Concerns about lasting heart damage in COVID-19 patients — 2 German studies

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Two studies from Germany paint a sobering picture of the toll that COVID-19 takes on the heart, raising the spectre of long-term damage after people recover, even if their illness was not severe enough to require hospitalisation. STAT News reports that one study examined the cardiac MRIs of 100 people who had recovered from COVID-19 and compared them to heart images from 100 people who were similar but not infected with the virus. Their average age was 49 and two-thirds of the patients had recovered at home.

More than two months later, infected patients were more likely to have troubling cardiac signs than people in the control group: 78 patients showed structural changes to their hearts, 76 had evidence of a biomarker signalling cardiac injury typically found after a heart attack, and 60 had signs of inflammation.

These were relatively young, healthy patients who fell ill in the spring, Valentina Puntmann, who led the MRI study, pointed out in an interview. Many of them had just returned from ski vacations. None of them thought they had anything wrong with their hearts.

“The fact that 78% of ‘recovered’ (patients) had evidence of ongoing heart involvement means that the heart is involved in a majority of patients, even if COVID-19 illness does not scream out with the classical heart symptoms, such as anginal chest pain,” she told is quoted in the report as saying. She is a cardiologist at University Hospital Frankfurt. “In my view, the relatively clear onset of COVID-19 illness provides an opportunity to take proactive action and to look for heart involvement early.”

The other study, which analysed autopsy results from 39 people who died early in the pandemic and whose average age was 85, found high levels of the virus in the hearts of 24 patients. “We see signs of viral replication in those that are heavily infected,” Dirk Westermann, a cardiologist at the University Heart and Vascular Centre-Hamburg, said in an interview. “We don’t know the long-term consequences of the changes in gene expression yet. I know from other diseases that it’s obviously not good to have that increased level of inflammation.”

Taken together, the two studies suggest that in many patients, COVID-19 could presage heart failure, a chronic, progressive condition in which the heart’s ability to pump blood throughout the body declines. It is too soon to say if the damage in patients recovering from COVID-19 is transient or permanent, but cardiologists are worried.

“These are two studies that both suggest that being infected with COVID-19 carries a high likelihood of having some involvement of the heart. If not answering questions, (they) prompt important questions about what the cardiac aftermath is,” said Matthew Tomey, a cardiologist and assistant professor of medicine at the Icahn School of Medicine at Mount Sinai Health System in New York. He was not involved in either study.

“The question now is how long these changes persist,” he added. “Are these going to become chronic effects upon the heart or are these – we hope – temporary effects on cardiac function that will gradually improve over time?”

Since the pandemic began, people with underlying cardiovascular problems such as high blood pressure, coronary artery disease, or heart failure have been known to be at higher risk for infection and death. The connection between COVID-19 and blood clots emerged later, after doctors began connecting the pulmonary embolisms, strokes, and heart attacks they were seeing to the virus.

Cardiac problems in recovering patients could belong to a pattern of lingering symptoms. Tomey sees signs of weakness in patients who had COVID-19 in March or April, when the disease was surging in New York.

“Patients come to my office saying, ‘Hey, I’m a 31-year-old who used to run and be completely unlimited in my exercise, and now I get palpitations walking across the street. Or I get out of breath climbing up to my second-floor apartment,’” he said. “Individuals are exquisitely tuned in to their own capacity for exercise, so I take that very seriously. Our challenge is to understand the why.”

Marc Pfeffer, a cardiologist at Brigham and Women’s Hospital in Boston, called both the autopsy and MRI studies a sobering warning. He was not involved in either. He’s concerned about relatively young people losing their cardiac health reserves, which typically decrease with age and can set the stage for heart failure.

“We knew that this virus, SARS-CoV-2, doesn’t spare the heart,” he said. “We’re going to get a lot of people through the acute phase [but] I think there’s going to be a long-term price to pay.”

In an editorial about the two studies, Clyde Yancy, a cardiologist at Northwestern’s Feinberg School of Medicine, and Gregg Fonarow, a cardiologist at UCLA’s Geffen School of Medicine, pushed for more research into the problem.

“If this high rate of risk is confirmed, … then the crisis of COVID-19 will not abate but will instead shift to a new de novo incidence of heart failure and other chronic cardiovascular complications,” they wrote. “We are inclined to raise a new and very evident concern that cardiomyopathy and heart failure related to Covid-19 may potentially evolve as the natural history of this infection becomes clearer.”

