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Circulation on the Run

Sep 14, 2020

This week’s episode includes author Jeffrey Testani and Associate Editor Justin Grodin as they discuss empagliflozin heart failure, including diuretic and cardio-renal effects.


Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Centre and Duke National University of Singapore.

Dr Greg Hundley: And I'm Greg. I'm the director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, the SGLT-2 inhibitors have really revolutionized heart failure treatment, but we still need to understand a bit better how they work. And today's feature paper is so important, talking about diuretic and cardio-renal effects of Empagliflozin. That's all I'm going to tell you though, because I want to talk about another paper in the issue very related. And it's from John McMurray from the University of Glasgow with insights from DAPA-HF. But maybe a question for you first. Have you ever wondered what to do about loop diuretics doses in patients with heart failure and whom you're thinking of initiating an SGLT-2 inhibitor, Greg?

Dr Greg Hundley: Absolutely, Carolyn. That comes up all the time and how do you make that transition.

Dr Carolyn Lam: Exactly. And so this paper is just so important, and Dr McMurray and his colleagues showed that in the DAPA-HF trial, the SGLT-2 inhibitor, dapagliflozin, first, just as a reminder, reduce the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. And in the current paper, they examined the efficacy and tolerability that dapagliflozin falls in relation to background diuretic treatment and change in diuretic therapy, following randomization to dapagliflozin or placebo. They found that 84% of patients randomized were treated with a conventional diuretic, such as the loop or thiazides diuretic. The majority of patients did not change their diuretic dose throughout follow-up. And the mean diuretic dose did not differ between the dapagliflozin and placebo group after randomization. Although a decrease in diuretic dose was more frequent with dapagliflozin than with placebo, the between-group differences were small. So treatment with dapagliflozin is safe and effective regardless of diuretic dose or diuretic use.

Dr Greg Hundley: Very nice, Carolyn. That's such a nice practical article. I really enjoyed your presentation of that. My next article comes from Professor Karlheinz Peter, and it's investigating the reduction of shear stress and how that might impact monocyte activation in patients that undergo TAVI. So this group hypothesized that the large shear forces exerted on circulating cells, particularly in the largest circulating cells, monocytes, while passing through stenotic aortic valves results in pro-inflammatory effects that could be resolved with TAVI. So to address this, the investigative team implemented functional essays, calcium imaging, RNA gene silencing and pharmacologic agonist and antagonist to identify the key mechanical- receptor mediating the shear stress sensitivity of the monocytes. In addition, they stained for monocytes in explanted, stenotic, aortic human valves.

Dr Carolyn Lam: Lots of work done in a very translational study. So what did they find Greg?

Dr Greg Hundley: They found monocyte accumulation at the aortic side of the leaflets in the explanted aortic valves. That was the human subject study. In addition, they demonstrated that high shear stress activates multiple monocyte functions and identify PZ1 as the main responsible mechanoreceptors representing, therefore, a potentially druggable target. So reducing the shear stress from a stenotic valve promotes an anti-inflammatory effect and, therefore, could serve as a novel therapeutic benefit of those undergoing TAVI procedures.

Dr Carolyn Lam: Really nice, Greg. Thanks. We're going to switch tracks a bit, Greg. What do you remember about Noonan's syndrome?

Dr Greg Hundley: Oh boy. Impactful, congenital disease for both the probands, as well as the family.

Dr Carolyn Lam: That's truly beautifully put and you're right. Noonan syndrome is a multisystemic developmental disorder characterized by common clinically variable symptoms, such as typical facial dysmorphism, short stature, developmental delay, intellectual disability, as well as cardiac hypertrophy. Now the underlying mechanism is a gain of function of the RAs MAPK signaling pathway, kinase signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, really remains limited. So today's paper contributes significantly to our understanding and is also notable for the methods that these authors use to uncover this novel potential therapeutic approaches. The paper is from Dr Cyganek and Wollnik as co-corresponding authors from the University Medical Center Göttingen in Germany. And they presented a family with two siblings, displaying an autosomal recessive form of Noonan syndrome with massive hypertrophic cardiomyopathy. As the clinically most prevalent symptom caused by allelic mutations within the leucine zipper like transcription regulator 1. They generated induced pluripotent STEM cell derived cardiomyocytes of the effected siblings and investigated the patient-specific cardiomyocytes on the molecular and functional level.

