Primary Aldosteronism & Resistant Hypertension – Prof. Dr. Morris Brown (London, UK)

Dr. Morris Brown presents the current knowledge on pathogenesis, diagnosis and treatment of primary hyperaldosteronism, and on aldosterone-synthesis inhibitors as a drug class in resistant hypertension.
Dr. Morris Brown is Professor of Endocrine Hypertension at Queen Mary University of London, and the William Harvey Heart Centre, London, UK. He is past president of the British Hypertension Society, and conducted landmark studies on antihypertensive treatment, including PATHWAY 1, 2 and 3, TIME, BrigHTN, INSIGHT and ACCELERATE. He also published seminal studies on the pathogenesis of primary hyperaldosteronism.

The interview was recorded on October 16th, 2023.

Moderators: Prof. Dr. Marcus Säemann (Vienna, Austria), Prof. Dominique Guerrot (Rouen, France) and Prof. Dr. Gunnar Heine (Frankfurt, Germany).

Articles discussed:

Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies.
Williams B, …, Brown MJ; British Hypertension Society programme of Prevention And Treatment of Hypertension With Algorithm based Therapy (PATHWAY) Study Group.
Lancet Diabetes Endocrinol. 2018
doi: 10.1016/S2213-8587(18)30071-8

Effect of AZD9977 and spironolactone on serum potassium in heart failure with preserved or mildly reduced ejection fraction, and renal impairment: A randomized trial.
Squire IB et al.
Clin Transl Sci. 2022
doi: 10.1111/cts.13377

A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease.
Filippatos G, …, Pitt B.
Eur Heart J. 2016
doi: 10.1093/eurheartj/ehw132.

Inhibition of aldosterone synthase: Does this offer advantages compared with the blockade of mineralocorticoid receptors?
Ando H.
Hypertens Res. 2023
doi: 10.1038/s41440-023-01188-z.

Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis.
Agarwal R, Filippatos G, Pitt B, Anker SD, Rossing P, Joseph A, Kolkhof P, Nowack C, Gebel M, Ruilope LM, Bakris GL; FIDELIO-DKD and FIGARO-DKD investigators.
Eur Heart J. 2022
doi: 10.1093/eurheartj/ehab777.

Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT).
Brown MJ et al.
Lancet. 2000
doi: 10.1016/S0140-6736(00)02527-7

Medical Research Council trial of treatment of hypertension in older adults: principal results.
MRC Working Party.
BMJ. 1992
doi: 10.1136/bmj.304.6824.405.

Effect of amiloride, or amiloride plus hydrochlorothiazide, versus hydrochlorothiazide on glucose tolerance and blood pressure (PATHWAY-3): a parallel-group, double-blind randomised phase 4 trial.Brown MJ et al.; British Hypertension Society’s Prevention and Treatment of Hypertension with Algorithm-based Therapy (PATHWAY) Studies Group.
Lancet Diabetes Endocrinol. 2016
doi: 10.1016/S2213-8587(15)00377-0

Telmisartan, ramipril, or both in patients at high risk for vascular events.
ONTARGET Investigators; Yusuf S et al.
N Engl J Med. 2008
doi: 10.1056/NEJMoa0801317

Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension.Freeman MW, …, Brown MJ; BrigHTN Investigators.N Engl J Med. 2023doi: 10.1056/NEJMoa2213169.Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.
Williams B, …, Brown MJ; British Hypertension Society’s PATHWAY Studies Group.
Lancet. 2015
doi: 10.1016/S0140-6736(15)00257-3.

The Unrecognized Prevalence of Primary Aldosteronism: A Cross-sectional Study.
Brown JM, Siddiqui M, Calhoun DA, Carey RM, Hopkins PN, Williams GH, Vaidya A.
Ann Intern Med. 2020
doi: 10.7326/M20-0065

The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline.
Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M, Young WF Jr.
J Clin Endocrinol Metab. 2016
doi: 10.1210/jc.2015-4061

[11C]metomidate PET-CT versus adrenal vein sampling for diagnosing surgically curable primary aldosteronism: a prospective, within-patient trial.
Wu X, Brown MJ.
Nat Med. 2023
doi: 10.1038/s41591-022-02114-5

Primary aldosteronism: molecular medicine meets public health.
Azizan EAB, Drake WM, Brown MJ.
Nat Rev Nephrol. 2023
doi: 10.1038/s41581-023-00753-6

Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production.
Wu X, Azizan EAB, …, Brown MJ.
Nat Genet. 2023
doi: 10.1038/s41588-023-01403-0.

