June 2020 Discover Circ Res - a podcast by Cynthia St. Hilaire, PhD & Milka Koupenova, PhD

This month on Episode 13 of the Discover CircRes podcast, host Cindy St. Hilaire highlights three featured articles from the June 5 issue of Circulation Research and gives listeners an inside scoop on the cutting-edge ideas in the June 19th Compendium on Atrial Fibrillation. This episode also features an in-depth conversation with Dr David McManus on emerging technologies for identifying AFib. 

 

Article highlights:
 

Zhang, et al. ACEI/ARB on COVID-19 in patients with hypertension

Sakamoto, et al. ERR Signaling and Cardiac Maturation

Xie, et al. CIRP Governs the Heart Rate Response to Stress

Cindy St. Hilaire:           Hello and welcome to Discover CircRes, the podcast for the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire, from the Vascular Medicine Institute at the University of Pittsburgh.

Today, I'm going to share with you three articles selected from the June 5th issue of Circulation Research as well as give you an overview of the Compendium on Atrial Fibrillation also coming out in June. We'll follow that by having a discussion with Dr David McManus regarding his review on the emerging technologies for identifying AFib in the general population. So first, the highlights.

The first article I'm sharing with you is titled Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients with Hypertension Hospitalized with COVID-19. The first author is Peng Zhang and the corresponding author is Hongliang Li and they're from Wuhan University in Wuhan, China.

Patients with hypertension have increased risk of death from COVID-19. While the high blood pressure itself is likely to contribute to this, concerns have been raised that medications used to treat hypertension, specifically ACE inhibitors and Angiotensin II receptor blockers may worsen coronavirus infection. Research in animals showed that these drugs increased expression of ACE-2, the protein on lung epithelial cells that is used by the virus to gain entry into the host cell where it can then replicate.

However, other conflicting evidence has shown that these drugs might reduce lung injury in pneumonia patients, which is also a complication of COVID. To weigh up the benefits and risks of ACE inhibitors and Angiotensin II receptor blockers, Zhang and colleagues performed a retrospective analysis of 1,128 patients with COVID-19 and hypertension who are treated at nine hospitals in Hubei Province, China. Of the patients, 188 took the hypertensive medicine during their hospital stay and 940 did not. The ages, sexes and comorbidities of the two groups were very similar.

After 28 days of follow up, 99 of the patients had died, seven from the group taking the hypertensive medications, equivalent to 3.7% and 92 from the group that did not or 9.8%. The team concludes that treatment of hypertension patients with hypertension medications does not increase risk of COVID-19 mortality and may even reduce the threat. However, a much larger sample size would be necessary to fully confirm.

The second article I want to highlight is titled A Critical Role For Estrogen Related Receptor Signaling and Cardiac Maturation. The first authors are Tomoya Sakamoto and Timothy Matsuura and the corresponding author is Daniel Kelly from the University of Pennsylvania.

 From fetal to postnatal development, the human heart goes through significant changes, including the expansion of mitochondrial numbers, a change in fuel utilization within the mitochondria and replacement of fetal contractile proteins for the adult ones. Further, there is increases in ion uptake and release. Transcription factor estrogen-related receptor was known to drive postnatal mitochondrial biogenesis and now this group has shown that it also drives these developmental changes.

They developed a genetic model to knock down expression of estrogen-related receptor in early postnatal mice. When the animals were five weeks old, they performed transcriptomic analysis. In mice lacking estrogen-related receptor, there was a reduction in expression of genes involved in ion channeling in handling, fatty acid oxidation, which is the major metabolic process in the adult heart, as well as adult versions of the contractile proteins. By contrast, expression of genes and coding field contractile proteins and factors, specifically those involved in glycolysis, was upregulated. In heart failure, cardiomyocytes can revert to fetal-like cells. The authors, therefore, suggest that boosting estrogen-related receptor might be a way to counteract such pathology as well as a way to induce and study cardiomyocyte maturation and cultured progenitor cells.

The next article I want to share with you is titled Cold-Inducible RNA-Binding Protein Prevents the Excessive Heart Rate Response to Stress by Targeting Phosphodiesterase. The first authors are Duanyang Xie and Li Geng and the corresponding author is Yi-Han Chen and they're from the China Ministry of Education.

