key: cord-0857976-wj8dzxh7
authors: Ródenas-Alesina, Eduard; Rodríguez-Palomares, José; Bach-Oller, Montse; Jordán, Pablo; Badia, Clara; Herrador, Lorena; García-de-Acilu, Marina; Clau-Terré, Fernando; González-del-Hoyo, Maribel; Fernández-Galera, Ruben; Servato, Luz; Casas, Guillem; Bañeras, Jordi; Ferreira-González, Ignacio
title: Echocardiographic assessment of COVID19 sequelae in survivors with elevated cardiac biomarkers
date: 2022-04-29
journal: Int J Cardiol
DOI: 10.1016/j.ijcard.2022.04.070
sha: fded4665bf39dfb5fd941e5c7b83b9446c58998b
doc_id: 857976
cord_uid: wj8dzxh7

AIMS: We sought to determine, using advanced echocardiography, the prevalence and type of cardiovascular sequelae after COVID19 infection with marked elevation of cardiovascular biomarkers (CVB), and their prognostic implications. METHODS: All patients admitted from March 1st to May 25th, 2020 to a tertiary referral hospital were included. Those with cardiovascular diseases or dead during admission were excluded. Patients with hs-TnI > 45 ng/L, NT-proBNP>300 pg/ml, and D-dimer >8000 ng/ml were matched with COVID controls (three biomarkers within the normal range) based on intensive care requirements and age, and separately analyzed. RESULTS: From 2025 patients, 80 patients with significantly elevated CVB and 29 controls were finally included. No differences in baseline characteristics were observed among groups, but elevated CVB patients were sicker. Follow-up echocardiograms showed no differences among groups regarding LVEF and only slight differences between groups within the normal range. Hs-TnI patients had lower myocardial work and longitudinal strain. The presence of an abnormal echocardiogram was more frequent in the elevated CVB group compared to controls (23.8 vs 10.3%, P = 0.123) but mainly associated with mild abnormalities in deformation parameters. Management did not change in any case and no major cardiovascular events except deep vein thrombosis occurred after a median follow-up of 7 months. CONCLUSION: Minimal abnormalities in cardiac structure and function are observed in COVID19 survivors without previous cardiovascular diseases who presented a significant CVB rise at admission, with no impact on patient management or short-term prognosis. These results do not support a routine screening program after discharge in this population.

Coronavirus disease 2019 (COVID19) causes a broad spectrum of clinical manifestations, ranging from asymptomatic presentation to irreversible multiorgan damage and failure leading to death (1) . Elevated levels of high-sensitivity troponin I (hs-TnI), N-terminal proB-type natriuretic peptide (NT-proBNP), and D-dimer have been described in a high percentage of patients being associated with disease severity and worse prognosis (2, 3) . Cardiac damage has been confirmed both from necropsies (4) and imaging studies (5-10), but the underlying physiopathology remains unclear.

Whether these cardiovascular biomarkers (CVB) elevation is associated with potentially long-lasting cardiovascular abnormalities, a baseline cardiovascular disease, or hemodynamic imbalances during hospitalization still needs to be defined. Right (RV) and left ventricular (LV) systolic dysfunction has been associated with COVID19, CVB elevation (5-7,10,11) and higher mortality (5, 8) . Thus, an echocardiographic evaluation during hospitalization is advised to guide treatment and risk-stratification (11) . After discharge, some authors have described the presence of cardiovascular abnormalities as sequelae in patients with an acute CVB rise (12) (13) (14) .

However, there is no evidence about the real impact of these elevations of CVB over cardiac function and the patient's prognosis at follow-up. Therefore, we sought to determine, using transthoracic echocardiography and advanced myocardial deformation techniques, the prevalence and type of alterations in the cardiac structure and function at discharge in patients without previously known cardiac diseases who presented a significant elevation of cardiovascular biomarkers in J o u r n a l P r e -p r o o f Journal Pre-proof the acute phase of a COVID19 infection, as well as the impact of these abnormalities on short-term prognosis.

From March 1 st to May 25 th 2020, 2025 consecutive patients admitted to Vall d'Hebron University Hospital in Barcelona, a tertiary hospital and referral center for COVID19 in Catalonia (Spain) were screened. Patients ≥18 years-old with a COVID19 diagnosis confirmed by a positive reverse-transcriptase polymerase chain reaction assay for severe acute respiratory syndrome-related coronavirus 2 in respiratory tract samples were considered for inclusion. Patients with any elevated biomarker were prospectively included as cases (hs-TnI > 45 ng/L, above the 99 th percentile; NT-proBNP > 300 pg/mL, the recommended cut off to rule out heart failure (15) ; and D-dimer > 8000 ng/mL, above the 95 th percentile in our sample). Patients who died during admission or in the first 30 days after discharge were excluded. Patients with a reported history of previous heart failure, left ventricle ejection fraction (LVEF) <50%, pulmonary hypertension, coronary artery disease, inherited or congenital cardiomyopathy, valvular heart disease greater than mild, or with any type of cardiac device were also excluded.