Who and How Should We Screen for Primary Aldosteronism?
Funder JW.
Hypertension. 2023
doi: 10.1161/HYPERTENSIONAHA.123.20536

Dear colleagues in partnership with the and the FR Marcus at home welcomes Professor Morris Brown in London United Kingdom with whom we would like to discuss firstly the diagnosis and treatment of primary hyperism and secondly and somewhat overlapping novel therapeutic approaches in resistant hypertension Dear Professor Brown dear

Moris thanks so much for taking the time thanks so much for being our guest tonight it’s my pleasure Dr moris Brown is Professor of endocrine hypertension at the Queen Mary University of London and the William Harvey Heart Center again in London UK and past president of the British hypertension Society during

More than four Decades of laboratory and clinical research on the pathogenesis and treatment of hypertension he has published countless seminar papers in the field with more than 20 Publications in the New England Journal and last it alone he has conducted Landmark studies on anti-hypertensive treatment including

Pathway one to a three time Wren insight and accelerate to name just a few a further major focus of his clinical and academic work are studies on the most common cause of secondary hypertension which is primary hyperism which may revolutionize the way we detect and treat affected patients in

The future thank you very much for asking me and I thought I would start with a few slides on how we currently diagnose and treat hyper jism and what we are doing to try and modernize some of that I one disclosure I should start with which is that I was a member of

Scientific vaj Board of Sor and they have now been taken over by astroica so next year will be the 70th anniversary of the discovery of the first patient with what became called cons syndrome and because of the limitations of the Technologies of the time this patient turns out to have a rather

Extreme phenotype both biochemically and size of a tumor and to a degree that put doctors off for Scent of a much commoner type of Prim arism for following decades and in part that also led to a rather arduous course before one can diagnose the patient and then find out

Whether the patient has unilateral or bilateral arism with the unilateral type being the iso the subtype that could can be cured by surgery so I’m not going to go through the 10 herles that I’ve shown here but I might mention that it’s difficult at the start because of the

Need to withdraw interfering treatment before diagnostic tests are undertaken and even at the end of the hurdle race it’s a TOS of a CO before we know which patients are going to be completely cured of their hypertension by surgical treatment so that hurdle races a view of what the current guidelines for

Treatment of prime Aldo teaches us and I will briefly go through what we should currently be doing and then suggests some possible changes this is the key algorithm in the guideline with multiple steps and it is true that if you begin at the beginning screening all patients at increased risk

And end of the end removing the unilateral cause of hyperestrinism most patients with prime alism would be diagnosed and effectively treated but currently fewer than 1% of such patients are found and diagnosed and treated to simplify this diagram a little I’ve drawn a line between the first part which looks at diagnosing

Primal jism itself and the second part which looks at subtyping into unilateral and bilateral disease and for the DI nosis itself there are two ways of doing this either the patient has what I call the trilogy of high aerone low potassium and suppressed rening or if any of those

Are missing the patient needs to have one of four suggested confirmatory tests and then in the second part which is to do with subtyping and then treatment the available test is an invasive test called adrenal vein sampling which very few centers can do and it leads us to a surgical treatment

Which maybe was appropriate when con syndrome was a curiosity but in the absence of long-term data showing efficacy it’s more doubtful whether surgery can be justified as a treatment for a condition we now know to be of a cause of between five and 133% of all hypertension so before leaving this I

Just want to add a couple of suggestions for making the guidelin more practically applicable one is to focus on patients with high sodium levels and and low potassium levels even when these aren’t actually outside the normal range and and the second is to be less concerned about drugs interfering with

Measurements with the only serious interfering drug being beta blockers which work by blocking release or rening so the rest of what I’m going to say is about the patients below the line in whom the diagnosis has been made where we’re insul in trying to find a

Unilateral cord and and cure it and in in terms of what we currently do conventional management has scarcely changed in the last 30 years and much of it not in the last 50 years but alongside this unchanging practice in the clinic the last decade or so has been an exciting time in our

Molecular understanding of prime aism and I will be saying a little bit about new tests which allow us to image the adenoma to study the adenoma immunohistochemically after it’s removed and to understand what’s causing it by looking for somatic mutations in the tumor and this is not now just

Scientific curiosity but allows us to begin to change our practice and the the changes which I will illustrate our molecular Imaging or petct ablating the individual nodules rather than removing the whole adrenal using tests based on our understanding of genotype for predicting which patients can be completely cured of

Hypertension by removing the adrenal and then trying to get away from any intervention by uh developing new treatments which will inhibit alest Durant production by the tumor so the PET CT scan that we uh developed uses an old veter anesthetic called carbon Le metomidate and xvivo it is a non-selective

