Jun 1, 2021
In this week’s podcast, articles “The Cardiac Late Sodium Channel Current is a Molecular Target for the Sodium-Glucose Co-Transporter 2 Inhibitor Empagliflozin” by Light et al (www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.053350) and “Metabolic effects of empagliflozin in heart failure: A randomized, double-blind, and placebo-controlled trial (Empire HF Metabolic) by Jensen et al (www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.053463) are discussed.
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia,
Dr. Carolyn Lam:
Greg, it's double feature day. And guess what? Both papers that we're going to talk about are regarding the SGLT2 inhibitors, and really look at the mechanism of action of these amazing compounds, from both a pre-clinical and clinic point of view. That's all I want to say, because we've got to tune in, a very interesting discussion coming right up.
Dr. Carolyn Lam:
But first I'd like to ask you a question. What do you think is the association between health-related quality of life and mortality in heart failure around the world?
Dr. Greg Hundley:
Well, Carolyn, I would think that, actually, they might be linked.
Dr. Carolyn Lam:
That's a really clever answer. Thanks Greg. Well, the authors are actually going to tell you with this next paper. It's from Dr. Salim Yusuf from Population Health Research Institute and McMaster University in Hamilton, Canada, and colleagues, who looked at the global congestive heart failure, or GCHF study, which is the largest study that has systematically examined health-related quality of life, measured by the Kansas City Cardiomyopathy Questionnaire, which is the largest study that has systematically examined health-related quality of life and its association with outcomes in heart failure, across eight major geographic regions, spanning five continents.
Dr. Greg Hundley:
Wow, Carolyn. So what did they find here?
Dr. Carolyn Lam:
Health-related quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire, or KCCQ, really differs considerably between geographic regions, with markedly lower quality of life related to heart failure in Africa compared to elsewhere. Health-related quality of life was also a strong predictor of death and heart failure hospitalization in all regions, irrespective of symptoms class, and with both preserved and reduced ejection fraction.
Dr. Carolyn Lam:
Indeed, this paper really highlighted a great need to address disparities that impact health-related quality of life in patients with heart failure in different regions of the world.
Dr. Greg Hundley:
Fantastic, Carolyn. Well, I have two studies to discuss, Carolyn, and they're kind of similar, so we're going to do them back to back. The first study reports the results of the Sort Out X Trial, a large scale randomized multi-center, single-blind, two-arm, non-inferiority trial, with registry based follow-up designed to evaluate the Dual Therapy Sirolimus-Eluting, and CD34 positive antibody coated combo stent or DTS versus the Sirolimus-Eluting Orsiro Stent or SES.
Dr. Greg Hundley:
And the study comes to us from Dr. Lars Jakobson, from Arhus University Hospital. The primary endpoint target lesion failure, or TLF was a composite of cardiac death, myocardial infarction, or target lesion revascularization within 12 months, all analyzed using intention to treat.
Dr. Carolyn Lam:
All right, Greg. So the DTS compared to the SES, what did they find?
Dr. Greg Hundley:
Thanks, Carolyn. So the DTS did not confirm non-inferiority to the SES stent for target lesion failure at 12 months. The SES was superior to the DTS, mainly because the DTS was associated with an increased risk of target lesion revascularization. However, rates of death, cardiac death, and myocardial infarction at 12 months did not differ significantly between the two stent groups.
Dr. Greg Hundley:
Now Carolyn, in this same issue, we have another study evaluating endothelial function and implantation of intercoronary stents. And this second study comes to us from Professor Alexandra Lansky, from the Yale University School of Medicine and Yale Cardiovascular Research Group. And Carolyn, the study evaluated whether implantation of an intercoronary stent that facilitated endothelialization after the four to six weeks smooth muscle anti-proliferative effects post-stent implantation would be non-inferior to traditional drug-eluting stents.
Dr. Carolyn Lam:
Okay, another interesting study. And so, how did they do that? What did they find?
Dr. Greg Hundley:
Yeah, so Carolyn, a total of 1,629 patients were randomly assigned in a two to one fashion to the supreme DES stent, so 1,086 patients, or the DPDES stent, which was 543 patients. And there were no significant differences in rates of device success, clinically driven, target lesion revascularization, or stent thrombosis at 12 months.
