Cardiac Troponin I but Not N-Terminal Pro-B-Type Natriuretic Peptide Predicts Outcomes in Cardiogenic Shock

This study investigates the prognostic value of cardiac troponin I (cTNI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients with cardiogenic shock (CS). Data regarding the prognostic value of cardiac biomarkers in CS is scarce, furthermore, most studies were restricted to CS patients with acute myocardial infarction (AMI). Therefore, consecutive patients with CS from 2019 to 2021 were included. Blood samples were retrieved from day of disease onset (day 1) and on days 2, 3 and 4 thereafter. The prognostic value of cTNI and NT-proBNP levels was tested for 30-day all-cause mortality. Statistical analyses included univariable t-tests, Spearman’s correlations, Kaplan–Meier analyses and multivariable Cox proportional regression analyses. A total of 217 CS patients were included with an overall rate of all-cause mortality of 56% at 30 days. CTNI was able to discriminate 30-day non-survivors (area under the curve (AUC) = 0.669; p = 0.001), whereas NT-proBNP (AUC = 0.585; p = 0.152) was not. The risk of 30-day all-cause mortality was higher in patients with cTNI levels above the median (70% vs. 43%; log rank p = 0.001; HR = 2.175; 95% CI 1.510–3.132; p = 0.001), which was observed both in patients with (71% vs. 49%; log rank p = 0.012) and without AMI-related CS (69% vs. 40%; log rank p = 0.005). The prognostic impact of cTNI was confirmed after multivariable adjustment (HR = 1.915; 95% CI 1.298–2.824; p = 0.001). In conclusion, cTNI—but not NT-proBNP—levels discriminated 30-day all-cause mortality in CS patients.


Introduction
Cardiogenic shock (CS) is characterized by ineffective cardiac output resulting in persistent hypotension unresponsive to fluid administration [1,2]. Thereby, CS leads to tissue hypoxia and end-organ failure, which require the need for catecholamine therapy and/or the insertion of mechanical support (MCS) devices [2][3][4][5][6][7]. Despite ongoing improvement of intensive care medicine, CS is still characterized by short-term mortality rates of approximately 50% [8]. Ongoing demographic changes contribute to significant changes in characteristics of patients admitted with CS. Acute myocardial infarction (AMI) still represents the major cause of CS despite improved revascularization strategies and the increasing number of high-volume tertiary centers, however, the number of patients with non-AMI related CS, mainly attributed to acute decompensated heart failure (ADHF), was The present study prospectively included all consecutive patients presenting with CS admitted to the internistic ICU at the University Medical Center Mannheim, Germany, from June 2019 to May 2021, as recently published [28,29]. All relevant clinical data related to the index event were documented using the electronic hospital information system as well as the IntelliSpace Critical Care and anesthesia information system (ICCA, Philips, Philips GmbH Market DACH, Hamburg, Germany) implemented in the ICU, organizing patient data such as admission documents, vital signs, laboratory values, treatment data and consult notes.
Important laboratory data, ICU-related scores, hemodynamic measurements and ventilation parameters were assessed on the day of admission (i.e., day 1), as well as on days 2, 3 and 4 thereafter. Furthermore, baseline characteristics, prior medical history, length of index hospital stay, data derived from imaging diagnostics, as well as pharmacological therapies were documented. Documentation of source data was performed by intensivists and ICU nurses during routine clinical care. Values of left ventricular ejection fraction (LVEF) and tricuspid annular plane systolic excursion (TAPSE) were retrieved from standardized transthoracic echocardiographic examinations commonly performed during the first 24 h of ICU hospitalization. LVEF measurements were performed in two-and four-chamber apical projections and calculated using the Simpson's biplane method, and TAPSE was measured in four-chamber apical projections according to the European guidelines [30].
The present study is derived from an analysis of the "Cardiogenic Shock Registry Mannheim" (CARESMA-registry), representing a prospective single-center registry including consecutive patients presenting with cardiogenic shock being acutely admitted to the ICU for internal medicine of the University Medical Center Mannheim (UMM), Germany (clinicaltrials.gov identifier: NCT05575856). The registry was carried out according to the principles of the declaration of Helsinki and was approved by the medical ethics committee II of the Medical Faculty Mannheim, University of Heidelberg, Germany. Because of the registry design with no influence on patient care and solely data assembled in daily clinical routine were used, written informed consent was not required from patients in accordance with the medical ethics committee.

