Virus World

Background:

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a prothrombotic state, but long-term effects of COVID-19 on incidence of vascular diseases are unclear.

Methods:

We studied vascular diseases after COVID-19 diagnosis in population-wide anonymized linked English and Welsh electronic health records from January 1 to December 7, 2020. We estimated adjusted hazard ratios comparing the incidence of arterial thromboses and venous thromboembolic events (VTEs) after diagnosis of COVID-19 with the incidence in people without a COVID-19 diagnosis. We conducted subgroup analyses by COVID-19 severity, demographic characteristics, and previous history.

Results:

Among 48 million adults, 125 985 were hospitalized and 1 319 789 were not hospitalized within 28 days of COVID-19 diagnosis. In England, there were 260 279 first arterial thromboses and 59 421 first VTEs during 41.6 million person-years of follow-up. Adjusted hazard ratios for first arterial thrombosis after COVID-19 diagnosis compared with no COVID-19 diagnosis declined from 21.7 (95% CI, 21.0–22.4) in week 1 after COVID-19 diagnosis to 1.34 (95% CI, 1.21–1.48) during weeks 27 to 49. Adjusted hazard ratios for first VTE after COVID-19 diagnosis declined from 33.2 (95% CI, 31.3–35.2) in week 1 to 1.80 (95% CI, 1.50–2.17) during weeks 27 to 49. Adjusted hazard ratios were higher, for longer after diagnosis, after hospitalized versus nonhospitalized COVID-19, among Black or Asian versus White people, and among people without versus with a previous event. The estimated whole-population increases in risk of arterial thromboses and VTEs 49 weeks after COVID-19 diagnosis were 0.5% and 0.25%, respectively, corresponding to 7200 and 3500 additional events, respectively, after 1.4 million COVID-19 diagnoses.

Conclusions:

High relative incidence of vascular events soon after COVID-19 diagnosis declines more rapidly for arterial thromboses than VTEs. However, incidence remains elevated up to 49 weeks after COVID-19 diagnosis. These results support policies to prevent severe COVID-19 by means of COVID-19 vaccines, early review after discharge, risk factor control, and use of secondary preventive agents in high-risk patients.

Published in Circulation (Sept. 20, 2022):

https://doi.org/10.1161/CIRCULATIONAHA.122.060785

Using cardiac MRI, researchers found myocardial injury in more than half of patients hospitalized with severe COVID-19 and elevated troponin a few months after hospital discharge.  “We found evidence of high rates of heart muscle injury that could be seen on the scans a month or two after discharge. Whilst some of this may have been preexisting, MRI scanning shows that some were new, and likely caused by COVID-19,” Marianna Fontana, MD, PhD, professor of cardiology at University College London, said in a press release. “Importantly, the pattern of damage to the heart was variable, suggesting that the heart is at risk of different types of injury. While we detected only a small amount of ongoing injury, we saw injury to the heart that was present even when the heart’s pumping function was not impaired and might not have been picked up by other techniques. In the most severe cases, there are concerns that this injury may increase the risks of heart failure in the future, but more work is needed to investigate this further.” 

For this analysis, researchers included 148 patients from six hospitals (mean age, 64 years; 70% men) with severe COVID-19 infection and elevated troponin levels, all requiring hospitalization (32% requiring mechanical ventilation), who underwent convalescent cardiac MRI and adenosine stress perfusion at a median of 68 days after discharge. “Raised troponin levels are associated with worse outcomes in COVID-19 patients. Patients with severe COVID-19 disease often have preexisting heart-related health problems, including diabetes, raised blood pressure and obesity,” Fontana said in the release. “During severe COVID-19 infection, however, the heart may also be directly affected. Unpacking how the heart can become damaged is difficult, but MRI scans of the heart can identify different patterns of injury, which may enable us to make more accurate diagnoses and to target treatments more effectively.”

Myocardial injury in COVID-19

Patients with abnormal troponin levels were offered a cardiac MRI after discharge and were compared with a control group of patients who did not have COVID-19 and 40 healthy volunteers. Researchers observed that left ventricular function was normal in 89% of the overall cohort (mean ejection fraction, 67%). Late gadolinium enhancement and/or ischemia was found in 54% of participants hospitalized for severe COVID-19 infection, which included a myocarditis-like scar in 26%, MI and/or ischemia in 22% and dual pathology in 6%. According to the study, myocarditis-like injury was limited to three or fewer myocardial segments in 88% of patients with no LV dysfunction, of which 30% had active myocarditis. In addition, MI was observed in 19% and inducible ischemia in 26% of patients who underwent stress perfusion after discharge. Moreover, of patients with ischemic injury, 66% had no prior history of coronary disease. Researchers found no evidence of diffuse fibrosis or edema in the remote myocardium.