Dr Greg Hundley: Carolyn, is such a thorough investigative initiative. So what did they find?

Dr Carolyn Lam: They found that the patients induced, pluripotent STEM cell cardiomyocytes recapitulated the hypertrophic phenotype and uncovered, a so far not described, causal link between this leucine zipper like transcription regulator 1 dysfunction and ras map, kinase signaling hyperactivity, as well as, the hypertrophic gene response and cellular hypertrophy. Calcium channel blockade and MEK inhibition could prevent some of the disease characteristics providing a molecular underpinning for the clinical use of these drugs in patients with Noonan syndrome. In a proof of concept approach, they further explored a clinically translatable intronic CRISPR repair and demonstrated a rescue of the hypertrophic phenotype. Massive amount of work in a beautiful paper.

Dr Greg Hundley: You bet, Carolyn, and boy giving hope to address some of that adverse phenotype in the heart. What an outstanding job.

Dr Carolyn Lam: You're right, Greg. But now switching tracks a yet again. What do you know about ischemic preconditioning? Ischemic preconditioning refers to the process in which non-lethal ischemic stress of the heart prevents subsequent lethal ischemia reperfusion injury and provides important intrinsic protection against ischemia reperfusion injury of the heart, as well as other organs. So in this paper co-corresponding authors, Doctors, Zhang, Xiao and Cao from Peking University and colleagues provided multiple lines of evidence that a multifunctional TRIM family protein, the Mitsugumin-53 or MG53 is secreted from the heart in rodents in response to ischemic, preconditioning or oxidative stress. Now this secreted MG53 protected the heart against ischemia reperfusion injury. In the human heart, MG53 was expressed at a level about 1/10th of its skeletal muscle counterpart. And MG53 secretion was triggered by oxidative stress and human embryonic STEM cell derived cardiomyocytes, while deficiency exacerbated oxidative injury in these cells.

Dr Greg Hundley: Very nice, Caroline. Tell me the take home message. How do I incorporate this information, maybe even clinically?

Dr Carolyn Lam: Well, these results really defines secreted MG53 as an essential factor, conveying ischemic preconditioning induced cardioprotection. Now, since systemic delivery of MG53 protein restored ischemic preconditioning mediated cardioprotection in deficient mice, recombinant human MG53 protein could perhaps, or potentially be developed, into a novel treatment for various diseases of the human heart in which indigenous MG53 may be low.

Dr Greg Hundley: All right, Carolyn. I'm going to tell you about a couple of letters in the mailbag. First, there's a research letter from Richard Vander Heide regarding unexpected feathers in cardiac pathology in COVID-19. And then, there's a large exchange of letters between Dr Yuji MIura, Chuanli Ren and Laurent Azoulay regarding a prior publication, entitled "Aromatase Inhibitors and the Risk of Cardiovascular Outcomes in Women With Breast Cancer, A Population-Based Cohort Study." And then finally, Carolyn, there's another research letter from professor, Nilesh Samani, entitled "Genetic Associations with Plasma ACE2 Concentration: Potential Relevance to COVID-19 Risk."

Dr Carolyn Lam: Wow, interesting. There's also an "On My Mind" paper by Dr Kimura on "contextual imaging, a requisite concept for the emergence of point-of-care ultrasound." There's an ECG challenge, by Dr Dewland, with a case of an intermittent -wide QRS complexes. There's a cardiovascular case series presentation by Dr Nijjar on "a solitary left ventricular septal mass and amaurosis fugax."

Dr Greg Hundley: That's great, Carolyn. How about we move on to the feature discussion.

Dr Carolyn Lam: Let's do that.

Dr Greg Hundley: Well listeners, we are here to discuss again, another important paper related to SGLT-2 inhibition. And we have with us, Dr Jeff Testani from Yale New Haven and our own associate editor, Dr Justin Grodin from University of Texas Southwestern Medical Center. Welcome gentlemen. Jeff let's start with you. Can you describe for us some of the background behind this study, and then also the hypothesis that you wanted to address?