Inclusion and Exclusion Criteria, Study Endpoints
For the present study, all consecutive patients with CS and measurement of cTNI on day 1 were included. No further exclusion criteria were applied. The diagnosis of CS was determined according to the current recommendations of the Acute Cardiovascular Care Association of the European Society of Cardiology [31,32]. Accordingly, cardiogenic shock was defined by hypotension (systolic blood pressure (SBP) < 90 mmHg) for more than 30 min despite adequate filling status or need for vasopressor or inotropic therapy to achieve SBP > 90 mmHg. Additionally, signs for end-organ hypoperfusion must be present such as oliguria with urine output <30 mL/h, altered mental status, cold clammy skin and increased lactate >2 mmol/L. Further risk stratification was performed by the presence or absence of AMI as an underlying cause of CS according to current international guidelines [33][34][35]. ST-segment myocardial infarction (STEMI) was defined as a novel rise in the ST segment in at least two contiguous leads with ST-segment elevation ≥2.5 mm in men <40 years, ≥2 mm in men ≥40 years or ≥1.5 mm in women in leads V2-V3 and/or 1 mm in the other leads. Non-STsegment myocardial infarction (NSTEMI) was defined as the presence of an acute coronary syndrome with a troponin I increase above the 99th percentile of a healthy reference population in the absence of ST-segment elevation but persistent or transient ST-segment depression, inversion or alteration of T wave, or normal ECG, in the presence of a coronary culprit lesion.
All-cause mortality at 30 days was documented using the electronic hospital information system and by directly contacting state resident registration offices ('bureau of mortality statistics'). Identification of patients was verified by place of name, surname, day of birth and registered living address. No patient was lost to follow-up with regard to all-cause mortality at 30 days.

Measurement of cTNI and NT-proBNP
cTNI was measured with the SIEMENS Atellica Solution CH 930™. The lowest detection limit of the assay was 0.015 ng/mL, with a linearity range of 0.025 to 25 ng/mL. The 99th percentile, measured from a healthy reference population, was 0.045 ng/mL, with a coefficient of variation of 10% [20,36]. NT-proBNP determinations were performed as a direct chemiluminescence sandwich immunoassay on the Atellica Solution IM (Siemens Healthineers, Erlangen, Germany). The linear quantification range of the assay for serum and plasma is 35-35,000 pg/mL (4.13-4130 pmol/L). The clinical decision threshold for the NT-proBNP assay to separate healthy from sick patients is 125 pg/mL for patients aged <75 years and 450 pg/mL for patients aged ≥75 years.

Statistical Methods
Quantitative data are presented as mean ± standard error of mean (SEM), median and interquartile range (IQR) and ranges depending on the distribution of the data. They were compared using the Student's t test for normally distributed data or the Mann-Whitney U test for nonparametric data. Deviations from a Gaussian distribution were tested by the Kolmogorov-Smirnov test. Qualitative data are presented as absolute and relative frequencies and were compared using the Chi-square test or the Fisher's exact test, as appropriate. Box plots for the distribution of cTNI and NT-proBNP levels were created for the comparisons of 30-day survivors and non-survivors on days 1, 2, 3 and on day 4. Spearman's rank correlation for nonparametric data was used to test for the association of cTNI and NT-proBNP levels with medical and laboratory parameters on day 1. C-statistics were applied by calculating the receiver operating characteristic (ROC) curves and investigating the corresponding areas under the curves (AUCs) within the entire cohort in order to assess the diagnostic performance of cTNI and NT-proBNP during the course of ICU hospitalization with regard to the 30-day all-cause mortality. The AUCs for the prognostic performance were compared using the method of Hanley et al. [37]. An optimum cut-off value was determined in accordance with the maximum Youden index.
Kaplan-Meier analyses according to the cTNI and NT-proBNP levels on day 1 were performed within the entire study cohort and stratified by patients with AMI-and non-AMI-related CS. Univariable hazard ratios (HRs) were given together with 95% confidence intervals. Multivariable Cox regression models were developed using the "forward selection" option.
Results of all statistical tests were considered significant for p ≤ 0.05. SPSS (Version 28, IBM, Armonk, NY, USA) was used for statistics.

