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Circulation on the Run: November 7, 2023

  • Carolyn S.P. Lam, MBBS, PhD orcid
  • W. Gregory Hundley, MD orcid
  • Peder L. Myhre, MD, PhD orcid
Originally published 10.1161/podcast.20231106.465546

Dr. Greg Hundley:

Welcome, listeners, to this November 7th issue of Circulation on the Run. And I am one of your associate editors, Dr. Greg Hundley from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I'm Dr. Peder Myhre from Akershus University Hospital and University of Oslo in Norway.

Dr. Greg Hundley:

Peder, this week we have a really interesting feature discussion, looking at how we might or might not adjust apixaban dosing in patients with atrial fibrillation but that also have chronic kidney disease. But before we get to that discussion, which is going to have a lot of clinical relevance, let's also dive into some of the other articles in this issue. Would you like to go first?

Dr. Peder Myhre:

Yes, please. I would love to. Greg, we are going to start off with a very interesting paper related to lipids. Angiopoietin-like 3, ANGPTL3, is a key factor in the regulation of lipoprotein transport in genetic. And pharmacological intervention of ANGPTL3 in mice are associated with significant reduction in plasma total triglycerides and total cholesterol. And in humans, complete ANGPTL3 deficiency due to inactivating mutations cause familial combined hypolipidemia characterized by marked reductions of LDL cholesterol, HDL cholesterol and VLDL.

And Greg, it was recently reported that the inhibition of hepatic ANGPTL3 synthesis by vupanorsen, a specific antisense oligonucleotide against ANGPTL3 was associated with increases in liver steatosis in a dose dependent manner. Therefore, to estimate the effect of targeting ANGPTL3 production in hepatocytes these authors, led by corresponding author Nathan Stitziel from Washington University School of Medicine characterized hepatic fat content as well as extra hepatic fat distribution by using magnetic resonance in participants with either partial or complete ANGPTL3 deficiency due to inactivating mutations.

They then studied a large population cohort, namely the UK Biobank to determine if reduced concentrations of ANGPTL3 were causally associated with changes in apathic fat content using two sample Mendelian randomization.

Dr. Greg Hundley:

Wow, Peder. A lot going on here. We have ANGPTL3 and that is associated with hypolipidemia. And then also, you're going to look at whether or not there's an ANGPTL3 deficiency and whether there's an association with hepatic fat. Very interesting. What did they find?

Dr. Peder Myhre:

Yeah, exactly. This is really focusing on the hepatic steatosis of this association. And participants with ANGPTL3 deficiency exhibited significantly lower total cholesterol. And there was a difference from 78.5 milligrams per deciliter in those with complete deficiency to 172 milligrams per deciliter in partial deficiency. And 188 milligrams per deciliter in wild-type as well as lower plasma triglycerides with the same trend.

However, this was without any significant difference in apathic fat. Those with complete deficiency had 7.9% partial deficiency 6.4%, and wild-type 6.9%, without any significant difference. And in addition, ANGPTL3 deficiency did not alter the distribution of extra hepatic fat.

And then over to the UK Biobank analysis because the results from those MR analysis, Mendelian randomization analysis in 36,703 participants demonstrated that genetically determined plasma ANGPTL3 protein levels were causally associated with LDL cholesterol, triglycerides but not hepatic fat.

Dr. Greg Hundley:

Right. Peder, lots of data here. And looks like, again, examining ANGPTL3 deficiency, the presence of intrahepatic fat and what happened to total cholesterol levels or what was the association with total cholesterol levels. Put this all together for, what are the clinical implications here of the results of this study?

Dr. Peder Myhre:

Yeah, Greg. the clinical implications are that therapeutic approaches that are now emerging to inhibit hepatic ANGPTL3 production should not generally be expected to result in increased hepatic steatosis.

Dr. Greg Hundley:

Very good. Beautiful summary, Peder. And a lot of complex data all assimilated using several different study designs embedded in one manuscript. A fantastic job.

Well, Peder, this next paper comes to us from the world of preclinical science. And interferon gamma signaling plays a complex role in atherogenesis. And interferon gamma stimulation of macrophages permits exploration in vitro of pro-inflammatory mechanisms and the development of novel immune therapies.

