Doppler signal through the lateral tricuspid annuus and measuring the amount of longitudinal motion. So the greater the descent of the base insistently the better the R V systolic function. And then we can also measure what's known as tissue Doppler s prime velocity. So this is acquired in a similar fashion except we place a tissue Doppler signal along that lateral trica aulus. And we're looking at peak systolic velocity which is a measure of longitudinal motion. However, the pitfall of both taps and uh tissue Doppler s prime is that you really need to see the entire free wall um and that lateral segment throughout the cardiac. So you can underestimate an velocity if your interrogation is not exactly parallel to that plain of motion. And the other area where some of these longitudinal measures fail is in a phenomenon known as ventricular arterial and coupling. So the R V has a very thin wall that's comprised of circumferential myo fibers in the sub epicardium and longitudinal fibers in the endocardium. And as such, the major vector of con contraction is along the longitudinal plane. What happens as R V afterload increases though is that you have spherical of the R V chamber and it actually becomes um tethered leftward. So here you can see that the R V is clearly abnormal but the basal segment is moving just fine. So this is a patient who has early signs of the R V beginning to fail um based off a pulmonary afterload. So tay and tissue Doppler at prime are not going to be reflective of the overall systolic integrity of the right ventricle here. So, markers of longitudinal function are really only useful in early disease development. But as soon as you have geometric abnormalities in your R V, this is going to not be reflective and will overestimate R V function. So let's talk about this a little bit more. In animal models. The R V functions as an end organ mechanistically where hypertrophy is the initial adaptive response to P H. So in an effort to increase contractivity, there's an increase in tissue thickness and mass by means of circo Genesis hypertrophy, though is followed by a progressive contractile dysfunction that's followed by chamber dili in an effort to maintain cardiac output. So with sustained pressure, overload, the contractile uh increases are simply insufficient to maintain cardiac output. And this results in progressive of chamber dilatation. So there's an increase in chamber internal radius to increase volume through this increased pressure. What we see is spirit ization of the R V free wall. So there's a change in the ratio of the longitudinal to circumferential length and that is associated with heart failure. And for those of us who take care of these patients, you know, we're all very used to seeing echocardiograms that look like this. So this is the an echocardiogram of a 66 year old woman with glama who presented with shortness and breath here, we see the paranal short axis view. So a very small D remodeled L V with a huge R V on top here, that's hypertrophy. We see abnormality in the eccentricity index in cystine and diastole. From the A four chamber view. You can see that the R V is markedly enlarged. The L V is small, the apex is tethered leftwards, the right atrium is also enlarge and look here, even the intraatrial septum is Boeing from right to left. So all of this is consistent with severe pressure and volume overload. There are also a few other important considerations when looking at echo and pulmonary hypertension. So the first is that as the R V begins to spirit, you have to change the direction of your longitudinal dimension here. So I see a lot of people just bisecting the R V. This longitudinal dimension should really follow the direction of the um interventricular septum. When you're looking at the um at these patients, you should also look at the eccentricity index and make sure you're commenting on that as best as you can. Um when you're, when you see a traction, um you know, just as a reminder that those longitudinal measures are going to overestimate how well the R V is actually functioning and you should be labor, the point of performing a fractional area change, which is more reliable in that setting and then also look for adjunctive signs. So, um across the R V O T, you're going to have a shorter acceleration time and the peak velocity will begin to happen in early to mid um cyst um as a triangular shape early in the disease. And then over time you get this midsystolic notching or a W sign and this is associated with elevated pulmonary vascular impedance and decreased compliance. And then in advanced pulmonary vascular impedance and R V failure, the later P ays flow is actually diminish and reversed. We can also perform what's known as R V deformation imaging. So, echocardiographic quantification of regional and global myocardial function can be noninvasively measured using both tissue Doppler and speck based strain. Uh Both of these techniques provide comparable data quality, but again, tissue drop is angle dependent while spec tracking is not. And so that's really why speckle tracking has fallen in favor as a preferable technique. And what we do here is that an offline software is applied to previously acquired two D images optimally taken at 40 to 80 frames per second. And this provides detailed information about regional and global deformation. Speck tracking technology is based off of um ultrasound tissue interactions. So as the ultrasound beam hits the