Dr. Greg Hundley:
And the safety composite of cardiovascular death and target vessel revascularization or myocardial infarction was 3.5 versus 4.6% with the supreme DES stent compared to the DPDES stent. But target revascularization for this new stent was two and a half fold higher.
Dr. Greg Hundley:
So Carolyn looking at these two papers, what have we learned? So first, the Jakobsen, et al, tested whether the stainless steel COMBO Sirolimus-Eluting Stent coated luminally with CD34 positive antibody could theoretically capture endothelial progenitor cells and regrow endothelium.
Dr. Greg Hundley:
And the investigators observed that this stent had higher, not lower or equivalent, target lesion revascularization relative to the current generation Cobalt-Chrome Stent that only eluted sirolimus.
Dr. Greg Hundley:
In the second study, Lansky and associates examined an approach which was touted as enhancing endothelial recovery, where the early erosion of material and release of drug was thought to allow earlier endothelial recovery enhancing vascular response. Non-inferiority of the rapid release was demonstrated, but rather than hints of superiority, there were signs of inferiority. Hereto, target lesion revascularization was problematic and was two and a half fold higher.
Dr. Greg Hundley:
And so, Carolyn, there's a wonderful editorial from Professor Elazer Edelman from the Massachusetts Institute of Technology entitled, “Karnovsky's Dictum that Endothelium is Good Looking and Smart,” where Dr. Edelman emphasizes that while some endothelial cells may have been present after deployment of these devices, perhaps a fully constituted functioning endothelium may not have been achieved.
Dr. Greg Hundley:
And as we know, it is a fully functioning endothelium with nitric oxide release, buried platelet adhesion that is most protective. It is a really provocative read that reflects on previous thoughts from Morris Karnovsky, who suggests preservation of endothelial function is optimized by minimizing injury to it. And so, Carolyn, these combined articles really highlight the current state of new developments within interventional cardiology to thwart re-stenosis and highly recommend them to our readers.
Dr. Carolyn Lam:
Wow, thank you, Greg. That was amazing. But you know what, so's this next paper, because it really provides novel insights into that enigma of the role that the epicardium plays in the pathogenesis of arrhythmogenic cardiomyopathy.
Dr. Carolyn Lam:
Now, to delineate the contributions of the epicardium to the pathogenesis of arrhythmogenic cardiomyopathy, doctors Marian from University of Texas Health Science Center at Houston, Texas and colleagues performed a series of elegant mouse experiments using conditional deletion of the gene encoding desmoplakin in the epicardial cells of mice. Mutations in genes and coding desmosome proteins, including desmoplakin are known to be major causes of arrhythmogenic cardiomyopathy.
Dr. Greg Hundley:
Wow, Carolyn, very interesting. So what did they find here?
Dr. Carolyn Lam:
Epicardial derived cardiac fibroblasts and epithelial cells expressed paracrine factors, including TGF-β1 and fibroblasts growth factors, which mediated epithelial mesenchymal transition and contributed to the pathogenesis of myocardial fibrosis, apoptosis, arrhythmias, and cardiac dysfunction in a mouse model of arrhythmogenic cardiomyopathy. These findings really uncover contributions of the epicardial derived cells to the pathogenesis of arrhythmogenic cardiomyopathy.
Dr. Carolyn Lam:
Greg, there's a whole lot of other interesting stuff in today's series, as well. There's an exchange of letters among doctors Mehmood, doctors Moayedi and Dr. Birks regarding the article “Prospective Multicenter Study of Myocardial Recovery Using Left Ventricular Assist Device.” There's an ECG challenge by Dr. Ezekowitz on a silent arrhythmia. How would you treat this patient? Go quiz yourself.
Dr. Carolyn Lam:
There is an AHA Update by Dr. Churchwell on how federal policy changes can advance the AHAs mission to achieve health equity. And finally, a Perspective by Dr. Talbert on rheumatic fever and the American Heart Association, The Nearly 100 hundred-Year War. Well, that wraps it up for the summaries. Let's go to the double feature, shall we?
