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Neurohormone in the pathobiology of PH: RAAS
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In this presentation, filmed at the 2016 CHEST Annual Meeting, Dr. Zeenat Safdar discusses the role of the renin angiotensin aldosterone system in pulmonary arterial hypertension (RAAS).

This transcript is software driven, please understand there may be errors.  Should any inaccuracies or omissions be found, please notify transcripts@MedEdOTG.com for correction.

Hello. This is Zeenat Safdar.  I'm the director of the Pulmonary Hypertension Care Center and Clinical Research in Houston Methodist Hospital, acting Associate Professor over there. I’m going to talk about neurohormones in the pathobiology of pulmonary hypertension with special emphasis on renin-angiotensin-aldosterone system.

The system is outlined here.  The low perfusion per pressure leads to release of renin that activates the angiotensin system leading to production of angiotensin II, and angiotensin II binds to different receptors, an angiotensin I receptor, which produces the vasoconstrictive and inflammatory effects, the pathological effects of the angiotensin II, whereas activation of angiotensin II receptor leads to vasodilatation, antioxidant, anti-inflammatory effect, and there is a third angiotensin, I and VII, which is also came into limelight and activation of that through mass receptor also has vasodilatory and anti-inflammatory effect.

The other thing that angiotensin does is it a stimuli for the release of aldosterone from the adrenal medulla.  Aldosterone has been shown to be detrimental not only in left heart failure, but we feel that in right heart failure the increased activation of the system leads to vascular remodeling in the pulmonary vascularization.

This is a study looking at captopril in the treatment pulmonary hypertension by Rich, and this was many, many years ago, as you can see.  In this study, what he did was over a period of two days, 48 hours, they gave a total of 450 mg in incremental doses to these patients and then at the same time looked at or monitored their pulmonary artery pressure and pulmonary vascular resistance and they did not find any correlation between the dose and the degree of reduction in pulmonary artery pressure, or PVR, suggesting that maybe in this short period of time there is no change.

This is another study in which what they did was again they did a hemodynamic evaluation and rest and then exercise.  It’s a 12-week study in which the patient received captopril over this period of time and again they did not show any reduction in the pulmonary artery pressure, though the mean blood pressure did reduce in these patients.
In another study looking at captopril in pulmonary hypertension showing that there was reduction in pulmonary artery pressure and reduction in blood pressure with no other significant change in cardiac output, suggesting that maybe in some studies it does help and in other studies it does not, giving way to this study that was done by de Mann in Amsterdam showing that the levels of neurohormones were elevated, specifically renin, angiotensin I, angiotensin II, in these patients.  This elevated level was higher in follow-up patients who were in heart failure or worsening of PH. They had explanted lung tissue available in these patients and it showed that in patients with IPH there was increased angiotensin II type I receptor expression that was increased and when they isolated pulmonary artery endothelial cells from these patients, they found that exposing them to angiotensin I increases the production of angiotensin II that was blocked in those cells that got Enalapril.

It’s a nice proof-of-concept study and they went on to show it in animals also that using losartan in these animals, rats with monocrotaline models, decreases the pulmonary artery vascular remodeling or thickness of the vessel.

There is some data suggesting that yes, it maybe aldosterone also blocking in PH maybe have some favorable effect on these patients and this is a study by Bradley Maron showing that the level of aldosterone was elevated in PH patients and this correlated with the pulmonary artery pressure and the PVR.

This is our study that we published recently looking at aldosterone level and following these patients for almost five to six years and showing that, although the aldosterone level was elevated to a minimal degree, this level of activation did not translate into a worse survival.  We looked at the aldosterone level in terms of the median level and also in terms of the normals and we did not find a correlation or a suggestion of poor outcome in patients who had an elevated aldosterone level.

Now, what about in any clinical trials or in animal studies?  This is a study by Dr. Preston looking at spironolactone in animals, two different models showing that in these animals there is increased aldosterone, mineralocorticoid receptor activity, and blocking it with the spironolactone is helpful in reversing the vascular remodeling in these animals.

There are two ongoing clinical trials, if you look at clinical trials on gov website.  One is the effect of spironolactone on collagen metabolism, and the other one is spironolactone in PAH.  I’m going to talk about this study; this is what we are doing in Houston.

We have proposed that aldosterone is elevated and maybe the circulating level may not be elevated, it may be the tissue level that is increased, and that through the TGF pathway leads to collagen synthesis and vascular fibrosis and worsening PAH.  We have enrolled 46 patients were consecutively screened, but 35 patients have completed the study and this is briefly the baseline characteristics of these patients. 

Our preliminary report suggests that there were no adverse events in terms of hyperkalemia, increased creatinine or liver abnormalities over a 16-week period.  I should point out this is a crossover study so every patient got eight weeks of spironolactone or placebo and at the end of the eight weeks it was randomly switched such that patients who got placebo for the first eight weeks got spironolactone for the next eight weeks and vice versa.  None of the patients in our study withdrew because of study-related side effects and there were no other LFTs or potassium abnormalities.

In conclusion, we showed that RAAS activation is activated.  The data is there, but we are still awaiting studies which are ongoing looking at the effect of spironolactone as a therapeutic option in PH patients.  Further studies are needed and awaited.

Thank you very much.