CESAR

To the extent the SARS-CoV-2 (COVID-19) pandemic has evolved, it has been determined that cardiovascular disease has a fundamental role in the development and prognostics of the infection, becoming the most important risk factor related with mortality alongside age. Specifically, it is known that COVID-19 infection is associated with a high risk of developing cardiac complications (heart failure, myocardial injuries or ischemia, myocarditis, arrhythmia…), with a high percentage of fatal outcomes.

The CESAR project proposes a non-invasive approach to develop a “liquid biopsy” based on a profile/panel of circulating biomarkers that makes it possible to stratify the risk of cardiac conditions and adverse clinical evolution in COVID-19+ patients. Because cardiomyocyte insults, systemic inflammation and interstitial myocardial fibrosis have been proposed as key mechanisms in the cardiac pathology that occurs with COVID-19 infection, the ones related with those processes will be considered on the biomarker panel, in addition to the ones identified after creating a more general cardiovascular proteomic and inflammatory profile using high-performance proteomic technology.

Consequently, this project has the following goals:

1. Analyse the relevant biomarker associations, with ecocardiographic parameters basally and during patient monitoring, of patients with COVID-19 To those ends biomarkers for interstitial myocardial fibrosis, systemic inflammation and cardiac insult/injury will be determined in blood samples using specific immunoassays and proteomic analysis with high-performance technology, and electrocardiograms and echocardiograms will be done on patients infected with SARS-CoV-2 basally and during monitoring on three visits: at 15 days, 2 months and 9 months after admission.
2. Analyse the associations of the specified biomarkers with relevant clinical events that occur while monitoring the patients
3. In light of the results obtained, develop a profile/panel of prognostic biomarkers present in
   COVID-19+ patients that are easy to analyse and interpret, so they might have a clinical application, and evaluate their prognostic capacity to improve the stratification of the risk of adverse clinical evolution in those patients, beyond traditional clinical models
   In summary, the CESAR project intends to develop a product (diagnostic biomarker profile/panel) that is useful for improving early handling of COVID-19 sufferers and implement precision personalised medicine in Navarre in the field of SARS-CoV-2 and cardiac diseases.

The CESAR project ended successfully. We included 171 patients from the 2nd, 3rd and 4th wave of the COVID-19 pandemic who were admitted to the Hospital Universitario de Navarra (HUN) and the Clínica Universidad de Navarra (CUN). Of those 171 patients, 145 completed the entire monitoring study. In addition, we did a retrospective cohort study of 119 patients who were admitted to the CUN during the first wave of the pandemic (March – May 2020), who were also monitored for the first three months after infection. The cohort made it possible for us to do the first screening analysis to obtain potential short term post-COVID-19 cardiac candidates. From that analysis, we determined that CITP/MMP-1, which is a collagen quality marker, specifically of the degree of collagen cross-linking (or cardiac stiffness), is the indicator that best predicts post-COVID-10 cardiac insult in the short term.

When the cohort of 171 patients and a year of monitoring, where we identified all the biomarkers of cardiac fibrosis (PICP, CITP-1:MMP-1, TIMP-1, PIIINP), cardiomyocyte insults (NT-proBNP and hs-TnT) and inflammation  (VCAM, IL-18,IL-6, Gal-3, ST-2, PCR), as well as 92 proteins associated with cardiovascular disease using high-performance proteomic analysis, were analysed we were able profile a group of 6 proteins that can predict cardiac damage one year after SARS-CoV-2 infection. Specifically, we found that the CITP:MMP-1 quotient (cardiac fibrosis marker), Gal-3 and VCAM (inflammation markers) and hs-TnT and NT-proBNP (cardiomyocyte insults markers) were increased in patients who developed post-COVID-19 heart damage in comparison with ones who did not, both in the acute phase and after one month of infection. Likewise, cardiovascular proteins like myoglobin (MB), urokinase (t-PA), leukotactin 15 (CCL15), and the EpCAM cellular adhesion molecule, behave the same way, which all together suggests that the mechanisms of cardiac fibrosis, inflammation and heart damage are activated by SARS-CoV-2.  Of those biomarkers, only NT-proBNP, hs-TnT, MB, t-PA, EpCAM and CCL15 show an association with post-COVID-19 heart damage, independently of potentially misleading factors like age, gender, DM2 or HTA, and the high values of those biomarkers are associated with a higher accumulated incidence of cardiovascular events.

Given that we extended the patient monitoring time to one year (more real with the goal), the last phase was slightly delayed, so we are currently finishing the validation study of those six molecules in order to establish firm and conclusive results. Nevertheless, everything points to those six molecules being able to constitute a molecular map that makes it possible to identify people more susceptible to developing post-COVID-10 heart damage, and who could consequently benefit from preventive or diagnostic measures in an effective and efficient way. Furthermore, those molecules can help understand which mechanisms are activated in the infection and cause heart damage.