GENERAL COMMENTARY published: 23 February 2022 doi: 10.3389/fcvm.2022.856592 Commentary: A Review of Prognosis Model Associated With Cardiogenic Shock After Acute Myocardial Infarction Oriol Iborra-Egea 1 , Cosme García-García 2,3,4 and Antoni Bayés-Genís 1,2,3,4* 1 ICREC Research Program, Health Sciences Research Institute Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain, 2 Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain, 3 Cardiology Service, Germans Trias i Pujol University Hospital, Badalona, Spain, 4 Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain Keywords: cardiogenic shock, CS4P, biomarker, precision medicine, prognosis A Commentary on Edited by: A Review of Prognosis Model Associated With Cardiogenic Shock After Acute Gian Marco Rosa, Myocardial Infarction San Martino Hospital, Scientific by Wang, J., Shen, B., Feng, X., Zhang, Z., Liu, J., and Wang, Y. (2021). Front. Cardiovasc. Med. Institute for Research, Hospitalization and Healthcare (IRCCS), Italy 8:754303. doi: 10.3389/fcvm.2021.754303 Reviewed by: Giuseppe Mascia, INTRODUCTION University of Genoa, Italy Cardiogenic shock (CS) is a deadly complication of myocardial infarction (MI), as well as other *Correspondence: Antoni Bayés-Genís cardiovascular diseases (CVD), including decompensated heart failure or myocarditis (1–3). CS is abayesgenis@gmail.com estimated to affect between 2 and 4 million people each year, and its incidence is growing rapidly, at a 9% compounded annual growth rate (4). CS mortality rates are close to 50%, and clinicians do Specialty section: not have efficient prognostic tools that help them manage these emergencies, leaving the patients This article was submitted to (and their relatives) with no real information of their potential clinical evolution and burdening General Cardiovascular Medicine, healthcare systems with poor capital allocation. a section of the journal As for its management, CS requires admission to an intensive care setting and fluid Frontiers in Cardiovascular Medicine resuscitation to correct hypovolemia and hypotension. Although it’s very scarce, patients also Received: 17 January 2022 need prompt initiation of pharmacologic therapy to maintain blood pressure and cardiac Accepted: 31 January 2022 output (Aspirin/heparin, diuretics and Inotropic and/or vasopressor drug therapy) as well as Published: 23 February 2022 early restoration of coronary blood flow (mainly via percutaneous coronary interventions) (5). Citation: Advanced therapies leveraging mechanical circulatory support devices (such as Veno-Arterial Iborra-Egea O, García-García C and Extracorporeal Membrane Oxygenation [VA-ECMO], intra-aortic balloon pumps [IABP], Impella Bayés-Genís A (2022) Commentary: A or TandemHeart) are being tested in clinical trials, and may pose the first life-saving solution for Review of Prognosis Model Associated With Cardiogenic Shock these patients (6), but these procedures are highly invasive and costly. Indeed, CS is estimated to After Acute Myocardial Infarction. average ∼45.000 USD per patient of total hospital cost. Front. Cardiovasc. Med. 9:856592. Early and accurate risk stratification is crucial for efficient identification of the sickest patients doi: 10.3389/fcvm.2022.856592 who may benefit from these advanced therapies. Unfortunately, no molecular tools for its Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 February 2022 | Volume 9 | Article 856592 Iborra-Egea et al. Commentary: CS4P Clinical Translational Perspective prognostic have been developed yet. This hamper the physician’s CS4P improved reclassification of 32% of patients when added ability to optimize the patient’s management, as well as restrict to the CardShock risk score. their clinical decision-making. DISCUSSION THE IMPORTANCE OF RELIABLE PROGNOSTIC TOOLS IN CS In this original review, Jingyue Wang et al. have made an impressive summary of the main prognostic strategies There are several reasons why prognostic factors are important available to clinicians working on CS. The authors not only in CS. First, by determining which variables are prognostic describe the two main clinical scores, and current gold- of outcomes we gain insights on the biology and natural standard for CS prognosis, the IABP-Shock II score and history of the disease. CS is not only determined by cardiac the CardShock score, but also highlights broad severity dysfunction, but a wide multisystemic failure instead, scales, including APACHE, SAPS and SOFA scores, as encompassing respiratory, hepatic, renal and inflammatory well as general cardiovascular risk scores and CS-specific affectations. Taking this holistic view using unbiased biomarker risk scores. discovery techniques, instead of the classic heart-centered In this work, the CS4P stands out as the only fully molecular approach, can lead to novel therapies for CS patients. score, independent of any clinical variable, which bares several Second, appropriate treatment strategies may be optimized advantages over current alternatives. The proteins can be and personalized based on the prognostic factors of an measured in a simple and rapid blood test without prior individual patient. Third, prognostic factors are often used in information of the patient, with much higher discrimination the design, conduct, and analysis of clinical trials to evaluate capabilities and can reflect the clinical evolution of the patient therapeutic advances as companion tests. Finally, patients and within hours, also assessing if the therapy under use is working their families can be informed about the risk of recurrence in a personalized