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Pulmonary Hypertension - 12/18/2012

posted Dec 18, 2012, 7:33 AM by Rohit Das   [ updated Dec 27, 2012, 6:36 AM by Purnema Madahar ]

On a continuum from last time, I thought I’d write about a pretty dense topic – Pulmonary Hypertension (PH). PH can occur as an isolated disease, termed idiopathic pulmonary arterial hypertension (IPAH – which can be sporadic or inherited), but more commonly, it occurs in the context of various other illnesses. A lot to talk about here, and I shall do my best to summarize…

·         How is pulmonary hypertension classified, and why was it classified into different groups?

·         What are the clinical manifestations of pulmonary hypertension? How is pulmonary hypertension diagnosed?

·         Why does the diagnosis matter – what’s the prognosis and how can we treat it?

How is pulmonary hypertension classified, and why was it classified into different groups?

·        There is some history to this question which is worth knowing. The first classification of PH occurred in 1973, at which time it was classified as either primary PH (PPH) or secondary PH. In 1998, some gurus decided to change the schema, so as to group etiologies that shared similar pathologic mechanisms and treatment options – this led to the 5 classes we are taught now. In 2003, they met AGAIN, and decided to abandon the term PPH, and replaced it with the term pulmonary arterial hypertension (PAH), and they also abandoned the term “secondary PH.” They also made some minor terminology changes in 2008…which leaves us 5 different groups, as follows:

·         Group 1 – Pulmonary Arterial Hypertension (PAH) – This group encompasses patients with idiopathic/familial PAH, and PAH in the setting of various other etiologies, including connective tissue diseases, HIV, portal hypertension, drug-induced, schistosomiasis, hemolytic anemias, congenital heart disease and a few others. The common theme here is diseases that localize to the pulmonary arterial vasculature, leading to similar pathologic mechanisms in the development of PAH. The attached NEJM article provides a nice overview of the mechanisms involved in PAH, mainly highlighting an imbalance of vascular effectors that leads to vasoconstriction, endothelial proliferation, and microthrombosis. The overall prevalence of PAH is around 5-15 cases per million patients/year, but varies with different etiologies. Of note, systemic sclerosis commonly leads to PAH, occurring in 10-12% of patients, and probably has the worst overall prognosis within this subgroup. See below for therapeutic options…

·         Group 2 PH Owing to Left Heart Disease – Ok, this one’s a little more straightforward. Though the pathology is complex, conceptually, increased LVEDP leads to increased LA pressure, which passively transmits back to the pulmonary vasculature…and thus PH is born. This can occur with LV dysfunction, left-sided valvular disease, and with diastolic dysfunction with preserved ejection fraction. Overall, this is the most common cause of PH, and occurs in 60% of patients with severe LV dysfunction and up to 70% of patients with isolated LV diastolic dysfunction. Treatment of heart failure is the approach in this group, and advanced PAH therapy is not recommended.

·         Group 3 PH Owing to Chronic Lung Disease/Hypoxia – Big players here are COPD, ILD, and sleep disordered-breathing (i.e., OSA). In particular, emphysema, due to its combined obstructive and fibrotic changes, has a very high incidence of PH, estimated to be around 90% in GOLD Stage IV patients. In general, though, the PH in these cases are mild-moderate, usually not exceeding a mean pulmonary arterial pressure of 35 mmHg. Estimates for the incidence of PH in OSA and ILD are not clear, but definitely contributors. Treatment of the underlying lung disease and supplemental oxygen is the approach here, as there is not enough data to support the use of advanced therapy.

·         Group 4 PH Owing to Chronic VTE Disease (CTEPH) – The incidence of this is not clear, though estimates are that around 5% of patients with an acute PE develop CTEPH, though only 40% of patients CTEPH actually had a clinically apparent acute PE episode. One of the unique aspects about this subgroup is that, via pulmonary endarterectomy, CTEPH is actually curable in a select group of patients. Lifelong anticoagulation is necessary. Advanced PAH therapy has a weak recommendation in patients who need pre-operative medical therapy, and also in patients with predominantly distal disease not amenable to surgical therapy.

·         Group 5 Everything Else…There’s a whole lot of stuff in this bag that I don’t really want to go into…some interesting ones that you might see are sarcoidosis, myeloproliferative disorders and thyroid disease… for a more thorough review, please see the classification review attached.

What are the clinical manifestations of pulmonary hypertension? How is pulmonary hypertension diagnosed?

