Review of New Scientific Statements in Cardiovascular Health

Interview With Rakesh Gopinathannair, MD, MA, FAHA, FHRS, and Elaine Y Wan, MD, FAHA 

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In this episode, EP Lab Digest features 2 interviews about new scientific statements from the American Heart Association. Featured first is our interview with Rakesh Gopinathannair, MD, MA, FAHA, FHRS, about the scientific statement on “Cardiac Arrhythmias and Autonomic Dysfunction Associated With COVID-19.” In the second interview, we talk with Elaine Y Wan, MD, FAHA, about the scientific statement on “Cardiac Contributions to Brain Health."

This scientific statement ("Cardiac Arrhythmias and Autonomic Dysfunction Associated With COVID-19") addresses both immediate and long-term cardiovascular impacts of COVID-19. How does this statement reflect the latest understanding of the relationship between COVID-19, cardiac arrhythmias, and autonomic dysfunction in patients during recovery?

The pandemic phase is behind us, but COVID-19 is still around and we are now in an endemic phase where there are still infections and new strains being identified. The severity of infections has gone down substantially and only a small fraction of patients now end up in the hospital. However, we continue to see arrhythmias, post-acute sequelae SARS-CoV-2 (PASC), of which autonomic dysfunction is a major concern. We still see those patients. The writing group felt that there was sort of a gap between the acute phase and how these arrhythmias are happening during follow-up, how surveillance is being performed, what kinds of drugs are being used, and types of interactions with cardiac drugs, etc. We also dedicated a section in the scientific statement to address the pathophysiology as well as the treatment strategies for COVID-associated autonomic dysfunction.

One of the main focuses of the scientific statement is what happens to these survivors. Interestingly, there were a lot of papers focusing on arrhythmias and cardiovascular manifestations when we were in the pandemic phase, but there has not been a lot of follow-up information on these patients. We reviewed and summarized all the available data, focusing on the patients who survived. What we noted was that of the patients who developed COVID-associated arrhythmias during the pandemic phase, their arrhythmic risk continued to remain higher during longer-term follow-up. A couple of large registry studies found there was at least a 2.5-time increase in atrial arrhythmias compared to those patients who did not get COVID. There was also about a 1.5 times higher risk of ventricular arrhythmias in these COVID survivors during follow-up.

So, arrhythmic manifestations continue to happen in these patients. This calls for heightened surveillance, evaluation of how clinically significant these are, and appropriate treatment for what the guidelines advocate for the specific arrhythmia. What we noted was that the arrhythmic risk seems to be on the higher side during follow-up. Major ventricular arrhythmias and sudden cardiac death incidence have abated; however, residual myocardial inflammation and associated arrhythmias that are still being seen. 

The other major change is that, when compared to the medications we used during the pandemic phase, we are now mostly using oral therapy to reduce the severity of the COVID infection and prevent patients from going to the hospital. There are important drug interactions that physicians and practitioners need to be aware of when using Paxlovid (Pfizer, Inc), especially in cardiac patients. There are interactions with antiarrhythmic drugs, anticoagulants, and certain antibiotics. So, in a patient who has heart disease or heart failure, they need to make sure that there are no significant contraindications for Paxlovid. New strains are being identified and we are in a situation where we are not trying to avoid COVID, but instead living with it.

The scientific statement discusses various pathophysiological mechanisms for the cardiac arrhythmias observed in COVID-19 patients. Could you elaborate on the most significant mechanisms identified?

The mechanisms typically differ for different arrhythmias. A lot of these data comes from the early and late pandemic phase. In the acute phase, there were various mechanisms including a  hyperadrenergic state, inflammation associated with the infection as well as direct viral injury. These were thought to contribute to atrial and ventricular arrhythmias. Prior studies have shown that there was cardiac infiltration by the SARS-CoV-2 virus; however, the risk of arrhythmias could have been driven primarily by the inflammatory response rather than direct viral injury. As we know, the COVID virus gets into the body through the ACE receptors, which are plentiful in the heart. So, that may explain some predilection to cardiac arrhythmias. In the follow-up period of those with prior COVID infection who developed arrhythmias later, mechanisms are a bit unclear. One possibility is that the prior inflammation could lead to scar formation or fibrosis that could result in atrial and ventricular arrhythmias. Autonomic dysfunction, especially a hyperadrenergic state, could persist into recovery in some people. This could be a manifestation of a long COVID kind of scenario, and that could also contribute to arrhythmias. Especially for atrial arrhythmias and ventricular arrhythmias, if you developed these arrhythmias during the acute phase, there is a much higher risk of them developing during recovery and long-term follow-up. In terms of slow heart rates and incidence, it is a little less understood how it happens, but it is possible that they could be secondary to some myocardial injury and inflammatory damage to the pacemaker cells. Antiviral drugs used to treat COVID, especially remdesivir in hospitalized patients, was associated with almost 20% increased risk of bradycardia. The other concern is with Paxlovid and other drugs—if you are not careful about drug interaction, they could prolong QT interval and lead to potentially dangerous ventricular arrhythmia. This is a summary of what we know. Again, exact mechanisms for specific patients are not yet well understood and we need more research on that.