Dr. Greg Hundley:
You bet.
Dr. Carolyn Lam:
Wow, today's feature discussion is really all about SGLT2 inhibitors, and that question that we're still asking, how do they work? And today, we are discussing two papers, very interestingly, looking at it from different aspects, one from a preclinical lens, finding a very novel target for SGLT2 inhibitors, and the other from a clinical lens, and really looking at the metabolic effects of the SGLT2 inhibitors in a way you've not seen before.
Dr. Carolyn Lam:
I'm very pleased to have with us the authors of these very exciting papers. We have Dr. Jesper Jensen from Herlev and Gentofte University Hospital in Denmark. We have Dr. Peter Light from University of Alberta, in Canada, and we have our associate editors, Dr. Thomas Eschenhagen from University Medical Center, Hamburg, and Dr. Justin Ezekowitz from University Alberta.
Dr. Carolyn Lam:
So, welcome gentlemen, thank you so much for joining us today. I suggest, let's start from the mice before we go to the men, and Peter, if you don't mind by starting us in, please tell us about this novel target you found, why you looked at it, how you found it, what it means.
Dr. Peter Light:
Hi, Carolyn, yeah, happy to discuss that. So, we all know that through numerous clinical trials, there's a very unexpected and exciting cardioprotective effect against heart failure with the SGLT2 inhibitors. And we decided to investigate some of the molecular mechanisms, which may underlie that protection. And in looking at the literature previously, and from my own lab's work, we're very interested in control of electrical excitability and ionic homeostasis in cells.
Dr. Peter Light:
So we investigated a known target or a known iron channel, which is involved in the etiology of heart failure as well as cardiac arrhythmias. And that would be the cardiac sodium channel. So, we investigated the effects specifically on a component of the cardiac sodium channel called the late sodium current, which is only induced in disease states, and they could be that during heart failure or ischemia, or can actually be in congenital conditions such as Long QT Syndrome Three, which involves certain mutations in this sodium channel.
Dr. Peter Light:
So we basically investigate the effects of empagliflozin, dapagliflozin and canagliflozin, in several different models of a sodium channel dysfunction, including mice with heart failure. And really what we've found is that this class of drug, and this is a class effect, it's not specific to just one of these SGLT2 inhibitors, what we found, they are very good inhibitors of this late current of the sodium channel. And in fact, they don't even affect the peak current at all.
Dr. Peter Light:
And when we did this and we analyzed the data, we found the IC 50s were in the low micromolar or even sub micromolar range for these drugs, which is exciting. And we extended those studies into cardiac myocytes and looked at calcium handling in those cardiac myocytes and saw that we get a very nice reduction in abnormal calcium handling in cardiac myocytes.
Dr. Peter Light:
We also used in silico molecular docking of these drugs to the cryo-EM structure of the NaV1.5, which is the cardiac sodium channel and identified that these drugs bind to a known region of that channel, which also binds the local anesthetics or anti-arrhythmic drug, Lidocaine, as well as the anti-anginal drug, Ranolazine.
Dr. Peter Light:
And finally, we showed that these drugs also reduce inflammation through the NLRP3 inflammasome in an isolated beating heart model. So collectively, we provide evidence that the late component of the sodium channel is a really important, or maybe a really important target for the molecular actions of this drug, and may underlie those observations received from the clinical trials relating both to heart failure, as well as sudden cardiac death.
Dr. Carolyn Lam:
Thomas, could you put this in context for us?
Dr. Thomas Eschenhagen:
Thanks, Carolyn. I mean, we immediately liked the story because as you said, and Peter as well, these drugs have amazing effects and every clinical paper and indeed some new ones, but it's really unclear how they do that. And what is, besides the established target, the SGL2 in the kidney, what could be the reason for all of this or some of this?
Dr. Thomas Eschenhagen:
And then, of course, other examples proposed, like the sodium hydrogen exchanger, but this story didn't go so far. So we saw now this data from Peter showing that, and this is, of course, for a pharmacologist, just like me, very important, it's very potent binding. It's not a binding which happens in a millimolar or high micromolar, but as Peter said in low micromolar range. So that makes it a very realistic effect, for example, much more potent than ranolazine.
