COVID-19’s Enduring Impact on the Heart? Some Clues and Predictions

Diffuse thrombosis, infarctions, and STEMI mimics, Takotsubo and myocarditis, arrhythmias and sudden cardiac arrest: COVID-19’s wide-ranging cardiac effects during the acute phase of the illness are now well established. But a new question now looms—what lasting impact will the disease have on the heart?

“This is a completely new disease, so we’ve got absolutely no idea. On the basis of other viral etiologies in myocarditis, we know that the vast majority of patients tend to have quite mild cardiac involvement, but there are a small group of patients whose cardiac involvement is more extensive. Not only do we start to see acute inflammation and focal fibrosis, we also see reductions in LV ejection fraction,” John P. Greenwood, MBChB, PhD (Leeds Institute of Cardiovascular and Metabolic Medicine, England), told TCTMD.

“Typically in myocarditis, the vast majority of patients make a very good recovery or full recovery and whilst there might be a little bit of scar that we can see on the cardiac MR scan, usually the ejection fraction goes back completely to normal,” he continued. “But with this disease, we’ve got no idea of what the sort of short- to medium-term outcomes are going to be and certainly no idea what the long-term outcomes are going to be from a heart perspective.”

Experts who spoke with TCTMD agreed—long-term cardiovascular damage is unlikely in the majority of patients who survive a brush with SARS-CoV-2. But the severely ill, particularly those who spend time in the ICU or on a ventilator and present with elevated biomarkers, will need careful follow-up in the months and years to come. Just what proportion of patients this entails or how best to follow them remains unclear, although a number of recent imaging studies offer some clues.

Echo in the Acute Setting

Back in June, Marc Dweck, MBChB, PhD (University of Edinburgh, Scotland), and colleagues, writing in the European Heart Journal: Cardiovascular Imaging, reported a retrospective, international survey of echocardiographic abnormalities in the setting of confirmed or suspected COVID-19. Among 1,216 patients from 69 countries who had an echo during their acute illness, 55% were found to have abnormal echocardiograms and of these, 39% had left ventricular abnormalities, 3% had new myocardial infarction, 3% had myocarditis, and 2% had Takotsubo cardiomyopathy. Right ventricular abnormalities were seen in 33% of patients and cardiac tamponade and endocarditis were also picked up at a rate of 1% each. Taken together, severe cardiac disease was seen among one in seven patients in this cohort.

With this disease, we’ve got no idea of what the sort of short- to medium-term outcomes are going to be and certainly no idea what the long-term outcomes are going to be from a heart perspective. John P. Greenwood

Speaking with TCTMD, Dweck stressed that the findings apply to a highly selected group, namely patients who were already critically ill in the hospital. All also had an indication for echo—typically signs of left (40%) or right-sided heart failure (20%) or elevated biomarkers (26%). And while some of the cardiovascular disease was likely preexisting, merely unmasked by the viral illness and hospitalization, other causes of left and right heart dysfunction carry different prognoses.

“I think it's actually really important that we understand what the mechanisms are, because that's going to govern not only treatment but also the long-term implications,” Dweck said. “If it's all stress cardiomyopathy, then we expect it all to get better with no problems. But if it's all myocarditis and myocardial infarction then potentially we're going to be left with quite a large population of patients with heart failure. That's the next phase of the studies that we need to do.”

Convalescent Cardiac MR

As a recent comparative review in SN Comprehensive Clinical Medicine points out, echocardiography in COVID-19 has the advantages of being widely available, being feasible in the acute setting, and not requiring contrast. However, it may miss instances of cardiac damage that aren’t causing hemodynamic impairment. That important caveat is borne out in a research letter published last week in Circulation. Here, lead authors Daniel Knight, MBBS, MD, and Tushar Kotecha, MBChB, PhD (both Royal Free London NHS Foundation Trust, London, England), report the results of their single-center patient series in which cardiac MRI was used to track patients who’d had troponin elevations at the time of their critical illness.

Among the 828 patients admitted, 586 had elevated high-sensitivity troponin T tests and 239 (41%) of these people died in the hospital. By comparison, of the 242 troponin-negative patients, just 20 died. Of the 347 troponin-positive patients discharged alive, 51 were ultimately followed up with a cardiac MRI scan that unveiled a cardiac cause for the troponin result in 22 patients, including acute coronary syndromes and pulmonary embolism; other patients were found to have a history of ischemic heart disease. Further tests in the 29 patients with elevated troponin of unknown etiology revealed a mix of ischemic and nonischemic myocardial injury, with late gadolinium injury suggesting a “myocarditis-like” pattern in 45% of patients.

