key: cord-0761884-iuw642nh
authors: Lazzeri, Chiara; Bonizzoli, Manuela; Batacchi, Stefano; Cianchi, Giovanni; Franci, Andrea; Fulceri, Giorgio Enzo; Peris, Adriano
title: Cardiac Involvment in COVID-19–Related Acute Respiratory Distress Syndrome
date: 2020-07-13
journal: Am J Cardiol
DOI: 10.1016/j.amjcard.2020.07.010
sha: daf63fbbd16b171c587713b8b3dc81d501852c87
doc_id: 761884
cord_uid: iuw642nh

The cardiac involvement in (COVID-19) Coronavirus disease is still under evaluation, especially in severe COVID-19-related Acute Respiratory Distress Syndrome (ARDS). The cardiac involvement was assessed by serial troponin levels and echocardiograms in 28 consecutive patients with COVID-19 ARDS consecutively admitted to our Intensive Care Unit from 1(st) March to 31(th) March. Twenty-eight COVID-19 patients (aged 61.7 ± 10 years, males 79%). The majority was mechanically ventilated (86%) and four patients (14%) required veno-venous extracorporeal membrane oxygenation (ECMO). As of 31(th) March, the ICU mortality rate was 7%, while 7 patients was discharged (25%) with a length of stay of 8.2 ±5 days. At echocardiographic assessment on admission, acute core pulmonale was detected in two patients who required ECMO support. Increased systolic arterial pressure was detected in all patients. Increased Troponin T levels were detectable in 11 patients (39%) on admission. At linear regression analysis, troponin T showed a direct relationship with CRP (R square: 0.082, F: 5.95, p=0.017). In conclusions, in COVID-19-related ARDS, increased in Tn levels was common but not associated with alterations in wall motion kinesis, thus suggesting that troponin T elevation is likely to be multifactorial, mainly linked to disease severely (as inferred by the relation between Tn and CRP). The increase in systolic pulmonary arterial pressures observed in all patients may be related to hypoxic vasoconstriction. Further studies are need to confirm our findings in larger cohorts.

Coronavirus -19 disease (COVID-19) is an emerging worldwide pandemic, whose clinical course, in up to 15% of infected patients, can evolve in a severe form of acute respiratory syndrome (ARDS) requiring mechanical ventilation and admission to Intensive Care Unit (ICU). A metaanalysis (1) , including 341 patients 36% with severe disease (2) (3) (4) (5) reported that troponin (Tn) I were increased in patients with severe SARS-CoV-2 infection compared to those with milder disease. The clinical and/or prognostic role of increased Tn is still under evaluation, especially in severe COVID-19-related ARDS. We describe our initial experience as of 31 th March with 28 consecutive patients with COVID-19-related ARDS admitted to our ICU. We specifically investigated the cardiac involvement by COVID-19 infection, by assessing serial troponin T levels and serial echocardiograms during ICU.

In this case series study we enrolled all patients with COVID-19 ARDS consecutively admitted to our ICU (which is an ECMO referral center) from 1 st March to 31 th March. The study protocol was approved by our Ethical Committee (n.17024, approved on March 31 th 2020). ARDS was defined according to the Berlin definition (6) .

On ICU admission we measured: Troponin T (pg/ml), N-terminal-pro Brain Natriuretic Peptide (NT-BNP, pg/ml), C-reactive Protein (CRP, mg/dl) creatinine (mg/dl), Lactose dehydrogenase (LDH, UI/L), alanine transaminase (ALT, UI/L), D-dimer (ng/ml), procalcitonin (PCT, ng/ml) and interleukin 6 (IL-6, pg/ml). Troponin T and CPR were measured every day and peak levels were recorded.

According to our standard protocol, an echocardiogram was performed on ICU admission and, afterwards on clinical judgment, as previously described (7) . The right ventricle size was assessed by the RV end-diastolic area (EDA) and the ratio between EDAs of the right and left ventricles was calculated (RVEDA/LVEDA). Systolic pulmonary artery pressure (sPAP) was obtained using the simplified Bernouilli's equation: 4 • (Vmax tricuspid regurgitation) 2 + central venous pressure (CVP). Each measure was performed three times, and the mean value was recorded. Tricuspid Annular Plane Excursion (TAPSE) was also measured, as the difference of displacement during diastole and systole.

Echocardiogram was repeated at least once a week, in case of increased Tn levels, on clinical judgment (i.e. Onset of atrial fibrillation, need of increased dose of vasoactive drugs) and at discharge. The echocardiographic examination was blinded to the troponin T results. Myocarditis was defined according to American Heart Association (8) .

Electrocardiogram testings' (ECG) were performed simultaneously to the echocardiograms on ICU admission ECG was repeated whenever increased Tn I values were detected.

Data have been stored in a dedicated data-base and analyzed with SPSS for Windows 20.0 (SPSS Inc., Chicago, IL). P value less than 0.05 was considered statistically significant. Categorical variables are reported as frequencies and percentages; continuous variables are reported as mean ± standard deviation (SD) or median (range), as needed. Pearson's linear regression analysis was used to detect correlations between both troponin T levels and C-RP. Between group's comparisons are performed by means of chi-square (categorical data) or, for continuous data, with with Student's t test.

Our population included 28 consecutive COVID-19 patients, admitted to ICU, mainly males (22/28, 79%). The main age was 61.7 ± 10 years and more than a half showed a BMI ≥28.

Hypertension was the commonest risk factor (89%), while diabetes was detected in 39%. Previously known ischemic heart disease was present in about one third of the entire population (28.6%). The majority of our patients were mechanically ventilated (86%) and four patients (14%) required venovenous extracorporeal membrane oxygenation (ECMO).