myocardium pixels or speckles um are generated within the myocardium from random reflection refraction and scattering of the ultrasound beam. And then during offline analysis, all we do is we cha trace the endocardial border. And here this is an example of L V um strain imaging of the A four chamber, but this can also be performed on the R V. Um And then all you're doing is tracing the endocardial border from medial mitr annuus and ending at the lateral mitr emus. And and, and then the software begins to track frame by frame using a mathematical algorithm. And so what we're seeing in this example is that the dotted line is a segment of all six segments that are visualized here. Um And you're seeing an expression of deformation as a percentage from dias to cly as a function of time. So here we see the onset of ventricular cysty signified by the beginning of the QR S and a less negative strain. So there's systolic shortening and the strain number is becoming more negative at aortic valve closure. We have peak systolic shortening and then the onset of diastole. So the strain is less negative. Here, here we see a plateauing of the signal. So this is isovolumetric relaxation and then the peak Diallo relaxation velocity. And these same techniques again can be applied to the R B free wall with or without inclusion of the intraventricular septum. So with that as a background, I wanna use systemic sclerosis as a case study of pulmonary hypertension. So this is a complex heterogeneous autoimmune disease. It's characterized by a prominent vasculopathy disregulation of the immune system And widespread fibrosis of multiple organ systems including the heart. And there's a common association with Ray not's phenomenon. It's a relatively rare disorder of the annual us incidence is 240 cases per million with a very strong female predilection. So about four times greater than men and most women present in their 4th and 5th decade of life. African American women tend to be at greater risk for diffuse subtypes and the age and gender. Uh sex adjusted mortality rates are five times greater and survival rates strongly de are dependent on the degree of organ involvement with an average of 70 to 80% 10 year survival. There are two main subtypes of scleroderma. So, the limited subtype is characterized by a high incidence of anti centromere antibody. Um in about 70 to 80% will have positive anti centromere. Um These patients tend to have diffused tita, as we see here in this example, longstanding ray nodes without sclerodactyly. Here is an example of a patient with ray nodes and digital amputations from ischaemic necrosis. And overall the limited subtype has less severe visceral involvement and a better prognosis. Except when pulmonary arterial hypertension develops as a late complication, diffusive type. On the other hand, is notably anti centro antibody negative. It carries a worse prognosis. About 30% will be um positive or anti topoisomerase. The onset of Rhinos occurs within one year onset of skin changes. And so here we see an example of um a facial thickening as well as a a male distribution of the Lanta with the restriction of the oral aperture. Um Here we see an example of sclerodactyly with severe contractures and overlying de pigmentation and AC T scan demonstrating diffused intercision, lung disease, uh systemic sclerosis uh can affect the heart in several ways. So, cardiac involvement is quite common. It can be primary from direct cardiac involvement. We have um uh circular evidence of abnormalities and calcium handling in these patients. It can also be secondary due to um R V P A, uh ventricular arterial uncoupling and pulmonary arterial hypertension I L D or kidney disease. Regardless of the subtype, it's often unrecognized until lead. Clinical involvement, widely varies from 15 to 35% depending on the diagnostic technique. And overall it portends a poor prognosis. So 14 to 36% of these patients will die, die from cardiac involvement. Uh more commonly the diffuse subtype. But again, it does present late and limited sclero uh systemic sclerosis as severe P A H and indeed pulmonary arterial hypertension and R V failure is the main cause of death in these patients. So, in 2007, Ginny Stein and the Georgetown group performed a retrospective review of all scleroderma related deaths across several major centers over a 30 year time period. And over this time period, about 60% of all scleroderma related deaths were attributable to P A H and pulmonary fibrosis from I L D versus in a concomitant decrease in renal crisis related deaths. And in fact, development of PH has the strongest correlation with increased mortality and this affects about 10-12% of patients. We recently published a study. However, looking at our cohort pre and post the introduction of upfront combination therapies of P H and what we found was that there was an improved 60% 5 year transplant free and mortality pre um improvement in survival in patients with group one pulmonary arterial hypertension. But scleroderma patients also get both group two and group three disease and there is very little improvement in those mortality rates when we talk about pulmonary arterial hypertension. Again, this is a diagnosis of exclusion. So it's characterized by basal constriction of the distal pulmonary vascular bed that leads to um medial hypertrophy, intimal fibrosis and plexiform lesions of the dysvascular that results in an increase in pulmonary vascular resistance and