Inhibitor of the enzymes which make alerin or cortisol but in the patient pre-treated with three days of dexamethasone this um example shows a patient who on the coronal CT you can see if there a lower and upper adoma only Valera adenoma is hot and when we look at the axial through those two

Levels you can see the upper adoma cold lower adoma very hot and this corresponds to what we find after the tum the gland is removed that the tumor at the top does not express any of the enzyme CB2 or alerin synthes but a little of the enzyme making cortisol or

C 11 B1 whereas for tum at the bottom which is hot on the scan stains densely for the enzyme making out of stero and only a little bit for the enzy making corol so this sort of patient assures us that our de method own pre-treatment renders carbon Le

Metomidate a highly selective ligant for the enzyme making alerin we’ve recently published a a trial in nature medicine in which all patients had both investigations and and that allowed us if I just summarize what we found to say that metomidate carbon 11 momate is at least as good as

Non-inferior mechnical jargon to Arenal vein sampling in detecting unilateral primst jism one of the secondary objectives of this study which is a rare prospective trial in primalis jism was to look at which patients are completely cured and the trial itself showed that only 30% of patients even those positive by both

Adrenal vein sampling and momate petct come all treatment and have a normal blood pressure and it turns out that the genotype of a tumor is the best predictor of outcome on on in this slide here we see the number of patients in whom each of the six genes in in which

Sematic imitations have been found by us others um were present and it’s apparent that there are two most commonly mutated genes of pottassium Channel Casi and J5 first reported in 2011 and a calcium channel will be reported in 2013 but a very striking ethnic variation that the black patients mainly

Have the calcium channel mutation and and the white and Asian patients more likely to have the case in J5 so the the question Jam had asked was whether the difference in these would predict patients who are completely cured of hypertention so here I’ve replotted the data only showing the the number of

Mutations in patients who are completely cured and it’s apparently it’s really only the case in J5 mutant patients who are are left standing and on a listic regressional analysis the genotype of a tumor trumps all other variables now this is not just a scientific curiosity um because in the

Same trial we validate validated a surrogate measure for genotype so-called hybrid steroids that a number of investigators had shown are only secreted by cells which make both cortisol and alerin and when we plot the ratio of the hybrid steroid to cortisol against genotype you can see there’s almost clear blue water between

The high levels in those with Cas in J5 genotype and other patients so in the future and we are going to test this again in our current perspective trial we think that the measurement of hybrid steroids will predict patients who can be completely cured of hypertension by

Surgery but uh the carbon L momate has one limitation which is it has a 20 minute halflife and has to be used in hospitals with an on-side cyclotron so in the same study we also validated na fluro analog more recently developed by colleagues in nsalo and Cambridge and

I’ve shown two examples one the a large tumor one with a a small tumor and each case you can see that the metomidate and C images look vertically identical and in analysis of all 31 patients who had both scans you can see in the orange part of the column those who were high

Probability fatal disease there was only one patient who didn’t have the same result by both scans so we’ve now started using this 18 flu analog which is made in in Cambridge and delivered to us at St bolus hospital and other hospitals around the land can shortly follow

I’m turning for the final part of this presentation to newer treatments and the first is linked to the petct because the pet C also showed us that on the left hand side the the adrenal is very close to the stomach something not always so obvious on the axial view where the

Pancreas seem to intervene and that opened up the possibility of abling the left side nodules through the endoscope with an alround probe in the stomach visualizing the atoma this atoma is only a centimeter or so away from the alround probe and my my next slide illustrates um the

Ablation a number of of of burns with the cathet in different places are undertaken which uh maximizes the safety of the procedure avoids stimulation of the adrenal medala and you can see this white appearance developing which is the the infarcting tumor during the cause of

A 10 to 20% burn so the whole procedure is over in 5 to 10 minutes and it’s very exciting when um the patients where viation is complete are cured of their hypertension and here’s one example a patient with a hot adenoma before the ablation completely disappeared afterwards and by doing finally the

Aspiration of of the tumor before ablation we can prove that what we’ve ablated is is something that is positive for the Duran synthes 11 B2 and and weak or negative for the enzyme making cortisol so I might sum up here and say that for the case in J5 mutant patients

Predicted by hybrid steroids surgery May remain an attractive option in the future delivering complete cure but for for everyone else medical treatment and maybe radio frequency oblation if validated by larger studies uh will be the treatment of Cho um of course we need a trial we’re now about a quarter

Of the way through a head-to-head comparison 110 patients half having surgery and half radio frequency ablation but medical treatment would clearly be more attractive than any intervention for years we’ve had SP lactone and that we’ll talk about that in in a moment but uh of excitement is

