Heart transplantation (HT) is the treatment of choice for advanced heart failure in patients without contraindications and who are not candidates for other established treatments.1–3 The physical stress of surgery causes an elevation in both cardiac and noncardiac biomarkers, which normalize once clinical stability is achieved. The most widely used and available biomarkers in this context are high-sensitivity troponin T (for myocardial necrosis), N-terminal pro-B-type natriuretic peptide (NT-proBNP) (for myocardial stress), creatinine (for renal dysfunction), and lactate (for tissue perfusion).4 The international literature lacks clear definitions of “normal” biomarker levels and cutoff points for identifying patients at risk of severe complications in the early post-HT period. We hypothesized that by building standard curves for various biomarkers, we might be able to predict severe complications (death or severe primary graft failure [PGF]) following HT. We also believed that these curves might help identify cutoff points to better discriminate between patients with favorable and poor prognoses.

The aim of this study, therefore, was to determine whether consecutive measurements of certain biomarkers in patients with advanced heart failure undergoing HT can predict poor outcomes and if these biomarkers have sufficient discriminatory power to reliably identify patients with a poor prognosis.

This was a prospective longitudinal noninterventional study of consecutive patients undergoing HT between July 2017 and July 2023. Exclusion criteria were age < 16 years, multiorgan transplantation, and retransplantation.

Serial biomarker measurements were obtained before HT and at 6, 24, 48, 72, and 96hours post-HT. The markers chosen are used to assess myocardial necrosis (high-sensitivity troponin T [ng/mL]), myocardial stress (NT-proBNP [ng/mL]), renal dysfunction (serum creatinine [mg/dL]), and tissue perfusion (lactic acid [mg/dL]). Following the identification of a compatible donor, the biomarkers were measured within 6hours of transplant in all cases, while awaiting definitive confirmation of the feasibility of the procedure and explantation. For the discriminatory analysis, the biomarkers were measured at 24hours.

The primary composite outcome was death or severe primary graft failure (PGF). Death was defined as in-hospital mortality (patients who died while hospitalized for HT). PGF was defined as heart failure occurring in the first 24hours after HT and categorized as mild, moderate, or severe according to the definitions in the 2014 Consensus Conference guidelines.5 Severe PGF was characterized by the need for mechanical circulatory support, including venoarterial extracorporeal membrane oxygenation (VA-ECMO). Patients who died while on circulatory support were included in the death category not the PGF category.

The study was approved by the Biomedical Research Ethics Committee of Instituto de Investigación Sanitaria La Fe and adhered to the ethical principles outlined in the Declaration of Helsinki for medical research involving humans.

HT is a well-established treatment for advanced heart failure. Despite standardized surgical techniques, the procedure remains highly complex.1–3 One of the most serious complications in the immediate posttransplantation period is PGF.7,8 As with other forms of heart surgery, HT induces hemodynamic and functional alterations detectable in blood tests, such as elevations in humoral markers of myocardial stress,9 cardiac necrosis,10 kidney dysfunction,11 and tissue perfusion.12 The aim of this study was to assess increased serum levels of these biomarkers in patients undergoing HT and analyze changes following the procedure, particularly in patients who subsequently developed severe complications (death or severe PGF). We also sought to identify cutoff points for biomarkers measured at 24hours post-HT that could predict favorable or poor outcomes. We found that NT-proBNP and troponin levels remained very high throughout the posttransplant observation period and then stabilized after the first 24hours post-HT. Creatinine stabilized after 48hours and lactate after 24hours. All biomarkers were strongly associated with the primary composite outcome of severe PGF or in-hospital mortality (P < .0001). NT-proBNP had the strongest discriminatory power, with a value of 10 000 pg/mL at 24hours post-HT predicting a severe complication with a sensitivity of 90% and a specificity of 80%.

The baseline characteristics of the patients in this study are similar to those reported in other national and international HT series.8,13 Based on data for Spain, HT patients in 2022 were predominantly men (71%) and, with a mean age of 48 years, were younger than the patients in our series. In 37% of cases, HT was performed as an urgent procedure. Since 2018, the percentage of urgent HTs in Spain has fallen to levels similar to that observed in the current series (33%). The ischemic time in our study was 164minutes, which is shorter than the 240-minute threshold beyond which the risk of complications increases. This shorter time confirms the trend towards reduced ischemic times observed in recent years.8,14 Length of stay in the resuscitation unit was shorter than that reported in other series, probably reflecting the recipient profile. The ASIS-TC study analyzing the use of short-term mechanical circulatory support devices as a bridge to urgent HT in Spain reported a median ICU stay of 18 days posttransplantation.15