Dr. Thomas Eschenhagen:
And, of course, now the question is, to which extent could this, now I would say, establish the effect on the late sodium current, explain some of the findings which came out of the clinical studies, and actually, a question I would have to Peter, now that I think most of you know, the late sodium current is a reason for the increased sodium for LQT3 syndrome, very rare.
Dr. Thomas Eschenhagen:
But, of course it would be tempting to say, okay, maybe that would be a very good drug, particularly for people with LQT3. Did you think about that, Peter? Is it something on your list, mexiletine has been tried.
Dr. Peter Light:
Yeah, so I think that it's a certainly intriguing possibility. In fact, in our study, we did test out several different Long QT3 mutations and saw a reduction in the late component as also sodium channel. It's tempting to speculate that, indeed, these could actually be a rather effective anti-arrhythmic drug in patients with these LQT3 mutations or specific ones. I would love to be able to test that in at least some of the genetic mouse models of Long QT3 and to see whether this concept holds water or not.
Dr. Carolyn Lam:
Wow, this is incredible. SGLT2 inhibitors from anti-diabetic to now anti failure, and now anti-arrhythmic drugs? That's just amazing. Thank you, Peter. We should move on to this next paper, and this one all the way on the other spectrum, a clinical paper called Empire Heart Failure, Empire Heart Failure Metabolic, actually. Jesper, could you tell us about your trial and what you found?
Dr. Jesper Jensen:
Sure, thanks for the invitation to take part in the podcast, first of all. I'll tell you a little bit, we designed this study to try to get behind mechanisms, so the clinical benefits of the SGLT2 inhibitors in order to try to make a clinical outcome trial. But as you know, the DAPA-HF and the EMPEROR-Reduced were competed very fast, demonstrating the clinical benefits in HFrEF patients.
Dr. Jesper Jensen:
So, the data of our study provides some detailed mechanistic insights to these findings. And from the literature, we know that SGLT2 inhibitors improve glucose metabolism in patients with diabetes, and these changes might not be surprising in the diabetes population, but moreover, alterations in glucose metabolism may not be the main mechanism for the early occurring clinical benefits.
Dr. Jesper Jensen:
However, we know that many of our heart failure patients without diabetes are insulin resistant as a metabolic feature of the heart failure, and the insulin resistance is associated with an increased risk of developing future diabetes, which in turn reduces the long-term survival and quality of life. So, the targeting insulin resistance in HFrEF patients is, therefore, of clinical relevance to our patients.
Dr. Jesper Jensen:
So, the population of the Empire HF Metabolic consisted of patients with chronic HFrEF, with or without type two diabetes, who are on a stable guideline directed heart failure therapy, and have also indicated on anti-diabetic therapy. And we randomized patients to receive empagliflozin 10 milligrams once daily, or matching placebo as an-add on for 12 weeks.
Dr. Jesper Jensen:
And this was a modest sized randomized control trial, including 120 patients. A very large proportion of patients received guideline directed heart failure therapy, and they generally consisted of the best one third of atypical HFrEF population, and only 10% had concomitant history of type two diabetes.
Dr. Jesper Jensen:
We then, at baseline and after 12 weeks, we formed an oral glucose tolerance test to assess the hepatic and a peripheral insulin sensitivity and performed a whole body DXA scan to investigate alterations in body composition. We know that patients lose weight when they get an SGLT2 inhibitor with and without diabetes, but we don't know what it consists of in a HFrEF population.
Dr. Carolyn Lam:
Tell us what you found after 12 weeks.
Dr. Jesper Jensen:
Yeah, so a large proportion, actually half of the patients without a history of diabetes, had a new onset diabetes, or impact glucose tolerance at baseline. So even though few have no diabetes, this population were at very high risk of developing future diabetes. And the main finding was that empagliflozin improved insulin sensitivity. So the hepatic insulin sensitivity was improved by 13% and the peripheral insulin resistance was improved by 20% compared to placebo.