The development of a new class of drugs that were works by inhibiting the production of alestone and the challenge over the years has been that the enzyme making alone is very similar in structure 93% identical to the one making cortisol and it’s only in the last few years for drugs have been

Developed that are sufficiently selective to inhibit one without the other and my my last couple of slides of from a phase two trial we published earlier this year showing that backat the the first of his highly selective Inhibitors is is an effective treatment in patients with resistant hypertension

A condition which I and and I think several others would regard as effectively being Primal jism until PR otherwise so in this trial 240 patients had Placebo or one or three doses of baka with an active treatment period of of 12 weeks and the results show a procceed corrected for in systolic blood

Pressure at the highest dose of 11 mm which is very similar to what we previously showed with SP lactone in our par 32 trial and there’s the diastolic pressure data so to sum up uh over the course of the decade since the discovery of con syndrome 70 years ago we are able to

Find ever smaller tumors but the conventional methods for the process have not changed but newer methods are available and I briefly talked about petct endoscopic ablation looking for the tumors which are most likely to be cured by surgery and briefly introduced to to Arin synthes Inhibitors lots of

People have course have taken part in the work that I’ve described to you and uh here’s a picture of some of us at one of our summer parties I’d like to pay special tribute to Shen wo who’s first author of the nature medicine paper L as

An who helped us discover many of the sematic mutations and my clinical colleague will Drake and Mark anell in Cambridge thank you so thank you very much um Professor Morris for this um fascinating and um surely eye openening talk that you just gave um I think we have many questions

Maybe I can start um the adrenal venal s Venus sampling is indeed a challenge at least in the whole country Austria there’s not a single Center who has a large volume um of patients where an experienced physician can do this analysis so we have the diagnosis and

They often cannot refer we sent them to Germany and some centers there um do you think that what you just have published in in nature medicine um that the pet C could be the substitutes in the near future for this Venus sampling well I’m confident that what we’ve shown in in

The study and the followup with the 18 flow analog provides an accurate alternative and and the question now is how soon that PET CT liant can be rolled out to be delivered to hospitals such as yours in Austria there is no reason in principle why an 18 flu Lian but two our halflife

Cannot be made in one country and send to hospitals and another and that happens every day of a week with fdg which has the same to our half life so it’s it’s it’s a matter of finding a probably a com commercial supplier who will take this on or else an academic

Center in if not every country at least some countries who are interested in IM delivery so yes I think the answer is yes but we’re not yet at the full implementation stage so in your Center V sampling is his history now uh that’s not in fact what’s

Happened um as you know changes take place slowly in medicine and also as the results in our match study showed there are still some patients who are only positive on one or other technique and the petct is definitely preferred for the patients where the C2 MRI has

Shown an adoma but would be less useful if if you suspect unilateral disease without a definite adoma so I do think we’ll be bearing it quite yet so so we uh largely come from nephology and we we several years ago we were we became aware of yeah that um chronic hidden

Disease patients um can be affected by hyperism and then we were very sensitive and applied tests in many patients and uh somehow a little bit exaggerated with thought in our sent it’s a kind of epidemic we see so much so many patients and I think there’s still a

Lack of how to treat them when the kidney is affected because the GL filtration rate goes down then there you see a progression of kidney disease when they’re treated and so on um but regarding the tests also for the extr moral testing some some Advocates just

Do um the AL alone renin ratio in inde dependent of what they are taking because the the threshold is somehow arbitrary just to find them do you think this is true should we do the test deliberately so I do think the scope for being more pragmatic and that one of the

Reasons for very low diagnosis rate as I said less than 1% is that it all looks too hard for for many Physicians ever to get started on that hle race and the main interfering drug is be blockade and and in the UK that’s largely dropped out of the second or

Third line use in hypertension and and I feel that in patients whose main drugs are a rise inhibitor and calcium blocker even if th are diuretic none of those are going to stop you from diagnosing a true case of prime Aris jism and if anything if reing remains suppressed which is the

Main driver of Al reing ratio if the reing is um suppressed despite being on a rise inhibitor then you’re even more likely to have Prime Alo than when the re’s low off or treatment so I’m broadly with you and encouraging a more pragmatic response ironically when we do

Our research trials we don’t want to embark on four years of work and then have reviewers tell us are but your patients didn’t have primary Aldo so in match we were white of and white and followed the rule book to the to the n Only to be greeted by reviewers who said

This is artificial most patients are not so strictly diagnosed in the real world so for our next Tri we’re not been quite so strict with ourselves and still then a confirmatory test such as salt loading is a requirement you think so I would reduce it to to saline infusion or