afterload on the R V. So here we see an MRI at the level of the main P A and the right P A. And here we can see that it's markedly enlarged at 4.3. In comparison to dim um uh ascending aorta, I notice here that the lung prima is otherwise normal, which is a necessary feature in the diagnosis of group one, given the high morbidity and mortality from group one uh P H in this population, there has been an increased attention on screening for this devastating complication and clinically what we use is known as a detect algorithm. This is the most widely accepted clinical tool out of uh the NASH group at University of Michigan. So in this study, scleroderma patients were recruited across several clinical sites based off of their risk for P A H which was defined as a disease duration of greater than three years and normal P F T S. And data from 319 patients were used to construct this algorithm. So in step one, uh you combine eight variables, you look for tylan tasia serum, uh anti centromere antibody positivity. So this is screening for limited subtype which have a higher prevalence of P A H. You also look at the anti prob MP to rule out a group two diseases, muric acid as well as some features on your P F T S. Also part of this is looking for right axis deviation um on uh an electrocardiogram that then screens into whether or not you get an echo. And if your echo has a dilated R A and a tier of velocity of greater than 2.8, you then moved on to get a right heart cap. So using this two step process, um we see the following detect test characteristics. So 96% sensitive and a great negative predictive value, but specificity and positive predictive value were actually quite low and there's several reasons for that. So number one, this was made in 2014 before the PH diagnosis uh change. It's only in patients who have certain features on their pulmonary function test. So limited generalize to patients who have I L D and that's a very frequent confounding factor in scleroderma that we should be accounting for especially in light of the fact that we see very high persistently high mortality rates from group three pulmonary hypertension and scleroderma. It also relies on resting tier velocity and the right atrial area which you know, as I shared previously, we may be underestimating the severity of P H using resting tier velocity alone and right area is really a uh an abnormal finding in patients with chronic elevation and pressure and volume. So the 2015 European uh guidelines from the Joint European Society of Cardiology and the European Respiratory Society aim to improve these test characteristics by employing a screening algorithm in all in all spoder patients regardless of what their P F T S showed. And they standardized assessment to the level of P H probability using tier velocity. And a second step that includes characteristic two D findings of pressure overload. So the test characteristics here are a bit better, but there's limitation to this methodology as well. So again, we see that they're using resting T R velocity and then the characteristic two D findings are actually what we saw in that example of severe P H. So they're looking for um flattening of the septum, they're looking for rapid acceleration time. Um They're looking for enlarged right atrium. So none of these are directed really at screening, they're more for detection of P H. And why this is important is that what your functional class is at the time of pulmonary hypertension diagnosis is strongly related to whether or not you survive. So here we see two different studies where the functional class of three and four at the time of diagnosis was associated with severely diminished survival rates at five and six. And these findings really highlight that by the time pulmonary arterial hypertension develops over 50-70% of the vasculature has already been affected. And in fact, even mild hemodynamic abnormalities may actually represent advanced pulmonary vascular disease. And so how can we use the uh tools that we have to improve early detection? So two D uh echo is highly useful for the detection of cardio pulmonary involvement. So briefly here, again, from the A four chamber view, we can look at right atrial size fractional area change. We can also measure that tricuspid annular systolic plane excursion. We can look at septal curvature, we can look at um flow uh using the acceleration time across the R V into the P A. And again, non-invasive hemodynamic measurements can also be performed using the Beli equation. So all of these features have actually been shown in pulmonary hypertension to predict heart failure and mortality right at right ventricular chamber enlargement is directly related in scleroderma to the onset of heart failure and mortality. Echo measures of R V contractivity including taps C tissue Doppler S prime. The tie index have all been shown to strongly correlate with decreased survival, Noninvasive measures of pulmonary vascular resistance and rate of change in these parameters. Also correlate with clinical outcomes including the six minute walk test and DLCO. And so we took that as a background to then look and see how R V deformation imaging actually performed in these patients. And we studied uh consecutive scleroderma patients who were asymptomatic from P H and R V failure. They were just having, you know, routine standard of care echoes and we strain of the R V free wall. And what we found here was a very interesting pattern. And