Patients with all three CVB below the prespecified threshold (except from Ddimer, for which a cut-off of <1000 ng/ml was used (16)), were considered as controls.

Each case was matched with a control-based upon age and if they required intensive care unit (ICU) admission. Matching with replacement was used, so more than one case was allowed to match the same control if no other similar control was found in the sample.

J o u r n a l P r e -p r o o f Journal Pre-proof Baseline demographic variables, comorbidities, need for invasive mechanical ventilation, use of vasoactive drugs, laboratory findings, medication at discharge, and in-hospital clinical events were obtained from electronic records. Clinical events during hospitalization were recorded and categorized as ischemic events (myocardial infarction, stroke, pulmonary embolism, or deep vein thrombosis) or bleeding events (defined as a transfusion of 2 packed red blood cells, a drop in more than 2 g/dl, fatal bleeding or bleeding in a critical organ (17)). After discharge, patients have been followed-up until November 25 th 2020, at which point the study was considered complete. We reported the incidence of major cardiovascular adverse events (MACE), comprising all-cause death, admission for heart failure, myocardial infarction (as defined in the 4 th universal definition of myocardial infarction (18)), ventricular arrhythmias, systemic emboli (stroke or peripheral emboli), or venous thrombosis (deep vein thrombosis or pulmonary embolism). The follow-up was complete for all patients.

All patients enrolled provided their informed consent and the study was approved by the local ethics committee (PR(AG)437/2020). Patient were not involved in the design of the study.

At least 30 days after discharge to allow for recovery from the acute infection, all patients underwent a comprehensive echocardiographic assessment performed in the Cardiovascular Imaging Department and using the same equipment (Vivid E9 or Vivid E95; GE Healthcare, Horten, Norway). Four-chambers' dimensions, LV volumes, mass, ejection fraction (LVEF), RV function, and LV diastolic function were assessed as recommended by clinical guidelines (19, 20) . Systolic pulmonary artery pressure was estimated using tricuspid regurgitation peak velocity and adding the estimated right atrial pressure based on the collapsibility and diameter of the inferior vena cava. Advanced myocardial deformation techniques were used to assess for subclinical abnormalities. LV global longitudinal strain (GLS) was measured using images in 4, 3, and 2-chamber at 50-80 frames per second (21) . Peak systolic RV free wall longitudinal strain (RVFWLS) was measured using an RV-focused 4-chamber view. Noninvasive brachial artery blood pressure using a standard blood pressure cuff was obtained at the time of the echocardiographic acquisition to enable myocardial work calculation (22) , including global work index (GWI) and global work efficiency (GWE). Images were analyzed using specific software (EchoPAC v. 203, GE Healthcare) by two different cardiologists who were blinded to the patient's status.

To categorize the results, several parameters were dichotomized as normal or abnormal based on previously described reference values. Pulmonary hypertension (PHT) was considered elevated if tricuspid regurgitation velocity was >2.8 m/s or indirect signs of PHT (septal systolic shift towards the LV or pulmonary acceleration time <80 ms with mid-systolic notch) were observed. Left atrial (LA) pressure was considered to be increased according to the current guideline-recommended algorithm (20) . RV enlargement was considered if two of the basal, mid, or longitudinal diameters exceeded their reference values (41 mm basal, 35 mm mid, and 83 mm for longitudinal RV), and with systolic dysfunction (TAPSE <17 mm, RV s' <9.5 cm/s or RV FAC <35%) (19) . To allow for comparisons between groups, the global result of the echocardiographic study was also dichotomized as normal or abnormal. An echocardiogram was considered abnormal if any of the following was found: LVEF <50%, GLS >-16%, RVFWLS >-19% (23), GWI <1550 mmHg%, GWE <91% (24), dilated RV, RV systolic dysfunction, pulmonary hypertension or an estimated increase in left atrial pressure. provided. Statistical significance was tested with the log-rank test. A two-tailed p-value <0.05 was considered to be significant. All analyses were performed using Stata 15.1.

The patients' flow-chart is displayed in 

Echocardiographic follow-up was performed 4.3 months (IQR: 3.5-5.3) after discharge, and results are displayed in Table S2 . There was no missing data for conventional echocardiographic measures, but GLS could not be measured in 28% patients and RVFWLS was available in only 56% patients. All patients were in sinus rhythm. No differences were seen among groups regarding LVEF, LV or RV diameters, Figure S1 ). Figure 2 and Table S3 display the echocardiographic findings. Even though differences among groups were non-significant, a tendency towards more RV dysfunction (14.3% vs 0%, P=0.125) and low GWI (14.3% vs 0%, P=0.125) was found in patients with elevated hs-TnI when compared to controls.

However, as shown in Table S4 

To the best of our knowledge, this is the first study to report the results of the systematic advanced echocardiographic assessment in COVID19 survivors. Our study (Graphical abstract) reveals that in patients without previous structural heart disease who survive a COVID-19 infection, there is a minimal impact of the infection on myocardial structure and function despite having presented a marked elevation of CVB.