Capap and of those two I found that end ologists still broadly prefer the saline infusion whereas those of us like myself who come more from a hypertension background um prer the Capal tests because especially in resistant hypertension uh we worry about taking patients off drugs which uh we may be

Necessary for a reasonable blood pressure control and the captal test probably gives you uh twice as much for your money in the sense that as I just said if your rening stays suppressed through throughout the test despite having the ace inhibitor and the AO does not suppress then you can um be pretty

Confident the patient truly has primality maybe finally an nephology specific questions um I was impressed that we had three patients born in the 90s coming to the emergency department with a systolic blood pressure of 250 hypoc calic and largely damaged kidneys with a creatinine of 56 um and then we couldn’t substantiate

That that they had a primary H hyper ELO um is it possible that due to ischemic kidney injury the rine there’s a leakage and therefore rine may be high yeah that’s a good question and there’s been a number of um papers on the subject of normal renic primard

Stonm and I too have had patients like that it does make it more difficult to make the diagnosis uh and a confirmatory test would be required the view is not so much that those patients can’t to Prim Aldo it’s it’s I think the conservatism is driven

By that hurdle race and knowing what the patient has to go through to be diagnosed and treated there’s anxiety about letting patients start who statistically you might say are a bit less likely to have the diagnosis than if they fit P trilogy St but I agree I

Think an important message is there are so many thresholds for for making the diagnosis but one has to be flexible and and regard these as guidelines thresholds there are exceptions to all of them and and in the presence of someone who’s had hypokalemia especially hypokalemia of the sodium over 140 I I

Would be very suspicious of of the diagnosis of Prim Alo I will I will speak speak with my Nuclear Medicine guy that we get the the Tracer right on if if I may thanks a lot for your great work and for this presentation um I’d like to start with a

Very practical question building on what you were discussing with Marcus we quite frequently see abnormal aldosterone reenan ratios but not enough elevated aldosterone to meet the diagnostic Criterion um I of course understand you say these are not uh well one one single specific diagnostic Criterion to follow

But how do you follow these patients who do not meet the criteria for the diagnosis even after the confirm confirmatory test do you rule out the diagnosis or do you do the follow follow them for years and see well a few years later they will probably have primary

Aldo how how do you follow these patients um so again a very key question uh and I can tell you what I might do now and and what is coming up quite fast on the Horizon so once again if the clinical or biochemical suspicion is is high but they’re not meeting the

Threshold then you have a medical and surgical option you want to know whether it’ be appropriate you want to know whether the patient might do better on spinal actone or another alternative my current drugs and and realistically if if you’re not controlling the high potential of conventional drugs and some

But not all point are towards Primal jism you’re going to give them a trial of medical treatment when it comes to considering whether they might be an option for surgical treatment I probably have a lower index um for proceeding to do a CT scan of the adrenals and and if

You and the patient think that removing adrenal might be attractive if they were found to have unilateral disease I wouldn’t be put off doing a CT because not everything is is fitting um what the guideline says what I think is going to make this a bit less hidden Miss is is

The use of urine 24 urine maybe overnight urine AR Duro and this was sparked um partly by a paper from Boston in 2020 anal Internal Medicine um by Anan V’s group showing that maybe the true prevalence of prime Aldo would be doubled if if we used urine Aldo rather

Than blood Aldo and that was follow by recognition how variable blood out and hence ARR measurements are and since it coincided with one of our nature genetics papers where we found a particular Gene to be mutated that adhesion molecule one that regulates biological clock genes in adrenal and

The index case that had a cyclical form violism where most measurements were not diagnostic but one was we are suspicious that we are missing many patients whose levels of aerin are fluctuating and and we have a current research study uh where the research Dr uni Lee is collecting 24 urine we

Measuring tetrahydro sterin and even on the first 20 patients we can see that there are many subjects like the ones you you describe where it takes multiple measurements to nail a diagnosis on a blood sample but a single TN F urine is clearly above threshold so there isn’t enough evidence to say

Everyone should be having 24 urinal and there isn’t a routine acid available at the moment uh but I I and I I know the group in in Boston are optimistic that that’s going to solve the problem you you mentioned okay thanks I have another diagnostic question which is more seldom

Uh you you spoke about the somatic mutations in in the tumor um what about the geraline mutations which patient should be screened for geraline mutations in genes that are prone to cause apep yes so germline mutations are very uh much less common whereas the sematic mutations the adrenal probably

Some of the commonest in in medicine but some of the the genes uh such as case in J5 itself uh can occur in the germ line and paradoxically was first recognized clinically as a familiar problem two or three years before by the same group by Rick lifton’s group um before he found