In relation to the use of biomarkers in HT, it is important to recognize that there has been a need to identify donor and recipient characteristics linked to PGF since the early days of HT. The RADIAL16 and PREDICTA17 models emerged in recent years to predict PGF after HT, but neither of them uses blood or serum biomarker levels in their risk calculations. Although biomarkers have been used as noninvasive tools for predicting organ rejection8,19 and recipient responses according to levels observed in donors,20,21 our study is the first to analyze the ability of biomarkers to predict PGF. The 4 biomarkers selected are closely aligned with clinical practice and can be quickly and easily measured in practically any setting. Measurements were taken at 6, 24, 48, 72, and 96hours post-HT. We believed that levels at 24hours after transplantation would provide the most reliable predictions of severe PGF or death, as PGF typically occurs within the first few hours.5

NT-proBNP and troponin levels were very high throughout the posttransplant observation period and then more or less stabilized after the first 24hours. The most likely explanation is the interruption of ischemia-induced heart damage and destruction of cardiac cells following the removal of the diseased heart. In addition, a decrease in NT-proBNP and troponin levels would be expected after transplantation as a notable percentage of HT recipients have a history of acute coronary syndrome.8,15 Creatinine levels stabilized after 48hours posttransplant, while lactate levels stabilized after 24hours. In both cases, the change was probably linked to the effects of extracorporeal circulation on kidney function22,23; these effects can also increase NT-proBNP levels.24 Elevated lactate levels, reflecting anabolic metabolism, indicate tissue hypoperfusion due to an imbalance between oxygen supply and demand.25 Studies similar to ours have reported a correlation between lactate levels and mortality in patients placed on mechanical circulatory support prior to urgent transplantation.26

All 4 biomarkers were strongly associated with the primary composite outcome of severe PGF or in-hospital mortality (P < .0001). The cumulative incidence of this outcome, for example, increased by 45% for each 1000-pg/mL increase in NT-proBNP. NT-proBNP has been widely studied as a noninvasive marker of acute rejection in HT recipients,18,19 but its value as a predictor of adverse outcomes in this setting is not well understood.

ROC curves were used to select optimal cutoff points in the discriminatory analysis.27 We observed that biomarker levels at 24hours post-HT were able to identify patients with a poor prognosis. All the biomarkers showed good predictive correlations, but NT-proBNP was particularly effective. A level of ≥ 10 000 pg/mL 24hours post-HT predicted severe PGF or in-hospital mortality with a sensitivity of 90% and a specificity of 80%. This statistically significant result is even more relevant because of its biological plausibility: NT-proBNP is a marker of cardiac stress/distensibility and, accordingly, an elevation in levels would indicate myocardial distress, potentially preceding ventricular dysfunction. Considering that PGF typically occurs within the first 24 to 48hours of transplantation and is the leading cause of early mortality in HT (accounting for 20% of deaths in the first year and 40% of deaths in the first month6,7), biomarker-based tools capable of predicting PGF would be particularly valuable, as they would enable close monitoring and early institution of support measures where necessary. Our findings indicate that NT-proBNP is statistically the most powerful biomarker for predicting death and severe PGF in HT recipients.

The main limitation of this study was the small sample size. However, because this was a single-center study, recruiting more patients would have taken too long and the additional time might have led to protocol changes and a loss of homogeneity. The single-center prospective design can be viewed as a strength, as it allowed for careful planning and definition of the study variables. Finally, our study is the first to conduct a detailed prospective analysis of biomarkers widely used in routine clinical practice.

Post-HT increases in clinical biomarkers have prognostic implications. Significant increases are linked to death and the need for circulatory support. Of the biomarkers analyzed, NT-proBNP is the most powerful predictor of prognosis. A level of 10 000 pg/mL predicted severe PGF or in-hospital mortality with a sensitivity of 90% and a specificity of 80%.

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The study was approved by the Biomedical Research Ethics Committee of Instituto de Investigación Sanitaria La Fe and adhered to the ethical principles outlined in the Declaration of Helsinki for medical research involving humans. Informed consent was obtained from all patients included. Sex and gender were reported in accordance with international guidelines.

Artificial intelligence has not been used.

All authors have made substantial contributions to this work. They participated in writing or critically reviewing the manuscript and reviewed and approved the final version. They agree to be accountable for all aspects of the work, ensuring that issues related to the accuracy or integrity of any part of the work will be appropriately investigated and resolved.

Study design: R. López-Vilella and L. Almenar Bonet. Research and data compilation: R. López-Vilella, J. Martínez Solé, S. Huélamo Montoro, and L. Almenar Bonet. Data analysis: all authors. Writing of manuscript: R. López-Vilella, J. Martínez Solé, V. Donoso Trenado, I. Sánchez-Lázaro, I. Zarragoikoetxea Jauregui, P. Carmona García, M. Pérez Guillén, C. Domínguez Massa, L. Martínez Dolz, and L. Almenar Bonet.

Review of manuscript: R. López-Vilella, V. Donoso Trenado, I. Sánchez-Lázaro, I. Zarragoikoetxea Jauregui, P. Carmona García, M. Pérez Guillén, C. Domínguez Massa, L. Martínez Dolz, and L. Almenar Bonet.

None.