These authors in combination with corresponding author, Dr. Julius Decano, from Brigham and Women's Hospital and Harvard Medical School hypothesized that study of macrophage subpopulations could lead to anti-inflammatory interventions. And so, to address this hypothesis, Peder, primary human macrophages activated by interferon gamma underwent single cell analyses by RNA sequencing, time course cell cluster proteomics, metabolite consumption, immunoassays, and then functional tests, phagocytic, afrocytic and chemotactic.

And RNA sequence data was analyzed in the library of integrated network-based cellular signatures to identify compounds targeting the macrophage interferon gamma subpopulations.

Dr. Peder Myhre:

Nice. I knew that macrophages had a role in atherosclerosis. And now this team is going to teach us some of the mechanisms that underlie dissociation between macrophages and atherosclerosis. What did they find?

Dr. Greg Hundley:

Right, Peder. They found that single cell RNA sequencing identified two major clusters in macrophage interferon gamma, an inflammatory population and a phagocytic population. Now the inflammatory population had higher amino acid consumption and elevated expression of inflammatory chemokines compared to the phagocytic population. The phagocytic population were more, as we would think, phagocytic and chemotactic with higher Krebs cycle activity and less glycolysis than the inflammatory population.

Human carotid atherosclerotic plaques contained both macrophage clusters. And bioinformatic analysis of the library of integrated network-based cellular signatures using the RNA sequence data identified BI25036 as a potential compound to decrease the macrophage inflammatory subpopulation.

Peder, in summary, this team used cellular data with a cell signature drug library to identify this novel compound that targets a subset of macrophages involved in atherosclerosis. And the team's approach utilized a precision medicine strategy that may also identify new drugs that target atherosclerosis as well as other inflammatory diseases.

Dr. Peder Myhre:

Oh, beautiful, Greg. Really nice summary and important future clinical implications with this precision medicine strategy to target atherosclerosis. Okay. Our next original research article is super important, Greg. I want everyone, even clinicians to pay attention because we are going to learn about CaM kinase and heart failure.

And this preclinical science study really uses the novel technique of CRISPR/Cas9 based editing to look at how they can manipulate this gene. And Greg, calmodulin-dependent protein kinase II delta CaM kinase II delta is one of many CaM kinase isoforms and a key regulator of cardiac physiology and signaling. And chronic over-activation of CaM kinase II delta has been implicated in the pathophysiology of heart failure as it disregulates cellular calcium hemostasis and induced myocardial inflammation, apoptosis and fibrosis, culminating in loss of cardiac function.

And even though there have been significant efforts to design effective CaM kinase II delta inhibitors pharmacologically, they have not yet been successful and there is no clinical drug available today for patients. Thus, further optimized strategies to target CaM kinase II delta are needed.

And in the present study, Greg, the investigators led by corresponding author, Eric Olson from University of Texas Southwestern Medical Center, used CRISPR/Cas9 adenine-based editing strategy in the mouse germline to ablate the autophosphorylation site of CaM kinase II delta. Thereby rendering the enzyme insensitive to pathogenic hyperactivation.

Dr. Greg Hundley:

Very interesting, Peder. Looking to see, so what is the effect of this ablation of autophosphorylation of the site of the CaM kinase II delta? What did they find?

Dr. Peder Myhre:

Yeah, Greg. The authors use this mouse model for heart failure where they induce heart failure by severe transverse aortic constriction, aortic banding. And within two weeks after the aortic banding surgery, 65% of the wild-type mice died. And the surviving mice that did not die in the control group showed a dramatic impaired cardiac function.

In contrast to the wild-type mice, CaM kinase II delta gene edited mice showed a mortality of only 11% and exhibited a substantially improved cardiac function. Moreover, CaM kinase II delta gene edited mice were protected from heart failure related aberrant changes in cardiac gene expression, myocardial apoptosis and subsequent fibrosis which were observed in wild-type mice after aortic banding. Greg, to conclude, ablation of CaM kinase II delta autophosphorylation by adenine-based editing may offer a potential broad-based therapeutic concept for human cardiac disease.

Dr. Greg Hundley:

Very nice, Peder. What a fantastic summary. Well, let's jump into what is in the mailbag. And listeners, Tracy Hampton brings us several articles. Remember Tracy goes and looks in other journals and finds key articles that she wants to emphasize. And the first one has a really interesting title. It involves daily sweets and fats change the brain's rewards circuits. And that was published in the Journal Cell Metabolism.