What specific arrhythmias are associated with COVID-19, and what key considerations should electrophysiologists take into account when developing treatment plans for patients experiencing arrhythmias post-COVID-19?

During the pandemic phase, bradyarrhythmias were reported in almost 20% to 30% of patients. But there are conflicting reports; some of the reports show much lower incidence. So, we are dealing with a lot of data, and how accurate they are is a little tough to say in that period. We talked about remdesivir use, which commonly causes bradycardia that resolves with drug withdrawal. If you look at the available data, only about 0.3% or so of patients had severe bradyarrhythmias that required pacemaker implantation. Regarding atrial arrhythmias, atrial fibrillation (AF) is by far the most common cardiac arrhythmia noted, with the incidence about 18% to 22%, with new-onset AF happening in approximately 5% to 13%. Typically, when looking at the risk factors, patients tended to be older and had underlying cardiac disease that contributed to AF.

Fortunately, ventricular arrhythmias were uncommon. In the early stages of the pandemic, it was higher. But if you look at follow-up studies, like at least a year out, they were much lesser, in the 1% to 2% range. However, ventricular arrhythmias were associated with poorer outcomes. Thankfully, the arrhythmic risk is much lower during the current endemic phase with the less virulent strains. Outpatient data on ventricular arrhythmia occurrence is not very well known. There was one study that looked at ventricular arrhythmias at 3 months after hospitalization for COVID using 24-hour ambulatory monitoring. They found that a higher percentage of patients had frequent premature ventricular beats and some non-sustained ventricular tachycardia, but there were no sustained arrhythmias. So, there could be some signs that they were having more arrhythmias, but nothing that could lead to sudden cardiac death. A large study that evaluated over 13,000 hospitalized COVID-19 patients showed that sudden cardiac death occurred in 1.8% of patients and in 10% of those who died. But again, in the long-term endemic phase, it is a little less clear who is experiencing sudden cardiac death and how that is related to COVID. We also talked about when following these patients over 1 year, a couple of large studies have shown that both atrial and ventricular arrhythmia incidence is significantly higher compared to those patients who did not get COVID infection. So again, it is important to understand this, as we think about longer term rhythm monitoring for surveillance.

The statement identifies important knowledge gaps concerning the long-term effects of COVID-19 on cardiac health. What specific areas of research do you believe are critical for improving our understanding of post-acute sequelae and their implications for clinical practice?

I think the long-term risk of arrhythmia still needs to be better understood. We have some data, but we need more. The use of wearables and other tools that we have at our disposal should be helpful in identifying these patients. In this scenario, it has not been very well studied, but I think if a patient already has a history of arrhythmia related to COVID infection, there is value in having some sort of rhythm monitoring to better understand recurrent arrhythmia that could be treated appropriately. 

Autonomic dysfunction continues to be a very challenging topic in the sense that its mechanisms are not well understood. There are several theories, including direct COVID infection, and some concern related to deconditioning, but it is not very clear. Symptoms typically happen weeks to months afterwards, such as fatigue, dizziness, a lot of nonspecific symptoms, brain fog, etc. Most people have either inappropriate sinus tachycardia or postural orthostatic tachycardia. The treatment strategies are not well understood and currently there is no specific treatment that can be recommended other than how we treat other patients with autonomic disorders per the current syncope/autonomic dysfunction guidelines. There is really a need to understand the long-term outcomes of these patients, because we are still seeing these patients and they recover at various times. Is it possible to make that recovery quicker? Those are some of the things that we need to understand better. 

The other “hot potato” item is the association between vaccines and heart rhythm issues. If you look at long-term data, or at least the available data on vaccines and arrhythmias, there is no clear evidence that vaccines cause a higher risk of arrhythmias compared to COVID infection. We still do not have a clear understanding of the long-term effects of myocardial inflammation and how that impacts patients down the road. It would be nice to have long-term rhythm monitoring in these patients to have a better idea. 

Lastly, I think COVID is here to stay with us, so we must stay up to date with the cardiovascular consequences of future infection. Even though the virulence has gone down and the infections have become milder, again, it is a respiratory virus, so we must be cognizant of potential cardiovascular and arrhythmic outcomes in these patients.

The transcripts were edited for clarity and length.