 

Abstract 1
Importance: Coronavirus disease 2019 (COVID-19) continues to cause considerable morbidity and mortality worldwide. Case reports of hospitalized patients suggest that COVID-19 prominently affects the cardiovascular system, but the overall impact remains unknown.
Objective: To evaluate the presence of myocardial injury in unselected patients recently recovered from COVID-19 illness.
Design, Setting, and Participants: In this prospective observational cohort study, 100 patients recently recovered from COVID-19 illness were identified from the University Hospital Frankfurt COVID-19 Registry between April and June 2020.
Exposure: Recent recovery from severe acute respiratory syndrome coronavirus 2 infection, as determined by reverse transcription–polymerase chain reaction on swab test of the upper respiratory tract.
Main Outcomes and Measures: Demographic characteristics, cardiac blood markers, and cardiovascular magnetic resonance (CMR) imaging were obtained. Comparisons were made with age-matched and sex-matched control groups of healthy volunteers (n = 50) and risk factor–matched patients (n = 57).
Results: Of the 100 included patients, 53 (53%) were male, and the median (interquartile range [IQR]) age was 49 (45-53) years. The median (IQR) time interval between COVID-19 diagnosis and CMR was 71 (64-92) days. Of the 100 patients recently recovered from COVID-19, 67 (67%) recovered at home, while 33 (33%) required hospitalization. At the time of CMR, high-sensitivity troponin T (hsTnT) was detectable (3 pg/mL or greater) in 71 patients recently recovered from COVID-19 (71%) and significantly elevated (13.9 pg/mL or greater) in 5 patients (5%). Compared with healthy controls and risk factor–matched controls, patients recently recovered from COVID-19 had lower left ventricular ejection fraction, higher left ventricle volumes, higher left ventricle mass, and raised native T1 and T2. A total of 78 patients recently recovered from COVID-19 (78%) had abnormal CMR findings, including raised myocardial native T1 (n = 73), raised myocardial native T2 (n = 60), myocardial late gadolinium enhancement (n = 32), and pericardial enhancement (n = 22). There was a small but significant difference between patients who recovered at home vs in the hospital for native T1 mapping (median [IQR], 1122 [1113-1132] ms vs 1143 [1131-1156] ms; P = .02) but not for native T2 mapping or hsTnT levels. None of these measures were correlated with time from COVID-19 diagnosis (native T1: r = 0.07; P = .47; native T2: r = 0.14; P = .15; hsTnT: r = −0.07; P = .50). High-sensitivity troponin T was significantly correlated with native T1 mapping (r = 0.35; P < .001) and native T2 mapping (r = 0.22; P = .03). Endomyocardial biopsy in patients with severe findings revealed active lymphocytic inflammation. Native T1 and T2 were the measures with the best discriminatory ability to detect COVID-19–related myocardial pathology.
Conclusions and Relevance: In this study of a cohort of German patients recently recovered from COVID-19 infection, CMR revealed cardiac involvement in 78 patients (78%) and ongoing myocardial inflammation in 60 patients (60%), independent of preexisting conditions, severity and overall course of the acute illness, and time from the original diagnosis. These findings indicate the need for ongoing investigation of the long-term cardiovascular consequences of COVID-19.

Authors
Valentina O Puntmann; M Ludovica Carerj; Imke Wieters; Masia Fahim; Christophe Arendt; Jedrzej Hoffmann; Anastasia Shchendrygina; Felicitas Escher; Mariuca Vasa-Nicotera; Andreas M Zeiher; Maria Vehreschild; Eike Nagel

Abstract 2
Importance: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be documented in various tissues, but the frequency of cardiac involvement as well as possible consequences are unknown.
Objective: To evaluate the presence of SARS-CoV-2 in the myocardial tissue from autopsy cases and to document a possible cardiac response to that infection.
Design, Setting, and Participants: This cohort study used data from consecutive autopsy cases from Germany between April 8 and April 18, 2020. All patients had tested positive for SARS-CoV-2 in pharyngeal swab tests.
Exposures: Patients who died of coronavirus disease 2019.
Main Outcomes and Measures: Incidence of SARS-CoV-2 positivity in cardiac tissue as well as CD3+, CD45+, and CD68+ cells in the myocardium and gene expression of tumor necrosis growth factor α, interferon γ, chemokine ligand 5, as well as interleukin-6, -8, and -18.
Results: Cardiac tissue from 39 consecutive autopsy cases were included. The median (interquartile range) age of patients was 85 (78-89) years, and 23 (59.0%) were women. SARS-CoV-2 could be documented in 24 of 39 patients (61.5%). Viral load above 1000 copies per μg RNA could be documented in 16 of 39 patients (41.0%). A cytokine response panel consisting of 6 proinflammatory genes was increased in those 16 patients compared with 15 patients without any SARS-CoV-2 in the heart. Comparison of 15 patients without cardiac infection with 16 patients with more than 1000 copies revealed no inflammatory cell infiltrates or differences in leukocyte numbers per high power field.
Conclusions and Relevance: In this analysis of autopsy cases, viral presence within the myocardium could be documented. While a response to this infection could be reported in cases with higher virus load vs no virus infection, this was not associated with an influx of inflammatory cells. Future investigations should focus on evaluating the long-term consequences of this cardiac involvement.

Authors
Diana Lindner; Antonia Fitzek; Hanna Bräuninger; Ganna Aleshcheva; Caroline Edler; Kira Meissner; Katharina Scherschel; Paulus Kirchhof; Felicitas Escher; Heinz-Peter Schultheiss; Stefan Blankenberg; Klaus Püschel; Dirk Westermann

STAT News report

 

JAMA Cardiology abstract 1

 

JAMA Cardiology abstract 2

 

JAMA Cardiology editorial

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