This is demonstrated by a low prevalence of mild echocardiographic alterations (23.8%) with no impact on the patient's management or short-term prognosis. Therefore, an indiscriminate routine echocardiographic study may not be justified in this population.

The existence of image-proven myocardial damage during the acute phase of COVID19 is well established and is associated with the elevation of CVB (11), more severe illness and higher mortality (5, 8) . Although it may change clinical management in the acute setting (11), echocardiographic screening during hospitalization is challenging due to personal safety concerns and overwork. In the acute infection, several cardiac abnormalities have been described, especially RV systolic dysfunction but also low LVEF or LV GLS patients with TnI >0.015 and controls, but the CVB elevation was only mild, no other CVB were assessed and abnormalities in myocardial deformation were not explored (29) . All of the above results would be in line with our results; however, our study covers an unexplored area regarding patients with marked elevation of biomarkers during admission and also implements strain and myocardial work analysis in the evaluation of COVID patients, but data regarding reversibility should be interpreted with caution due to the small number of abnormal echocardiograms during the acute phase.

Using CMR, Huang et al found in 26 recovered patients, with residual cardiovascular symptoms, a high burden of edema, fibrosis, and RV dysfunction (13) .

Likewise, another study recruited 29 recovered patients with an unjustified troponin T elevation during admission and found that 30% of patients had inducible ischemia, 69%

showed late gadolinium enhancement (LGE) and edema, with preserved LV and RV function in all cases (14) . The largest CMR study yet published included 100 patients in the early convalescent phase after COVID19, but only 5% had hs-TnT above the 99 th J o u r n a l P r e -p r o o f percentile. When compared with healthy controls from a historical cohort with normal CMR, COVID19 patients exhibited prolonged T1 and T2 times reflecting more diffuse fibrosis and edema, and LGE (also in 30% of cases) (30) . These findings showing mild cardiac involvement with little impact on the right and left systolic ventricular function in the acute phase of COVID19 are concordant with our results, with a low prevalence of LV or RV dysfunction and mildly abnormal subclinical parameters such as myocardial work or deformation, especially in the group with elevated hs-TnI. This is remarkable in our population, with high CVB, given the small percentage of patient with elevated CVB in CMR studies. We also suggest that performing a systematic echocardiogram does not change the management of these patients nor does it predict the presence of cardiovascular events at follow-up.

Considering the increasing prevalence of COVID19, the costs of assuming a screening program searching for cardiac sequelae of COVID19 would be extremely high, as well as an overwhelming workload for cardiac imaging laboratories and outpatients' evaluations. Our study demonstrates that a systematic echocardiographic follow-up study is not necessary after a COVID infection, not even in those patients who presented a significant elevation of CVB. Therefore, serial echocardiography should focus on those patients with previous structural heart disease or with persistent symptoms after discharge in whom an echocardiogram could provide relevant information for their management and follow-up.

Although patients were prospectively included after hospital discharge, no protocol was established at the first wave of the pandemic period regarding CVB determination, and, thus, hs-TnI, NT-proBNP, and D-dimer were only ordered according to the clinical judgment, presumably in patients with a higher pre-test J o u r n a l P r e -p r o o f Journal Pre-proof probability of having a cardiac condition. Though a limitation, this fact may have increased the chance of finding cardiac abnormalities during follow-up and make our results more consistent. Missing data for some echocardiographic parameters (GLS, GMW, RVFWLS) may have reduced the statistical power to show significant differences. Also, we present data from a single-center study, and the sample size may be small, however, our hospital was one of the centers throughout the country that treated the most cases of COVID-19 during the pandemic, so we believe that our results could be extrapolated to the rest of the populations. Despite our sample size may not have the statistical power to identify small differences in echocardiographic parameters, it is reassuring that only a minority of patients had echocardiographic abnormalities and, when present, these were minor and did not impact mid-term outcomes.

Finally, our results do not apply to patients with previously known cardiovascular diseases or to the acute phase of COVID-19 infection. However, this was not the aim of the study, since we intended to describe the echocardiographic findings and their prognostic value in the short-term follow-up in a high-risk population.

Because of this short-term follow-up, it may not be inferred from our results that late deterioration cannot occur, especially in those patients with subclinical abnormalities.

In COVID19 survivors with no previous cardiovascular diseases, the impact on myocardial structure and function evaluated by echocardiography and advanced deformation techniques is minimal even in those with elevated CVB during the acute phase. These abnormalities are mostly mild and related to myocardial deformation parameters, with no impact on patient management or short-term prognosis. These -Abnormalities are only borderline and mainly in myocardial deformation parameters.

-Male patients, with hsTnI >45ng/l or admitted to ICU have more abnormal findings.

-Abnormalities correlate with excellent prognosis and no change in management.

-Our data do not support routine echocardiographic screening of COVID19 survivors.

J o u r n a l P r e -p r o o f

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No conflicts of interest are declared by any author regarding this topic. 

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