Dr Jeffrey Testani: Our lab is very interested in understanding volume overload and heart failure, why does the kidney retain sodium and why it stops responding to loop diuretics. Several years ago, when the SGLT-2 first came out, we saw them as a diuretic with the side effect of glucosuria. Back when they were still being thought of as primarily diabetes medications. But as the story unfolded and we saw that the SGLT-2 seemed to be doing something much more than just control blood glucose in diabetics and was demonstrating, particularly, a pronounced effect on heart failure outcomes, we got very interested in, better understanding this.

We know that loop diuretics, they're really a double-edged sword. Loop diuretics are our mainstay of therapy to relieve congestion and heart failure patients, but they do so at the expense of quite a bit of toxicity. And we know that the loop diuretics directly cause neuronal activation, elaboration of rennin, norepinephrine, etc. through their effects directly on the kidney. In addition to causing normal moral activation through the volume depletion they cause. And as we all know, blocking the neurohormonal activation is one of the primary therapies we use in heart failure. So even though it helps our patients keep the fluid off, it does that at an expense of potentially some very negative effects.

The interesting thing with the SGLT-2 inhibitors is, we've seen that in the diabetic populations, that they seem to actually improve volume status in diabetics, more so than one would really expect by the week diuretics that they are. And by and large, they were doing that without a pronounced activation of the neurohormonal system. So this led us to the conclusion that we really need to rigorously study this in heart theory and see what exactly are these effects of diuretics volume status and how much negative impact will any of those effects bring towards normal activation, kidney dysfunction, etc.

Dr Greg Hundley: Very clever, Jeff. How did you go about addressing this question? What was your study design and what was your study population? Who did you enroll?

Dr Jeffrey Testani: We wanted to have a pretty clean mechanistic study here. We weren't looking at ethnicity. We were really trying to understand a mechanism here and what are these agents doing to sodium handling in the kidney, etc.

We enrolled diabetic patients that were stable. Per their advanced heart failure position, they were at added at a stable volume status. They hadn't had recent changes in medications diuretics, and we use the crossover design where we brought the patient in for about an eight-hour rigorous GCRT type study where we administered empagliflozin in 10 milligrams and then did some pretty rigorous characterization of them. As far as body fluids spaces, renal function, normal activation, your sodium excretion. Then they would continue that therapy for two weeks, come in for a terminal visit, that was a very similar protocol. Then we'd wash them out for two weeks and cross them over to the alternative therapy. And they were randomized whether they had placebo or epilobium first in order.

Dr Greg Hundley: Very good. So a crossover design. And what were your study results, Jeff?

Dr Jeffrey Testani: We were quite interested in the overall effects and it was actually quite surprising. We know the loop diuretic resistance is common and when physicians and patients are not responding well enough, oftentimes we add thiazides. And thiazides waste potassium. They waste magnesium. They increase uric acid. They usually cause renal dysfunction and significant normal activation. That was the default hypothesis that we would see that. And to the contrary, we pretty much saw the opposite of what a thiazide did. We saw a modest, but clinically significant natriuresis. So as a monotherapy, these drugs are quite weak. Although we saw a doubling of a baseline level of sodium excretion, that's sort of a clinically irrelevant amount as an acute diarrheic. However, when we added the eplerenone to a loop diuretic, we got a 30, 40% increase in sodium excretion. And just to benchmark that, if you look at the dose trial where they compared low dose to high dose Lasix, which were one X versus two and a half X, their home loop diuretic, they got a similar increase in sodium excretion.

So even though 30, 40% increase in sodium excretion doesn't sound like a lot, it's all of our normal interventions. It's actually a pretty significant increase. We found that happened acutely. And to our surprise, that natriuretic effect had not completely gone away by two weeks. So the patient was still in a negative sodium balance at the two-week time point. And they actually had a reduction in their blood volume, in their total body water, in their weight, as a result of that kind of slow persistent, natriuresis that had happened over those two weeks.