I'm sorry, the arrow is a little bit misplaced. It should actually be down here where um there was this heterogeneous pattern of regional contractivity such that the overall R V free walk uh strain was diminished, but the base was actually hyper contractile. You see here that it's hyper negative. And so this was really interesting to us, you know, is basal hypercontractility of the R V free wall, actually a marker of impending P H. And this is important because mortality from R V failure is significantly higher in scleroderma P H. When you compare to other P H abnormalities, these patients suffered from disproportionately poor outcomes and diminished treatment response. So this was a study of scleroderma patients versus idiopathic pulmonary arterial hypertension patients. You can see here that both had severe P H. Um but the P H was a little bit less severe in the scleroderma patients. And despite this, they had the same cardiac index. So at lower pulmonary pressures, the R V was already beginning to fail. And indeed, when we looked at the cap of my occurs of these patients, the mortality was significantly diminished. So we then applied strain and said, great, you know, how do we use strain as a screening tool and we found the same thing at the loading conditions, the global R V strain was worse and square during my patients compared to IP H. And it was driven by this loss of baseball hypercontractility. But when we gave these patients medicines, the basal segment actually improved along with other measures. Uh even after restricting for delta change in RBS P. So R V strain has been used in P H. This was an older study back in 2011 where 80 patients um with variable P H ideologies were studied over a four year period of time. And the decrease in strain using a cut-off of 13 correlated with decreased survival. And we show that in our population as well. So um when the free wall strain hits less than 13, you really start to worry about four year of mortality, Disney and shortness of breath and derma is, is often multifactorial. So we've also um been placing some attention on the use of exercise in this population. So here, um in this study, we looked at 57 patients who were at the risk for pulmonary hypertension. So they had scleroderma, it would shortness of breath. And we refer them for a bicycle stress echo. And we measured hemodynamics at rest and peak stress. So we measured E to E prime as well as R V S P tap C tissue do or S prime and then performed offline strain analysis and what we found again, was this basal hypercontractility at rest. But then with stress, the other segments appropriately became negative, but the bay segment really didn't change very much. And in some cases actually worsened, we then subdivided the population based off of what their resting R V S P was. And so in patients that had a resting R V S P, that was less than 35 the mid and a segments increased appropriately. But in patients who had a greater that are equal to 35 resting R V S P, there was no increase in any of the segments. And actually the chamber began to dilate and these non-invasive fine needs correlate well with gold standard pressure volume loop. So here, this was again, a study of IP H patients versus systemic sclerosis patients um at similar degrees of severe P H to generate a PV loop. All you're really looking at is volume, plotted against pressure at multiple time points during a cardiac, a single cardiac cycle. And you're looking at the s pressure to the stroke volume and this uh the slope of this relationship is called E E S and that's how contractile the R V is. So, in normal healthy adults, when you exercise, the slope is kind of lifted upwards into the left. But in sclero German patients, you can see here that Sclero German patients with P H actually maintain their stroke volume and augment their cardiac output by dilating to increase preload and what that means functionally. Um in terms of using echocardiography is that stress echo actually in our population was predictive of pulmonary vascular disease. So we determined that in a 5 to 10 year follow up time, the use of this segmental strain and in particular, the behavior of the base improved our prediction of patients that went on to develop incident pulmonary vascular disease. We also determine that basal strain improves the performance of detect so positive and negative predictors. Um In this study, um we look, we use a deep neural network and machine learning techniques and this agnostically identified that basal strain was a strong predictor. So then in step two, we We did was we applied strain to the detect score. And we can see that um you know, even in this small group of about 20 patients that we reduce the number of misclassification from 6-3 by applying strain. And then lastly, I'll just end that echo can also help you distinguish whether or not you have precapillary or postcapillary. So some general features, precapillary patients are are typically younger. They may or may not have left heart more uh co morbidities, especially in younger patients. They won't, their EKG may have uh R V strain. And then there's this idea of the right phenotype. So the left heart is normal, the R V is dilated. Um We spoke about the E index will have a short acceleration time. Um and other features of primary pulmonary arterial hypertension, postcapillary patients. On the other hand, will have this left phenotype. So, in normal, right heart, until late in the