Why We Should Care about the Mysteries of Pulmonary Hypertension

The more you know about pulmonary hypertension, the more mysterious it becomes. You may believe that, while knowledge has a half-life, the mysteries live forever. But the news here is that mysteries also have a half-life!

I will start with an easy example: the question of why pulmonary arterial wedge pressure (PAWP) is normal in pulmonary veno-occlusive disease (PVOD). As we all know, PVOD is a rare disease that primarily affects the small postcapillary pulmonary veins in which the venous perfusion resistance increases excessively. This leads to a strong increase in pulmonary capillary pressure but not in PAWP. How is this possible? The solution to this mystery is very simple: PAWP does not reflect the pulmonary capillary pressure but rather the pressure in the large pulmonary veins, which is very similar to the left atrial pressure and does not increase in PVOD. For this reason, the Fifth World Symposium on Pulmonary Hypertension has discouraged the use of terms like “P_C” or “PCWP” for the PAWP. ¹

The next mystery is much more difficult and may have no real solution. The mean value (± standard deviation [SD]) of pulmonary arterial pressure (PAP) has been reported as 14.0 ± 3.3 mmHg. ² This would normally imply a border between normal and abnormal at the average value plus 2 SDs (i.e., 20.6 mmHg). Pulmonary hypertension has, however, been defined as a pressure ≥25 mmHg, although there is no evidence to support this value. ³

Understanding this mystery may only be possible from a historical perspective. Experts used to speak of primary pulmonary hypertension, which is now called idiopathic pulmonary arterial hypertension (IPAH). Upon diagnosis, patients had a mean PAP (±SD) of 55 ± 15 mmHg, which would define a lower limit for this disease as 55 mmHg minus 2 SDs (i.e., 25 mmHg). On the other hand, in healthy control patients, the resting PAP very rarely exceeds 25 mmHg, whereas it would exceed 20.6 mmHg at a rate of 2.3%, based on the assumption that the distribution of PAP among healthy control patients follows a Gaussian distribution. There may be no hard scientific evidence for using 25 mmHg to define pulmonary hypertension, but doing so avoids a lot of false-positive findings.

In 2008, a new method for noninvasive assessment of PAP was patented. It uses the fact that the stroke volume that is pumped into the pulmonary trunk gets caught in a vortex if the mean PAP is elevated, and it is sensitive even to borderline elevation of PAP. ⁴ The pressure determination relies on the relationship between the duration of the vortex and the mean PAP. So where is the mystery here? We have no clue as to why the vortex forms so reliably and why its duration is linearly related to the mean PAP with almost mathematical precision.

We know of a multitude of pathologic changes and mechanisms in IPAH, but most of them are mechanical, molecular, or genetic changes in response to pulmonary hypertension. There is just one well-established causative factor, the mutation of the BMPR2 receptor, but we still do not understand the molecular mechanism that drives BMPR2 mutations to cause pulmonary hypertension. We have not even identified the BMPR2 haplodeficient primary cells that initiate the pulmonary arterial remodeling. It is possible that the mutation primarily affects the function of the pulmonary arterial smooth-muscle cells, but it might be even more likely to affect the pulmonary arterial endothelial cells or some bone marrow cells. ⁵ To find a cure for PAH, it would be of utmost importance to clarify these primary disease mechanisms.

You may think that the causes of pulmonary hypertension in chronic lung disease, alveolar hypoxia, and chronic lung inflammation are well established and that there are no open questions, but there is recent evidence that pulmonary vascular remodeling involves distinctively different genetic pathways in severe idiopathic pulmonary fibrosis and severe chronic obstructive pulmonary disease. ⁶ So we know that there are pathologic mechanisms specific for pulmonary disease, but we have not been able to decipher them.

We have always thought that local pressure and shear stress in the pulmonary vascular wall induce local vascular remodeling, but a French surgical group showed that this may not be true. ⁷ They compared piglets with right lung ischemia with right pneumonectomy and analyzed the remodeling of the pulmonary arteries of the remaining left lung after 8 weeks. Ischemia of the right lung caused remodeling, but right pneumonectomy did not. This speaks in favor of circulating factors rather than local mechanisms as the cause of remodeling of the pulmonary arteries. The question is what these circulating factors might be.

We have always thought that pulmonary vascular remodeling and pulmonary vasoconstriction are more or less two facets of the same pathologic mechanism, yet when we look at the pulmonary arteries of the ovalbumin-sensitized asthmatic mouse, we are impressed by massive vascular remodeling that is not associated with pulmonary hypertension. ⁸ Obviously, remodeling and vasoconstriction are two separate issues. It is just a shame that we still do not know the true link between chronic vasoconstriction and proliferative remodeling in pulmonary hypertension.

The smoking mouse starts to develop pulmonary vascular remodeling after 4–6 months. After that, it also develops pulmonary emphysema. ⁹ This is a bit of a mystery but not the big one. The big mystery is that both knocking down the inducible NO-synthase (INOS) and pharmacologic block of INOS prevent vascular remodeling and emphysema formation in line with the deleterious effects of INOS, whereas endothelial NO-synthase (ENOS) has beneficial effects in the same model. Both INOS and ENOS produce the very same highly diffusible NO. The mystery is why ENOS is beneficial and INOS destroys the smoker's lung.

There is also a big mystery even in the well-established hypoxic mouse model of pulmonary hypertension. The chronic hypoxic mouse reliably develops pulmonary hypertension within a few weeks. If the mice are forced to run regularly, it can be expected that PAP and pulmonary vascular shear stress will increase excessively, promoting remodeling. Actually, the running mice were protected from both remodeling and pulmonary hypertension. ¹⁰ Obviously, such beneficial effects occur also in human pulmonary hypertension patients. ¹¹ The reasons for such impressive and highly unexpected effects of exercise are unknown.

As I have said, the gap between knowledge and mysteries may increase with time, but this is no reason to give up. Instead, we should increase our efforts to better understand pulmonary hypertension in the search for a cure.