Coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), disproportionally affects patients with cardiovascular risk factors. Myocardial injury, particularly seen in severe and hospitalized COVID-19 and evidenced by raised cardiac troponin, heralds worse outcomes (1, 2). However, the mechanisms of injury remain only partially understood, and the potential coronary microcirculatory sequelae remain incompletely characterized (3). Several ischemic and non-ischemic mechanisms have been proposed, including supply-demand mismatch (type-2 myocardial infarction) and microangiopathic thrombosis (4). Accumulating evidence suggests that the vascular endothelium plays a critical role in the pathogenesis of severe COVID-19 as a nidus for both pro-coagulant and inflammatory dysregulation and may offer a unifying pathway through which all these sequelae may occur (5, 6). Autopsy results have shown microthrombi to be associated with myocyte necrosis (7). The implications for survivors and the potential long-term effects on coronary microcirculation remain unknown. Cardiovascular magnetic resonance can determine not only myocardial function, remodeling, and scar burden, but also quantify the stress myocardial blood flow (MBF), which has been validated invasively and against ¹³N–NH₃ PET (8–10). A recent pilot study of n = 22 recovered COVID-19 patients used coronary sinus flow by cardiovascular magnetic resonance (CMR) to evaluate the myocardial perfusion found with significantly lower myocardial perfusion reserve (MPR) compared with an unmatched cohort of health controls and values similar to a cohort with hypertrophic cardiomyopathy (HCM) (11). We aimed to further evaluate the pattern of stress MBF in recovered COVID-19 patients.

In this multicenter study of COVID-19 survivors, we demonstrated that at 2 months after severe, hospitalized infection, the global stress MBF is comparable to the propensity-matched controls with proven unobstructed coronaries and no scar. However, over half of the COVID patients have evidence of either infarct or myocarditis-like scar, and almost a third had evidence of regional ischemia, suggestive of occult coronary artery disease, including a quarter of those with an otherwise normal CMR. While microvascular thrombosis may also play a role, there is little evidence here to suggest a significant impact on the global myocardial perfusion in surviving patients.

Myocardial damage during acute COVID-19 illness predicts the severity (18) and outcomes of acute infection, with CMR scans demonstrating infarction and inflammation in convalescent patients (12). In accordance with previous publications, the prevalence of LGE in this cohort was high, but the overall burden and functional impact were relatively low (19). However, the effects of COVID-19 on myocardial perfusion have so far remained incompletely characterized. We demonstrated that stress myocardial blood flow after severe COVID-19 shows no difference to risk factor matched controls; importantly stress blood flow was not predicted by COVID status but by common risk factors for coronary artery disease.

While MPR was found to be slightly reduced in the COVID cohort compared with the controls, this was driven primarily by a higher resting MBF. In a recent study by Drakos et al., there was a significant reduction in MPR in n = 22 patients with persistent symptoms post-COVID-19 when assessed by coronary sinus flow, driven by both a lower stress MBF and higher resting MBF (11). This study had several methodological and technological differences to this study (assessment of MBF by coronary sinus flow, unmatched cohorts, inclusion of patients with persistent symptoms only, and exclusion of severe COVID-19). There are alternative explanations for higher resting MBF in our cohort compared with the controls (which may include differences in heart rate and medications between cohorts), thus we do not believe that these small borderline significant differences provide convincing evidence of microvascular dysfunction.

The finding of inducible ischemia in almost a third of the patients suggests that the putative mechanism of troponin elevation reflected a supply-demand-mismatch, whether epicardial or microvascular (20), representing “a COVID stress test”. It is important, however, to acknowledge the multiple mechanisms of troponin elevation in the context of severe illness (21). We hypothesize that the high burden of infarct-pattern LGE was pre-existing, and driven more by the demographics of included patients (older, high incidence of cardiovascular risk factors), than by the COVID-19 illness, especially given the relatively modest troponin rise seen. This is particularly relevant as our sample reflects a relatively sick group of patients (all admitted, 44% to ICU; 85 out of 90 with elevated troponin). The prevalence of the infarct pattern scar is similar to the previous studies which cited a rate of 17% of occult MI by CMR in a cohort with a similar cardiovascular risk profile. Our group has previously shown the rate of infarct pattern scar in a contemporary chest pain cohort referred for adenosine-stress CMR to be as high as 29.5% (22, 23). Cardiovascular magnetic resonance is the most suited non-invasive modality for the assessment of unexplained troponin rise, as it can confirm the presence, type, and extent of myocardial injury. Interestingly, nearly half of the troponin-positive patients (39/85) had no evidence of scar on CMR. This suggests that while troponin leak is associated with poor prognosis in acute illnesses, in many cases it is not followed by medium-term structural or functional effects, including sensitive LGE imaging or global MBF quantification.