Discussion
The present study comprehensively investigates the prognostic value of cTNI and NT-proBNP among consecutive CS patients with and without concomitant AMI admitted to an internistic ICU from 2019 to 2021. The main findings of the study can be summarized as follows: -cTNI levels were consistently higher among 30-day non-survivors as compared to survivors in consecutive CS patients. -cTNI, but not NT-proBNP levels, were able to discriminate 30-day non-survivors, alongside increased risk of 30-day all-cause mortality in patients with higher cTNI levels. - The negative prognostic impact of increased cTNI levels was demonstrated irrespective of AMI-or non-AMI-related CS and confirmed even after multivariable adjustment.
Natriuretic peptides, such as BNP and NT-proBNP, represent quantitative biomarkers to reflect the presence and severity of cardiac stress and HF, which were shown to be increased in patients with high wall stress, cardiac filling pressure and intra-cardiac volume. Related to their high diagnostic accuracy for HF, the measurement of natriuretic peptides is recommended in patients with HF-related symptoms [38]. In addition to HF, NT-proBNP levels may be increased in patients with acute cardiovascular diseases, including AMI, pulmonary embolism or atrial fibrillation [39][40][41]. In contrast, limited data regarding the prognostic significance of NT-proBNP levels in CS are yet available, with conflicting findings, whereas most studies were limited by a small sample size.
Katayama et al. identified BNP as an independent predictor of all-cause mortality among 42 patients with AMI-related CS [42]. In line with this study, NT-proBNP was shown to indicate poor prognosis in 58 CS patients, especially when combined with interleukin-6. Thus, NT-proBNP levels were specifically shown to correlate with prognosis in patients with successful coronary revascularization [43]. The prognostic impact of NT-proBNP was confirmed by Sharma et al. in 42 patients with STEMI-related CS, suggesting reliable prediction of in-hospital mortality (AUC = 0.748) [26], which may be attributed to more advanced stages of left ventricular dysfunction but may be aggravated by prevalent acute kidney injury or concomitant sepsis. Thus, NT-proBNP may be increased as a consequence of concomitant septic cardiomyopathy, type 2 AMI or drug toxicity, however, our study group recently suggested NT-proBNP levels did not differ among sepsis survivors and non-survivors, alongside with a poor predictive accuracy with regard to 30-day all-cause mortality in 162 patients with sepsis and septic shock [20,44]. Within the present study, NT-proBNP levels correlated with inflammatory markers such as CRP and WBC count, and more than half of the patients suffered from concomitant infectious disease. However, NT-proBNP was a poor predictor of 30-day all-cause mortality within the present study including consecutive CS patients with and without AMI. This is in line with a study by Pöss et al. including 51 CS patients demonstrating NT-proBNP levels failed to predict outcomes following CS [45]. However, the generalizability of these studies may be limited related to the rather small sample size. Even in the present study including consecutive CS patients on admission, NT-proBNP levels were infrequently measured in only 44% of the included patients with cTNI measurement, which may have influence on the lack of the prognostic impact of NT-proBNP measurement. Of note, the present study is still one of first studies to investigate the predictive value of NT-proBNP in consecutive CS patients. Furthermore, the present study-for the first time-demonstrated the prognostic value of cTNI was superior compared to the predictive value of NT-proBNP.