Dr. Jesper Jensen:
And moreover, both fasting and postprandial glucose were significantly reduced. And regarding the body composition, patients in a mean lost at 1.2 kilos, or 2.6 pounds, which mainly consisted of a loss in lean mass and no significant changes were observed in fatness, and this is from the DXA scan.
Dr. Carolyn Lam:
Hmm. Justin, could you shed some light on what the editors thought about this, and there's lots of questions still, huh?
Dr. Justin Ezekowitz:
Yeah, absolutely, Carolyn, and thanks Jesper for sharing this paper with Circulation. Thanks for summarizing it so well. I think the questions that come up and the reason why we liked it so much was we're all trying to understand mechanism of how these medications work so profoundly for our patients.
Dr. Justin Ezekowitz:
Now, in this predominantly non-diabetic population, the fact that the liver and the peripheral insulin sensitivity improves, how does that bear out for the fact that there is no fat loss in the early stages, yet that's all been linked to later improved exercise capacity and increased fat loss later on in life.
Dr. Justin Ezekowitz:
So, do you think those two are going to be linked if you went to say from 12 weeks beyond the 52 or two years down the road?
Dr. Jesper Jensen:
Yes, that is what we've seen from diabetes populations, at least. So you could imagine that the same would be the case also in the HFrEF primarily non-diabetic population, but again, we don't know. But early loss is the mass loss.
Dr. Justin Ezekowitz:
So Jesper, when you think about the peripheral insulin sensitivity improvement, is that largely indicating mostly muscle based insulin sensitivity improvement, and that would indicate that the muscles, perhaps, are functioning better in the short term with just a simple change in therapy.
Dr. Jesper Jensen:
Yeah, that could be a way to put it. I would agree upon that.
Dr. Justin Ezekowitz:
So thanks, Jesper, I think that may indicate the quality of life improvement that we may be seeing in the functional status there, Carolyn.
Dr. Carolyn Lam:
Yeah, but as you said, Justin, there just seems so many other questions. To Jesper, I want to know, what further might you want to do to find out what's happening with this? The loss of lean mass surprised me, frankly. I thought it would have been fat mass. So, what are you doing to look at that? And then to Peter, I want to go the other direction. What are you planning next that might bring this closer to humans and a clinical study? So maybe I'll ask Jesper to go first.
Dr. Jesper Jensen:
So, I definitely agree with you, Carolyn. We would also have to put our money on the fat from the beginning, before the study. So with respect to the weight loss, then a loss in lean mass is not preferable if it represents muscle. So however, the weight loss works to mediate the observed change in insulin resistance. And additionally, a significant loss in muscle would result in reduced insulin sensitivity. And we observed the opposite. Therefore, the observed loss in lean mass may be speculated to represent water and pointing towards the early diuretic effect SGLT2 inhibitors. So, the DXA scan is good at looking at body composition, but it has difficulties in separating lean mass from whether it's muscle or water, but combined with the findings on the insulin resistance, we speculate that the lean mass loss is more.
Dr. Carolyn Lam:
Thank you. And Peter, could you very quickly tell us what are next steps, in your view?
Dr. Peter Light:
Yeah, obviously we were studying mouse model of heart failure. We'd like to make a more of a translational step in the next experiments we do by studying human tissues. So getting access to ventricular tissue from ex-planted hearts, human hearts, too, and then measure electrical activity as well as some calcium imaging.
Dr. Peter Light:
Looking at some of these Long QT3 animal models would be another thing that we're going to do. And also start looking at to see whether we can get access to any electrophysiological data from electronic medical records to start looking for DCGs and measuring QT interval, for example, would be another nice step to that.
Dr. Peter Light:
And then, more of a drug development side of things, we are actively synthesizing new derivatives of these drugs and seeing whether we can enhance the cardio-protective effects on the late sodium current, but actually remove the ability to inhibit SGLT2. So we would no longer have a glucose-lowering drug, but we'd have a cardioprotective drug. So, it's all very exciting work going on right now.
Dr. Carolyn Lam:
You've been listening to Circulation on the Run. From Greg and I, don't forget to tune in again next week.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.