Is there going to be long-term scar and what's the consequence of that? Time's going to tell. Daniel Knight

“If you actually look at our patients who had myocarditis-like features on their cardiac MRI, they all had normal cardiac function. So you need an imaging modality that gives you tissue characterization to look for edema or swelling, to look for scar, and then what sort of pattern of scar that is: is it a heart attack-type pattern or is it a myocarditis-type pattern? And that's something echo can't actually give you,” Knight told TCTMD.

Timing is important, he added. For this study, patients were imaged after they’d been discharged from hospital, but before too much time had passed. “For a diagnosis of myocarditis, ideally you do the MRI within a couple of weeks of the illness to try and actually see the edema because that heals and, in our patients, certainly there was no real significant residual edema. So the question is, what are we seeing? Is there going to be long-term scar and what's the consequence of that? Time's going to tell,” said Knight. “We're going to actually follow these patients up with a serial scan at 6 months or maybe a year to see how these people are and see if those changes are still there.”

Prevalence and Impact

Greenwood, the current president of the British Society of Cardiovascular Magnetic Resonance, is heading up a National Institute for Health Research-funded study dubbed COVID-HEART, now underway at over 20 hospitals across the United Kingdom, all of which have cardiac MRI facilities capable of doing baseline and follow-up imaging tests in COVID-19 patients. The trial is enrolling approximately 320 patients with a positive troponin test who will undergo early cardiac MR, followed by a second test 6 months later.

As Greenwood explained to TCTMD, the study has multiple aims. The first is to identify the actual prevalence of acute myocardial injury—either infarction or myocarditis secondary to COVID-19, as opposed to a troponin rise related to other triggers such as hypoxia or sepsis.

The second aim is to gauge the extent of myocardial recovery 6 months later and to see whether that recovery relates in any way to traditional risks factors “such as age, sex, ethnicity, and cardiovascular comorbidities, diabetes, hypertension, heart failure, coronary disease—all of these have been very linked with mortality and COVID-19,” Greenwood noted.

Third, researchers hope to identify any differences in groups of patients according to the degree of myocardial recovery at 6 months and assess whether those differences can be explained by demographics, genetics, comorbidities, etc, and further, whether these have an impact on patient quality of life and functional capacity.

Last but not least, the study is also designed to include an artificial intelligence component to see if machine learning can detect any ECG changes, invisible to the human eye, that could help differentiate between the ECGs of patients with viral myocarditis and those of a historical group with classic STEMI.

“I think this has got a wider application to potentially many other viral etiologies of acute myocarditis,” Greenwood said. “Even before COVID-19, we saw quite a lot of young patients who had viral myocarditis coming to the cath lab in the middle of the night, being treated as if they had an ST-elevation MI only to find they had completely normal coronary arteries. . . . It's a well-known and recognized phenomenon that myocarditis does overlap with STEMI on the basis of the ECG, and I think if we can find some subtle markers on the ECG that are more specific for myocarditis, it has the potential to be more applicable to diseases outside of COVID-19.”

Late Effects

Just what kinds of more-permanent damage COVID-19 might be inflicting on the heart and other organs is unclear. The question has dogged Craig Thompson, MD, who heads up the cardiac cath lab at NYU Langone Health in New York City and has treated many patients with signs of cardiac damage when the virus had that city under siege. As he told TCTMD, he and his colleagues celebrated every patient who they were able to wean from a ventilator and discharge, but he does worry some will come back with chronic problems down the road.

“I think for folks that are out in the community that were asymptomatic, minimally symptomatic, or even tested positive and had a clinical illness that really wasn't of the level of severity where they needed to be hospitalized, I would think that, all in all, they will probably do equally as well long term as if they did not have the disease,” Thompson told TCTMD.  

I think for the coming months and years, we're probably going to start seeing these patients in heart failure clinics or turning up to our chest pain clinics with ongoing symptoms. Tushar Kotecha

For people who were “ICU-level sick,” on the other hand, “my concern is that we may find a population of them that will struggle,” he said. From a pulmonary perspective certainly this is a concern, he said, although the long-term effects from a cardiology angle are less clear, particularly since so many of these patients didn’t survive to hospital discharge—a point made abundantly clear in Knight and Kotecha’s series, where a positive troponin test was associated with such a high proportion of deaths.

