Question 1

At the start of your talk you said group 1 pulmonary hypertension was once often fatal, but that the multidisciplinary approach has changed this. Can you say more?

Dr. Biswarup Purkayastha · Accepted Answer

Even when I was training, group 1 pulmonary hypertension meant death within a few years; care amounted to leaving the patient to die in peace with friends and family. Today patients are put on combination therapy with sotatercept, a very expensive drug at around 10,000 US dollars a vial, given once every three weeks. In the trial, death or adverse outcome was 17% against almost 55%. That cannot be a statistical artefact or a marginal difference; it is a clear-cut indication that this therapy is a game changer for group 1 pulmonary hypertension.

Question 2

You suggested low-dose phosphodiesterase 5 inhibitors. Given that these drugs are also used for erectile dysfunction, how do you handle that effect in treatment?

Dr. Biswarup Purkayastha · Accepted Answer

Once you start anybody on a phosphodiesterase 5 inhibitor, you have to inform them of two things: they may have dizziness or syncopal episodes from low blood pressure, and they may have erections more easily, rarely a prolonged erection lasting more than four hours, which needs urgent medical attention. In a younger male, counselling with a counsellor or clinical psychologist is usually needed, to explain that there is nothing wrong with him and that this is part of the treatment. As the dose is built up, patients become less bothered by it and learn ways to manage, such as wearing looser clothing. My starting dose of tadalafil is always 2.5 mg for a patient under 60 kg and 5 mg for anyone over 60 kg, building up to the standard pulmonary hypertension dose of 40 mg once daily.

Question 3

What are the three major pharmacological pathways targeted in pulmonary hypertension?

Dr. Biswarup Purkayastha · Accepted Answer

There are three classic pathways you want to target. The nitric oxide pathway: inhibit phosphodiesterase 5, or stimulate soluble guanylate cyclase, so that there is vascular relaxation. The endothelin pathway: block endothelin receptors, which otherwise drive vasoconstriction and smooth muscle growth. And the prostacyclin pathway: stimulate it with prostacyclin analogues or selexipag for vasodilatation.

The philosophy so far was to stimulate one receptor or enzyme or another to cause vasodilatation; nothing acted directly on the remodelling of the vessel itself. Sotatercept, a newer fourth pathway, works somewhat like an anti-proliferative drug: it blocks activin signalling and prevents smooth muscle proliferation in the pulmonary vasculature, reducing pulmonary vascular resistance and pulmonary arterial pressure. That is the game changer.

Question 4

What pulmonary vascular resistance threshold, in Wood units, should trigger medical therapy in pulmonary hypertension?

Dr. Biswarup Purkayastha · Accepted Answer

Today, pulmonary hypertension is defined by a mean pulmonary artery pressure over 20 mmHg, and pre-capillary disease by a PVR of more than 2 Wood units, on right heart catheterisation. A patient confirmed to have group 1 pulmonary arterial hypertension who is not vasoreactive should be started on therapy: at least a phosphodiesterase 5 inhibitor together with an endothelin receptor antagonist such as macitentan, ambrisentan or bosentan. You may not want to use selexipag or an oral prostacyclin analogue at first, but you definitely have to put these patients on double therapy. If on follow-up risk assessment they remain at intermediate or high risk, introduce the third component, triple therapy, and look for signs of improvement. Patients who show acute vasoreactivity, with a fall in pulmonary artery pressure on testing with inhaled nitric oxide during right heart catheterisation, normally have a better course and outcome and are treated with high-dose calcium channel blockers.

Question 5

If the patient remains symptomatic, what is the next option?

Dr. Biswarup Purkayastha · Accepted Answer

The next option is to add an endothelin receptor antagonist such as bosentan or ambrisentan. If the patient is still symptomatic, start oral selexipag. Beyond that, sotatercept (Winrevair) deserves a definite trial. We currently have a patient who came in with an RV systolic pressure of 138 mmHg measured at right heart catheterization, and whose pulmonary arterial systolic pressure had come down from 138 about two weeks after starting it. So sotatercept may be an answer, but only once triple therapy has failed to produce a response for at least six months to a year.

Question 6

Why does pulmonary hypertension cause right ventricular failure rather than left ventricular failure initially?

Dr. Biswarup Purkayastha · Accepted Answer

Pulmonary hypertension is, by definition, a pressure overload, and it sharply increases RV afterload. The RV is a volume-handling ventricle, not a pressure-handling one. It is used to a lot of preload: you can put a great deal of volume into the RV and it will not fail, because its shape is designed to accommodate volume. The LV, on the other hand, is the pressure-handling ventricle; it is thick, and a lot of pressure will not kill it, though it may hypertrophy. Under pressure overload the RV hypertrophies up to a point, and beyond that point it simply fails. That is why pulmonary hypertension makes the RV fail earlier than the LV.

Question 7

Which antihypertensives are safe in pregnancy? Is amlodipine safe?

Dr. Biswarup Purkayastha · Accepted Answer

Yes and no. The established first-line options in pregnancy are labetalol, nifedipine and methyldopa. Amlodipine is reasonably safe on the data available, although nifedipine is the calcium channel blocker with the most experience in pregnancy. ACE inhibitors and angiotensin receptor blockers must be avoided.

Question 8

Why is P2 loud in pulmonary hypertension?

Dr. Biswarup Purkayastha · Accepted Answer

The pulmonary valve opens into a high-pressure circuit, so when it closes it does not close gently: it slaps shut. That forceful closure produces the loud P2. Normally the pulmonary valve opens and closes gently and P2 is soft; if it slaps shut, no matter how small the valve is, P2 will still be loud.

In tetralogy of Fallot, P2 is usually soft or inaudible, and a loud single second sound usually comes from the anteriorly placed aorta. In my board finals, though, I had an adult with tetralogy and a loud P2. There is a very rare but real physiology in which pulmonary stenosis does not necessarily mean low pulmonary flow: collaterals can create high pulmonary flow, raising pulmonary arterial pressure and causing pulmonary hypertension. In that case, despite the tetralogy and the RV outflow stenosis, P2 will still be loud.

Question 9

What is the mechanism of pulmonary hypertension in patients with HIV?

Dr. Biswarup Purkayastha · Accepted Answer

Two mechanisms operate together. Viral proteins such as Nef, Tat and gp120 injure the endothelium of the small pulmonary arteries, causing endothelial dysfunction. At the same time, chronic inflammation and immune activation drive smooth muscle proliferation. Endothelial injury and smooth muscle hyperplasia together narrow the vessels from within, producing the same plexiform lesions seen in idiopathic pulmonary arterial hypertension. That is the mechanism of pulmonary hypertension in a patient with HIV.

Live Discussion with Dr. Biswarup Purkayastha