We were unable to detect any signs of normal MAL activation with this. There was actually a statistically significant better change in norepinephrine during the dapagliflozin period versus placebo. And there's some evidence that, that might be an actual finding of saccharolytic effect of these drugs. As in many of the other trials we've seen no, despite a reduction of blood pressure and probably volume status, heart rate stays the same or even goes down. And we saw an improvement in uric acid. We saw no additional potassium wasting. We saw an improvement in serum magnesium levels. So really kind of like I started this way is the opposite, in many ways of what we see, side effect wise, with the diuretic is what we saw with addition of an SGLT-2 inhibitor.

Dr Greg Hundley: Listeners, we're going to turn now to Dr Justin Grodin, who's one of our associate editors and is also an editorialist for this paper. And Justin, we've heard some really exciting results here. The addition of a dapagliflozin to a loop diuretic enhancing the neurohormonal access and receiving some unexpected benefits on the electrolyte portfolio. Can you tell us a little bit about how you put this work in the context of everything else that we have been reading about this exciting new class of drug therapy?

Dr Justin Grodin: This certainly is exciting because with the release of the DAPA-HF clinical trial, just about a year ago, we've really come to recognize that there really are substantial, long-term beneficial effects with SGLT-2 inhibition in patients with heart failure, and as Jeff alluded to, a lot of these effects, we saw that they were beneficial in individuals that are high risk or who already had heart disease and diabetes. And we weren't sure if that was going to translate to individuals with heart failure. We really saw beneficial effects in both, individuals with heart failure, with or without diabetes. So this is an interesting paradigm because, although we saw dramatic effects in long-term survival quality of life, the mechanism was actually somewhat murky. And a lot of this was transitive based on prior works. We obviously had a strong hypothesis that they would work through reducing incident heart failure and diabetics, but then we were left questioning what is the mechanism? And I think Jeff highlighted it quite well.

There was the early thought that this was perhaps just a weak diuretic and that it was additive, and these patients were just getting long-term natiurer recess. And then others thought that there might've been, perhaps, some positive influence by some very low level, blood pressure reduction with these therapies.

So in that sense, I think Jeff's paper really is put in context and when we reviewed it, we thought it was quite fascinating because I think as Jeff showed in his paper quite elegantly and actually in a very, very careful study, which the reviewers and your editorial staff appreciated, we really saw that there was a probably more robust response to natriuresis than we had anticipated. And importantly, this was independent of glycosuria, which is a very important observation. And if I might take a 10,000-foot view of at least this therapy and how we might think about it as an incremental therapy in heart failure, it's really doing something else. So we thought that with SGLT-2 inhibition, you get a little sodium and a little natriuresis, maybe perhaps a little bit extra, as it complexes with glucose.

I think if you look at what the potential physiology would be with this therapy is that it's doing far more than that. And I think Jeff's study at least supports some of the speculation. And again, I'm going to perhaps look beyond SGLP-2 inhibitor, and then more so focus on the physiology of the proximal convoluted tubule. And given the location of the blockade, this is really priming the kidney, or at least Jeff's manuscript, and Jeff's analysis, supports the hypothesis that SGLT-2 inhibitors influence the proximal tubule environment, such that the kidney is ready to reset in natriuresis. And I think Jeff's data it at. least supports that because if we look at the proximal tubule physiology, there's really a lot more going on, then SGLT-2 inhibition.

There are other receptors that it can influence that might also promote natriuresis. It can also promote increased distal sodium delivery to other areas of the nephron. And in essence, this almost, and in Jeff has put it this way before, which I totally agree. This gives the opportunity for the kidney to taste the salt, as opposed to the more common state that we have in somebody with heart failure and congestion, where, and I talk about this on rounds all the time, the kidney's response to a failing heart is to retain salt and water. So this kidney is in this perpetual state of dehydration. And I think the idea that Jeff's analysis is at least supporting, is that somehow, we were influencing the physiology in the proximal convoluted tubule, we are actually priming the kidney and readying it. We're almost hitting reset, where the kidneys may lose this physiology, thinking that the body is dehydrated and in essence, really readying it to assist with decongestion.

