Discussion
In the largest community-based study to-date with cardiac MR follow-up over 1 year in a mainly non-hospitalised, post-COVID-19 cohort with little prior cardiac disease, we report three new findings. First, CMR abnormalities were common (one in five individuals at 6 months) and commonly persisted (three out of five individuals at 12 months). Second, CMR abnormalities were found even without acute COVID hospitalisation (83/462, 18%). Third, cardiac blood biomarkers and symptoms were not predictive of composite CMR abnormalities but abnormal individual CMR parameters (eg, LVEF, 3D global longitudinal strain and cardiac T1) were associated with ongoing CMR findings, lower quality of life or reduced symptom severity at 12 months.
Characteristics and trajectory of cardiac abnormalities
Our results indicate that, despite women being more affected by Long COVID, men have higher risk of cardiac abnormalities.15 Potential contributory factors include: influence of biological sex on expression and regulation of ACE 2, sex differences in genetic and hormonal regulation of immune responses,16 sex-dependent patterns of coagulation, smoking or drinking.4 5 17 18
Published CMR studies in Long COVID vary by study design, cohort, follow-up duration, definition of cardiac abnormalities and estimated prevalence of cardiac abnormalities (26%–60%).6 11 19–23 A recent review9 highlighted under-representation of affected individuals from community-based settings, especially monitoring non-hospitalised individuals over time, which we address in this study. When COVID-19-related and classical myocardial injury are compared,8 only 9% of individuals fulfil acute myocarditis criteria and those with more severe disease are more likely to exhibit chronic inflammation and impaired cardiac function. We report prevalence of CMR abnormalities (19% and 15% at 6 and 12 months) consistent with previous studies, providing standardisation of metrics and definition, which can be used at scale in research and practice to document and monitor cardiac abnormalities.6 11 16 19 20 We confirm that abnormalities in T1 (in line with previous research,6 9–11 19 22 T2 and LGE, as well as functional abnormalities,5 11 23 24 are most common in Long COVID patients. Acute COVID can present with myocardial inflammation; ongoing COVID-19 patients can also have myocarditis, but it is harder to diagnose, and often missed with echocardiography. More pertinently, the observed functional changes may be due to inflammation and other aetiologies (eg, pulmonary disease, microinfarctions, metabolic dysregulation), and further mechanistic work is required to explore associations with CMR markers seen here.
In 58 hospitalised individuals, 3 months post-COVID-19, there were persistent abnormalities in cardiac T1 (26%) and multiple organs (eg, 29% with increased cortical T1, a marker of kidney inflammation). At 6 months, 52% had persistent symptoms and CMR abnormalities.19 In the first 201 individuals in our study, we observed multiorgan impairment (29%; cardiac: 26%; renal: 4%).11 In 443 individuals, 10 months after mild-to-moderate COVID-19, subclinical multiorgan impairment was associated with CMR abnormalities (reduced left and right ventricular systolic function).10 At 12 months, the longest follow-up duration to-date, we confirm 54% of individuals with CMR abnormalities do not fully recover.
Impact of acute hospitalisation for COVID-19 on cardiac abnormalities
Most individuals presenting with CMR abnormalities at baseline did not require acute COVID-19 hospitalisation (81%). One individual with elevated cardiac-related blood biomarkers had CMR abnormalities at 6 months and acute COVID-19 hospitalisation. Blood biomarkers and symptoms did not differentiate hospitalised and non-hospitalised groups. On MRI, cardiac T1 abnormalities4 25 and multiorgan involvement (particularly renal)5 11 19 were more prevalent in those with CMR abnormalities and acute COVID-19 hospitalisation, as in other published studies.8 13 26 27
Clinical management pathways in Long COVID populations at risk of cardiac abnormalities
Cardiac-related blood biomarkers may be raised in early convalescence from COVID-19,28 but did not aid detection of CMR abnormalities in Long COVID in our study, despite 19% having CMR abnormalities, supported by other research.5 23 24 Burden and improvement in symptoms 6 months after COVID-19 were neither correlated with resolution on CMR nor lung parenchymal recovery.5 Early MRI assessment may identify organ-specific impairment (including cardiac), leading to early referral for appropriate specialist assessment and treatment, in contrast to the experience of many patients who are currently having multiple appointments with multiple specialists for multiple assessments. In a cluster-randomised design, the STIMULATE-ICP trial is currently evaluating whether multiorgan MRI (Coverscan) can aid diagnosis and follow-up of cardiac and multiorgan impairment in Long COVID, and reduce burden to healthcare systems, already struggling due to COVID-19-related lack of resources and backlogs, while achieving integrated care.29
Cardiac findings could inform design of Long COVID treatment algorithms. Abnormal GLS is associated with cardiac remodelling (indicative of more severe cardiac disease),26 and predictive of low quality of life at 12 months. Elevated T1 was predictive of lower symptom severity at 12 months. There may be multiple cardiac subgroups in Long COVID, potentially detected by CMR early postinfection. These subtypes may be related to pulmonary hypertension,13 pre-existing comorbidities27 and post-COVID-19 myocardial inflammation,8 but require further study and validation.
Comprehensive multiorgan MRI assessment may help clinical decision making and improve healthcare access and provision. Evidence of cardiac involvement could guide follow-up assessment and identification of Long COVID subtypes in research and practice. Interventional trials with prespecified subgroup analysis and improved definitions of cardiac abnormality (not only myocarditis centred), are required to inform cost-effective therapies.
Strengths and limitations
This is the largest longitudinal study to-date of cardiac abnormality in Long COVID with detailed biochemical and imaging characterisation of multiorgan function starting in April 2020. We included healthy, age-matched controls. All MRI was non-contrast. We recruited a real-world cohort at lower risk of COVID-19 severity and mortality. Unlike other studies,30 our approach offers quick, scalable assessment using standard MRI scanners. There are limitations. First, our CMR protocol excluded gadolinium contrast, the main reason for this was to reduce the scanning times, contact-time between the patient and the healthcare worker, and to avoid potential renal complications related to COVID-19. This was backed by previous research, supporting the use of native non-invasive T1 mapping to characterise myocardial inflammation,26 and did not have sufficient statistical power in cardiac T2 collection, relying on native non-invasive T1 mapping to characterise myocardial inflammation, validated for acute myocarditis.31 Second, we are not able to define whether these individuals presented with multiorgan abnormalities before their COVID-19 infection, although clinical diagnoses were recorded. Third, we did not have follow-up scans on individuals without impairment at baseline and a third of patients with CMR abnormalities at baseline withdrew or were lost to follow-up. Fourth, we did not have pre-COVID-19 cardiac or multiorgan imaging available in participants. Fifth, our study population was not ethnically diverse, and COVID-19 has disproportionately affected non-white individuals. In addition, our study recruited patients during the first wave of the pandemic, when testing was not broadly available, mainly via patient support groups rather than a systematic screen of post-COVID-19 patients, as Long COVID clinics were only set up at the end of our recruitment and this may represent a bias.