disease, the left atrium will be dilated. The E F is typically normal the L V S hypertrophied and there are significant my or bowel disease. And these patients also will have a pathological e over E prime ratio. And here are some echocardiographic examples of what that would look like. So here we see a patient with primary pulmonary arterial hypertension, a very big R V small de remodeled L V, very enlarged right atrium, a dilated pulmonary artery abnormalities in the e centrality index and a dilated I V C and hepatic vein. And here we see a postcapillary theater type. So the A uh L V here is dilated, the R V is not particularly enlarged although it is hypertrophy and then there's severe mit regurgitation with evidence of effect. So some key points that I'll leave you with in terms of echo um is to look for abnormal abnormalities and hemodynamics, whether or not there's abnormal regurgitant lesions and then abnormal chamber size and function. So now let's move to the other modalities. Um com uh chest computed tomography, imaging is also integral in pulmonary hypertension to evaluate for um again, the presence of interstitial lung disease, uh presence of lung disease plus abnormal P F T suggests group three. So here we see a transaxial image showing an enlarged pulmonary artery and there's no evidence of pulmonary embolism. And then using the long window, we see extensive diffuse ground glass of pacification and honeycombing. There's some interlobular and uh and interstitial thickening Bracho. So this is a cic sclerosis with um I L D using C T, you can also look at pulmonary artery size. So the diameter of the main P A compared to the ascending aorta correlates well with mean pulmonary arterial pressures on right heart cats um with the sensitivity and specificity of around 80. So you're looking at the main P A to ascending aorta ratio C T has not been shown though to be predictive of P H as accurately as as two D echo or C M R. There's a newer technology called dual G C T and pulmonary hypertension. So this is a technique that acquires C T and geographic imaging of the pulmonary vascular at two different energy levels after the administration of I B contrast. And due to the uh different attenuation properties of the iodine contrast at these two different energy levels, the quantity of iodine inside the pulmonary vascular can then uh serve as a surrogate for pulmonary perfusion. And it can be isolated and measured. You can also um measure what's known known as um the pulmonary blood volume, which is the total amount of iodine inside the pulmonary vasculature at a certain time point and the total degree of the P PV to the main P A ratio also uh correlates with mean pulmonary arterial pressure. So some key points is that C T is really integral in ruling out group three and group four disease. You wanna make sure you exclude any abnormalities of the lug prick up And also assessed for a Q Pe or chronic throne bolic pe in group four disease. Quantitative measures are really looking at that main P A in comparison to the ascending A order at the same level. In terms of nuclear imaging VQ scans is integral in ruling out group four disease. So this is the um precapillary chronic thromboembolic pulmonary hypertension. And this is a disease of obstructive P A modeling as a consequence of major vessel thromboembolism. And the incidence here is really unknown. So you can see that there's a wide range because uh we we typically are not seeing these patients until they present with pulmonary hypertension. But we do know that in the acute phase P A thromboembolism and vessel obstruction remodeling will lead to progressive increase in PV R unless there's adequate anticoagulation. So the diagnosis of CTE is obtained at least after three months of affected ac in order to discriminate this condition from sub acute pe this again is precapillary. So the wed pressure will be normal. Um It also requires the evidence of mismatched for fusion defects on B Q scanning and then specific diagnostic signs from C T A G O M R Imaging or Pulmonary AY and V Q scans have high sensitivity and specificity in the diagnosis of group four P H, outperforming C T A other nuclear medicine techniques. Um so any increase of stress on the right heart will result in increase in myocyte VIIS. And this can be measured uh by pet imaging as well. So, increased F D G uptake in the R V can be seen in P H and correlates with me uh mean pulmonary arterial pressure associated with clinical worsening of death. Um and decrease F D D uptake is seen with effective P H directed therapies. So, nuclear imaging and pulmonary hypertension. Um Here we see um uh it, it can be again used for V Q scanning to rule out group four disease. And then experimentally pet is being used um in patients with pulmonary hypertension to measure therapeutic uh improvement. So, here we see um a patient with a 52 year old woman with emphysema and group three pulmonary hypertension F T G is injected. Um an image acquisition is taken about an hour after injection. And here we can see that there is F D G uptake in the diaphragm, infrahyoid muscles, intercostal muscles, uh which is all consistent with increased work of breathing during the examination. And then we look at the transaxial at the mid ventricular level. So you see abnormal uptake in the R V and then at the level of the P A, the P A is actually enlarged and there's abnormal F D D uptake in the right ventricular upload track. Here. Again, we