As of 31 th March, the ICU mortality rate was 7%, while 7 patients was discharged (25%) with a length of stay of 8.2 ±5 days. Troponin T levels upper the 99 th percentile (28 ng/ml) were detectable in 11 patients (39%), on ICU admission. At linear regression analysis, troponin T showed a direct relationship with CRP (R square: 0.082, F: 5.95, p=0.017). Table 2 depicts echocardiographic findings on ICU admission and at discharge in 7 patients and as of 31 th in the remaining 21 patients.

On ICU admission, a reduced left ventricular ejection fraction (LVEF < 50%) was detected in six patients, with previously known ischemic heart disease, among whom two patients had postischemic dilatated cardiomyopaty with severe reduction of LV systolic function (< 25%) and a cardioverter defibrillator implanted. Six patients exhibited segmental cynetic abnormalities in previously known ischemic heart disease. No other alterations in wall motion kinesis were detectable. Acute cor pulmonale was detected in two patients who required ECMO support. 

In our investigation, performed in 28 consecutive COVID-19 patients with ARDS requiring ICU admission, cardiac involvement was assessed by means of serial troponin T assessment, echocardiographic examinations and monitoring of arrhythmic events. The main findings of our study are as follows: a) increased Tn levels, though common, was not associated with echo wall motion abnormalities; b) a significant direct relationship was detectable between Tn and C-reactive protein. c) Systolic pulmonary arterial pressures were increased in all patients on ICU admission but significantly decreased during ICU stay.

In 187 COVID-19 positive patients with mild disease (9) , elevation of Tn was observed in about one third (27.8%) but echocardiographic assessment was not performed. In112 COVID-19 patients, retrospectively evaluated, Deng et al (10) observed that most patients had normal troponin T levels on admission, which increased during hospitalization in about one third (37.5%). Typical signs of myocarditis was not detectable on serial echocardiograms and electrocardiograms. Unlike our investigation, the study population assessed by Deng et al (10) included patients with less severe COVID-19 disease since only 26 patients (23.2%) were admitted to ICU.

We confirm this finding in a subset of severe COVID-19 ARDS, mostly requiring mechanical ventilation. Differently from previous studies, in presence of an increase in Tn levels, we simultaneously assesses LV wall motion by echocardiogram and we did not observe any new onset segmental wall motion abnormalities. The hypothesis of viral miocarditis and/or myocardial infarction as possible causes for increased Tn I levels may be ruled out by our findings which are in agreement with the recent report by the American College of Cardiology on the role of biomarkers in patients with COVID-19-19. In patients with COVID-19 infection, troponin T elevation is likely to be multifactorial, linked to disease severely and less likely due to coronary thrombotic occlusion (11, 12) . Indeed, in our series, Tn showed a positive direct relationship with CRP values, a marker of inflammatory activation in COVID-19 disease. Furthermore, Tn increase was observed Further studies should be performed in severe COVID-19 patients to assess whether Tn values could help to risk stratification, as previously reported in patients with mild COVID-19 disease (13) .

We did observe that systolic arterial hypertension is a common finding in severe COVID-19

ARDS. This may be related to the hypoxic vasoconstriction in compliant lungs (14) , factors which seems to characterize COVID-19-related ARDS, though mechanical ventilation itself might represent also a contributing factor (by increasing RV afterload). Deng et al (10) reported a lower incidence of pulmonary hypertension (13%) probably because their series was constituted mainly by patients with milder COVID-19 disease.

Furthermore, we observed a reduction in systolic pulmonary arterial pressure during ICU stay, which might be related to ventilatory strategies (protective mechanical ventilation and pronation). Further studies are needed to specifically assess the effects of strategies/therapies (pronation and/or inhaled nitric oxide) on pulmonary circulation in severe COVID-19 disease in a larger cohort of patients.

The small number of patients in a single center investigation may be a limitation, but our population is homogeneous, including severe COVID-19 ARDS requiring ICU. The strength of our study is the multimodal approach in assessing the cardiac involvement in severe COVID-19 disease (15) . 

Cardiac troponin I in patients with coronavirus disease 2019 (COVID-19-19): Evidence from a meta-analysis Progress in Cardiovascular Diseases

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

Clinical predictors of mortality due to COVID-19-19 based on an analysis of data of 150 patients from Wuhan, China

Acute respiratory distress syndrome: the Berlin Definition

Pulmonary vascular dysfunction in refractory acute respiratory distress syndrome before veno-venous extracorporeal membrane oxygenation

American Heart Association Heart, C. Transplantation Committee of the Council on Clinical, Recognition and Initial Management of Fulminant Myocarditis: A Scientific Statement From the American Heart Association

Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19-19)

Suspected myocardial injury in patients with COVID-19-19: Evidence from front-line clinical observation in Wuhan, China

American College of Cardiology: Troponin and BNP Use in COVID-19-19

High-Sensitivity Cardiac Troponin Can Be An Ally in the Fight Against COVID-19-19

Clinical course and risk factor for mortality of adult inpatients with COVID-19-19 in Wuhan, China: a retrospective cohort study

COVID-19-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome

Coronaviruses on the Cardiovascular System A Review

ALT (U/L) (median, range)

LDH (U/L) (median, range)

NT pro BNP (pg/ml) (median, range)

Procalcitonin (pg/ml) (median, range) 0.24 (0

Interleukin-6 (pg/ml) (median, range)

/ml) (median, range) 1571

Troponin T (median, range)

ECMO: extra corporeal membrane oxygenation