Dr Greg Hundley: I love the way you explained that. It's almost as if I'm on ward rounds with you that just knocks home a lot of the message here, and the importance of Jeff's work. Understanding the physiology of the proximal tubule and then readying the kidney, instead of moving into a mode of retaining salt and water, actually allowing that to flow and facilitating a diaresis. I'll start with you, Jeff, and then come back to Justin. You might have unlocked a really special key here. What do you see as the next steps in research in this particular field?

Dr Jeffrey Testani: I think Justin really, really captured the essence of what excites us so much about this is, most diuretics are a brute force sort of approach to getting salt out of the body. They are a stick, not a carrot and SGLT-2 inhibitors, when you look at them as how they would work as a brute force diarrheic, they are really wimpy and there is every opportunity for the kidney to defeat the of a SGLT-2 inhibitor, if it wanted to buy where they work and what they block. But the reality is, is that they really seem to be the carrot almost. if you think of resetting the sodium set point of the kidney, kind of quenching some of that salt first or sodium humidity that Justin was referring to.

And the thing that's really interesting is when we look at trials like DAPA-HF. So despite the fact that they do seem to have this natural effect in blood pressure lowering effect and these different effects, they don't tend to cause hypertension, over diaresis, it's a much more of a natural, where the kidneys regulatory mechanisms are still operative. we have this duality of not causing over diaresis but causing diaresis. So it's really when the body needs to get rid of salt, it helps it do that. And so I think the next steps, at least for our research program is, we want to understand taking these drugs out of the context of stable, relatively euvolemic chronic heart failure patients. And when we put them into the acute setting of actual volume overload, do we see more robust diathesis and that natriuresis in that setting.

The second thing is we want to dig into what is the internal mechanisms that are allowing the kidney to do these things. How is it that it's able to dump out salt when it's beneficial, but not leaked over to uresis. Since we're digging into those mechanisms, I think will give us some additional insight into this class.

Dr Greg Hundley: Justin.

Dr Justin Grodin: I think Jeff really encapsulated, or at least certainly highlighted some very important points, that are largely in parallel with where I foresee this. Because really, if you look at just study, a lot of these patients were quite stable. So the questions that come along are whether or not that this synergistic effect number one, is sustained long-term. Because there are some data, at least in diabetic individuals, that this might not be the case. So Jeff's paper elegantly highlights the influence of these therapies in two weeks. Now, whether that's sustained is certainly unclear. I think the logical next step is, "Okay. We show that we have a therapy that might prime the kidney for increased natriuresis" what are its effects and individuals that might need the natriuresis even more. So as Jeff highlighted individuals with more decompensated heart failure, that are more congested and more hypervolemic.

And then obviously individuals that might be quite diarrheic resistant. This is something that I think Jeff and I have given talks on. And Jeff is clearly one of the world's experts in this space, but it's obviously a very attractive possibility that this might influence individuals whose kidneys are teased or trained into just holding onto sodium, no matter what. Or really no matter what therapies we give the kidney. I don't know if Jeff mentioned this, but at least in his analysis, they also showed through indicator dilution methods that there was a reduction in plasma volume in these individuals. And I think that's really important because we at least hypothesize that in many heart failure phenotypes, plasma volume is certainly a component of decompensation. So whether these kidneys have a more pleiotropic effect on the fluid balance from your status between the interstitium and the vascular space, long-term is really unknown.

Dr Greg Hundley: I want to thank both Jeff and Justin. What an incredible, exciting discussion. And this paper, Jeff, were so thrilled to have the opportunity to publish it in circulation. And the clarity, helping us understand some of the mechanism of the efficacy of SGLT-2 inhibition. And then this unique combination of SGLT-2 with loop diuretics, potentiating, dieresis natriuresis without some of the harmful effects on serum electrolytes. And then I really appreciate both of you giving us an insight into the future where more work is needed to understand, is this a sustainable beyond two-week effect? And then, can these therapies, this combination, be helpful in those with decompensated heart failure.

On behalf of Carolyn and myself, we wish you a great week and we look forward to catching you next week on the Run.

This program is copyright, the American Heart Association 2020.