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Myth one, the traditional stepwise approach is still sufficient. Here are my disclosures again? The learning objectives of this talk are to describe the major pathophysiological pathways underlying PAH and how they inform therapeutic targets, and apply current international guideline recommendations to ensure evidence-based use of approved PAH therapies. Let's start with a polling question. In patients with newly diagnosed PAH and evidence of elevated pulmonary vascular resistance, which of the following best reflects the key pathophysiological pathways that drive disease progression and form the basis for current therapeutic targets? A, excessive activation of the renin angiotensin aldosterone system and reduced endothelin 1 signaling. B. Overexpression of nitric oxide synthase and increased prostacyclin production. C. dysregulation of endothelin 1, nitric oxide, prostacyclin, and active and BMP signaling pathways. D. Primary involvement of the sympathetic nervous system with reduced catecholamine clearance. E. Isolated pulmonary venous remodeling without arterial involvement. OK, we'll move on. So we'll start with the case. This is a 55-year-old man with type 2 diabetes and obstructive sleep apnea who presented to the ER in December 2023 with chest pain. He had a CTP study that showed no PE but mosaicism in air traffic. And he also had a transthoracic echocardiogram that had signs of pulmonary hypertension. There's the short axis view here, and you can see that there is some septal flattening. Here's a Doppler of the RV outflow track, and you can see that there is a a notching of this uh outflow track Doppler, which is consistent with significant precapillary pulmonary hypertension. And here's the four chamber apical view, and you can see that the right ventricle is moderately enlarged, in fact larger than the left ventricle, consistent with pulmonary hypertension, precapillary pulmonary hypertension. Now, at that time, the patient was referred to see an outpatient pulmonologist. They saw that uh pulmonologist the next month. Get PFTs that demonstrated mild restriction and a mildly decreased DLCO. So he was scheduled for right heart cath based on the findings on his echocardiogram that were concerning for precapillary pulmonary hypertension. A right heart catheterization, the following hemodynamics were obtained. The RA was 3. RV was 65/5. The PA pressure was 68/24, a mean of 39. The uh pulmonary capillary wedge pressure was 7. Cardiac output of 5.2, a cardiac index of 2.5 L per minute per meter squared. And a PDR that worked out to be 6.2 wood units. So these are all findings consistent with precapillary pulmonary hypertension. And, uh, consistent with his diagnosis, clinical diagnosis of pulmonary arterial hypertension. He had no response to nitric oxide. Other information? He endorsed WHO, functional class 3 symptoms. He was short of breath in the shower and getting dressed. His NTPro BNP was 551 g per milliliter. 6 minute walk distance was 250 m. So in this patient who underwent other studies, and again his clinical diagnosis is now PAH, what treatment options do we have? And today we really have 4 pathways that we can target, and I'll walk you through this. Uh, from left to right. We have here uh the endothelin pathway where uh pulmonary arterial hypertension is associated with increased levels of endothelin one that's uh binds to its receptors on smooth muscle cells. This promotes vasoconstriction and pulmonary vascular remodeling. So we can block this with ERA's endothelin receptor antagonists. Now the second pathway here is the nitric oxide pathway. Nitric oxide is secreted by endothelial cells, and then in smooth muscle cells, it activates soluble guanolate cyclase to generate cyclic GMT. And that leads to vasodilation and um improved uh vascular tone, and this pathway can be activated directly with an SGC stimulator such as Riotegut or by inhibiting the breakdown of cyclic GMP by inhibiting phosphodiesterase 5 inhibitor uh phosphodiesterase 5 inhibitors such as sildenafil or tadalafil. Then we have here the prostacyclin pathway, where prostacyclin is also secreted by endothelial cells and binds to its receptor on smooth muscle cells, the IP receptor. This will increase levels of cyclic AMP that promote vasodilation and positive vascular remodeling. Um, and so this we can target with prostacyclin pathway agonists or PPAs as shown here, but all, uh, improve pulmonary hypertension. And then our most recent pathway that's been identified for treating uh PAH is through inhibiting the activity of activin. So activin binds to its receptor and promotes abnormal pulmonary vascular remodeling that counteracts the beneficial signaling of the receptor BMPR2. BMPR2 is a receptor that is the most common mutation with loss of function mutations in hereditary pulmonary arterial hypertension. So, by blocking activin with activin signaling inhibitors that will literally bind activin and prevent it from signaling through its receptor, this is thought to rebalance signaling and effectively increase signaling by BMPR2, which acts as a quiescence factor and uh promotes normal uh pulmonary vascular um quiescence and counteracts the abnormal pulmonary vascular remodeling seen in TAH. So you can see here, we have a range of therapies, some of which are thought to act primarily as vasodilators, but also have some anti-proliferative effects. And then the ASIs, um, such as cetaricept, which are really thought to rebalance the pro and anti-proliferative signaling in these smooth muscle cells. So, that's good to know. We have these 4 pathways that we can target with therapies today, but how do we use them? So this comes to our next polling question. In patients with confirmed group 1 PH, that is PAH, who are not high risk at diagnosis and have intermediate risk features, e.g., who WHO functional class 2 to 3, and elevated antiprobin P and a reduced 6 minute walk distance, which initial treatment strategy is recommended by current international guidelines? A, start monotherapy with either an ERA or a PDE5 inhibitor. B. Begin sequential therapy only after 6 months of observation. C. Start triple oral therapy with ERA plus PDE5 inhibitor plus Celexa peg. D, initiate upfront dual oral therapy with an ERA plus a PD5 inhibitor. E, reserve combination therapy only for patients with high risk chemodynamics. All right, we'll move on. So, here you see the ERS ESC 2022 PH treatment algorithm, and I'll walk you through this. So once someone has been diagnosed with PAH, um, we'll, we're gonna focus on this side, the patients who don't have cardiopulmonary comorbidities. And what is um performed is a risk evaluation. And based on their risk evaluation, essentially whether they're lower intermediate risk or identified as high risk, for lower intermediate risk patients, they will start on dual oral therapy with an ERA plus a PDE5. That's a class one recommendation. For patients who are high risk, based on their initial presentation, you start with upfront triple therapy with an ERA PDE5 inhibitor and an IV or subcutaneous prostacyclin. Now, you then follow them up regularly at 3 months, and then you reassess their risk, and then based on that, if they have not achieved low risk status, um, you will then add therapy.