see um a, a patient with transposition of the great vessels. So this is group two pulmonary hypertension um before and after repair and then a noncontrast C T acquired at the time of of spec um shows normal radio tracer distribution in the in the L V with extension of uptake into the visualized portion of the R V consistent with P H. So, lastly, I will end with card cardiac magnetic resonance imaging, which is really the the reference standard in the assessment of R V structure and function. It's highly reproducible because it's quantitative measures of R B volume mass and ejection fraction. And it's also a useful tool for the serial follow-up and pulmonary arterial hypertension. So, using C M R, we can measure volumes and calculate ejection fraction. It's highly reproducible and it may detect subclinical deterioration of L B and R V function. Um We can also quantify global R V function across three coordinate directions, circumferential, radial and longitudinal. And this can be measured using dedicated sequencing such as uh sync imaging or postprocessing of C N A imaging. Using either feature tracking or multimodality, tissue tracking C M R also allows for tissue characterization um which you can see prior to any changes in functional parameters. So there are three types of images. There's T two waiting, early T one waiting um which is taken one minute after the injection of a contrast agent and then delayed enhanced contract uh imaging. So, late gaum enhancement which is taken about 10 to 20 minutes after uh injection and the assessment of native T one and postcontrast T One mapping can allow for the acute differentiation between acute and chronic phases of inflammation and connective tissue diseases. C M R also allows for characterization of fibrosis. So lake gadolinium enhancement is really the gold standard for in vivo assessment of replacement microscopic fibrosis. C M R can detect fibrosis in less than one centimeter cubed of tissue substantially um less than other techniques and has an excellent agreement with histological findings on animal and human studies. Using C M R. We can also quantify what's known as extracellular volume and matt can look for acute inflammation um versus interstitial fibrosis. So, myocardial fibrosis is really a common feature in connective tissue diseases such as systemic sclerosis and systemic sclerosis. Not is not only associated with replacement fibrosis detected by L G E but also interstitial fibrosis. So, this technique is very helpful. We can also do C M R perfusion and pulmonary hypertension. So this may allow for the investigation of characteristic disease, specific, specific findings beyond hemodynamic arrangements. So, perfusion C M R here is showing us a circumferential loss of perfusion within the sub endocardium suggestive of ischemia due to underlying microvascular disease. This is also taken from a systemic sclerosis patient with very active brain nodes, we can also measure C M R perfusion in P H. And prior studies from our group have shown that R V and L V myocardial perfusion index was globally reduced and inversely correlated with mean pulmonary arterial pressures. Lastly, we can look at C M R flow invasor reactivity. So this is more of a novel um in investigational technique where we look at blood flow velocity. And this is correlative with high PV R pulmonary hypertension. We've also shown that there's decreased pain to sensibility seen in pulmonary hypertension and this is also predictive of mortality. Um We use a technique with isometric hand grip and we actually um also showed that using C M R that there's abnormalities and P evasive reactivities seen in group one pulmonary hypertension patients with HIV. Here we see um CMR images from a 38 year old woman with group one pulmonary arterial hypertension. Uh This uh four chamber bright blood C M R image from N diastole shows a dilated and hypertrophy right ventricle, right atrium. There's also um Boeing of the intraventricular um septum. This is taken in late cyle. Again, you see the septal behavior here, here's a short axis view showing market hypertrophy of the R V free wall and septal bowing. Um and then late gadolinium enhancement shows prominent um at the anterior and inferior insertion points. There's prominent enhancement here which is also suggestive of uh tissue fibrosis. So C M R. Um we can look for abnormal right heart size and function in a quantitative um quantitatively. We can also look at abnormal tissue characterization using native T One mapping as well as L G E and um novel E CV techniques. We can look for abnormal perfusion and we can also look at abnormal datas reactivity. So I hope that I have proven to you that echocardiography, C T, imaging, nuclear imaging and C M R are all useful for the noninvasive screening classification, prognostication and monitoring of effectiveness of therapy and P H using systemic sclerosis as a case study. Since um four out of five of the pulmonary hypertension class, uh classes can occur in this group while right heart cath is the gold standard in the diagnosis and monitoring of these patients. It can be supplemented by these noninvasive imaging modalities to ensure that it's collectively and appropriately used. An earlier detection of P A and R V dysfunction using these common imaging modalities, hopefully will lead to earlier diagnosis and treatment uh which will ultimately improve clinical outcomes for these patients. And with that, I will end