·         The main symptoms resulting from PH are a result of decreased cardiac output, especially during exercise, as a result of RV dysfunction and consequent decrease in LV preload. Such symptoms include exertional dyspnea, chest pain (particularly if the pulmonary trunk is big enough to compress the left main artery) and syncope. Elevated right sided pressure chronically will lead to symptoms of right heart failure – lower extremity edema, and abdominal pain from congestive hepatopathy.

·         Progression of just PH to PH with RV hypertropthy à dysfunction is characterized by multiple key physical exam signs. RV hypertrophy can be accompanied by a right sided fourth heart sound and/or a parasternal heave, and RV failure may lead to a right sided third heart sound. Additionally, one can notice an increased P2 with RV hypertrophy, which evolves to widening split of S2 when the RV starts to fail.  Regarding murmurs, things to listen for are for the inspiration-augmented murmurs - PR (diastolic, best heard between the 2nd and 3rd intercostal spaces) and TR (holosytolic murmur, best heard at the lower left sternal border). Other important signs include elevated JVD and a pulsatile liver…

·         Workup includes testing for the different etiologies described above, and also the documentation of pulmonary HTN, now defined as a resting mean pulmonary arterial pressure of ≥25 mmHg (exercise-based criteria have been eliminated). The latter part is tough…EKG and chest films can be suggestive, but definitely not diagnostic. Even the easily obtainable TTE has a lot of flaws – it depends on TR to estimate PA pressures, and thus not a direct measure of PA pressures. In a series of 70 patients, in 50% of cases, right heart catheterization and TTE differed by 10 mmHg (higher or lower), and in most of those cases, the difference was significantly greater than 10mmHg (thought extent of underestimation was greater than overestimation). Bottom line, for an accurate diagnosis, you need a right-heart cath.

Why does the diagnosis matter – what’s the prognosis and how can we treat it?

·         PAH kills patients, and in those with PH due to Group 2-5 etiologies, it kills patients faster than those without PH. Symptomatic patients with idiopathic PAH have a mean survival of 3 years, whereas those with PAH associated with another disease have a worse prognosis. Patients with right heart failure usually die within one year. Prognostic scores have been published, particularly the REVEAL score, which was validated in a prospective cohort – that study and the PAH risk score is attached.

·         There are certain therapies that deserve consideration in all the groups. Diuretics treat fluid retention. Oxygen is the cornerstone of therapy in Group 3, and though it is inferred that patients with PAH and hypoxemia also benefit, there is no controlled, long-term data. Anticoagulants are the cornerstone of therapy in Group 4, but there is retrospective data to support its use in patients with IPAH and drug-induced PAH.

·         Calcium channel blockers have been studied mainly in the context of IPAH. In patients with a “positive vasoreactivity test” (defined as ≥ 10mmHg decrease in mean PAP, to reach a mean PAP of ≤ 40 mmHg with a normalized or increased cardiac output), OBSERVATIONAL studies have showed improved long-term survival. However, recent studies have showed that only 10% of patients have a positive test, and of those, 50% maintained functional improvement over one year. Despite the lack of controlled data, calcium channel blockers are the first line treatment in appropriate candidates.

·         Advanced therapy includes prostacyclin analogues (Epoprostenol, Iloprost, Beraprost), endothelin receptor antagonists (commonly here – Bosentan) and PDE-5 inhibitors (Sildenafil, Tadalafil). Studies looking at these agents alone and in combination have been done fairly extensively, or at least extensively enough that I don’t feel I can adequately summarize without putting you too sleep through what is already one of the longer dailies…anyway, Figure 1 of the attached treatment review gives an “evidence-based algorithm,” but when it gets to this point, I’d leave it to Dr. Zolty.

I’ve attached a bunch of articles to this one, the majority of which are from the 2008 4th PAH Symposium published in the Journal of American College of Cardiology in 2009. Complicated topic, though I think unique in how the experts have so ardently tried to organize it conceptually and practically…until next time…


Farber et. al., NEJM 2006, Volume 351: 1655-65

Updated Clinical Classification of Pulmonary Hypertension
Simonneau et. al., J Am Col Cards 2009, Volume 54(1): S43-54

Badesch et. al., J Am Col Cards 2009, Volume 54(1): S55-66

Hoeper et. al., J Am Col Cards 2009, Volume 54(1): S85-96

Benza et. al., CHEST 2012, Volume 141(2): 354-62

Barst et. al., J Am Col Cards 2009, Volume 54(1): S78-84



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