The sematic mutations in um common commonly in tumors then he went back to the the family in found they had it in The Germ line now partly answering your question the patients in the in the germline paper were two sisters and their teens and and the answer is that

It’s when Prime Aldo occurs at a very young age younger than 20 um if not even even younger those patients should be screened for The Germ line mutation patients later on I’m sure we miss a few but it’s sufficiently rare uh that I I wouldn’t recommend we routinely look for

Germline mutations in older patients we spoke to John fer I guess two years ago who was the first author of the 2016 guidelines and who’s very radical now actually in stating that we shouldn’t measure osrin at all uh and who suggests really now essays that are purely based

P re do we already know when we will see a new guideline because all you experts now are openly well rather reluctant to apply the 2016 guidelines so do we already have any news when the novel guidelines will will come so so that’s a simple answer because the there’s a new

Guideline Committee in operation at the moment and I’m I’m not a member of it but I I I think I probably know most of them and they’re hoping to bring a new guideline out early next year so there will be a new one and I I hope it will

Be more pragmatic um the problem is the DAR of really good evidence and and that makes it more difficult to find a Meeting of Minds uh when there haven’t been studies to resolve differences I I I agree with John fander I think the idea of using reing is is something

Maybe even rosing Comm ations between us because when I was in Cambridge working mainly in a hypertension practice I I would probably be measuring reing in most of my patients certainly the resistant hypertensives uh and other patients not responding to a Ras inhibitor at at a young age and if the

Reing is completely suppressed the AR probably will be elevated because aring is the main main driver and and uh as I was saying to Domin ique because I have a low threshold of getting a CT scan done if I think a patient might be IM meable for surgery I I might even

Request that while waiting for followup out dur so I agree with John on that and I have a second question Dominic before switching back to you um I have a problem in understanding one thing in this field so we all believe that elderone is something that is not only

Raising our blood pressure but also that is affecting our cardiomyocytes our R cells so people get CKD and heart failure how come that people who have a very low salt intake and who have very high adstone in reaction to this slow Sal intake are not affected by these cardiac

And renal disease like native people in some Asian Islands uh do we have any good explanation for that uh what usual answer is to State what you’ve nicely put as the fact namely it’s alerin Plus Salt which is toxic to the the cardom myosite and other cardiovascular tissues

Whereas high aerin in the absence of excess salt indeed in responding to low salt is is not cardiotoxic quite why or what the mechanism is for that level of tissue damage I don’t think is understood i i i sh a bit behind saying my interest has been very much more in

Release of Aldo than the response to Aldo questions but we did have some nice data in the match study where we did card Mr in a substudy of 50 patients and measured BMP in most of the patients before and after and very strikingly the surgically treated patients had a much

Greater benefit at um part level whether on CMR or BMP than did the the Medical Group and uh and that may be one reason why we shouldn’t necessarily be too sad that we’re not curing patients completely of hypertension in larger numbers does look for mardic data that even if patients

Don’t come off all their drugs as well as the benefit of taking fewer drugs which I’m not sure R justifies an operation um we are benefiting the heart but I know this isn’t the question you asked me but I I do think that there is a Public Health Challenge and issue

That we are doing major surgery without long-term evidence of benefit which was fine in the days when conotton syndrome was thought to affect fewer than 1% of patients but is not fine at the currently accepted prevalence levels I followed some patients who lost their kidneys because of hyper Aldo and

Then they were transplanted and they didn’t have any more hypertension didn’t need spirono lactone and I saw that the alone acts via the cenorin pathway and all these transplant patients take cenorin Inhibitors are you aware that maybe despite having a pathological AR therefore the effect is so to say um

Eliminated of aldosterone via taking calcin inhibitors I wasn’t aware of that it’s very interesting uh yeah I’m aware of the story of R transplantation curing some types of hypertension it probably wouldn’t surprise me because so many things are multifactorial that the level of hypertension achieved in in a prime Alo

Patient we concentrate on the alerin levels and its hyp secretion but it evidently is affected as well by what’s happening Downstream of Aldo and the receptor and if there are patients where despite a high level of Alo the receptor becomes unresponsive then that that’s interesting thank you for telling me

Yeah maybe we should study that but it’s not so easy yeah so questions now to the study of the New England Journal I have a few question on this New England Journal for back D you were talking about talking about pathophysiology Marcus um there’s one question that that this paper raised uh

There are a few patients who have hyponatremia uh with the the higher doses of backat do you think this is just volume dependent or do you think it’s because aldosterone is lower and there’s some interference with the function of the cortical collecting duct how do you see this because you you also