During a fight-or-flight situation, also known as the acute stress response, the heart rate increases rapidly due to the effects of adrenergic signaling on the cells in the sinoatrial node, which is the heart's pacemaker. Within sinoatrial node cells, levels of the signaling factor, cyclic AMP, ramp up and this, in turn, increases the cell's calcium handling and contraction rate, but excessive or prolonged racing heartbeat can be damaging and it is unclear what keeps the system in check. This group has now shown that cold-induced RNA-binding protein or CIRP puts the brakes on the heart by regulating cyclic AMP levels.

The team showed that while baseline rates between wild-type and CIRP-deficient rats were the same, triggering the adrenergic signaling via treatment with isoproterenol caused CRP-deficient rat hearts to beat faster for longer than in the wild-type counterparts. Cardiac tissue from the CIRP-lacking rats showed higher than usual levels of cyclic AMP after isoproterenol treatment. This was due to lower than usual levels of phosphodiesterase, the enzyme that normally degrades cyclical AMP. The team went on to show that CIRP normally binds and stabilizes phosphodiesterase's messenger RNA and sharing a ready supply of the enzyme to restrain cyclic AMP signaling. As well as revealing this crucial control mechanism, the work highlights CIRP as a potential new target for future heart rate lowering medications.

The last thing I want to share with you before we switch to our interview is our Atrial Fibrillation Compendium. Atrial fibrillation, or AFib, is a major cause of morbidity and mortality globally. There have been significant advances in the detection, management and treatment of AFib over the past two decades. However, the burden of the disease continues to increase. This Compendium on AFib features articles on epigenetics and transcriptional networks underlying atrial fibrillation, inflammasomes and proteostasis, novel molecular mechanisms associated with atrial fibrillation, emerging technologies with the identification of atrial fibrillation, epidemiology of atrial fibrillation in the 21st century, how will genetics inform the critical care of AFib, how will machine learning inform the clinical care of AFib, population-based screening for AFib, the molecular basis of AFib pathophysiology and therapy, the genetics of AFib in 2020, GWAS genome sequencing, polygenetic risk and beyond, is there hope for animal models of AFib and ablating AFib in 30 minutes, new technologies for safer and more efficient pulmonary vein isolation.

Okay. So we're now going to switch over to the interview portion of the podcast. I have with me, Dr David McManus, who is a professor of medicine in the Division of Cardiology and the Department of Medicine at UMass Medical Center in Worcester, Mass and he's also a cardiac electrophysiologist. And today, we're going to be discussing his recent Review on the emerging technologies for identifying atrial fibrillation, also known AFib, So thank you so much for taking the time to speak with me today.

David McManus: My pleasure. Thanks for inviting me.

Cindy St. Hilaire: Yeah, so before we dig into the review and about the emerging technologies for AFib, can you maybe give me a brief explanation of what is AFib, who gets it and what's the spectrum of disease severity in the patients that do get AFib?

David McManus: Sure, so atrial fibrillation is the world's most common sustained heart rhythm problem. It is associated with a number of different health conditions in terms of risk factors. The biggest risk factor for getting this rhythm problem is age, so it's most common in people over the age of 40 and it increases ... in fact, it doubles in terms of the incidents with each decade of life. So as you get into your 80s and 90, it's really quite common.

The additional risk factors are kind of common things that you might imagine and a few things you might not, things like diabetes and high blood pressure that are also risk factors forgetting plaque in your heart arteries are also risk factors for AFib, but some other risk factors that are a little more controversial with respect to heart artery disease, things like alcohol consumption, even if it's red wine, which otherwise might seem to have some benefit, is actually a risk factor too for AFib. In fact, in the old days, some doctors used to refer to AFib as holiday heart because of its association with acute alcohol intake around the holidays.

So, the fact is that AFib is related to some health behaviors like drinking. It's also related to a condition called sleep apnea or sleep-disordered breathing. Weight is associated with getting AFib. So all these things combined with your genetics, your family history and your age to contribute to getting this disease, so those are the most common risk factors.

The question about why it is important to diagnose? It was a disease that people sort of treated like gray hair for a long time. Something that you might not want to have, but is not particularly impactful, but some really important studies, especially in the 70s and 80s, started to establish a link between atrial fibrillation and clot-based strokes and so that is a very strong relationship that exists between people who get AFib and a much higher risk of having a clot form in the heart and traveling to the brain.

Cindy St. Hilaire: Which is obviously very dangerous. So how often does AFib go undetected? Because I think that's kind of at the core of using this new technology. Once you get AFib, do you know you have it right away?

David McManus: So, that's exactly right. The fact is that we don't truly know, right? Because by definition it's undiagnosed. We don't really know how long your average person goes before they're diagnosed and I think it varies a lot, but it's important to know a couple of things about AFib to sort of talk around the perimeter of this answer and try to kind of hone in a bit.

