Cardiac Magnetic Resonance Imaging Reveals Inflammation Post Covid-19 Recovery

Reference

Puntmann VO, Carerj ML, Wieters I, et al. Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020:e203557. doi:10.1001/jamacardio.2020.3557 [Epub ahead of print].

Study Objective

To determine if myocardial injury and/or inflammation is present after recovery from recent Covid-19

Design

Prospective observational study comparing cardiac magnetic resonance (CMR) of unselected participants who recovered from Covid-19 to healthy controls and to risk factor–matched controls

Participants

The study involved 100 patients, 53% male and median age 49, who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by reverse transcription–polymerase chain reaction on 2 swab tests of the upper respiratory tract and who after recovery underwent CMR. Patients with cardiac symptoms who were referred for CMR were excluded, as were those who had absolute contraindications for contrast-enhanced CMR. Researchers compared CMR findings from the 100 recovered patients to 50 age- and sex-matched healthy controls who were normotensive and on no cardiac medications. The researchers also compared the recovered group to 57 volunteers matched for age, sex, and cardiovascular risk factors. The median time interval from diagnosis of Covid-19 to CMR was 71 days.

Study Parameters Assessed

• CMR
• Blood tests:
• High-sensitivity C-reactive protein (hs-CRP)
• High-sensitivity troponin T (hs-TnT)
• N-terminal pro-b-type natriuretic peptide (NT-proBNP)

Key Findings

Of the 100 participants who recovered from Covid-19, 78% had evidence in the CMR imaging of cardiac involvement, while 60% had evidence of myocardial inflammation—statistically more CMR abnormalities than either comparator group. The recovered participants also had statistically significant lower-left ventricular ejection fraction and higher troponin T levels than both control groups. The extent of cardiac involvement did not correlate to severity of Covid-19 disease or symptoms; 67% of the participants had recovered at home.

Practice Implications

This paper has sparked concern in both medical and lay communities. The demonstration that cardiac inflammation and reduced left-ventricular ejection fraction can be present 10 weeks after resolution of Covid-19 is cause for concern, especially since the severity of infection did not correlate with the extent of cardiac sequelae. Cardiac inflammation was seen even in some who had mild disease: 67% of the participants recovered at home. The editorial in the same issue of JAMA Cardiology titled, “Coronavirus disease 2019 (COVID-19) and the heart—is heart failure the next chapter?”¹ raised much anxiety. The same issue also published the results of 39 consecutive autopsies of Covid-19-related deaths, which revealed viral particles in the heart.² The articles received ample press and were cited by colleges as they canceled football programs.

Basing any presumption of inevitable heart failure on a nonrandomized CMR study of 100 unselected participants is premature and potentially anxiety-provoking.

Almost immediately after publication, on a Twitter feed, Professors Darrel Francis and Graham Cole of the UK noted that the data points and results in Table 1 of the paper were mathematically impossible.³ Puntmann et al reanalyzed, added missing data, and wrote a response,⁴ and JAMA Cardiology corrected the initial online version (Errors in statistical numbers and data). In the re-analysis, left-ventricle mass was not statistically higher in the recovered group, but all other measures retained statistical significance.

Since Covid-19 was first reported less than a year ago, much has been ascertained about its relation to heart disease. The presence of preexisting cardiovascular disease and its risk factors of hypertension, diabetes, smoking, and obesity are associated with a higher rate of Covid-19-related hospitalization and death.⁵ Up to 40% of patients hospitalized with Covid-19 have preexisting cardiovascular disease.⁶ Myocardial injury, as measured by troponin, is common in patients hospitalized with Covid-19. In 1 series of 3,000 patients hospitalized at Mount Sinai Medical Center in New York City, 36% had evidence of myocardial injury.⁷ This was associated with higher incidence of death. In the aforementioned series of 39 consecutive autopsies of patients who died from Covid-19-related causes, 61% showed evidence of virus in cardiac cells.² In one 11-year-old girl who died from multisystem inflammatory syndrome related to Covid-19, the virus was seen in cardiomyocytes, endothelial cells, mesenchymal cells, and inflammatory cells.⁸ The authors hypothesized that the virus directly caused myocarditis in this child.

These studies raise the following questions:

• Does Covid-19 directly attack and permanently damage the heart?
• How long does cardiac inflammation last after Covid-19?
• Should inflammatory markers be used as screening tools in those with a history of Covid-19?
• Will cardiomyopathy and heart failure evolve from Covid-19-related cardiac inflammation?
• Even though CMR allows the visualization of cardiac inflammation, how should practitioners use it in clinical practice?

Basing any presumption of inevitable heart failure on a nonrandomized CMR study of 100 unselected participants is premature and potentially anxiety-provoking. Additional research is needed with long-term follow-up in select populations. Studies on survivors of Covid-19 are underway to help answer these questions and include cardiac follow-up of Covid-19 pneumonia (ClinicalTrials.gov NCT04501822), participants with cardiomyopathy (ClinicalTrials.gov NCT04468256), and survivors with acute coronary syndrome (ClinicalTrials.gov NCt04333407) among others.

What do we know and what can be safely done right now for the care of our patients? There are currently no proven herb or supplement treatments for Covid-19, but measures that are known to decrease cardiac inflammation and hold little to no risk may be indicated.

Correlational studies suggest consideration of vitamin D, omega-3 fatty acids, and melatonin. In a retrospective study of 489 patients who had a vitamin D level measured within 1 year before Covid-19 testing, 71 tested positive for Covid-19.⁹ The authors concluded that vitamin D deficiency (25-hydroxycholecalciferol less than 20 ng/mL or 1,25-dihydroxycholecalciferol less than 18 pg/mL) was associated with a 21.6% absolute risk of Covid-19 as opposed to a 12.2% risk in the vitamin D sufficient group.

The anti-inflammatory omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have proven cardiovascular benefit.^10,11 In a Cochrane review of 10 randomized trials with 1,015 patients with acute respiratory distress syndrome (ARDS), EPA and DHA supplementation improved O2 saturation, decreased length of hospital stay, and decreased mortality at 28 days.¹²

Melatonin is another candidate in the fight against Covid-19. Melatonin is a well-known antioxidant and anti-inflammatory with a good safety profile that is being studied in a double-blind, randomized, placebo-controlled trial in outpatients infected with COVID-19 (ClinicalTrials.gov NCT04474483).

Finally, 2 drug classes need mention: statins and ACE inhibitors. In a meta-analysis that included 8,990 Covid-19 patients, the use of statins correlated with approximately a 30% decreased incidence of severe disease.¹³ This is not surprising considering the anti-inflammatory effects of statins. During the first few months of the pandemic, there was fear that angiotensin-converting enzyme (ACE) inhibitors might increase infection since they lead to an up-regulation of ACE 2 receptors, the docking ligand for SARS-CoV-2. Recent reviews¹⁴ and a randomized trial¹⁵ indicate that these drugs can be safely continued in patients with Covid-19.

Both the drugs and supplements mentioned have immunomodulatory effects that decrease multiple pathways involved in cardiac inflammation. There are no data regarding the initiation of statins and ACE inhibitors during a Covid-19 diagnosis, but the evidence indicates that these drugs should not be discontinued during the illness. Vitamin D, omega-3 fatty acids, and melatonin are generally well-tolerated and have a good safety profile. Their initiation and continuation during Covid-19 is likely safe and possibly beneficial.

The most potent anti-inflammatory, in my opinion, is avoiding the stimulus of inflammation, in this case SARS-CoV-2. Prevention obtained through masking, physical distancing, and a healthy lifestyle are the most reliable means of avoiding the possible cardiac consequences of infection.