Second, she highlights another article, a very interesting study that compares artificial intelligence versus sonographer's interpretations for providing accurate heart evaluations from transthoracic echocardiograms. Very interesting looking at this comparison on the reading of these studies. And this particular trial is published in nature. It included 3,495 transthoracic echocardiographic studies, so a great read.

And then finally she emphasizes a third study also it was published in nature and it's entitled Fatty Acid and Maternal Milk Triggers Cardiomyocytes Metabolic Maturation. A really nice collection of summaries put together by Tracy.

Dr. Peder Myhre:

Excellent. Thank you, Tracy. And next we have an exchange of letters between Doctors Li and Sipilä regarding the article, “Severe Infection and Risk of Cardiovascular Disease: A Multicohort Study.” And finally, we have the Global Grand Rounds from Nigeria, “Cardiovascular Diseases in Nigeria: Current Status, Threats and Opportunities.” And now, Greg, let's head over to that featured discussion to learn more about apixaban dose and safety and effectiveness in patients with atrial fibrillation and severe chronic kidney disease.

Dr. Greg Hundley:

Absolutely. Let's go. Welcome, listeners, to this November 7 feature discussion. And we have with us today Dr. Jung-Im Shin from Johns Hopkins University and our editorial consultant, Dr. Sana Al-Khatib from Duke University. Welcome to you both. Well, Jung-Im, we will start with you. Could you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address?

Dr. Jung-Im Shin:

In clinical trial of apixaban for patients with atrial fibrillation, patient with severe CKD is excluded. Therefore, safety and efficacy of apixaban in this population is very limited. And also, dosing recommendation for apixaban based on kidney function is not consistent between the US FDA and European Medicines Agency. Basically the optimal apixaban dosing in this population is unknown. We hypothesized the reduced dose of apixaban may be associated with a lower risk of bleeding compared to a standard dose of apixaban without increasing the risk of stroke or embolism or other adverse outcomes. That was our hypothesis.

Dr. Greg Hundley:

Very interesting, Jung-Im. And so, a discrepancy between the US Food and Drug Administration and the European Medicines Agency. To address your hypothesis, what was your study design and who did you include in your study population?

Dr. Jung-Im Shin:

This is not a clinical trial, so we performed retrospective observational study using large electronic health record data. And because this is observational study, we tried to mimic a randomization of treatment assignment as much as we can. We used inverse probability of treatment waiting to make the two treatment groups as similar as possible.

Dr. Greg Hundley:

Very nice. And how many subjects did you include and what was the breakdown of men versus women?

Dr. Jung-Im Shin:

Total sample size is about 4,300 participant with CKD stage four and five, which is defined as eGFR less than 30. And then about half for women and half for men.

Dr. Greg Hundley:

And what was the age range?

Dr. Jung-Im Shin:

Age, a median age was 80, was pretty old. Yeah, old population.

Dr. Greg Hundley:

Very nice. Well, for our listeners, can you describe for us your study results?

Dr. Jung-Im Shin:

Yeah. As we hypothesized, so apixaban, the five milligram twice daily was associated with 60% higher risk of bleeding compared to a reduced dose, 2.5 milligram twice daily. And as we expected. And without actually the increasing risk of stroke or death. That was our main result. And in terms of the utilization, about 40% use a higher dose of apixaban, five milligram. And 60% use reduced dose of apixaban in this population.

Dr. Greg Hundley:

Very nice. And then again, across this older group of patients, can you give us some idea what was their average perhaps serum creatinine or their estimated glomerular filtration rate?

Dr. Jung-Im Shin:

The serum creatinine level was different between five milligram and 2.5 milligram. Five milligram was 2.7. And 2.5 milligram group is 2.5. And then average eGFR was similar between the groups and 24.

Dr. Greg Hundley:

Very nice. Very interesting result. Well, listeners, next we're going to turn to one of our associate editors that served as a consultant on this paper, Dr. Sana Al-Khatib. And Sana is an electrophysiologist and certainly someone that sees many patients with atrial fibrillation. How do we put the results of this study really in the context of others that are seeking to identify an optimal anticoagulation dose to prevent CVA, stroke, et cetera in patients with atrial fibrillation?