Mentioned hypernatremia as a potential diagnostic Criterion to to have a suspicion of APA so how I think think we in in that sort of study we have a great handle on on Downstream mechanistic um explanations and probably what I would rather say is that we did look quite closely at comparison of

Electrolyte shifts in the Brighton study with what we reported in the pathway 2 trial and in valan paper there we plotted the data as frequency plots um for each of the drugs that was crossover Tri of course to each patient was their own control and it’s it’s evident that

Serum sodium the distribution moves to the left on spinal Acton and potassium to the right and I don’t think we felt there was compelling evidence that the Autos synthes inhibitor was having on average any different an effect on electrolytes than we’d seen with spinal actone okay you think it’s just the

Diuretic effect correct yeah yes yeah and so building on what you were just talking about the com could you do a sort of head-to-head comparison spiron lacton back dra in terms of I mean for for a similar effect on blood pressure what would be the uh the side effect on

The tolerance and the Persistence of the patients on the treatment in other words what do you think it will replace byon alaon in the next years or not well that that’s a sort of $64,000 Question and and of course as often happens in drug develop the trial won’t get down at

Least not anytime soon but it’s a head-to-head comparison of the two so one’s left looking at at some theoretical Arguments for and against and then trying to pick um the fat off the bone of individual trials and see what might be different from from a

Theoretical point of view um I I I draw an analogy with the Advent of the arbs on the background of a decade or suras Inhibitors but for for years years after that the enthusiasts argue why one class might be more effective than the other but really the main advantage of arbs

Was a tolerability one and and that the 15% or so patients who develop dry cough on the E inhibit one or two% andronic edema was it was a non problem with arbs so I think the easiest win for the air size will be if there’s um Superior tolerability comp compared to the side

Effects that stop people taking higher doses of spinaca will that happen well the there were no of of Target side effects in in in Brighton and and on the theoretical basis I I look at the uh tissue expression of the Minal C coid receptor compared to expression of AOS

Synthes and whereas the latter is only expressed in one cell type of one organ namely the zg cells of the adrenal the Mr is in almost every every tissue uh so it’s more plausible that it would cause side effects but that’s now got to be demonstrated uh in Trials the other bit

Of theoretic what theoretical SL empirical data is that both in mice and humans there are Gene knockout um models and those are both um Concur and saying that r you uh need to knock out both copies of the gene Forin synthes before there’s a phenotype in the epod island

For the receptor knockout it’s the other way around there isn’t a homozygous knockout because it’s fatal and even the heterozygous knockout has quite a severe um phenotype so whether that will translate into saying that the AIS are generally better tolerated I I think it it well clearly at this stage that’s a

Hypothesis has to be tested okay so in the Brighton uh study it was essential resistant hypertension patients um do do you think uh patients with apas with severe apas in which we need very high doses of spironolacton to control the disease they may be controlled only with

Uh backat or do you think we may need combinations with M with airite how do you see yes uh so there is a study um results as yet unknown in Prim Alo looking at dose ranging up to higher do up to 8 milligrams um and so that may answer

Some of the questions you’re you’re asking regarding combination I I quite commonly use lowd do spiral or pinone with the meride I think that’s very effective in in primary Aldo and it’s tempting to think that a combination of inhibitor plus receptor blocker would be effective but again if

We remember what history taught us about combining an Ace and ARB and the On Target trial um then I don’t think that will will happen again soon uh I think the concern about um excess natures’s changing electrolytes um will warn people off going down the combination

Road thanks a lot I would also like to come back one more time to ulate because that’s available for us right now and you actually studied that also in path way two and three if I remember it right yeah on the background on these two studies so before we we get the new

Drugs where do you see the place right now in resistant hypertension when should we actually go for amid you said you sometimes also use the combination of the two of them so what are your ideas right now should we always start with spon electon and then maybe combine

Or would they also be patients in whom you would start right away with Amite that’s a great question and I sometimes say aid for most underused drug in medicine I I think that if you use it at the right dose which is probably 10 milligrams stter going up to 20 in par

32 was equivalent to 25 and 50 of spal lactone then it is effective and in pathway three it had a a mildly beneficial effect on blood glucose soin diabetic patients they might be particularly attractive the there’s there’s no hard evidence to answer your question which order of the spiron lactone and the mide

Would go but mide is remarkably well tolerated drug and and it’s what is probably lacking is the long-term outcome data that guides so much of what we do in in hypertension but then of course we don’t have outcome data in hypertension for spinal lactone its morbility mortality winds have been in in heart

Failure and um there are two trials in hypertension where aide but really too lower dose was combined with hydroc oride uh the mlc hypertension trial in the elderly um and one other we be commenting on in pathway three so a mide although not on its own does have some outcome data