Two new opportunities

“These findings give us two opportunities,” Fontana said in the release. “Firstly, to find ways of preventing the injury in the first place, and from some of the patterns we have seen, blood clotting may be playing a role, for which we have potential treatments. Secondly, detecting the consequences of injury during convalescence may identify subjects who would benefit from specific supporting drug treatments to protect heart function over time.”

Findings published in European Heart Journal (Feb. 18, 2021):

https://doi.org/10.1093/eurheartj/ehab075

Three-quarters of people who died of COVID-19 harbored the SARS-CoV-2 virus in their hearts, according to the most detailed study of cardiac tissue to date. Those people were also more likely than patients without cardiac invasion to experience abnormal heart rhythms before they died. The study offers insight into how the disease may damage the heart—and how certain treatments may help. The finding “paints a really nice picture” of the connection between the virus and heart problems, says Joseph Maleszewski, a cardiovascular pathologist at the Mayo Clinic who was not involved with the study.  Scientists have ample evidence of heart damage in COVID-19 patients. Some people, for example, show elevated levels of troponins, molecules released in the blood when the heart is injured. Others have experienced inflammation of the sac surrounding the heart—and inflammation of the heart itself. But it’s been unclear whether these problems were caused by the SARS-CoV-2 virus attacking the heart directly, or the damage is due to an overactive immune response. Part of the problem is that previous studies are mixed about whether SARS-CoV-2 can invade heart tissue. Many that haven’t found the virus use real-time polymerase chain reaction (RT-PCR), says James Stone, a cardiovascular pathologist at Massachusetts General Hospital. RT-PCR works by detecting viral RNA in tissue, then making many DNA copies of it. Once there’s enough DNA, a molecule called a fluorescent tag can stick to it and shine to reveal its presence. But Stone says that heart tissue is often processed and preserved using chemicals like paraffin, which can break down the RNA and prevent detection to begin with. So he and his team used another approach: in situ hybridization and NanoString transcriptomic profiling. Like RT-PCR, these techniques use special molecules to attach to and detect pieces of viral RNA, but they do so without having to make DNA copies first. The approach can identify viral RNA even after it’s broken into smaller pieces. The scientists also analyzed about 1000 pieces of heart tissue—more than 20 samples from each of the 41 patients they looked at. That’s double the number of samples per patient in most studies, Stone says. 

SARS-CoV-2 was present in 30 of the hearts, the team reports today in Modern Pathology. And only those patients experienced new atrial fibrillations, fast and irregular heart rhythms, or early or extra heartbeats, compared with the other patients in the study—a correlation Stone calls “pretty phenomenal.” Still, it’s unclear whether the virus attacked the heart directly in these cases. Most of the infected cardiac cells were immune cells, which SARS-CoV-2 could have invaded elsewhere in the body before they traveled to the heart. It’s also unclear whether the virus—rather than the immune cells themselves—is causing the problems. Regardless, the study may help explain why the steroid dexamethasone is so helpful to some patients. The drug was one of the first found to prevent deaths from severe COVID-19. It reduces inflammation, so it may have curbed the presence of SARS-CoV-2–harboring immune cells in the heart, Stone says. Only 50% of the patients treated with dexamethasone had the virus in their hearts, compared with 90% of patients who were not on the drug. But compared with large clinical trials, the number of patients in this new study is small, making it impossible to say that one drug protects the heart better than another, says Nicholas Hendren, a cardiology fellow at the University of Texas Southwestern Medical Center. Still, Maleszewski says the new findings are a call to action. Scientists need to probe more cardiac tissue, he argues, not just to see how COVID-19 kills patients, but to figure out how it hurts the hearts of those that survive. The disease may, for example, create scar tissue that can cause cardiac problems down the line. We’re starting to understand what COVID-19 does to patients when they have it, he says. “What’s not clear is what happens later on.”

Research Cited Published in Modern Pathology (March 17, 2021):

https://doi.org/10.1038/s41379-021-00790-1