 So first off, some people who develop AFib don't feel it or they have very minimal symptoms or they have symptoms that come and go so quickly. By the time they get in for an evaluation, the arrhythmia is gone so it can be what's called paroxysmal in its early stages, which means it can come and go. The duration of that AFib can be minutes or hours or even in some cases, seconds, and therefore elude a diagnosis.

The other thing is symptoms from AFib, when they do exist, are not always the sensation of palpitation, a sensation of an irregularity. Some people just feel short of breath when they go up a flight of stairs and-

Cindy St. Hilaire: Which you can associate with age.

David McManus:  ... they may attribute that symptom to being older. Yeah. Right. They may just think "I'm getting tired because I'm older," or "I'm out of shape." And so the simple answer is, I guess, I'd start with this statistic. A significant minority of patients with atrial fibrillation present with a stroke as their first clear manifestations, so they come in with stroke. The estimates on that vary considerably, but at least one in five patients who present with a stroke have a first diagnosis of AFib at the time of that stroke and about 5% of patients with AFib overall present with stroke as their first manifestation.

Those are two different statistics to kind of come at it different ways and that's what you're trying to prevent. You want to make the diagnosis of AFib before the stroke because we have a lot of really good treatments that can prevent stroke if you know you have it.

Cindy St. Hilaire: Right and so I think that gets to this idea of maybe screening patients of a certain age. I don't know what that age cutoff would be. But when you look at the guidelines right now, there is no clear guideline. The US Preventative Task Force says there's no good data to screen patients beforehand. I think the AHA and the ACC just don't have any guidelines regarding screening. But yet in Europe and Australia, they do perform opportunistic screening for AFib patients and this is in the clinic. This is now with ECGs. They screen for patients over 65. So based on this statistic you said that 20% of stroke patients had undetected AFib, why is there not a specific guideline? Where does that come from?

David McManus: I think you're spot on that there's a lot of controversy about this right now and that's good because the reason I think it's controversial is there's some emerging technologies and opportunities that didn't exist before. Because pretty clearly, before doing a conventional 12-lead EKG in the office, did not offer sufficient benefit over and above usual care to demonstrate to groups like the US Preventative Service Task Force, which issues the guidance around things like breast cancer screening and colon cancer screening, so they have to weigh costs, financial costs, harms from false-positive tests. And so, the reason there's controversy is because what we had previously was a pretty suboptimal situation for screening. We had intermittent tests, which were of significant costs and they were spaced so far apart and required coming in for clinical care that there was really no benefit to doing them over and above taking someone's pulse in the office.

But there's no question that there are groups. There's a group called the AF-SCREEN Group, for example, that is really challenging the research community and clinicians to revisit some of these assumptions about screening, given new technologies and how we might thoughtfully use them in a pharmacy, for example, or in a clinic or at home with commercial technologies to study that. Because, really, to make a recommendation that screening is clearly beneficial, you have to do some kind of a study or studies that show that not only can you diagnose more of the arrhythmia, but that by diagnosing it, you can do something about it and that that action, in this case, anticoagulation, leads to a reduction in stroke and without a significant increase in harm from that treatment and that's somewhat controversial because this is a disease…the technologies that we have now are creating new diseases, right?

So in a sense, we've created the new disease, undiagnosed AFib. And so, okay, we found it. Now, is it kind of like cancer where finding it earlier maybe has a different prognosis than finding it later in terms of risk? Some people think so. And in that case, you really have to prove that finding it early and treating that early form with the treatment that you have for the late form works as well and doesn't cause harm. So that's kind of where we are right now is there a number of really big studies going on that are hoping to help inform this more, which is pretty cool.

Cindy St. Hilaire: Yeah. And so on that note, my parents got new supplemental insurance. They're both retired and this new insurance came with a nurse that dropped by your house and just kind of did a wellness check. And that nurse came and checked my mom's pulse, asked her how she was feeling and checked it again and said, "You're going to your doctor. You're in AFib," and she had no symptoms of that. She's 69, she's very healthy, she's active. And essentially in the course of a couple of months, she went from what she thought was normal to not being able to take one step up one stair because her AFib got so bad and she obviously saw a cardiologist and they got her on blood thinners. And eventually, after two cardioversions, things stuck and it's now in control, but one of the things that we did was we immediately bought her an at-home KardiaMobile heart monitor. That is essentially what you're reviewing now and I'm wondering if you could maybe give us a little bit of information about this.

