Apr 12, 2021
For this week's Feature Discussion, please join authors Erik Näslund, Mehran Anvari, Editorialist Philip Schauer, and Associate Editor Ian Neeland as they discuss, in a panel forum, the articles: "Association of Metabolic Surgery With Major Adverse Cardiovascular Outcomes in Patients With Previous Myocardial Infarction and Severe Obesity: A Nationwide Cohort Study," "Bariatric Surgery and Cardiovascular Outcomes in Patients With Obesity and Cardiovascular Disease: A Population-Based Retrospective Cohort Study," and accompanying editorial "After 70 Years, Metabolic Surgery has Earned a Cardiovascular Outcome Trial."
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, Director of the Pauley Heart Center in Richmond, Virginia with VCU Health. Well, Carolyn, another double feature this week and investigating the world of metabolic, or as we also know, bariatric surgery and the impact of bariatric surgery on cardiovascular outcomes.
Dr. Greg Hundley:
But before we get to that double feature discussion today, how about we grab a cup of coffee and we jump into some of the other articles in the issue. I'll go first this week, Carolyn. The first article comes from Professor Andreas Schuster from University Medical Center in Göttingen. Carolyn, as you know, right heart catheterization using exercise stress represents a key method for the diagnosis of heart failure with preserved ejection fraction but carries the risk of that invasive procedure. These authors hypothesized that real time cardiovascular magnetic resonance exercise imaging with pathophysiologic data at excellent temporal and spatial resolution may represent a contemporary non-invasive alternative for diagnosing HFpEF.
Dr. Carolyn Lam:
Wow, Greg, you know how I love talking about HFpEF? I actually managed this paper. Could you just describe what they found? It's so exciting.
Dr. Greg Hundley:
Yeah, Carolyn. Even the methods are interesting here, where these authors created a situation where you're riding a bicycle and obtaining an MRI scan at the same time. Let's get to the results. The HFpEF stress trial, prospectively recruited 75 patients with echocardiographic signs of diastolic dysfunction and dyspnea on exertion with E to E primes greater than eight, New York Heart Association class greater than or equal to two. To then, undergo echocardiography, right heart catheterization and then this real time pedaling a bicycle CMR exam at rest and during exercise stress. And so what they found Carolyn, the real time CMR allowed a highly accurate identification of HFpEF during physiological exercise and qualifies, perhaps, as a suitable non-invasive diagnostic alternative to the invasive procedures. So Carolyn, I think these results will need to be confirmed in a multicenter prospective approach, but really interesting innovation here, in this particular study.
Dr. Carolyn Lam:
So Greg, the paper I want to talk about, actually, is the first indicative critical role of cardiac macrophages in pressure overload-induced cardiac fibrosis and dysfunction and reveal macrophage micro RNA-21 as a key molecule for the pro-fibrotic role of cardiac macrophages. Now, this comes from Dr. Engelhardt from Munich, Germany, and colleagues who show that within the myocardium, micro RNA-21 has the strongest expression in cardiac macrophages. Where it is also the single strongest express micro RNA among all micro RNAs. Targeted genetic deletion of micro RNA-21 in macrophages of mice prevented their pro-inflammatory polarization and subsequent pressure overload-induced cardiac fibrosis and dysfunction. Analysis of intercellular communication using cell sequencing identified the cardiac fibroblasts as the primary recipient cell of intercellular signals that emanate from activated cardiac macrophages and that are controlled by micro RNA-21.
Dr. Greg Hundley:
Oh, Carolyn, really interesting findings. What are the clinical implications?
Dr. Carolyn Lam:
Ah, glad you asked? What this implies is that interference with the activation of cardiac macrophages represents a promising therapeutic strategy in myocardial remodeling and dysfunction. In fact, synthetic oligonucleotide inhibitors against micro RNA-21 are currently undergoing clinical testing against fibrotic disease. This is really, really fascinating.
Dr. Greg Hundley:
Well, Carolyn, my next paper also comes from the world of basic science and it's from Dr. Anke Tijsen from Amsterdam University Medical Center, University of Amsterdam. Carolyn, as you know, titin, the largest protein in human, forms the molecular spring that spans half of the sarcomere to provide passive elasticity to cardiomyocytes. Mutations that disrupt the titin transcript are the most frequent cause of hereditary heart failure. These investigators evaluated the role of titin and specifically a class of circular RNAs for regulating splicing of key muscle genes in the heart.