Recently, the prognostic value of a risk score based on blood-derived biomarkers was developed within a sub-study of the CULPRIT-SHOCK trial. Ceglarek et al. created the so-called "CLIP" score, including cystatin C, lactate, interleukin-6 and NT-proBNP, to predict the risk of all-cause mortality following AMI-related CS, including 458 from a total of 706 patients originally enrolled in the CULPRIT-SHOCK trial. However, important preselection may be present, including only patients with AMI-related CS with concomitant multi-vessel disease. Furthermore, specifically cystatin C and interleukin-6 are not routinely measured in CS patients, whereas no distinct sub-analyses were performed regarding the prognostic role of cardiac biomarkers in CS [46]. The major strength of the present study lies in the consecutive recruitment of CS patients irrespective of underlying CS etiology. Although AMI was reported to be the main cause of CS within our study, 48% suffered from CS not related to AMI. CTN is characterized by a high sensitivity and specificity for the detection of myocardial necrosis and is embedded in the definition and decision-making of AMI [31,33,47,48]. Data from the "Global Registry of Acute Coronary Events" demonstrated increased risk of cardiac arrest, ventricular tachyarrhythmias, CS and moreover mortality in patients with increased cTN levels in more than 16,000 with non-ST-segment elevation acute coronary syndrome [49]. Even in patients with STEMI, elevated cTN levels were shown to indicate worse clinical outcomes including higher risk of all-cause mortality [50]. Furthermore, higher cTNI levels were associated with severity and progression of CAD [51].
Although it was demonstrated that increased cTN levels may increase the risk CS, very limited data are available focusing on the prognostic value of cTN levels in patients admitted with CS even though CS occurs in up to 10% of patients with AMI [52,53]. The association of cTNT levels in CS patients with concomitant VA-ECMO treatment was investigated by Li et al. within 72 patients. CTNT levels were significantly higher among non-survivors compared to survivors on days 2 and 3, whereas specifically the cTNT decline rate was associated with reliable prediction of ICU mortality [27]. Of note, Lim et al. investigated the prognostic role of myocardial ischemia, taking into account cTN levels, ECG and echocardiographic data, in 93 patients admitted to an ICU. They demonstrated that myocardial ischemia, diagnosed by a multi-modal approach, was present in one out of four ICU patients and associated with increased ICU mortality. In contrast, elevated cTN levels alone were not associated with outcomes, however, their study was performed including a general ICU population [54]. The present study is-to the best knowledge of the authors-the first that investigated the prognostic role of cTNI levels in consecutive CS patients with a reliable sample size. Interestingly, cTNI was able to discriminate 30-day mortality in CS patients, both in patients with AMI-and non-AMI-related CS. Therefore, the measurement of cTNI may be helpful to improve prediction of short-term outcomes following CS, which are still characterized by an unacceptable high risk of death.
This study has several limitations. Due to the single-center and observational study design, results may be influenced by measured and unmeasured confounding variables. For the present study, no sequential cTNI measurement during day 1 of CS, respectively, AMI was assessed. Furthermore, NT-proBNP was only measured in 44% of patients with cTNI measurement, which may limit the generalizability of the study. Related to the hemodynamic instability in the setting of CS, pre-existent treatment with heart failure pharmacotherapies was discontinued in the initial phase of CS, whereas the exact duration of discontinuation was not assessed for the present study. Finally, no information on long-term mortality was available for the present study.

Conclusions
In conclusion, the present study demonstrates for the first time that cTNI-but not NT-proBNP-was able to discriminate 30-day mortality in CS patients. Interestingly, elevated cTNI levels were associated with impaired risk of 30-day mortality in the presence or absence of AMI-related CS. The negative prognostic impact of cTNI was confirmed even after multivariable adjustment.

Informed Consent Statement: Not applicable.
Data Availability Statement: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Conflicts of Interest:
The authors declare no conflict of interest.