“Do these hearts kind of just bounce back and do better as opposed to maybe other organs that would scar down or have more chronic problems? I don't know,” Thompson mused. “If their first presentation was crushing chest pain, they looked like they were having an active heart attack, and we took them to the cath lab [only to find no acute blockages], what is the long-term sequela of that? I don't know, but I would be concerned that it's not as good as an age-adjusted population of somebody in whom the stimulus that brought them in was not coronavirus. . . . The long and short of it is, I think a lot of people are going to do really well, but I think there's some who are going to carry their battle wounds indefinitely.”

Knight believes it “bodes well” that despite evidence of injury on MRI, cardiac function was normal in the patient series he led with Kotecha. “But we don't know the long-term consequences: we know that scar in the heart can be a risk for rhythm disturbances, and we don't know [whether] if they have another hit—if COVID-19 has a second wave, or they get the seasonal flu or some other illness—will they have less reserve to tolerate any insults in the future? It's important to recognize that they have normal cardiac function at the time of the scan, that’s a good thing and it’s reassuring. But COVID has left its mark and whether or not that has a long-term consequence, I think we'll only find out as we follow these people up.”

Kotecha predicted that, as hospitals that have focused solely on the COVID-19 pandemic in recent months gradually return to normal, routine imaging tests will pick up scar related to COVID-19 that wasn’t identified at the time of the infection, potentially predisposing patients to arrhythmias and heart failure. There will also be the even larger pool of patients who developed heart failure and other chronic cardiovascular problems secondary to delays in seeking help for an ACS during the pandemic—a point also raised by Thompson.

“I think for the coming months and years, we're probably going to start seeing these patients in heart failure clinics or turning up to our chest pain clinics with ongoing symptoms,” Kotecha said.

Thompson also predicted that even in patients with a confirmed infection who weren’t hospitalized, prior COVID-19 may be considered a CVD risk factor down the road, given all the unknowns. Sorting out cardiac symptoms from lasting pulmonary effects will also be difficult, he noted, not only for physicians but for patients who assume the long-lasting lethargy often reported among survivors relates to their lungs, not other organ or vascular system damage, or is due to chronic pressure exerted by damaged lungs on the heart and other organs over time. All of this, Thompson said, should be “disentangled” over longer-term follow-up rather than fixing too closely on one organ system. “The heart's a part of this, not just the lungs, as are the kidneys, as is the liver, as is the brain—heck, all of the vascular system for that matter,” he said.  

Acute Considerations

Prior work has established that one-third of hospitalized patients with COVID-19 have troponin elevations and that outcomes are worse in patients with a positive test. While the biomarker is sensitive enough to pick up systemic challenges like hypoxia, hypotension, shock, and sepsis, more often than not a positive result points to some kind of myocardial injury. Moreover, noted Knight, prior research has already established that elevated troponin in other settings portends worse outcomes. For Kotecha and Knight, the findings from their MRI paper reinforce the message that troponin elevations always need to be taken seriously in the context of COVID-19—a point also made in a recent review. What to do about that troponin signal depends on the patient.

Do these hearts kind of just bounce back and do better as opposed to maybe other organs that would scar down or have more chronic problems? Craig Thompson

“There's a group of patients who have got what I would probably call uncomplicated COVID with a troponin rise: their COVID illness is relatively mild, they’ll get over it, and then they’re ready to go home,” Kotecha said. “Those are the sorts of patients that probably should have a convalescent MRI to work out what the mechanism of the injury was. And then you've got a second group who are more critically unwell in hospital, and there I think echo is probably the tool that's most widely available in that setting. [It also] allows you to get a hint of whether there was a regional wall motion abnormality and if so, that's pointing towards an acute coronary problem, then you're heading towards angiography and cath lab.”

Dweck, too, stressed that properly investigating cardiac complications during the acute phase, despite all of the other patient- and hospital-level factors complicating care, can have a marked impact on patient survival, even in the short term.

“Certainly at the beginning of the pandemic, there was a lot of concern about whether we should be doing echo in anyone, because of the risk of transmitting the virus and eating up masks and [personal protective equipment],” Dweck said. “But in selected patient groups it is a useful test that can lead to an important change in their care.”

In the study he led, echo scans led to changes in management in one in three patients. “These decisions about how much fluid do I give, do I give inotropes? Do I give more diuretics? All these questions are key to getting patients better, and that's long before you start thinking about heart failure treatments,” such as ACE inhibitors, beta-blockers, extracorporeal membrane oxygenation, and the like, over the long term.

As for any insights into longer-term damage to the heart, Greenwood hopes to have his nationwide study wrapped up within the year. “It's very difficult to make predictions,” he said. “I suspect the patients with the most cardiac involvement will have the most persistent, lasting damage and the implications of that, whether they suffer in the future from heart failure problems or arrhythmia problems, this is all to be worked out.”