Dr. Carolyn Lam:
Fascinating. Tell us what do they find.
Dr. Greg Hundley:
Yeah, Carolyn. In this study, the authors found that the back splice junction formed by circular RNAs creates a unique motif, which binds SRSF10, to enable it to regulate splicing. And furthermore, they show that one of these circular RNAs, cTTN1, distorts both localization of, and splicing of, RBM20. Carolyn, the authors demonstrate with this work that circular RNAs formed from the titin transcript are essential for normal splicing of key muscle genes by enabling splice regulators, RBM20 and SRSF10. This shows that the titin transcript also has regulatory roles besides its well-known signaling and structural function. So, really interesting new work involving titin.
Dr. Greg Hundley:
Well, Carolyn, as we transitioned to the other articles in the issue, I want to tell you about Dr. Maskoun. He has a cardiovascular case series entitled, A Plumbing and Electrical Problem: An Unusual Cause of Syncope.
Dr. Carolyn Lam:
I like that title. Well, there's also a perspective fees by Dr. Lindman on unloading the stenotic path to identifying medical therapy for calcific aortic valve disease, talking about its barriers and opportunities.
Dr. Carolyn Lam:
Tracy Hampton reviews the literature and fascinatingly highlights papers like how DNA base editing treats Hutchinson-Gilford progeria syndrome in mice, how some researchers have identified the protein involved in cardiac repair, which is the ZEB2 protein and more information on mapping early heart formation in the embryonic mouse heart.
Dr. Carolyn Lam:
We've got a research letter by Dr. Levine. This one is so fascinating. It's about the cardiac effects of repeated weightlessness during extreme duration swimming and how that compares with spaceflight. Is that cool?
Dr. Greg Hundley:
Yeah.
Dr. Carolyn Lam:
Anyways, this was just such a power-packed issue. Now, let's just go to our feature discussion. Shall we? I can't wait, Greg.
Dr. Greg Hundley:
You bet.
Dr. Greg Hundley:
Well listeners, we have got another exciting feature discussion today on this April 13th issue. We have with us Erik Naslünd from Karolinska Institute in Stockholm, Ari Doumouras from McMaster Institution in Ontario, Canada, Ian Neeland our own associate editor from Cleveland, Ohio, and Phil Schauer from Pennington Biomedical Research Center-LSU. Welcome gentlemen. Let's start with you today, Erik. Could you describe for us, what was the hypothesis that your study wanted to address and what were your study population and design?
Dr. Erik Naslünd:
Well, what we want to study was if metabolic surgery affects the outcome in patients with previous myocardial infarction. And in Sweden, we are lucky that every Swede has their personal identification number, which is connected to essentially anything that we do, including all healthcare and we then have several registries. One is in a metabolic surgery registry, and then we also have one for cardiovascular disease called SWEDEHEART. What we did was, we went into these registries and we found patients who had undergone metabolic surgery. And then, we went to the SWEDEHEART registry and we looked at those patients who'd had a previous myocardial infarction. And then, we were able to get a match cohort, the same BMI and so on, in the SWEDEHEART registry. We were able to compare these two. We got a cohort then of roughly 500 patients who'd had metabolic surgery without a prior myocardial infarction and 500 who'd had a myocardial infarction. We then, assessed to see what the outcome was.
Dr. Greg Hundley:
Very nice. And can you describe for us your results?
Dr. Erik Naslünd:
Yeah, what we found was... Our main outcome measure was in the major adverse cardiovascular event and we found that, that was lower in the group that underwent metabolic surgery. We also then looked at death, which was also lower. We also looked at the risk for new onset of heart failure, which was also reduced. We also then assessed the risk for a major complication of the surgery in the group that had undergone metabolic surgery. We compare that to our surgical registry and we found that that was essentially the same. There was not really difference in terms of outcomes in terms of severe complications after the surgery.
Dr. Greg Hundley:
Excellent. Now, Ari, you also have a study that is involving bariatric surgery or metabolic surgery. Could you describe for us your hypothesis and your study population and design?