manner. However, the authors also state that, or death and are empowered to take decisions that are “due to the development of proteomics, its clinical application more sensible. is limited.” In both of our articles cited here, the authors failed to emphasize that we validated our proteomic results with Enzyme- THE CS4P PROGNOSTIC TOOL Linked ImmunoSorbent Assay (ELISA) using external cohorts (CARDSHOCK patient cohort; n = 97), demonstrating its Currently, clinicians only have at their disposal clinical translation to the clinical setting. Albeit this was a retrospective scores that compile classic biochemical, disease history and validation, it demonstrates the potential of the CS4P to be used demographic variables to classify CS patients according to their with gold-standard clinical practices. mortality risk, and thus decide which therapeutic approach As the authors rightly point out, there is still the need to is better in each case. In an emergency situation, such as perform prospective validations in order to understand the real CS management, gathering these variables is impractical prognostic value of the CS4P. and time-consuming, which ultimately imply that this is To this aim, our group is currently developing mice implemented in very limited occasions. Moreover, many monoclonal antibodies (mAb) using complete recombinant of these variables are difficult or impossible to obtain proteins for each of our four target antibodies to immunize the sometimes, and even when the medical team is able to mice. Four BALB/c strain mice have been immunized with the acquire them, their predictive value is moderate and the antigen mixed with adjuvant subcutaneously (n = 16 animals), variables themselves are static, meaning that cannot reflect with a minimum of 3 rounds of antigen administered. The the clinical evolution of the patient. For all these reasons, the animals were bled after the second and third immunization decision-making process in CS is still mostly subjective to rounds and the determination of the titer was carried out this date. by indirect ELISA. The two animals with the best titer were To aid this situation, our group used the latest advances sacrificed and the B cells from the spleen were extracted for fusion in targeted proteomics and analyzed large, validated and with myeloma cells (obtaining the hybridomas). Said fusion was independent cohorts, with the aim of finding molecular data carried out by the classical method mediated by Polyethylene that would be useful, simple to use and rapidly transferrable to Glycol. General and differential screenings (to rule out cross the clinical setting (7–9). Here, we discovered that measuring reactivity) were also carried out by indirect ELISA. a panel of just 4 proteins, we can confidently predict We are developing these antibodies specifically to work the outcome of a patient entering the emergency room in a ChemiLuminescence ImmunoAssay (CLIA) platform, suffering from CS (AUC 0.83). The CS4P score is based which is much more sensitive and quicker than ELISA, and on the levels of liver fatty acid-binding protein, (L-FABP), recently received public funding to validate this prototype. Such beta-2-microglobulin (B2M), fructose-bisphosphate aldolase validation will start in 2022, and will include a comparison of our B (ALDOB), and SerpinG1 (IC1). These proteins are not mAb vs. the ELISA tests from our original article to compare its cardiac-specific but reflect multi-organ dysfunction, systemic performance. We will also investigate the values for the CS4P in inflammation and immune activation. More importantly, the retrospective cohort of healthy population (n = 100), as well as in Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 February 2022 | Volume 9 | Article 856592 Iborra-Egea et al. Commentary: CS4P Clinical Translational Perspective post-MI patients classified by the Killip scale (n = 50 patients per contributed to the discussion. All authors contributed to the Killip category). article and approved the submitted version. Finally, we will use this data to determine an appropriate CS4P cut-off value for each category and start a pilot prospective study FUNDING in CS patients (n = 40), which will allow us to monitor the patients at admission (t = 0), 6, 12, 24, and 48 h to reflect their This work was supported in part by grants from MICINN clinical evolution during the first critical hours of CS. (PID2019-110137RB-I00, PLEC2021-008194), Instituto de Salud Carlos III (PIC18/00014, ICI19/00039, ICI20/00135, AUTHOR CONTRIBUTIONS PI21/01700, PI21/01703), Red RICORS (PI21/01703), CIBERCV (CB16/11/00403) as a part of the Plan Nacional de I+D+I, and it OI-E has designed and written the article. CG-G has proof- was co-funded by ISCIII-Subdirección General de Evaluación y read the article and contributed to the discussion. AB-G el Fondo Europeo de Desarrollo Regional (FEDER) and AGAUR has supervised the manuscript, proof-read the article, and (2017-SGR-483, 2019PROD00122). REFERENCES 7. 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Outcomes in cardiogenic shock patients provided the original author(s) and the copyright owner(s) are credited and that the with extracorporeal membrane oxygenation use: a matched cohort study in original publication in this journal is cited, in accordance with accepted academic hospitals across the United States. Biomed Res Int. (2018) 2018:2428648. practice. No use, distribution or reproduction is permitted which does not comply doi: 10.1155/2018/2428648 with these terms. Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 February 2022 | Volume 9 | Article 856592