Autopsy studies of COVID-19 patients have demonstrated microvascular thrombosis in the lungs and heart (7, 24, 25). In the cardiac studies, microthrombi were identified as the cause of myocyte necrosis in 64% of patients after COVID-19 related death. Other studies have also identified these in intra-myocardial small vessels (26, 27). Many of these thrombi were not associated with any significant myocardial injury. It is plausible that microthrombisis may lead to exceptionally localized myocyte injury. Although this study was designed specifically to take advantage of identical scanner platforms and access to state-of-the-art quantitative myocardial perfusion and myocardial tissue characterization CMR technology [supported by MRI phantom quality controlled analysis (22)], very localized myocyte injury may be undetectable by the current CMR technologies (LGE or T1/T2/ECV/MBF mapping) or may have resolved without detectable damage in convalescent patients. This entity is potentially somewhat distinct from what would conventionally be referred to as a “microvascular disease”, which is commonly perceived as a global phenomenon in response to a systemic disease process (type 2 diabetes, for example), without demonstrable inducible perfusion defects or regional wall motion abnormalities (28).

Microvascular disease has also been shown to have regionality and may have a subendocardial distribution (29). The regional perfusion defects found in our study could be due to regional microvascular disease if the epicardial coronaries are found unobstructed. A normal global stress MBF in troponin-positive or persistently symptomatic individuals is reassuring to an extent but may not have the sensitivity to resolve regional microvascular complications.

Overall, multi-parametric stress perfusion CMR in convalescent post-COVID-19 patients identified previously unsuspected inducible ischemia, myocardial infarction, and myocarditis-pattern non-ischemic scar. The addition of stress perfusion imaging offers incremental information by the detection of regional ischemia in the absence of a scar. There is little evidence of a reduction in global perfusion after severe COVID-19 compared to matched controls, which may reflect the limited impact of microvascular thrombosis on overall perfusion in surviving patients even if it causes persistent regional differences in myocardial blood flow.

This study reports findings in a group of patients who survived COVID-19 infection and is therefore affected by survivor bias. Patients with contraindications to CMR were excluded, though this is a small minority of the patients. We have characterized the spectrum of myocardial injury and perfusion abnormalities in recovered, predominantly severe, COVID-19 illness that persists to a median of 2 months after the infection (community and mild disease were not investigated). This study does not offer insights into myocardial blood flow, structure or function during the infection or in the immediate post-infective period, nor can it, without longitudinal data, determine if abnormalities detected evolve or regress over time. The wide time interval between the admission episode and CMR further compounds this. Data on persistent symptoms at the time of CMR was not available for the majority of patients, thus we cannot draw conclusions pertaining to the association of these with MBF. Furthermore, without anatomical data, we cannot confirm the presence and cause (epicardial vs. microvascular) of perfusion abnormalities. However, this study yields pertinent preliminary data which may have important clinical implications for patients. Further granularity will be determined with future ongoing United Kingdom and international studies, some of which will acquire or capture coronary anatomical data [COVID-HEART [ISRCTN58667920]; CISCO-19 (30)].

This multicenter cohort of severe hospitalized COVID-19 infection identified no difference in the global stress MBF in COVID-19 survivors compared with the risk factor matched controls, but regional perfusion defects are common. Overall, the findings are reassuring that COVID-19 is unlikely to result in gross and persistent global microvascular phenomena. The high burden of regional ischemia may be due to regional microvascular disease but is more likely due to pre-existing coronary disease, but neither can be proven in the absence of anatomical imaging. This should therefore be considered hypothesis-generating for future studies.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the West Midlands – Edgbaston Research Ethics Committee for the use of patient's clinical data for research purposes (RFH and Imperial sites; REC reference 20/WM/0208) and from the Joint University College London/University College London Hospitals Research Ethics Committee (UCLH site; REC reference 07/H0715/101). The patients/participants provided their written informed consent to participate in this study.

GT: concept and design, writing for publication, revision of drafts, and submission of manuscript. TT: concept and design, data analysis, writing of manuscript, revision, and approval of final submission. MF, PK, GC, CM, RB, HX, RD, ASe, and DK: revision and approval of submission. JM, TK, KV, JB, LC, DA, SY, HK, JA, KK, ASe, and ASh: data analysis, revision of drafts, and approval of submission. List ASh with others who contributed data analysis, revision of drafts, and approval of submission. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

GT was supported by a British Heart Foundation (BHF) Clinical Research Training Fellowship (FS/CRTF/21/24128). DK and RB were supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Center. JM was directly supported by the (UCLH) and Barts NIHR Biomedical Research Centers and through a BHF Accelerator Award. MF and TT (ICRF #34374) are funded by a British Heart Foundation (BHF) Intermediate Fellowship.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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