Treadmill Exercise Stress Echocardiography Exposes Impaired Left Ventricular Function in Patients Recovering from Hospitalization with COVID-19 Without Overt Myocarditis Versus Historical Controls

Background Usual clinical testing rarely reveals cardiac abnormalities persisting after hospitalization for COVID-19. Such testing may overlook residual changes responsible for increased adverse cardiac events post-discharge. Methods To further elucidate long-term status, we performed exercise stress echocardiography (ESE) in 15 patients age 30-63 without myocarditis 3 to 31 months after hospital discharge. We compared patient outcomes to published data in healthy comparisons (HC) exercising according to the same protocol. Results Patients’ treadmill exercise (Bruce protocol), averaging 8.2 min, was halted by dyspnea or fatigue. Pre-stress baselines in recovering patients (RP) matched HC except for higher heart rate: mean 81 bpm for RP and 63 for HC (p<0.0001). At peak stress, RP had significantly lower mean left ventricular (LV) ejection fraction (67% vs 73%, p<0.0017) and higher peak early mitral inflow velocity/early mitral annular velocity (E/e’, 9.1 vs 6.6, p<0.006) compared with HC performing equal exercise (8.5 min). Thus, when stressed, patients without known cardiac impairment showed modest but consistently diminished systolic contractile function and diastolic LV compliance during recovery vs HC. Peak HR during stress was significantly elevated in RP vs HC; peak SBP also trended higher. Average pulmonary artery systolic pressures among RP remained normal. Conclusions Our measurements during ESE uniquely identified residual abnormality in cardiac contractile function not evident in the unstressed condition. This finding exposes a previously-unrecognized residual influence of COVID-19, possibly related to underlying autonomic dysfunction, microvascular disease, or diffuse interstitial changes after subclinical myocarditis; it may have long-term implications for clinical management and later prognosis. CLINICAL PERSPECTIVE New Findings (relative to a historical comparison group) Clinical Implications ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Partial support was received from Award # HU00012120008 from the Defense Health Agency to the Military Cardiovascular Outcomes Research program, Uniformed Services University, Bethesda, MD. No other payment was made to authors or their institutions from a third party for any aspect of the submitted work ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Walter Reed National Military Medical Center Institutional Review Board I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes There is no restriction regarding the availability of all data referred to in the manuscript. * E/e’ : early mitral inflow velocity/early diastolic mitral annular velocity ESE : exercise stress echocardiography EF : ejection fraction HC : healthy comparison subjects HR : heart rate LV : left ventricular PASP : pulmonary artery systolic pressure RAP : right atrial pressure RP : recovering patients TR : tricuspid regurgitation