Dr. Sana Al-Khatib:

Greg, this is a very important question. And before I address it, I first want to thank you for including me in this very interesting podcast. And I want to take a second to congratulate Dr. Shin and her team on completing this very interesting and potentially important study.

Certainly, this study addresses a very important clinical question because this question comes up very frequently when we see patients with AFib with a stage four or five chronic kidney disease and we're trying to determine the best dose of apixaban for those patients. It's not clear. We don't know what the right answer is, Greg. And I'm sure you are aware that there was an attempt at completing a randomized clinical trial that actually looked at five milligrams twice a day of apixaban, specifically the renal AF trial.

And unfortunately, that trial could not be completed because they were not able to enroll the target number of patients. And so, while a randomized clinical trial is the best study designed to address this question, short of being able to do a well-designed and well-conducted and powered randomized clinical trial, we have to try to learn from observational studies. And that's exactly what Dr. Shin and her team tried to show us here.

Certainly intriguing results without a doubt because many people have said that five milligrams twice a day is probably the best dose in these patients, but these results challenge the thinking in terms of showing us a higher risk of bleeding with the higher dose of apixaban. That would make sense clinically. However, I do want to make sure, I'm pretty sure Dr. Shin appreciates that this is still an observational study.

And we have to acknowledge the potential limitations and even though they applied very robust methods in terms of inverse probability weighted estimators and doing falsification endpoints and everything else, you still have confounding and selection bias that even the best statistical methods cannot fully addressed. While this is important in terms of providing some perspective on this important clinical question, it doesn't answer the question definitively. And I still believe that a well-designed, well-powered randomized clinical trial is the best way to go.

Dr. Greg Hundley:

Well, Jung-Im, I remember when we started, you made a comment about how recommendations may differ between the US Food and Drug Administration and the European Medicines Agency. Maybe could you highlight what those differences are. And then second in follow-up, how do the results of your study inform either of those groups and their current recommendations?

Dr. Jung-Im Shin:

The FDA, according to the USA FDA label, the dose reduction is recommended when there are two or more criteria among the patient characteristics. It's based on age, age older than 80, and body weight the less than 60 kilogram. Or serum creatinine greater than 1.5 milligram per deciliter. If more than two criteria, those reduction is recommended by FDA. On the other hand, European Medicines Agency, they recommend reduce dose of apixaban for patient with creatinine clearance between 15 to 30. And there is recommendation for no use for people with creatinine clearance less than 15.

I would say that in general the European label is more conservative than US label. And so, our result is more kind of supportive to a European label rather than FDA label. I think the FDA regulatory agency, I think they should look at our paper and think about it. I think current FDA label is from the clinical trial because this criteria is from the clinical trial like Aristo tell.

I think our one study may not be able to, as Dr. Al-Khatib said, is not a providing definitive answer, but we provide some kind of current labels safety concern. I think more randomized clinical trial focusing on drug dosing, optimal dosing for this very high risk population as well as replication from the observation studies, I think is necessary for the next step, I think.

Dr. Greg Hundley:

Very nice, Jung-Im. Beautifully described and really leading us to other studies on the horizon that we might want to consider. Sana, do you have anything to add here?

Dr. Sana Al-Khatib:

Well, first of all, again, I want to congratulate Jung-Im and per team on completing this study. While as I said, the randomized clinical trial is the best study design, I do think that this is important. If it doesn't do anything, it certainly encourages us to think about the randomized clinical trials that can best address this question.

And in the meantime, we still have to take care of patients day in and day out. And I think this study can help us include information as we have these shared decision-making encounters with our patients about starting an oral anticoagulant and how we dose it and everything. I do think that these results will inform those kinds of discussions with patients.

Dr. Greg Hundley:

Beautiful description really, of clinical relevance. Well, listeners, we want to thank Dr. Jung-Im Shin from Johns Hopkins University and Dr. Sana Al-Khatib from Duke University for bringing us this study highlighting a comparison of 2.5 milligrams. And in comparison with that, the use of five milligrams of apixaban was associated with a higher risk of bleeding in patients with atrial fibrillation and severe chronic kidney disease with no difference in the risk of stroke or systemic embolism or death.

Well, on behalf of Carolyn, Peder and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association, 2023. 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, please visit ajjournals.org.

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