Dr. Aristithes Doumouras:
Yes. Thanks, Greg. Our hypothesis, first and foremost, was very similar to Erik's that patients who underwent metabolic surgery, who already had a history of heart disease when compared to a group that didn't receive bariatrics or metabolic surgery would decrease the future cardiovascular risk through a MACE outcome. Our secondary hypothesis we had, that was that those with heart failure would actually have a greater effect of metabolic surgery because of the decrease in obesity compared to those without heart failure or patients with ischemic, just ischemic heart disease with no heart failure.
Dr. Aristithes Doumouras:
The setting of the study was Ontario, Canada, where we have a centralized bariatric surgery network called the Ontario Bariatric Network. Like Erik, in Ontario, we're able to have multiple databases that are connected. They have one unique identifier for each patient. And so we looked at all patients who underwent bariatric surgery in Ontario during a timeframe. To note, we have a very large private system. Most bariatric surgeries, more than 95%, happen in the public system so we're able to track a lot of our bariatric surgery patients and don't lose a lot. We tracked all of our bariatric patients and matched them, on a one-to-one ratio, with very similar patients who also had heart disease and access to cardiology care, access to family physician care and followed them over 10 years. And so the design was a retrospective matched cohort in this way, comparing these two groups.
Dr. Greg Hundley:
Thank you, Ari. And Ari, what did you find?
Dr. Aristithes Doumouras:
Once again, like Erik, we found that there was a lower rate of MACE outcomes in the patients who underwent metabolic surgery and the absolute values were actually quite high. The absolute risk difference between the two groups was 8% and actually that went up to almost 19% in patients with heart failure. There was no action causing interaction between ischemic heart disease and heart failure, so they were the same. And the risk was about 40% lower for future MACE events in the surgery group.
Dr. Greg Hundley:
Wow, a large difference. Ian, as an editorialist for Circulation, the American Heart Association, you see a lot of papers come across your desk, what attracted you to these two manuscripts?
Dr. Ian Neeland:
When I first read these excellent papers, I thought that first of all, it was globally diverse. One study was in Europe, the other one in North America. And nevertheless, they showed strikingly similar relative risk reductions in MACE. One of them showed between 40 to 50% and so did the other. That was one really striking thing, was the consistency of a risk reduction despite being globally diverse with different systems in each country. Second of all, the absolute risk reduction was astounding. Assuming you could translate the absolute risk reduction to a clinical trial, to real-world experience, you're looking at a number needed treat between five to 12 for MACE, which is astounding and much greater than many of the evidence-based therapies we have today. The magnitude of the findings were striking and the ability to generalize globally were really interesting.
Dr. Greg Hundley:
Thank you, Ian. Well listeners, we also have an editorialist that can help us put all of this in context of what we known previously about bariatric surgery or what we are calling metabolic surgery. So we're going to turn to Phil. Phil help us put the results of these two studies in the context of cardiovascular medicine specialists or even family practitioners, internists that are managing patients with cardiovascular disease that happened to be morbidly obese.
Dr. Phillip Schauer:
Yeah, Greg. Well, these are both outstanding observational studies. And congrats to Erik and Ari and their teams for putting these studies together. Now, what's unique about these studies, is that I think these are the first to actually look at metabolic surgery for secondary prevention. Now, there are nearly 30 studies looking at metabolic surgery as primary prevention. These are all observational. They're not prospective randomized trials, but they all show, nearly all of them, show mortality reduction and MACE event reductions. These two studies are the first to show that metabolic surgery is good for secondary prevention. This is really important because I think, up till now, cardiologists have been very reluctant to refer patients to metabolic surgery. Patients who've already had a heart attack because of the least perceived operative risk and surgeons have been reluctant to operate on these patients. And both Erik and Ari have showed that the perioperative risks were remarkably low for this population, operative mortality way below 1%.
Dr. Phillip Schauer:
And so within a very short period, within a year or two, the mortality reduction, by far, supersedes any perioperative risk. I think this is really very good news. We now have quite a large amount of observational data in the primary prevention side. These two studies, nearly identical, showing mortality, MACE event reductions, as Ian pointed out, 40 to 50%. That's a lot. That rivals almost anything else out there in terms of mortality reduction, whether it's an SGLT2 inhibitor, a GLP-1, or a statin, I mean, people dance in the street when you see a five and 10% reduction. With surgery, it looks like we're seeing 40 to 50%. So, this is remarkable news but we do have a little more work to do. Perhaps we can talk about that, your next question.
