February 8, 2023

May 2018, Toronto: This plenary session was part of Heart Failure Update 2018, hosted by the Ted Rogers Centre, which was Canada’s largest meeting on heart failure.

Thank you so the conditions we’re talking here are worldwide very prevalent in fact the world’s most common genetic conditions are thalassemia and sickle-cell anemia that affects where two-thirds of the world population lives and are an overload cardiomyopathy is particularly a major concern there this is this thing from the primary hemochromatosis which occurs in

The typical caucasian population in which there is increased gut absorption of iron as opposed to congenital anemias which requires frequent blood transfusion so the mechanism of iron overload are slightly different but ultimately they lead to – iron overload so in primary human crosses the process is a bit less aggressive there is a high burden of liver disease as

Opposed to secondary iron overload where heart disease is the primary driver of outcomes in these patients or screening protocols in these patients includes the use of cardiac mri and of course several important hematological markers which is of course part of the guideline as part of the reversible cause of cardiomyopathy that should be screened this is a seminal

Publication about 50 years ago which highlighted the important burden of heart disease in these patients this is a x-ray from a young man showing cardiomegaly pleural effusions venous redistribution a very distended abdomen splenomegaly and a bronze discoloration of the skin due to iron deposition so that’s a more severe form of iron overload and in fact it was a

Hematologist here in toronto in coordination with peter lu that made a seminal report nancy olivieri that showed that the survival in these patients are actually driven by their heart disease so so the question to us as translational scientist is why is there why is heart disease the primary driver of outcomes in patients with iron overload and this was documented

Both by nancy lowell very but also by gary breton ham from the us so – simultaneous study showing that heart disease and iron overload cardiomyopathy is the major concern in in these patients so the key for us to understand this condition is to understand what happens in iron overload so we have a typical mechanism transferring dependant iron optic which under

Iron overload condition is negatively regulated so it’s turned down to very minimal levels so what happens in iron overload is that you actually have non transferring bound iron that continues to enter into the myocardium that’s no longer on the negative control so our job was to figure out why that happens and to make a long story short we show that it’s actually

The l-type calcium channel a channel that normally regulates calcium entry is the channel that regulates calcium iron uptake into the heart so this was our seminal paper i was working i was in medical school and i joined the peter box and this is actually our first paper in which we use radioactive iron i don’t think they allow you to use that anymore this is

About 20 years ago and we showed that it does enter the heart enters in myocardial and you can block this by using calcium channel blockers so this was a very important very early step finding to show that calcium channels are important media to serve iron overload cardiomyopathy so the calcium channels are important triggers they’re shown here in the membrane

Trigger excitation contraction coupling and this is of course leads to systolic contraction in the heart so these channels are actually very pivotal in in mediating excitation contraction coupling in the cardiomyocytes and the channel itself is a very large protein in which the motif 3 & 4 have binding sites for various the various classes of calcium channel

Blockers in particular here we have dye hydro pyridine sites in the third and fourth motifs which is where are the drugs that we use to treat our patients bind to and block the current in these channels so the first thing we did was to make an animal model of iron overload and as you can see here we have very nice evidence of higher in their position in the in

The cardiomyocytes we can show that nicely with extra spectral analysis showing that these are iron-containing peaks we then went on inner animal models to show that if you give these mice for optimal and i’m low the pin you can actually significantly block myocardial iron uptake in in these animals quite significantly actually here the decrease in in levels are

Actually close to 40 to 50 percent in both a subacute and in a chronic protocol so very impressive findings in in in the preclinical model and this is very important a histological stain showing that the iron deposition in heart and in response to calcium channel blockers you can see that the intracellular buick unit blue accumulation of iron is what is reduced by

Calcium channel blockers so both drop them and i’m loaded pinos effective and the intracellular accumulation here of iron is actually unchanged so these drugs were preventing iron entry into the myocardium while leaving the intracellular iron intact we did quite the opposite we actually over expressed the l-type calcium channel in the heart and showed the opposite