So, there's multiple devices out there. There's the KardiaMobile. There's also the Apple Watch and the Fitbit that are starting to get these kinds of technologies. And so for us, it was at least reassuring to see her heart rate was something and now it's getting more normal with the medicine. And now even after the cardioversion, it's been a couple of months, she checks it once a day to make sure it's still functioning as it should. So can you tell us a little bit about these and about what this might mean for the future of AFib and clinical management?

David McManus: Sure. So you are using an FDA-cleared technology. You've referenced the AliveCor KardiaMobile. It's in a recent survey that the Heart Rhythm Society did. One of the most common ones that's purchased or advised to patients to buy by their cardiologists and healthcare providers and I think it was cleared about 2015. And what it is is it's a credit card-sized device that gets you a 1-lead EKG and it records about 30 seconds. And then that data, it can be transmitted directly to your cardiologist.

Cindy St. Hilaire: She actually would bring her phone in and show them, "Look at my last week."

David McManus: Yeah, you can do it that way or, like many of my patients are, just constantly emailing them or putting them in their electronic health record, which speaks to a whole other ball of wax. But that is a very valuable tool for people who are at risk for AFib or know they have it and want to monitor themselves for things like recurrences, to check their rhythm, check their rate, so that's an FDA-cleared device. And it also provides an automated read so that she is able to see at the top of the EKG what the computer thinks her heart rhythm is and that is a really nice technology that's been fairly well studied in a variety of different settings, including people like your mom who have had a prior cardioversion, to look for recurrences. So that's one approach that exists, which is for intermittent monitoring. And that's also in essence, the same approach that one of the two tools that an Apple Watch has embedded in it.

So the Apple Watch 4 and 5 are also FDA-cleared for similar analysis. So the Apple Watch has a EKG on the bevel of the watch. The thing you turn to change the time, not really in an Apple Watch, but in an old-fashioned watch. And so you can kind of put your finger on it and again, create that same circuit in your body to record a single-lead EKG and that similarly can present a 30-second EKG strip, so it's very similar to what AliveCor's KardioMobile does. Just in the watch. But again, that's an EKG-based approach and those approaches are not the only technologies that are out there.

There are a number of other devices that have CE marking designation in Europe. Other devices that are starting to become available in the US and we go through some of the performance of those devices in our review. And generally speaking, the ECG approach, the advantage is it's one of the more accurate approaches to AFib detection, but it does require, at least right now, that you intermittently check yourself.

 In contrast, there's a movement afoot, and Apple has a separate  FDA clearance, to use the lens and video camera on the back of the watch, that was previously used to measure your heart rate, to analyze the skin color changes that happen when your blood is flowing in and out of your wrist, to your hand. It looks at that skin color change, records it and analyzes it for irregularity. So it's an essence, like someone checking your pulse and it's called pulse plethysmography and that recording is similar to what other groups are analyzing. For example, there's something called FibriCheck, which is an app that is FDA cleared for AFib detection. But again, you put your finger on the camera of your iPhone or Android and it analyzes the pulse.

Cindy St. Hilaire: So a patient has to actively say, "I'm going to check this right now," as opposed to a background assessment?

David McManus: Yeah, so just to be clear. The background assessment is the automated sort of pulse check that the Apple Watch is doing and then it can prompt you to perform your own EKG, so that's the difference between kind of an intermittent-check approach versus a more near-continuous ... it's not truly continuous, but it's a near-continuous approach

Cindy St. Hilaire: So are there any drawbacks to people more regularly performing these in their kitchen? As a clinician, what are the drawbacks?

David McManus: It really is exciting and I think there are a lot of good reasons to pursue this. As you know, I'm sort of an early adopter of this idea and so I definitely would side with you that I think there were a lot of good reasons to be using these technologies. I just want to highlight though that there are a couple of issues.

So when commercial technology companies build medical-grade tech intended to diagnose or detect rhythm problems, those rhythm problems come to the clinics in a very different way and from a different type of patient, so they're not necessarily contextualized the same way a workup would happen if you came into the doctor, they prescribed a medical-grade patch monitor or a traditional monitor or did another type of medical test on you. You're kind of on your own. And so when you get the diagnosis or you get the possible diagnosis, you have very little information,  and it can be anxiety-provoking. In many cases, especially in younger people ... in fact, the majority of people who have Apple Watches are at really low risk from having a complication from AFib. So now, you're making an upstream diagnosis and you may not do anything about it other than introduce a word onto their chart. And so, yeah, I do think there's some things that warrant further study and evaluation about some of the unintended downstream consequences of making diagnoses earlier and worrying people about a condition.