Reference

1. Gopinathannair R, Olshansky B, Mina K Chung MK, et al. Cardiac Arrhythmias and Autonomic Dysfunction Associated With COVID-19: a Scientific Statement From the American Heart Association. Circulation. 2024;150(21):e449-e465. Epub 2024 Oct 14. doi:10.1161/CIR.0000000000001290

Can you elaborate on the mechanisms by which atrial fibrillation (AF) is believed to contribute to cognitive impairment beyond the risks associated with stroke?

Thank you for that question. AF is the most common clinical arrhythmia. What we’re learning is that AF not only increases the risk for stroke and heart failure, but in the scientific statement, we also wanting to focus on the connection between the heart and the brain. So, in the statement, we're clarifying that other than stroke, which may be a result of AF, AF itself as a heart rhythm is an independent risk factor for developing cognitive decline and dementia. So, one of the possibilities for an abnormal rhythm such as AF to cause dementia is hypoperfusion or decreased blood flow to the brain, and that hypoperfusion may lead to abnormal function of the tissue and changes in the microvascular circulation specifically, which may lead to cognitive decline and dementia. So, those are some of the possibilities. We wanted to focus not only on the heart, but also the vascular system, so in the scientific statement, we specifically look at heart failure as a cause for cognitive dysfunction, but also vascular dysfunction as a cause for cognitive dysfunction. So, microcirculation abnormalities are one of the ways in which AF could cause cognitive decline.

How do the findings presented in the statement impact clinical practice for managing patients with AF, particularly in relation to monitoring and addressing cognitive health?

The scientific statement was really an interdisciplinary effort between neurologists, cardiologists, and electrophysiologists. When we look at AF as a rhythm, we look at the heart rhythm and also possible effects on AF such as heart failure. But what we're really tasking here with the scientific statement is to have clinicians look beyond just the cardiac effects, but other effects on other organ systems like the brain. For example, in patients with AF, we have to be aware that long-term AF can also affect the brain and cause abnormalities in the function of the brain and cognitive decline. In a lot of the trials for AF, the end points are very short. For example, after ablation, we may look at recurrence of AF, but we need further long-term monitoring of our patients with AF, as in whether this abnormal rhythm in the heart for a long time can lead to other organ system decline, for example, in the brain, where long-term AF may cause dementia or cognitive dysfunction. So, I think this leads to us looking at more outcomes in clinical trials long-term, including how restoring normal rhythm may improve their function in other organ systems, for example, like the brain.

What key messages should health care providers communicate to patients with AF about the potential risks of cognitive decline?

The scientific statement really emphasizes our neurologists and cardiologists working together, because the vasculature system connects the brain to the heart, and whatever happens in the heart can affect the brain. So, what we have urged in the scientific statement is, for example, making sure that the patient is in good vascular health if they have coronary artery disease, so making sure that the blood vessels perfusing the brain aren't affected the same way that the coronary vessels are. Also, extending the relationship between heart failure, such as poor pump function leading to hyperperfusion of the brain, and abnormal heart rhythms leading to microcirculation abnormalities. So, we wanted to highlight the connection between the brain and the heart in this scientific statement.

What specific areas of future research do you believe are crucial to further understand the relationship between cardiac health and brain function, particularly in the context of AF?

I think one of the difficulties is that AF is well-studied in humans, but we really don't understand the other mechanisms behind AF. We've built a lot of tools such as more and more catheters to do faster ablations, but we really don't understand why AF occurs. I think one of the other limits is that we don't have good animal models or models to study AF. AF doesn't naturally occur in animals, so we don't understand the long-term effects of AF and it becomes more difficult to study. A lot of the animal models, if we do study them, are short-term, so we don't study long-term effects of AF. For example, in humans, AF may lead to cognitive decline, but we never test this in other models. So, I think those are the limitations. But I think this scientific statement is a good first step to raise and highlight the points that there is a heart-brain connection that we need to study further.

How can different specialties, such as cardiology and neurology, work together more effectively to address the cognitive aspects of AF in patient care and research?

In this scientific statement, we urge interdisciplinary care of the patient. For example, if a patient has coronary disease, we need to be cognizant that it's possible that the patient may have vascular disease elsewhere, such as in the brain, and to maintain good control of the blood pressure, as blood pressure not only perfuses the heart but also the brain. Also, be aware of microvascular dysfunction abnormalities and how we can work together to treat that. But really, treating the vascular system as a whole, where main organs such as the brain and heart are connected.

The transcripts were edited for clarity and length.

Reference

1. Testai FD, Gorelick PB, Chuang PY, et al. Cardiac Contributions to Brain Health: a Scientific Statement From the American Heart Association. Stroke. 2024 Oct 10. Online ahead of print. doi:10.1161/STR.0000000000000476