Result so these are transgenic mice in which they we were able to double the myocardial iron burden simply by over expressing that l-type calcium channels so very strong genetic evidence that going the opposite way up regulating that current leads to more uptake of iron and more myocardial damage so these were or a seminal paper here in in nature medicine back in

2003 this was followed by a study from a german group that showed a very similar finding with amlodipine they had a slightly different target the divalent metal transporter that may also be targeted by amlodipine suggesting that maybe liver iron is probably also deliver may also be protected by amlodipine subsequent to this preclinical work our colleagues in

In italy in brazil where are an overload cardema tea is particularly prevalent perform this very small clinical study using 15 patients so ten of which had the placebo control five of which had i’m loaded pin five milligrams daily and they show that a t2 star in the myocardium in these patients were elevated in response to i’m loaded beam therapy as early as six

Months and persisted at twelve months so the t2 star is the gold standard way in which you measure tissue iron levels using a cardiac mri and it’s inversely proportional to your burden of iron so the more i mean you have in heart the faster the t2 signal relaxes and therefore the lower the t2 value is so the elevation here in the elevation here in iron level in the

T2 value suggests that it was less myocardial iron overload this study was recently replicated in a phase two trial with amlodipine in which 62 patients were studied this is a multicenter double blinded randomized spasiba trial of amlodipine by the same group now with a large number of patients 62 and in the reduction group they were able to show that you have a

Significant reduction in myocardial iron burden and responds to 12 months of amlodipine therapy if you looked at the the prevention group there was no differences in myocardial iron levels so you you see the differences in a group in which are susceptible particularly to two iron overload so if not very earlier on in the disease process but there were nevertheless

In this larger group of patients there was a significant reduction in myocardial iron levels so very very impressive results and i know this trial is ongoing here in toronto looking at this and certainly i think we will need a larger phase three multi center trial to show hard clinical benefit from from amlodipine therapy however this is really a demonstration of

Precision based therapy in which you unfi the central pathophysiological basis the card in my oppinion heart failure and then you use a therapeutic agent to target that that process we’re fortunate here that the therapeutic agent is is an old drug a cheap drug a drug that’s widely available a drug that’s available in underdeveloped countries and which can be used

We hope widely at an international level so this is a therapy that as we get more clinical evidence that it really helps patients with are in overload but this is a therapy that can be rapidly taken up this is also important because it really is precision based medicine because you would not give up a lot of pain to non iron overload dilated cardiomyopathy in fact

It’s a country indicate it’s one of the country indicated drugs in heart failure and it comes from nada praise one trial not the original praise one trial which is positive it comes from this seminal follow-up study dupre’s to trial which was a negative trial from low the pain in in nuns quemic dilated cardiomyopathy so so it so i’m loaded pain doesn’t work in in

The non iron overload dilated cardiomyopathy but it works and iron overload cardiomyopathy because it specifically targets the pathophysiology in in that disorder so this is really truly precision based medicine so they left their final few slides i’ll just show you some of our more recent work in which we have actually tact with the pathophysiology of this process

So we were actually use a antioxidant compound that’s resveratrol to rescue genetic models of iron overload cardiomyopathy and as you can see here in these animal models you have a lot of fibrosis as ps are staining trichrome staining with resveratrol therapy in the fimo jubilant knockout mice this is one year of age these mice were markedly protected importantly

The calcium transporter the circuit to is market-leading regulated they are protected by resveratrol and many of the markers of heart disease including ecology and a and f bnp and beta myosin heavy chain the hallmarks of heart disease were markedly upregulated in these mice and dramatically suppressed by the resveratrol therapy in in this preclinical model we then

Went on actually and look at circa to their appeal as you know which made it into phase two clinical trial with the qp trial and we’re actually using that same i don’t know associated virus provided by raja hajar we’re able to over express the circa in these mice and and showed that we can actually markedly recover their their iron calcium transient and improve

The diastolic relaxation in these animals suggesting that circuiting regulation response to iron overload is a major driver of the diastolic and systolic dysfunction in these mice so just a few more slides so and then finally we have set up a program here at the mars in which we collect all of the explanted human heart so pediatric adults and of course all of the