David McManus: Now, some have argued that an early diagnosis, even if you wouldn't put someone on a blood thinner, as you call it or an anticoagulant ... Like for example, maybe you change your health behaviors, maybe you lose some weight or you get more active or you stopped drinking so much. So I happen to think that early diagnosis is a good thing, but I do think that we don't really have robust care-management systems across the country that can support people who are at home. It's really hard right now for your doctor to, on top of seeing 30 patients in the office, to find the time to respond to your new test that he didn't order or she didn't order.

Cindy St. Hilaire: I got this blip on my strips.

David McManus: Yeah, what do I do about this? Well, okay, now I got to see you, what tests are ordered, what's the process and I think there's a lot of opportunity for us to, especially in the COVID era, redesign how we're delivering heart care and integrating these technologies become a facilitator as opposed to a burden, so I think there's a lot of interest in incorporating them.

But right now, at least, they're kind of separate from your chart, in the electronic chart and your doctor has to sort of find a way of reviewing on your smartphone, in the office, finding extra time to do that. They're not really paid to do that, how do you protect the safety of that information and et cetera, et cetera. So there are all these sort of little, but they seem little, but they're actually kind of important downstream implications. So we talk a little bit about, and this is kind of a unique part of this Review, the clinical actionability of device-detected AFib. There's no debating the fact that AFib is bad, but the real impact of device-detected AFib remained something that we really need to define and so there's a lot of interesting work going on in this area.

Cindy St. Hilaire: And so, because we're still all at home because of the COVID epidemic, there's been some things in the news regarding some of these wearable technologies being able to detect or track trends in swaths of patient health. Where do you see this going in terms of either things like COVID and epidemics or even things regarding AFib and we always see those maps from the AHA with hotspots of diabetes, things like that, so how do you think that this kind of technology can help transition the future of medical care, specifically in the US?

David McManus: I think it's really exciting because everybody has a smartphone and that crosses age, sex, race, occupation, religion and I think people are increasingly understanding the connections between health behaviors and their heart health. And I think, for example, just using your heat map example, that there's a stroke belt and a diabetes belt and different areas in the United States, also tremendous rural health disparities, that mobile devices have a really remarkable opportunity to help us understand what is going on, what is driving these sort of risks? Is it stress, is it alcohol, food consumption, nutrition, activity, sleep, all the things we talked about?

And whether it be AFib or other cardiovascular conditions, these wearable devices and mobile devices and digital technologies allow for quantifying different health behaviors and mood and opinion and activity in ways that our  regular in-person exams that we do, when we see you for an hour or two every 365 days, we just really don't quantify. And I look forward to a time in the near future where your vital signs that are presented for your visit with your doctor over the internet is your activity, your blood pressure from your watch or heart rate from your watch or EKG, your oxygen levels at any of a myriad of other things that these devices can impact or will in the near future.

Cindy St. Hilaire: Yeah, I agree. I think it's great. And I think also it helps to empower the patient.

David McManus: Oh, for sure. I mean, if done well, it really connects you as a patient to your health more and it also, if done well, could connect you better to your healthcare team. I mean, a lot of people are afraid in the healthcare community of this technology replacing them, but that only will happen if we don't incorporate it as a tool into our relationships with our patients. I think if it's done in that way, it's a facilitator. It actually makes your mom maybe feel more connected to her cardiologist to be able to kind of run that list.

Cindy St. Hilaire: Yeah and she understands what she's looking at more, so it's been wonderful.

Well, thank you so much. This was an excellent Review; it was really timely and thank you again for the contribution and for taking the time to speak with me today.

David McManus: My pleasure and thanks for the invitation and I hope people will read the Review.

Cindy St. Hilaire: Great. Wonderful. Well, thank you so much, David.

David McManus: Good luck to you and your mom.

Cindy St. Hilaire: So that's it for the highlights from our June issues of Circulation Research and our compendium on atrial fibrillation. Thank you for listening.

Please check out the Circulation Research Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DiscoverCircRes. Thank you to our guests, Dr David McManus.

This podcast is produced by Rebecca McTavish and Ishara Ratnayaka, edited by Melissa Stoner and supported by the editorial team of Circulation Research. Some of the copy text for highlighted articles is provided by Ruth Williams.

I'm your host, Dr Cindy St. Hilaire And this is Discover CircRes, you're on-the-go source for the most up-to-date and exciting discoveries in basic cardiovascular research.

 

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