Dr. Greg Hundley:
What a great lead-in Phil. So listeners, striking results with this surgical intervention for patients with cardiovascular disease that have morbid obesity. Erik, let's start with you, but we'll go through all of our expert panelists here. Erik, what do you think is the next study that needs to be performed in this sort of area of research?
Dr. Erik Naslünd:
Well, I mean, the obvious answer to that is that we need to do a randomized control trial to verify these results. That's the number one. Number two, I think, we also need to tease out, if we can, which are the most suitable patients. And is there a difference between the most commonly performed metabolic surgery procedures. That's where I would suggest that you need to do next.
Dr. Greg Hundley:
Ari, how about you?
Dr. Aristithes Doumouras:
I agree with Erik. I think everyone's going to say the same thing. That I think a randomized trial is the next step when looking at bariatric surgery and the role of secondary prevention-based patients, as these are all observational studies. And they just need to be confirmed. We're starting on a pilot study for this exact randomized trial at our institution and obviously looking for more partners later on, but yeah, that's definitely the next step in the process for sure.
Dr. Greg Hundley:
Ian, what would you like to add?
Dr. Ian Neeland:
No, I definitely agree an RCT is needed. I think one that combines both primary and secondary prevention patients is important to try to understand that the difference. One could imagine that secondary patients may actually derive much greater benefit than prime prevention patients given their baseline risk. And if one can show that the operative morbidity, mortality is low in both populations, as both papers showed observationally, then I think there's a lot of benefit there. I also think it's important to try to randomize people to different procedures, to really try to understand is it the gastric sleeve? Is it the bypass? And which one has greater benefit in the setting of a RCT as well as how do the risks and safety outcomes differ between those two in the real-world RCT setting.
Dr. Greg Hundley:
Very nice. Well, Phil we've heard randomized trials, maybe also, do we need longer follow-up?
Dr. Phillip Schauer:
Yeah, Greg. In the title of my editorial, and I hope that the listeners actually do read it, is after 70 years, metabolic surgery has earned a prospective randomized trial, and it's true. This field is 70 years old, there's not a single prospective large randomized controlled trial. There are quite a few small studies that were powered for biomarkers, but not hard clinical end points. We need this and it is doable. For example, for coronary artery bypass surgery, there's over a hundred prospective randomized controlled trials. So we definitely need this type of study. It needs to be long follow-up, probably five years or more. As Erik and Ari pointed out, it should have a mixture of primary and secondary prevention.
Dr. Phillip Schauer:
I'll share with you right now, I'm working with a group in the US. Along with Steve Nissen, a very noted cardiologist, Bob Eckel, who's currently the president of the American Diabetes Association and a number of other experts. David Aterburn, Sonia Thomas, who are working together to try to develop a study. The question is who will fund this? And frankly, we've been talking to various funding organizations. And frankly, we need the help of the cardiology community to help us support this. This information is very important.
Dr. Phillip Schauer:
If I may say one more thing, it's interesting the entire field of obesity treatment, everybody who has obesity gets treatment to cause weight loss. Yet in 2021, we do not have data that shows that weight loss actually reduces morbidity and mortality. The closest thing we have is a look ahead trial, and it looked at weight loss via a lifestyle intervention. After 10 years, they got 6% weight loss, 6% weight loss is not enough. With metabolic surgery, we can get 25 to 30% weight loss. So we need to do this study, not just to show that metabolic surgery is effective, but to show that weight loss itself could actually reduce morbidity and mortality. And frankly, it's not just cardiovascular. The second most common cause of death in these studies is cancer. And that's the other interesting thing that should be looked at. Hopefully, we can get organizations like NCI to come in and support this initiative.
Dr. Greg Hundley:
Thank you. Well, listeners, what a wonderful discussion today, really a feature symposium. And we want to thank Erik Naslünd, Dr. Aristithes Doumouras, Ian Neeland and Phil Schauer for their time and expertise and sharing that with us today. Especially on this topic of bariatric, but now maybe more commonly called metabolic surgery, where these two studies have been demonstrating efficacy of these procedures now in patients with cardiovascular disease and even those post myocardial infarction.
Dr. Greg Hundley:
On behalf of Carolyn and myself, I want to wish you another great week ahead and we will catch you in that next week, on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021.