Supporting it its use in hypertension so I would I would just sum up and say I greatly agree with you that mide underused and undervalued uh but we’re lucky that we can use it I think many countries mide is no longer available as a single tablet like in Austria and Germany I

Guess also in France uh just just one last question on pathway so you decided first to randomize patients with resistant hypertension on four different drugs and then in the end everybody went to Amite if I remember that again correctly it was three actives and pro sorry yeah so why did you decide to

Choose this design and not to have the Amite right at the beginning as one of the four GRS to randomize on I I can still remember the day we discussed this and and the the answer was that we felt we needed 12 week Cycles because we did

A forc dose titration at six weeks and the spinal lactone really being a key drug um with its very long halflife and we have to be aware of wash out going into the next cycle the cycle had to be 12 weeks and then four times 12 is 48

And we felt that psychologically asking people to carry a crossover on for more than a year um we risk losing more than we gained um so we viewed the amide as as a run out um rather than making it part of the rotation we we could have

Done it differently um but that that’s the answer to your question my my last question um would be again to the Future now we see two or three different Inhibitors of the thin serves of uh mineral cuts and there’s even another drug class becoming the so-called modulators of The

Receptors is this just that so many different companies are right now interested in this field and develop their own you know it’s exciting that we have both the neuro nonsteroidal antagonists and and the Inhibitors with several in each class being developed and hopefully that will rekindle something of the excitement of the 80s

And 90s when my career started coinciding with the Advent of ACE inhibitors arbs calcium blockers uh and I think when there’s more than one in a class um that that’s a good thing there are interesting pros and cons for the receptor blockers and Inhibitors a key

Question is what’s going on in the heart where there’s apparently none of the enzyme that breaks cortisol an cortisone so I’ll be confident that it is Al sterone that is stimulating the cardio receptor in theory might say no and yet I’ve told you about data from the match

Study where we get these profound changes in CMR and BMP when we take out and out of the system uh I hope one day there will be a head-to-head morbility mortality trial um but I suspect realistically it will be when the drugs been around for a while and and an

Academic funder is able to take that on maybe a last question because we we have a minute to um you were talking about mras I’d like to have your viewpoints on find runon um do you think this is really because it have has a more specific effect on extrarenal Mr M

Or do you think it’s sort of a lowo spiron alaon because you see no blood pressure effect in fidelo and Figaro I’d like to have your viewpoint on this yeah I think until very recently I was a bit skeptical of the notion that an MRA could have all the benefits without

Blocking uh without leading to a rise in potassium uh and the the most reasonable explanation was the one you would use some of the other non antagonists are claiming Falls in blood pressure uh and being tested in resistant hypertension and that that is possible without so much rise in

Potassium uh as it happens I was talking to bird pit last week he came to Grand Rand I was doing in in New York and he he was is trying to persuade me that this is due to different distribution of the drugs I guess it’s conceivable that there’s more potassium lost than we

Currently pay attention to through the colon for instance and the if the the ne drugs don’t um um partition into another compartment that’s important that they wouldn’t all have the same effect on potassium but hypertension doctors are a skeptical lot and maybe because we’re

Simple and uh I I would need to see hard evidence to be convinced that the the mras are doing anything major other than blocking the S of Arin stimulation in the distal tube were collecting thanks yeah maybe maybe I can anecdotic add I try to treat a patient with Hyper Alo

With finon and it didn’t work so it has a half life of three hours and I think it’s as you said Dominique a super lowd do Spyro and it somehow reminds me on the discussion 20 years before NOS this about the the vitamin D analoges not having side effects like

Vitamin D and at the end of the day if you interfere with ELO profoundly you will get all the side effects um on the electrolytes in my view you get hyper calmia and so on um so why shouldn’t it be like that and I mean there are phase two studies

Done some years ago where they compareed the two and actually the differences on potassium were not so large once ferone was adequately doed so uh I guess we all remain a little bit skeptical and await the future if you have a hyper Alo patient and you cannot block so to say

The effects of aldosterone with um a non-steroidal MRA I think that’s the best exp explanation I mean it the hyper Alo overrides all the effect because of this freour um half life and this yeah it’s good for CKD patients but not for hyper patient I

Think so we told you before we are very very interested in this field and you you you saw we had a couple of very burning question so thanks so much for being our guest tonight but much more thank you for doing all This research in the last decades that have been so

Important in order to improve both diagnosis and treatment for our patients and we’re positive that we will see much more interesting data from you in the not so far future and we would be happy to meet you once again in some years uh to continue this discussion so have a

Nice evening and London thanks so much once again thank you