In recent years, the use of MCS has grown exponentially, with these devices predominantly being applied as a bridge to transplantation. The data from the 2018 Spanish HT registry indicated that 43.5% of transplants that year were performed in patients with prior circulatory support23. Internationally, this percentage has been around 50% since 201724. In fact, the latest clinical practice guidelines establish a class I recommendation with a B evidence level for the implantation of a left or biventricular assistance device in patients with advanced HF despite optimal treatment25.
Currently patients are selected for circulatory support based on fundamental clinical criteria including abrupt clinical deterioration, frequent hospitalizations due to decompensation and inotropic dependence amongst others. Monitoring of transaminase, creatinine, and lactate levels is used to evaluate the function of the target organs, since their progressive deterioration is also a criterion for MCS implantation. However, these tests and criteria are merely indicative without an established cutoff point, and high levels of these molecules usually indicate an ongoing failure in these organs.
The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) classification is used to establish the implantation device for patients needing an MCS, with this document supplying some prognostic and clinical criteria for the evaluation of the need, type, and duration of the MCS26. For example, those patients classified as INTERMACS 1 should be treated with peripheral venoarterial ECMO support, while INTERMACS 1–2 patients who are not in a critical condition should be treated with a short-term continuous flow DAV (such as Levitronix®), as this instrument can provide support for a longer time, with fewer long-term complications27.
The major determining factors for the success of MCS are patient selection and the timing of device implantation. Clinicians should remain acutely aware of the dual effect of early use, and find a balance between efficacy and device-derived complications. Both factors are often based on subjective criteria. The latest guidelines recommend the use of these devices early to limit the prolonged use of catecholamines and avoid the development of right ventricular dysfunction and/or multi-organ failure. Only five of the patients in the MCS group demonstrated any dysfunction in one or more of the target organs, with no statistically significant changes in any of the commonly assayed biomarkers (creatinine, transaminases, bilirubin, or lactate) when compared to the group without MCS.
Given these limitations it is critical to develop tools for the accurate assessment of patients and produce adequate stratification protocols describing their clinical situation based not only on their clinical, echocardiographic and hemodynamic data, but also considering more objective criteria. Thus, the purpose of our study was to define biochemical markers that can help us identify early patients with advanced HF whose short-term clinical evolution may lead to the need for circulatory support as a bridge to recovery, transplantation, or decision. To date, there are no other studies that have evaluated the usefulness of NUP153, IPO5, RanGAP1, and SERCA2a in the plasma in this clinical setting.
The choice of molecules used in this study was based on the results obtained by our group in previous studies. These studies demonstrated a correlation between the molecules involved in nucleocytoplasmic transport (nucleoporins, IMPs, EXPs, and Ran regulators), and the various parameters of ventricular dysfunction (left ventricular end-systolic diameter, left ventricular end-diastolic diameter, and left ventricular mass index) and advanced HF, as an expression of the remodeling process associated with the restructuring of the cytoskeleton and a series of mitochondrial alterations that result in an increase in the nucleocytoplasmic traffic machinery10–13. Additional studies have also shown a reduced expression of SERCA2a in HF and cardiac rejection18,19.
In our study, the plasma levels of NUP153, IPO5, and RanGAP1 did not show a statistically significant difference between the advanced HF group with MCS and the stable group without MCS, although NUP153 did demonstrate a trend toward significance (p = 0.07 ).
SERCA2a is in charge of taking Ca2+ back into the sarcoplasmic reticulum during the relaxation phase of the cardiac cycle, allowing enough Ca2+ to become available for the next contraction phase. Multiple studies have confirmed the importance of SERCA2a in the pathophysiology of heart disease, since it plays a very important role in regulating the progression of HF, directly contributing to the deterioration of the contraction and relaxation processes of the heart28,29. Apart from its role in the pathophysiology of HF and its value as a therapeutic target, SERCA2a has also been investigated as a modulator for other related pathological processes, including rejection after heart transplantation, where it has been shown to be significantly reduced30. In addition, a recent study by our group showed that the plasma levels of SERCA2a are an independent predictor of pathological rejection19.
Given this, we decided to investigate whether the levels of this enzyme can also be used to help clinicians identify patients with advanced HF whose short-term evolution requires MCS implantation. We were able to show that patients with MCS present with significantly lower levels of SERCA2a and that when these levels were represented as an ROC curve, they produced a good area under the curve with an optimal cutoff point of 0.84 ng/mL allowing for a sensitivity of 92% and a negative predictive value of 91% for MCS intervention.
Therefore, our data suggests that the plasma levels of SERCA2a are a highly accurate predictor of advanced HF with an unstable clinical outcome. This means that this biomarker could be applied to identify patients that require temporary support with MCS, allowing for their stratification from patients who electively receive HT without circulatory support. If these preliminary findings are validated in broader cohorts, the determination of SERCA2a could be consolidated as a useful tool in optimizing the selection criteria and determining the appropriate timing of MCS implantation in patients with advanced HF.