Lvad cords so this is a program that we established now about for the past eight years and we were fortunate in which we were able to collect the heart from an 18 year old young young lady who had a heart transplant because of beta thalassemia major she had over a decade of blood transfusions and ultimately resulted in iron overload cardiomyopathy and so we’re

Fortunate a collector expanding heart and what you can see here are this one beautiful demonstration of iron deposition in the myocardium and the digital mapping of these these granules so identical to what you saw in the animal model and the iron peaks are shown here in the same energy x-ray analysis of the myocardium probably more importantly is that the molecular

Signatures in this heart were identical to what we saw in the animal model so in fact we had the animal model data before we saw what we saw in a explanted human heart with iron overload cardiomyopathy so you have marked on regulation circa up regulation of sodium calcium exchanger several of these signaling pathways which are altered in the exact same manner in

Which we saw in the key module in our code mice so in summary iron overload cardiomyopathy is a very prevalent condition maybe maybe not so in in this part of the world and it is a major driver of morbidity mortality the preclinical models are valid models of iron overload cardiomyopathy and importantly the hema juvenile knockout mice are particularly important the

Current therapies that we use in treating these patients are limited is iron chelation therapy for for for thalassemia in sickle cell anemia and phlebotomy is for hemochromatosis and as i’ve shown you very nicely we have important experimental therapies that have now transitioned into clinical trials in particularly unloaded pain for iron overload cardiomyopathy and

Hopefully we can also start looking at visceral therapy in these patients and then finally i would like to acknowledge peter box and peter lu who are my phd supervisor who got me into involve in into iron overload cardiomyopathy over 20 years ago and the rajah hajar for providing us with the circuit virus and nancy andrews for providing us with the image overlay

Model and of course many of our trip my trainees hard-working trainees and their funding bodies thank you yeah so i have a question i think that body aim a you mentioned is but is there a plan trial to check for a clinical important outcomes in going or it will happen soon and what is going to be the inclusion exclusion gap year for example many of these pitching

Has will be restrictive or heart failure with preserved ejection fraction right good patients would reduce a big addiction fraction is clearly and if this is going to be used as an adjuvant therapy yes yes yes so the phase 2 trial came out in blood six months ago was exactly on top of chelation therapy standard of care so it was impressive that they were able to

See a reduction in iron level it’s very significant very earlier on within six months within six to twelve months even though patients are on chelation therapy so yes you would you would do a trial with amlodipine on patients on chelation therapy i think it’s important you’re absolutely correct it’s important you don’t go too late but you don’t start too early

So you need to have some degree of iron overload there and this is we’re doing the baseline cardiac mri and having it t to start to guide you is a way to go you do not want to be dealing with dilate end-stage dilated cardiomyopathy an advanced heart failure before you before you you you have this drug on board so i think you want to start fairly earlier on in the

Disease process and you’re really looking at early reduction early and prompt reduction sustained reduction in my cart all the iron levels i mean i’m low the pin is also an interesting drug i mean it’s been around for several decades now it has antioxidant properties it’s a bit of a forgotten property of amlodipine and it may be having some therapeutic values here

In in in in these patients so in addition to blocking the l-type calcium channels it may be having important antioxidant properties which actually fits with the resveratrol story so i think the calcium channel blocker they use for sure is i’m load of pain but i think we should we need to do the phase three trial which i think like they will have to be multi center

International trial to really prove that this drug improves clinical outcomes in the blood trial that did not see an improvement in injection fraction because over over six to 12 month period you’re not going to be seeing that dramatic change in in ejection fraction so so i think the pivotal phase through trial is still we still need that data and hopefully you

Know the international community can can come together and be able to to be able to do a trial like this yeah we’ll have you back on the panel okay great thank you very much

Transcribed from video
Dr. Gavin Oudit: Amlodipine therapy for iron-overload cardiomyopathy By Ted Rogers Centre for Heart Research